NASDAQ: NTHI

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Separate from this single-drug application, NEO100 is also being investigated as a drug delivery vehicle, and results from NeOnc’s preclinical studies suggest that combining NEO100 with other drugs may improve brain tumor delivery in patients via the intranasal route. Intranasal NEO100, mixed with levodopa (L-DOPA), is in the planning stages for a clinical trial in patients with Parkinson’s disease (PD). NeOnc’s laboratory experiments showed that intranasal NEO100 mixed with levodopa was able to reverse PD symptoms in mice. A Phase I clinical trial is planned to study the impact on human patients.

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Our initial application for the Phase I/IIa trial for NEO 100 focused on an enrollment population with recurrent primary brain tumors. Based on our Phase I results, NEO 100 showed greater promise in patients with IDH1/2-mutant Grade IV astrocytomas.

As we planned for a total of 25 patients for Phase IIa in our initial analysis, enrollment of recurrent Grade IV IDH1/2 mutants was limited because only 5-10 percent of Grade IV astrocytomas have IDH1/2 mutations. Independent biostatistical review of clinical progression patterns of recurrent IDH1,2-mutated Grade III astrocytomas compared to recurrent IDH1,2-mutated Grade IV astrocytomas revealed that these two tumors have the same prognosis. As a result, in June 2023 we requested that the FDA not object to the inclusion of patients with recurrent Grade III IDH1,2 mutant astrocytomas in the Phase IIa trial. The FDA did not object, and as a result, the pool of eligible patients for enrollment is now much larger. Because the prognosis of recurrent Grade III IDH1,2 mutants is similar to recurrent IDH1,2 Grade IV astrocytomas, the number of patients needed to be enrolled in the Phase IIa trial to assess the clinical efficacy of NEO100 in the population of high-grade astrocytomas did not change. The expanded patient population means there are a significant number of additional patients who can be targeted for potential enrollment in the Phase IIa study; in an initial review, we have identified approximately 25 grade III IDH1/2, mutation-positive candidates. Patients with residual measurable disease are now followed via MRI scans to determine if there is progression (recurrent disease), making them eligible for enrollment. We believe this targeted enrollment of both Grade III and IV IDH1,2 mutants may significantly expedite our trial process, and we project that the readout for our Phase II studies with respect to NEO100 could now be feasibly delivered by the end of 2024, advancing our original timeline by a full year from 2025.

Across our Phase I, Phase IIa, and compassionate-use cohorts, a total of 24 patients with recurrent WHO Grade III/IV IDH1-mutant astrocytoma received intranasal NEO100. In this combined analysis, 21% (5 of 24) of treated patients showed radiographic responses as evaluated by contrast-enhanced MRI, T2-FLAIR, and perfusion imaging, which exceeds the <8% response rates historically reported in salvage therapy settings for recurrent high-grade gliomas. Additionally, 44% of patients achieved six-month progression-free survival (PFS-6), compared to historical benchmarks of approximately 21–31% for recurrent IDH1-mutant high-grade glioma populations. Overall survival data indicated that 33% (8 of 24) of patients remained alive for at least 18 months after starting therapy. NEO100 was generally well tolerated, and no significant toxicity or treatment-limiting adverse events were observed, including among those who received prolonged and chronic intranasal treatment. All radiographic and clinical responses were assessed in accordance with Response Assessment in Neuro-Oncology (“RANO”) criteria. These findings provide preliminary clinical support for further development of NEO100 as a centrally penetrating metabolic therapy for recurrent IDH1-mutant gliomas. However, additional randomized or controlled clinical studies will be necessary to better evaluate its safety and therapeutic effectiveness.

Our second lead product, NEO212, a covalently conjugated molecule combining the chemotherapeutic drug temozolomide with perillyl alcohol, has completed preclinical testing and has received investigational new drug (IND) approval from the United States Food and Drug Administration (FDA), i.e., it has been authorized to proceed to clinical testing in cancer patients. We have designed a Phase I/II trial for oral NEO212, which began in the fourth quarter of 2023. In this trial, NEO212 will be administered orally to patients with primary brain tumors (i.e., malignant gliomas) and secondary brain tumors (i.e., brain metastases derived from peripheral tumors, such as tumors of the lung, breast, skin/melanoma, etc.). Furthermore, NEO212 is undergoing development towards intranasal application specifically for patients with uncontrolled brain metastases derived from peripheral tumors (lung, breast, skin, etc.), but has not yet been studied in human patients.

NeOnc has completed the dose-escalation portion of its NEO212-01 Phase 1/2 clinical trial and has formally notified the U.S. Food and Drug Administration that the maximum tolerated dose (MTD) was reached at Cohort 5 (810 mg, Days 1–5 of a 28-day cycle) following a second dose-limiting toxicity, in accordance with protocol-defined stopping criteria. Dose escalation has been discontinued, and the recommended Phase 2 dose (RP2D) has been established at 610 mg (Cohort 4), with a starting dose of 400 mg planned for the Phase 2a metastasis cohort. Although the Phase 1 portion of the study was designed to evaluate safety, tolerability, and dose optimization, preliminary observations suggested anti-tumor activity and disease control in heavily pretreated patients with recurrent glioblastoma and brain metastases. NEO212 is an oral bioconjugated formulation of temozolomide and perillyl alcohol designed to enhance central nervous system penetration and address known resistance mechanisms, including MGMT-mediated DNA repair, which is not significantly affected by conventional temozolomide. The Company plans to engage with the FDA through a Type B End-of-Phase 1 meeting to review safety, pharmacokinetics, preliminary efficacy, RP2D selection, and the proposed Phase 2 study design, including potential accelerated-approval pathways, as it advances the program to the next stage of clinical development.

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Currently, none of our product candidates have been approved for sale in the United States or elsewhere. We have no commercial products nor do we have a sales or marketing infrastructure. In order to market and sell our products we must conduct clinical trials on patients and obtain regulatory approvals from appropriate regulatory agencies, like the FDA in the United States, and similar organizations elsewhere in the world.

In 2025, we completed the acquisition of an intellectual property portfolio comprising artificial intelligence–driven drug discovery tools, rapid magnetic 3D bioprinting technology, and quantum molecular modeling capabilities, including U.S. Patent No. 11,788,057 B2. The total purchase consideration for the transaction was approximately $3.5 million, including $500,000 in cash and $3.0 million in shares of our Common Stock valued at $25.00 per share. The acquired technologies enable the rapid generation of patient-derived three-dimensional brain tumor organoids, AI-based prediction of CNS-penetrant and ultrasound-responsive compounds, and quantum-mechanical modeling of molecular behavior under focused ultrasound. We expect these capabilities to enhance and accelerate our preclinical and clinical research activities and to support collaborations, including our strategic partnership with Quazar Investment Group to expand clinical development efforts in the Gulf Cooperation Council region. In connection with the acquisition, Dr. Ishwar K. Puri joined our Board of Directors.

Using aspects of the acquired technology, a recent preclinical study conducted at the University of Southern California and published on bioRxiv in 2025 evaluated NEO100 with an AI-driven, 3D-bioprinted New Approach Methodology (NAM) platform. In this study, focused ultrasound was observed to enhance the antitumor activity of NEO100 across multiple tumor models, including glioblastoma, pediatric medulloblastoma, high-grade meningioma, and brain metastases derived from breast and lung. An AI-positive, unlabeled neural network trained on molecular descriptor data consistently predicted NEO100 as a compound responsive to ultrasound. These findings provide preclinical support for continued evaluation of NEO100 in combination with focused ultrasound in future clinical studies.

The Pipeline of NeOnc Drug

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Lead Product: NEO100

NEO100 is our most advanced product candidate based on POH. This naturally occurring monoterpenoid can be found as a constituent of essential oils from various botanicals, including peppermint, spearmint, lavender, bergamot, lemongrass, sage, thyme, cherries, and others. POH has been used in cosmetics, fragrances, and some cleaning products and as an ingredient in baked goods, frozen dairy, gelatine, puddings, beverages, and candies. However, clinical trials by other companies with an oral POH formulation administered to cancer patients were not successful for two presumed reasons: (i) after ingestion, not enough POH entered the bloodstream, because the liver (portal vein) quickly metabolized and thereby eliminated POH; in fact, it was not possible to demonstrate the presence of POH in the blood of these patients; and (ii) in an effort to overcome the rapid depletion of POH, physicians attempted to administer increasing amounts of oral POH, which resulted in significant gastrointestinal toxicity that became dose-limiting. As a result, efforts to introduce oral POH into the clinic were abandoned.

Under the direction of NeOnc, a novel manufacturing and delivery pathway was investigated which we believe may avoid the drawbacks of oral POH. Using derivatization of POH with a crystalline intermediate enabled the production of ultra-pure, pharmaceutical-grade NEO100. NEO100 received fast-track status in 2016 and orphan-drug designation in 2011 from the FDA. NeOnc’s novel approach uses intranasal, rather than oral, delivery. Our completed Phase I trial of intranasal NEO100 suggested that when given via the intranasal route: (i) the drug appeared to be well tolerated with no severe adverse effects being observed, despite consistent treatment over several months; and (ii) patients’ reported quality of life was unchanged. In one patient, we were able to obtain brain tumor tissue (based on surgery immediately following intranasal delivery of a dose of NEO100), which we analyzed for the presence of NEO100 (POH). The presence of NEO100 (POH) was confirmed in the tumor tissue, thus providing proof of principle that intranasal delivery of NEO100 reaches its tumor target in the brain. This is in contrast to the above-mentioned studies with oral POH, where the presence of drug could not be demonstrated in blood or tumor tissue of any patient. Among the group of 12 patients in our Phase I trial, there were several long-term survivors: At two years after start of intranasal NEO100 treatment, five patients (37%) were still alive, which is noteworthy, because recurrent glioblastoma patients (that is, patients where the tumor has returned after one or more rounds of traditional treatment) have an average life expectancy of about six months, and 24-month survival is rare. Another result from our Phase I trial is the fact that three patients (i.e., 25% of the original cohort of 12 patients), were still alive after 3 years. These outcomes will have to be investigated with a larger number of patients to establish statistical significance. This is currently being pursued in our Phase IIa trial, where we are planning to expand our clinical trial sites and potentially enrolling the remaining Phase IIa patients. A data read out for any patient enrolled in the clinical trial is expected beginning six months from the enrollment of such patient.

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The above chart illustrates what is currently known about NEO100’s mechanism of action. How NEO100 may block tumor growth is thought to result from its pleiotropic (multi-faceted) impact on tumor cells. In in vitro tests: (i) NEO100 has been shown to inhibit the activity of the Ras protein. Ras is a (proto) oncoprotein that stimulates mitogenic (growth-stimulatory) pathways inside cells. In tumor cells, it is often mutated, resulting in its increased activity and uncontrolled cell growth. Inhibition of Ras by NEO100 is thought to remove this aberrant growth stimulus from tumor cells, causing cell cycle arrest. (ii) NEO100 has been shown to block the activity of sodium/potassium (Na/K) adenosine triphosphatase (ATPase). Na/K-ATPase is an ion pump that sits in the plasma membrane and regulates the flux of ions across the membrane. In cancer cells, it can have abnormal activity and not only helps cancer cells resist chemotherapy, but also stimulates them to spread to other locations in the body. We believe that NEO100 may stunt these advantages for cancer cells. (iii) NEO100 has been shown to intercalate into the plasma membrane to disturb membrane fluidity and the function of some proteins that are located at or near the plasma membrane (including Ras and Na/K-ATPase). Among the consequences is an electrolyte imbalance that triggers endoplasmic reticulum (ER) stress. Cancer cells in general are less resistant to withstand prolonged ER stress. As a result, they undergo apoptosis (cell death) in combination with cell cycle arrest.

Therapeutic applications of NEO100 that are under development by NeOnc:

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Intranasal delivery that we hypothesize may bypasses the blood-brain barrier (BBB), which could permit delivery of drugs to the brain via cranial nerves I and V, and possibly allow delivery of other pharmaceutics to the brain. Proof of this principle has been observed in animal models, but has not yet been tested in human patients.

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At high concentrations, we are investigating whether intranasal NEO100 may be used as a therapeutic for treating brain cancers. In a Phase I trial there were preliminary signs of activity, based on several (25%) patients who have survived for at least 4 years, but validation of activity will have to await results from the ongoing Phase IIa and possible additional clinical trials.

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At low concentrations, NEO100 might act as a solvent and delivery vehicle for traditional large-molecule pharmaceutics, which could potentially bypass the BBB and enter the brain. Proof of this principle has been observed in animal models but has not yet been tested in human patients.

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Intra-arterial delivery of NEO100 could possibly create a temporary opening in the BBB, which might allow traditional large-molecule pharmaceutics to pass through and enter the brain. Proof of this principle has been observed in animal models, but has not yet been tested in human patients.

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NEO100 could potentially be covalently conjugated with other pharmaceutics to create novel fusion compounds that might enable superior BBB penetration ability and, potentially higher activity against brain cancer. Proof of this principle has been observed in animal models but has not yet been tested in human patients.

Intranasal NEO100 for the treatment of malignant glioma:

The FDA granted NEO100 Orphan Drug Designation (ODD) for the treatment of malignant glioma in 2011. Orphan drug designation qualifies sponsors for incentives, including tax credits for qualified clinical trials, exemption from user fees, and potential seven years of market exclusivity after approval. Upon approval, the exclusivity granted to orphan drugs provides seven years during which FDA may not approve any other sponsor’s application for the same drug for the same designated orphan disease or condition, regardless of whether such other sponsor files an Abbreviated New Drug Application (ANDA) for a generic version of the drug, or if another sponsor files a “full” new drug application (NDA). Orphan Drug Exclusivity does not, however, prevent FDA approval of applications for the same drug for a different indication, nor applications for a different drug for the same orphan indication. In limited circumstances, such as showing clinical superiority to the product with orphan drug exclusivity, the FDA may approve a competing application during the Orphan Drug Exclusivity period. However, the process of clinical development is inherently uncertain, and there is no guarantee that orphan drug designation will accelerate the timeline for approval or make it more likely that NEO100 will be approved.

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For clinical testing of NEO100, a combined Phase I/IIa trial was conducted, with the first patient enrolled in April 2017. NEO100 was administered intranasally 4-times a day to patients with recurrent glioblastoma. Patients enrolled in this trial had already undergone standard therapy, but the disease had returned and was deemed untreatable.

Among the inclusion criteria were the following: (i) Radiographically confirmed progression or recurrent grade IV glioma, and on a stable dose of steroid for at least 5 days; (ii) Patients must have failed previous radiation and temozolomide treatment; (iii) Age ≥ 18 years; (iv) ECOG performance status of 0-2, or KPS ≥ 60; (v) An expected survival of at least 3 months; (vi) Baseline MRI with gadolinium within two weeks of entry into the trial; and (vii) Seizures controlled on a stable dose of anti-epileptics for two weeks prior to enrollment. Furthermore, patients were screened with MR perfusion scan if there was a possibility that progression seen on a MRI scan represented pseudo-progression. Response assessment was performed by gadolinium-enhanced MRI and assessment by RANO (Response Assessment in Neuro-Oncology) criteria every two months. Adverse events were graded for severity using NCI Common Terminology Criteria for Adverse Events v.4.0.

The institutions that participated in the trial were Cleveland Clinic, University of Washington/Seattle, University of Wisconsin, and the University of Southern California. It was sponsored by NeOnc Technologies, Inc. (Los Angeles, CA) with ClinDatrix, Inc. (Irvine, CA), as the Clinical Data Management CRO (Contract Research Organization). A total of 12 patients were enrolled in Phase I, which was completed in 2020. The patients were divided into four cohorts, three patients per cohort in a dose escalating trial (384-1152 mg/day). Patients received the intranasal dosage using a nebulizer mask four times a day. The results suggested that intranasal NEO100, even at the highest dose given, appeared to be well tolerated, and there were no serious adverse events reported in any of the patients, i.e., there were only minor side effects, such as a runny nose or nasal discomfort.

Results from Phase I preliminarily suggested that intranasal NEO100 might have exerted therapeutic activity in some of these patients, although statistical analysis was limited by the small number of 12 patients, which means that statistically firm conclusions cannot be drawn. Most patients (55%) survived for more than one year, four patients (33%) survived for over two years, and three patients (25%) remained alive at the 3-year mark.

Primary endpoints for Phase I were to determine maximum tolerated dose (MTD) and progression free survival (PFS). NEO100 did not reach MTD, as the results suggested that NEO100 was well tolerated by the 4 patients in cohort 4. The recommended Phase II dose was therefore at 1152 mg/day. PFS at 6 months was 33%.

Survival Data from NeOnc’s Phase I Clinical Trial with Intranasal NEO100

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Patient Survival: NeOnc’s Phase I Trial

Secondary endpoints were evaluated for: a) pharmacokinetic endpoints of POH and perillic acid (PA) metabolism, b) objective tumor response according to RANO criteria, and c) adverse events.

Pharmacokinetic measurements were performed in patients at the time of trial entry and used to measure the ability of patients to properly inhale NEO100. All patients had the expected rapid elimination of NEO100 within 30 minutes from serum, and elimination of its PA within 2 hours.

Objective tumor response to NEO100 was determined by RANO criteria. NEO100 performance by RANO criteria was reported as follows:

The third secondary endpoint was adverse events, as characterized by type, frequency, and severity (NCI common terminology for adverse events were reported as follows:

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Moreover, our Phase I clinical trial indicated that patients harboring an IDH1 mutation in their tumor cells responded to treatment more favorably than those without the mutation. Among the 12 patients, five presented with IDH1 mutant status. Among these five, four patients (80%) survived longer than the seven patients without IDH1 mutation. As of February 12, 2021 three of them were still alive four years after the recurrence of their original tumor and initiation of NEO100 treatment.

A potential advantage of intranasal NEO100 is that intranasal delivery via a nebulizer device does not require surgeries, infusions, or other invasive procedures that would require medical visits. Rather, intranasal delivery could be done conveniently at home (or while traveling) by the patients themselves. Compared to the well-known toxicities of many chemotherapeutic agents, NEO100 appeared to be well tolerated at the doses tested in the limited Phase I trial, and none of the typical side effects of other cancer pharmaceutics (nausea, debilitating fatigue, anemia, infections, diarrhea, hair loss, etc.) were observed. It, therefore, suggests that NEO100 may not lead to deterioration of quality of life for patients (Schönthal AH et al., Neuro-Oncol. Adv. 3:1, 2021).

NeOnc Phase IIa studies describe the first time NEO100 is given to the intended treatment population. The studies are undertaken to confirm dosing requirements identified in Phase I testing (such as how much, how often and to whom the drug should be given) are correct. They are sufficiently powered (statistically) to determine how well the drug performs at the prescribed dose and for the intended outcome. Work in future trials may be needed to further understand results obtained in Phase IIa testing (i.e., dosing, effect on a patient sub-population) and randomized, controlled Phase III testing may be required prior to marketing authorization. Details regarding the ongoing Phase IIa trials of NEO100 and the ongoing Phase I/II trial of oral NEO212 are as follows:

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“An Open-Label, Phase I/IIa Dose Escalation Study of Safety and Efficacy of NEO100 in Recurrent or Progressive Grade III or IV Gliomas with IDH1 Mutation” (NEO100-01)

Enrollment

Number of Patients to be Treated: 25

Patient Sub-Populations Tested: Radiographically-confirmed progression of, or recurrent, primary or secondary Grade IV glioma (the original study population) and radiographically-confirmed progression of, or recurrent, primary or secondary Grade III astrocytoma.

Primary Endpoint:

1. Progression free survival at six months.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

Secondary Endpoints:

1. Objective tumor response to NEO100 as determined by RANO criteria.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

2. Progression free survival.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

3. Overall survival.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

4. Perillic acid measurement.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

Safety Endpoint:

1. Adverse Events characterized by type, frequency, severity, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0), seriousness and relationship to study therapy NEO100.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

2. Changes from baseline in vital signs and clinical laboratory parameters (hematology and chemistry), as well as ECOG performance status will be assessed.

NEO100 Performance – Cannot be reported until completion of the Phase IIa portion of the study.

Number of Patients Currently Enrolled: 20

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2.
“An Open-Label, Phase II Study of NEO100 in Participants with Residual, Progressive or Recurrent High-Grade Meningioma” (NEO100-02)

Number of Patients to be Treated: 29

Patient Sub-Populations Tested: Radiographically-confirmed progression of, or recurrent, WHO Grade II or III meningioma

Primary and Secondary Endpoints:

Primary Endpoint: Progression free survival at 6 months

Secondary Endpoint:

1. Objective tumor response by RANO criteria

2. Progression free survival

3. Overall survival

4. Perillic acid measurement and level

Number of Patients Currently Enrolled: 6

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“An Open-Label, Phase I/II Dose Finding, Safety and Efficacy Study of Oral NEO212 in Patients with Astrocytoma IDH-Mutant, Glioblastoma IDH-Wildtype or Uncontrolled Metastasis to the Brain in Patients with Select Solid Tumors (NEO212-01)

Number of Patients to be Treated:

Phase I: Up to 36

Phase IIa: 12

Phase IIb: 27 per cohort

Patient Sub-Populations Tested:

Phase I: Radiographically-confirmed astrocytoma IDH-mutant, glioblastoma IDH-wildtype following previously radiation therapy or treatment with temozolomide and radiation or a select solid tumor with uncontrolled brain metastases (e.g., melanoma, NSCLC, SCLC, HNSCC, urothelial carcinoma, gastric cancer, renal cell cancer, colorectal cancer)

Phase IIa: Radiographically-confirmed astrocytoma IDH-mutant, glioblastoma IDH-wildtype following previously radiation therapy or treatment with temozolomide and radiation

Phase IIb: Select solid tumor with uncontrolled brain metastases (e.g., melanoma, NSCLC, SCLC, HNSCC, urothelial carcinoma, gastric cancer, renal cell cancer, colorectal cancer)

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Primary and Secondary Endpoints

Primary Objectives

1. Assess the safety and tolerability of increasing dose levels of orally administered NEO212 in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype and patients with select solid tumors with uncontrolled metastases to the brain.

2. Identify the maximum tolerated dose (MTD) of NEO212.

3. Determine the recommended Phase II dose (RP2D) of NEO212.

Secondary Objectives

1. Characterize the pharmacokinetics (PK) of NEO212.

2. Evaluate anti-tumor activity of NEO212 in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype and patients with select solid tumors with uncontrolled brain metastases.

Number of Patients Currently Enrolled:

Phase I: 12

Phase IIa: Not Open to Accrual

Phase IIb: Not Open to Accrual

Pipeline Product Candidates

NEO212

NEO212 (chemical structure shown on the right) was designed as a hybrid compound where NEO100 was covalently conjugated to temozolomide (TMZ), an alkylating agent that represents the current standard of chemotherapeutic care for patients with glioblastoma. Based on the recognition that amphipathic NEO100 in research has suggested it may permeate biological barriers and cellular membranes, we hypothesized that this novel covalent molecule might penetrate the blood-brain barrier, possibly enabling a dual approach against malignant lesions in the brain. Our preclinical characterization of NEO212 in various mouse tumor models suggests that this multifunctional agent may show activity against a variety of cancer types. In preclinical studies, results suggested that NEO212 demonstrated activity against primary and secondary brain cancers as well as cancer types that were chemoresistant to other commonly used cancer therapeutics (Chen TC et al., Molecular Cancer Therapeutics 13:1181, 2014; Chen TC et al., Cancer Letters 358:144, 2015; Chen TC et al., Journal of Biomedical Sciences 22:71, 2015; Cho HY et al., Molecular Cancer Therapeutics 13:2004, 2014; Jhaveri N et al., Cancer Letters 371:240, 2016; Marin-Ramos NI et al., Oncoscience 5:148, 2018; Marin-Ramos NI et al., Molecular Cancer Therapeutics 17:625, 2018). So far, the activity of NEO212 has not yet been studied in humans.

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NEO212 demonstrates an interesting feature that its demonstrated activity in preclinical studies may be greater than the sum of its parts. That is: merely applying its individual constituents, NEO100 and TMZ, as a mix of two independent compounds (akin to the conventional combination therapy mode) may not mimic the potential of the conjugated hybrid molecule. The toxicological studies in rodents and dogs suggest that NEO212 was tolerated. When administered at the same dosages as those that suggest activity in mouse cancer models, there were no detectable side effects in mice, rats, or dogs.

The demonstrated activity in preclinical studies of NEO212, along with its low toxicity profile, contributed to our IND application for oral administration that was approved by the FDA in 2023. FDA approval provides an opportunity for Phase I/IIa clinical trials, primarily focusing on patients with intracranial malignancies. We are designing clinical trials that evaluate two different modes of NEO212 delivery: oral and intranasal. Oral NEO212 during Phase I will be administered to patients with brain malignancies that include primary and secondary brain cancers (so-called “all comers”). Phase IIa will focus on newly diagnosed, primary glioblastoma. Intranasal NEO212 will be used in a Phase I/IIa trial in patients with metastatic brain cancer, i.e., where brain lesions originated from cells that were disseminated by tumors from outside the brain, such as lung cancer, breast cancer, or melanoma. All these patients represent a cohort in dire need of better therapies, and NEO212 may hold the potential that might improve their prognosis and survival.

The FDA granted NEO212 Orphan Drug Designation (ODD) for three different indications: (i) glioma (2014), (ii) brain metastases from breast cancer (2017), and (iii) nasopharyngeal carcinoma (2017). As stated above, if a product that has ODD subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusive approval (or exclusivity), which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years (except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity). However, the process of clinical development is inherently uncertain and there is no guarantee that orphan drug designation will accelerate the timeline for approval or make it more likely that NEO212 will be approved.

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Three Drug Delivery Pathways Potentially Enabled by NEO100

Cancerous tissue in the brain is protected from systemically circulating drugs by the blood-brain barrier (BBB), which prevents the brain entry of most pharmaceutical agents. We are using NEO100 to develop three different methods of overcoming the obstacle placed by the BBB:

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Intranasal delivery: As part of a direct nose-to-brain route, this pathway could potentially allow direct brain access without interference from the BBB.

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Monotherapy with NEO100: At higher dosages, intranasal delivery of NEO100 is in clinical testing for patients with glioblastoma.

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Combination therapy with NEO100: At lower dosages, intranasal NEO100 might be used as a carrier for the co-delivery of established therapeutics to the brain. This has been observed in animal models, but it has not yet been studied in humans.

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Conjugated delivery: Stable conjugation of NEO100 to other therapeutic agents (such as temozolomide, creating NEO212) indicated a possible increase in the ability of the fused compound to penetrate the BBB and enter the brain. This has been observed in animal models, but it has not yet been studied in humans.

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Permeable delivery: Intra-arterial delivery of NEO100 may create temporary (up to 4 hours) openings in the BBB, that we believe could potentially enable drugs (Adriamycin®, Velcade®, etc.) and therapeutic antibodies (Herceptin®, Opdivo®, etc.) to enter the brain and reach the tumor bed. This has been observed in animal models, but it has not yet been studied in humans.

All three drug delivery pathways potentially enabled by NEO100 are being investigated by NeOnc and are at different stages of development. Only one of these pathways, monotherapy with intranasal NEO100, has moved into clinical testing, where Phase I studies have been completed and Phase IIa studies are ongoing. The other pathways, including combination therapy with NEO100, conjugated delivery (e.g., NEO212), and permeable delivery have not yet reached the clinical stage and have not yet been studied in humans. In these latter pathways, preclinical studies are currently ongoing to provide further results and IND-enabling data, so that in the future these principles can be studied in human cancer patients.

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We believe these three delivery areas (details below) may be key to a potential shift in physicians’ ability to treat brain diseases. They represent potential pathways for possible reliable delivery of pharma-therapeutics to the brain, potentially mitigating problems and side effects from current methodologies, and potentially providing an alternative treatment protocols to existing pharma manufacturers for their drugs.

Intranasal Delivery of NEO100: Administration of NEO100 into the nose is accomplished by a standard nebulizer that aerosolizes NEO100 into fine particles that reach the olfactory mucosa and its embedded nerve endings in the nasal cavity. Uptake by these and other nerve cells enables direct nose-to-brain transport of NEO100 so it can reach the tumor sites without interference from the BBB. This direct mode of brain-targeted drug administration is thought to deliver higher levels of the drug to the brain tumor site as compared to oral delivery of a given drug, also because this route of transport avoids drug breakdown in the liver. It also lowers total drug exposure to the rest of the body; therefore, it’s hypothesized there may be fewer side effects. This principle was observed in the Phase I clinical trial with glioblastoma patients above-mentioned (Schönthal AH et al., Neuro-Oncol. Adv. 3:1, 2021). And the actual presence of NEO100 (perillyl alcohol), along with its major metabolite, perillic acid, has been observed in brain tumor tissue (Schönthal AH et al., J. Neurosurg. Case Lessons 4:case22215, 2022).

Ongoing activities for intranasal delivery of NEO100:

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The Phase IIa component of our clinical trial is ongoing in patients with recurrent Grade IV glioma (further details are provided below).

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A similar Phase IIa trial of intranasal NEO100 (NEO100-02) for patients with malignant skull based meningioma is also ongoing. Meningiomas are slow-growing tumors originating in the meninges, the membranous layers surrounding the brain and spinal cord. We initiated this because these patients lack effective treatment options. These tumors are notoriously difficult to access, and conventional methods like surgery often lead to significant neurological deficits. Additionally, radiation therapy has shown limited effectiveness. The trial was officially launched in July 2023. As NEO100 uses the same treatment platform as the malignant gliomas, we bypassed the Phase I trial and received FDA approval for a Phase II trial within just 30 days.

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Intranasal NEO100, mixed with levodopa (L-DOPA), is in the planning stages for a clinical trial in patients with Parkinson’s disease (PD). NeOnc’s laboratory experiments showed that intranasal NEO100 mixed with levodopa was able to reverse PD symptoms in mice. A Phase I clinical trial is planned to study the impact on human patients.

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Stable Conjugation of NEO100 to Other Therapeutic Agents: Many drugs work quite well for diseases in the rest of the body but do not reach the brain due to the BBB obstacle. Our pre-clinical results suggested that stable conjugation of several such drugs to NEO100 may increase their ability to reach lesions located in the brain. Temozolomide (TMZ) is widely used to treat malignant glioma—even though it enters the brain sub-optimally, its modest therapeutic impact is an expression of this limitation. However, when conjugated to NEO100, creating NEO212, the molecule may cross the BBB, and in preclinical mouse models, various types of brain malignancies have shown therapeutic activity. NEO212’s IND application was approved by the FDA in May 2023. (Further details on NEO212 are provided below.)

Intra-arterial Injection of NEO100: Our preclinical studies in mouse models with brain cancer suggest that intra-arterial delivery of NEO100 might open the BBB up to four hours, which could allow other therapeutic agents to enter the brain from the bloodstream or a catheter in those models. The mechanism appears to be via a transient opening of the tight junctions between the brain endothelial cells. Catheters can be used to deliver NEO100 to specific parts of the brain, particularly to the sites where the tumor bed is located, so that co-delivered pharmaceutics can immediately access the malignant tissue. In this manner, NEO100 and any other co-delivered therapeutic agent might impact the tumor. While this principle has been established in our preclinical studies, it has not yet been tested in human patients., Well-known side effects of the brain cancer agent temozolomide (TMZ) are bone marrow suppression and resulting infections. We believe these side effects may be reduced or possibly avoided if the bone marrow can be spared from whole-body exposure to TMZ, as is a consequence of the typical oral ingestion of TMZ. This catheter-based approach is based on the co-delivery of another agent (as a mix). It is distinct from the above described stable conjugation of NEO100 to another compound, such as TMZ, which creates a single fusion molecule (as in NEO212).

Our Markets

The global central nervous system (CNS) treatment market is expected to grow at 8.6% CAGR to reach $267.6 billion by 2034, and the global brain tumor drug market is expected to grow at CAGR of 9.8% reach $4.6 billion by 2032, according to Fortune Business Insights.

Radiation therapy still accounts for 38% of the brain cancer treatment market, while drug treatment remains second mostly due to current inefficiencies of drug delivery, according to Grandview Research.

We also address the malignant glioblastoma multiforme (GBM) treatment market. The GBM drug market is expected to grow at 9.8% CAGR to $4.4 billion by 2023, according to iHealthcare Analyst, with the market being driven by rising geriatric population, growing incidence cases, and a pipeline of new products.

GBM accounts for up to 54% of gliomas and 16% of all primary brain cancers, according to research published in the journal, Glioblastoma. By creating an alternative delivery mechanism for GBM drug therapy, we believe we can significantly impact market demand in this sector.

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Our Strategy

Our goal is to change the cancer therapeutic landscape by developing novel therapeutic approaches leveraging dual approaches of novel drug delivery methods in combination with novel drug candidates that potentially lead to better therapeutic results with low side effects.

The following five clinical applications of our drugs are at different stages of preclinical or clinical development:

1.
Intranasal delivery of NEO100 to patients with IDH mutant malignant glioma (Phase IIa clinical trial has started).

2.
Intranasal delivery of NEO212 to patients with brain metastasis (IND approved).

3.
Intranasal delivery of NEO100 alone, and in combination with doxorubicin for pediatric brain tumors (IND approved).

4.
Intranasal co-delivery of NEO100 with levodopa for Parkinson’s disease (preclinical stage).

5.
Intra-arterial delivery of NEO100 to open the patient’s blood-brain barrier, allowing brain entry of BBB-impermeable pharmaceuticals or biologics (preclinical stage).

6.
Oral NEO212 for primary brain cancer, including glioblastoma (IND approved).

Details: 1. Intranasal delivery of NEO100 to patients with IDH mutant malignant glioma (Phase IIa clinical trial has started).

NEO100 is our most advanced product candidate. Its chemical structure (Figure 1) is based on the natural compound perillyl alcohol (POH). We have investigated a novel manufacturing and delivery pathway that avoided the drawbacks of oral POH and capitalized on its recognized properties. The FDA granted NEO100 Orphan Drug Designation (ODD) for treating malignant glioma.

Figure 1: Chemical structure of NEO100

NeOnc sponsored a Phase I clinical trial, where NEO100 was administered to patients with recurrent glioblastoma. All enrolled patients had already undergone standard therapy for this disease, consisting of radiation treatment combined with chemotherapy. Still, this standard therapy had stopped working, and patients were no longer benefiting from it. At this stage of the re-emerging glioblastoma disease, there is no clear clinical recommendation for specific further treatment because effective treatments do not exist for this patient group. Rather, the prognosis is dismal, and the average median survival is only 6-9 months.

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After enrollment in our study, patients received intranasal NEO100 four times daily, using a standard nebulizer and nasal mask. After initial instructions by a nurse, patients can self-administer this treatment at the convenience of their home. Four cohorts of 3 patients each received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 consecutive days of treatment was recorded as one cycle. Adverse events were documented, and radiographic response via RANO criteria was evaluated every two months. Progression-free and overall survival were determined after 6 and 12 months, respectively (PFS-6, OS-12).

The trial was completed in 2020, and after peer review, the results obtained from these 12 patients were published in 2021 (Schönthal AH et al., Neuro-Oncology Advances 3(1):1-12, 2021). Data analysis suggested that intranasal NEO100 may be well tolerated at all four dose levels, and even at the highest dose levels, no severe adverse events were noted. Minor side effects included a runny nose or nasal discomfort. PFS-6 was 33%, OS-12 was 55%, and of the three cohorts’ median survival was 15 months (Figure 2, left panel). Four patients (33%) survived >24 months. Thus, compared to historical controls and what is commonly observed in clinical practice, average patient survival in our clinical trial with these 12 patients might be improved (see further comparison details below). As important, there were none of the typically harsh side effects of many conventional chemotherapies, such as nausea, debilitating fatigue, anemia, infections, diarrhea, hair loss, etc.). Treatment with intranasal NEO100, therefore, did not lead to deterioration of quality of life for patients. However, further research is needed to confirm these results.

Figure 2: Survival of all 12 patients (left) and survival in relation to IDH status (right).

From: Schönthal AH et al., Neuro-Oncology Advances 3(1):1-12, 2021

Further analysis of our Phase I trial suggested that patients with the highest response to intranasal NEO100 were those whose tumors harbored a mutation in the isocitrate dehydrogenase 1 (IDH1) gene (Figure 2, right panel). In the five patients with this mutation, 4 (80%) survived a minimum of 24 months while being treated with intranasal NEO100. In contrast, seven patients without this mutation succumbed to disease earlier—although their average median survival of 11 months was still longer than what might have been expected based on historical experience in the clinic.

Prompted by these observations from our Phase I clinical trial, a Phase IIa continuation of intranasal NEO100 was started in 2021 for high-grade glioma patients with IDH1 mutations. In December 2025, the Company reported updated clinical observations from its ongoing Phase 1/2a study and compassionate-use experience evaluating intranasal NEO100 in patients with recurrent WHO Grade III/IV IDH1-mutant astrocytoma. At the time of the update, the study remained ongoing and the Phase 2a portion had not yet been completed. A total of 25 patients were enrolled across Phase 1, Phase 2a, and compassionate-use settings; however, 18 patients were considered evaluable for efficacy analyses based on a minimum follow-up period of 6 months. Among the overall cohort, radiographic responses, as assessed by Response Assessment in Neuro-Oncology (RANO) criteria, were observed in 6 of 25 patients (24%). In addition, 44% of patients achieved progression-free survival at six months (PFS-6), and 36% (9 of 25) remained alive at least 18 months following treatment initiation, indicating the potential for extended survival in a subset of patients. Intranasal NEO100 was generally well tolerated, with no significant treatment-related toxicities observed, including in patients receiving prolonged or chronic administration. These findings are preliminary, derived from a small, non-randomized patient population, and the study was not powered to evaluate efficacy; however, the observed clinical outcomes and safety profile may inform ongoing clinical development and the design of future studies in this indication.

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Details: 2. Intranasal delivery of NEO212 to patients with brain metastasis.

NEO212 is a hybrid compound where NEO100 is covalently conjugated to temozolomide (TMZ) via a carbamate bridge (Figure 3). While TMZ has been widely used as the standard of care for the treatment of glioblastoma, it does not penetrate the BBB effectively; unsurprisingly, its clinical efficacy is relatively modest. Also, its activity could be further reduced when applied to tumors that are positive for O6-methylguanine methyltransferase (MGMT). This DNA repair protein protects tumor cells from killing by TMZ. Our preclinical studies suggest that NEO212 may potentially be able to overcome these drawbacks and exert its activity even against tumor cells that are positive for MGMT. The FDA granted NEO212 Orphan Drug Designation (ODD) for three different indications: (i) glioma, (ii) brain metastases from breast cancer, and (iii) nasopharyngeal carcinoma.

Figure 3: Chemical structure of NEO212: NEO100 conjugated to temozolomide.

NEO212 was initially designed as a therapeutic molecule with potential enhanced capability of crossing the blood-brain barrier to address the urgent clinical need for better treatments of intracranial malignancies, such as glioblastoma and brain-metastatic lesions from peripheral cancers. In mouse models data indicated that orally-administered1 NEO212 enters the brain in higher quantities than oral TMZ alone. While NEO212 has been investigated in multiple preclinical studies, it has so far not been studied in humans. Based on preclinical studies, the following potential beneficial features of this compound can be summarized as follows:

●

Preclinical studies suggest that NEO212 may demonstrate enhanced anti-tumor activity relative to temozolomide, including in MGMT-expressing tumor models associated with temozolomide resistance, potentially due to its ability to inactivate MGMT. In addition, NEO212 has shown a favorable preclinical safety profile, with indications of reduced systemic toxicity and myelosuppression compared to temozolomide. Pharmacokinetic evaluations in preclinical models have demonstrated increased central nervous system exposure, including a higher brain-to-serum concentration ratio relative to temozolomide. Furthermore, available data suggest that the conjugated molecule exhibits properties distinct from the simple combination of its individual components, temozolomide and perillyl alcohol, which do not appear to replicate the observed activity of NEO212 in vitro or in animal tumor models. (Chen TC et al., Molecular Cancer Therapeutics 13:1181, 2014; Chen TC et al., Cancer Letters 358:144, 2015; Chen TC et al., Journal of Biomedical Sciences 22:71, 2015; Cho HY et al., Molecular Cancer Therapeutics 13:2004, 2014; Jhaveri N et al., Cancer Letters 371:240, 2016; Marin-Ramos NI et al., Oncoscience 5:148, 2018; Marin-Ramos NI et al., Molecular Cancer Therapeutics 17:625, 2018).

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●
In mouse tumor models, NEO212 displayed intracranial therapeutic activity not only against glioblastoma (Cho HY et al., Molecular Cancer Therapeutics 13:2004, 2014; Jhaveri N et al., Cancer Letters 371:240, 2016; Marin-Ramos NI et al., Oncoscience 5:148, 2018; Marin-Ramos NI et al., Molecular Cancer Therapeutics 17:625, 2018; Minea RO et al., PLoS One 15(9):e0238238, 2020) but also against brain-metastatic breast cancer xenografts (Chen TC et al., Molecular Cancer Therapeutics 13:1181, 2014) (Figure 4).

●

Besides intracranial tumors in mouse tumor models, NEO212 showed activity against peripheral cancers in mouse tumor models, including subcutaneous melanoma (Chen TC et al., Cancer Letters 358:144, 2015), nasopharyngeal carcinoma (Chen TC et al., Journal of Biomedical Sciences 22:71, 2015; Xie L et al., Oncotarget 7:1651, 2016) ovarian carcinoma (Song X et al., Journal of Experimental and Clinical Cancer Research 38:239, 2019), lung cancer (Song X et al., Cell Death & Disease 9:202, 2018; Song X et al., Scientific Reports 6:22762, 2016; Chang M et al., Journal of Experimental and Clinical Cancer Research 37:250, 2018), cutaneous T-cell lymphoma (Silva-Hirschberg C et al., Therapeutic Advances in Medical Oncology 11:1758835919891567, 2019), and cytosine arabinoside-resistant leukemia (Schönthal AH et al., Cancers 13(14):3385, 2021).

●
The activity of NEO212 was also documented with the use of primary patient samples implanted into mice, including glioblastoma stem cells (Jhaveri N et al., Cancer Letters 371:240, 2016; Marin-Ramos NI et al., Oncoscience 5:148, 2018) as well as xenografts of a variety of TMZ-resistant glioma and melanoma lines, where drug resistance was based on different molecular mechanisms (Chen TC et al., Cancer Letters 358:144, 2015; Cho HY et al., Molecular Cancer Therapeutics 13:2004, 2014).

●

In all tested in vivo models, NEO212 was administered orally in the range of 5-50 mg/kg (once per day, repeat dosing). This dose range seemed well tolerated by mice, rats, and dogs and did not result in detectable signs of toxicity.

Figure 4: Representative result showing survival of mice with brain-metastatic breast cancer.

Source: Chen TC et al., Molecular Cancer Therapeutics 13:1181, 2014

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The observed activity of NEO212, which was recapitulated in a variety of preclinical tumor models, along with its low observed toxicity profile, led to our IND application to the FDA which was approved in May 2023. FDA approval allowed us to proceed for Phase I/IIa clinical trials, primarily focusing on patients with intracranial malignancies (metastatic and malignant primary brain cancer types). Although NEO212 also showed activity against peripheral cancer types (melanoma, lung cancer, breast cancer, and others) in pre-clinical studies, our first clinical trial will focus on patients with aggressive brain cancer types because the clinical need is the greatest here; due to the significant clinical need because no therapies exist. Because NEO212 was designed for blood-brain barrier penetration, we would expect it to have its greatest impact in patients with brain malignancies.

The Company initiated a Phase 1/2 clinical trial (NEO212-01) evaluating NEO212, an oral bioconjugated formulation of temozolomide and perillyl alcohol, in patients with recurrent central nervous system malignancies, including glioblastoma and brain metastases. The Phase 1 portion of the study was designed as a dose-escalation trial to evaluate safety, tolerability, and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), which constituted the primary objectives, while secondary objectives included characterization of pharmacokinetics and assessment of preliminary anti-tumor activity. Patients received NEO212 on a 5-day dosing schedule within a 28-day treatment cycle across multiple escalating dose cohorts. The dose-escalation portion reached the MTD at Cohort 5 (810 mg administered on Days 1–5 of a 28-day cycle) after a second dose-limiting toxicity, and, in accordance with protocol-defined stopping rules, further dose escalation was discontinued. The RP2D was established at 610 mg (Cohort 4), and a starting dose of 400 mg has been selected for a planned Phase 2a metastasis cohort. NEO212 was generally tolerated across dose levels evaluated, and although the Phase 1 portion of the study was not designed or powered to assess efficacy, preliminary observations included indications of anti-tumor activity and disease stabilization in a subset of heavily pretreated patients. NEO212 is designed to enhance central nervous system exposure and address limitations associated with conventional temozolomide, including resistance mechanisms such as MGMT-mediated DNA repair, which is not significantly reduced by standard temozolomide therapy. These early clinical observations, together with supporting preclinical data, provide the basis for continued clinical development of NEO212. The Company has notified the U.S. Food and Drug Administration of the completion of the dose-escalation portion of the study and intends to request an End-of-Phase 1 (Type B) meeting to review safety, pharmacokinetics, RP2D justification, and the design of subsequent Phase 2 studies, including potential accelerated approval pathways.

Details: 3. Intranasal co-delivery of NEO100 with levodopa for Parkinson’s disease (preclinical stage).

Our preclinical research in mouse brain tumor models indicated that intranasal delivery of NEO100 may facilitate nose-to-brain transport of NEO100 itself and potentially enabled co-delivered pharmaceutics to be carried along this axis and enter the brain as well. For example, intranasal co-delivery of NEO100 with bortezomib (a drug marketed under the trade name Velcade®) seemed to allow bortezomib to enter the mouse’s brain resulting in activity against brain cancer. Without NEO100, bortezomib could not enter the brain (Wang W et al., Journal of Neurosurgery 132(3):959, 2019).

Given preclinical results of NEO100’s ability to act as a vehicle to carry other pharmaceutics into the brain, we considered its application to neurological diseases, such as Parkinson’s disease (PD) or Alzheimer’s disease (AD), which are increasing in numbers as the U.S. population is aging. PD Patients are treated with levodopa (L-Dopa) pills, which must be dosed precisely. These pills have common side effects, such as hypotension, nausea, confusion, and dyskinesia. Therefore, intranasal delivery with direct nose-to-brain transport would be highly desirable because it is could potentially offer better brain-directed delivery without exposing the entire body to the drug, minimizing the undesirable side effects. As well, smaller doses can be given. In our work, we used mice with PD-type lesions in their brains and co-administered NEO100 together with L-Dopa by intranasal delivery. Our results suggest that intranasal co-delivery of NEO100 and L-Dopa suppresses PD symptoms in these mice. Intranasal delivery of L-Dopa without the added NEO100 did not achieve this beneficial effect (Figure 5).

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Figure 5: Mixture of NEO100 with L-Dopa (red underline), when given intranasally, could potentially restore healthy brain function of PD in mice as does a subcutaneous injection of apomorphine (blue underline).

From: Wang W et al., manuscript in preparation.

The health benefits of this approach in the mice were analyzed by determining the physical activity of the mice, in particular their ability to rotate to one side. Untreated PD mice are sick and unable to perform rotations, which is a symptom of the disease. But mice receiving intranasal NEO100 combined with L-Dopa appear to be physically active and perform rotations (bar graphs of mice in Figure 5 with the label underlined in red). The figure also shows that mice injected with apomorphine recover from PD (label underlined in blue). However, compared to the ease of intranasal delivery, injections are invasive and do not support brain-targeted delivery due to the resulting systemic distribution of the injectate.

Details to 4. Intra-arterial delivery of NEO100 to open the patient’s blood-brain barrier will allow brain entry of BBB-impermeable pharmaceuticals or biologics (preclinical stage).

While intranasal applications of NEO100 may exploit direct nose-to-brain access routes and thereby circumvent the obstacle placed by the blood-brain barrier (BBB), an intra-arterial path of administering NEO100 has suggested that it also might directly confront the BBB and “open” it, diminishing its barrier function to potentially enable mostly unrestricted permeation of otherwise BBB-impermeable compounds. We established this procedure, characterized it in preclinical mouse tumor models, and shown that it may have advantages over the currently established clinical method of opening the BBB with mannitol (Wang W et al., Neuro-Oncology 23(1):63, 2021).

We used mouse models of brain-metastatic breast cancer positive for human epidermal growth factor receptor 2 (HER2). In humans, HER2+ breast cancer is usually treated with trastuzumab (Herceptin), a humanized monoclonal antibody, and this treatment often shows success. However, HER2+ breast cancer has a propensity to metastasize to the brain, and trastuzumab may not work as effectively because it cannot effectively penetrate the BBB. Our work has established that intra-arterial NEO100 might open the BBB of mice for a few hours, potentially allowing a brain influx of therapeutic agents that are circulating in the bloodstream. In the case of mice with HER2+ metastases in their brains, a single application of BBB opening with NEO100 seems to enable brain influx of trastuzumab that had been given by intravenous injection, and this approach resulted in the recovery of several of the animals (Figure 6).

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Figure 6: BBB opening by intra-arterial (IA) NEO100 achieves the absence of brain cancer of several brain-metastatic mice treated with intravenous (IV) trastuzumab.

From: Wang W et al., Neuro-Oncology 23(10):1656, 2021

Recent cancer therapy breakthroughs have introduced immune checkpoint-inhibitory antibodies as novel tools to treat cancer. However, as with other antibody-based therapies, these biologics’ applications may be limited due to the BBB, which prevents their brain entry, i.e., brain metastases and primary malignant brain tumors such as glioblastoma. Therefore, we utilized our BBB opening method with intra-arterial NEO100 to a glioblastoma mouse model, where mice received a one-time dose of a checkpoint-inhibitory antibody within the mixture of intra-arterially applied NEO100. The outcome showed that all six mice treated in this fashion showed absence of brain cancer (blue line in Figure 7). In contrast, all other mice died within 4-7 weeks, including those treated with checkpoint-inhibitory antibodies in the absence of NEO100.

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Figure 7: BBB opening by intra-arterial (IA) NEO100 achieves the absence of brain cancer for all glioblastoma mice treated with checkpoint-inhibitory antibodies.

From: Wang W et al., Journal of Neurosurgery, Feb 3:1-9, 2023 [online ahead of print].

Other recent breakthroughs in cancer therapy include the production of CAR T cells, where T lymphocytes are being modified to harbor a chimeric antigen receptor (CAR). While such cells have yielded impressive therapeutic advances, their activity—similar to the case of therapeutic antibodies—may be limited by their poor entry into the brain. Therefore, we applied our BBB opening method with intra-arterial NEO100 to a mouse model with intracranial lymphoma (lymphoma in the brain), where mice received a one-time dose of intravenous lymphoma-targeted CAR T cells, along with BBB opening by intra-arterial NEO100. The outcome showed that all six mice treated in this fashion showed absence of brain lymphoma (blue line in Figure 8). In comparison, most mice that received CAR T cells without BBB opening with intra-arterial NEO100 died within the first three weeks.

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Figure 8: BBB opening by intra-arterial (IA) NEO100 shows the absence of brain cancer in all brain-lymphoma mice treated with lymphoma-directed CAR T cells.

From: Wang W et al., manuscript submitted.

Details to 5. Oral NEO212 for advanced cancer types, including leukemia (preclinical stage).

NEO212 was initially
designed as a therapeutic molecule designed to achieve enhanced capability of crossing the blood-brain barrier to address the urgent
clinical need for better treatments of intracranial malignancies, such as glioblastoma and brain-metastatic lesions from peripheral
cancers. At the same time, however, NEO212 has demonstrated potential potency, along with low toxicity, against cancer types outside
the brain, such as lung cancer, melanoma, ovarian cancer, leukemia, and others (Chen TC et al., Cancer
Letters 358:144, 2015; Chen TC et al., Journal of Biomedical Sciences 22:71, 2015; Xie L et al., Oncotarget
7:1651, 2016; Song X et al., Journal of Experimental and Clinical Cancer Research 38:239, 2019; Song X et al., Cell Death
& Disease 9:202, 2018; Song X et al., Scientific Reports 6:22762, 2016; Chang M et al., Journal of Experimental
and Clinical Cancer Research 37:250, 2018; Silva-Hirschberg C et al., Therapeutic Advances in Medical Oncology
11:1758835919891567, 2019; Schönthal AH et al., Cancers 13(14):3385, 2021).

Among the most striking examples of NEO212’s potential therapeutic impact on peripheral cancer types, as established in mouse tumor models, is its effect on leukemia, particularly drug-resistant acute myeloid leukemia (AML), which in daily clinical practice remains very difficult to treat and often is fatal. First-line treatment of AML usually includes intravenous cytarabine. Still, often the tumor becomes resistant to this drug, which precludes further cytarabine treatment and generally requires subsequent hematopoietic stem cell transplantation. In our experiments, treatment of mice harboring cytarabine-resistant AML with NEO212 suggested a positive result and tolerability. Oral NEO212 was administered once daily for five days, followed by 7-14 days of a treatment holiday; this cycle was repeated twice more for three cycles in total (green arrows in Figure 9); there were no further treatments after week 8. All mice in this treatment group survived beyond 200 days, which might be interpreted as a positive outcome (Figure 9).

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Figure 9: Treatment of mice harboring cytarabine-resistant AML with NEO212 results in the absence of brain cancer in all treated animals.

From: Schönthal AH et al., Cancers 13(14):3385, 2021.

In light of the activity of NEO212 against a variety of tumor types studied in mouse tumor models, the initial Phase I clinical trial will be conducted with patients harboring brain cancers, including primary brain cancers (such as recurrent glioblastoma) and secondary brain cancers (metastases derived from lung, breast, and melanoma). NeOnc has received the IND approval for this Phase I trial. Phase I is expected to last up to one year, followed by Phase II, which is expected to last about two years.

Extending the above, we are also designing a Phase I/IIa trial of oral NEO212 that will specifically focus on patients with newly-diagnosed glioblastoma. With current standard of care, these patients have an average life expectancy of only 15 months after initial diagnosis. Based on the encouraging results from our extensive preclinical studies, our extensive preclinical studies suggest that NEO212 may provide some benefit.

Competition and Competitive Factors

NEO100 and NEO212 address different aspects of the global central nervous system (CNS) treatment market and the brain tumor drug markets which are highly competitive, dynamic, and rapidly evolving areas of the pharmaceutical and healthcare industries. In both markets, success often hinges on a combination of clinical effectiveness, regulatory approvals, market access, pricing strategies, and effective marketing. The competition is further intensified by ongoing advances in medical science and technology, making it essential for companies to stay at the forefront of innovation and research.

Our NEO100 and NEO212 candidates will need to differentiate themselves based on efficacy, safety, cost, ease of administration, and other therapeutic benefits. As we continue our research and development, we are cognizant of these competitive dynamics and are strategizing accordingly to ensure our products bring unique and tangible benefits to patients. As a clinical company, we face many of the challenges outlined below.

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Global Central Nervous System Treatment Market:

The competitive conditions in this market are:

●
Wide Range of Indications: The CNS treatment market encompasses a broad range of neurological and psychiatric disorders, including epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and more. Each indication has its own set of competing treatments.

●
Established Players: Large pharmaceutical companies, such as Pfizer, Roche, and Novartis, have a strong presence in the CNS market, with well-established drugs and therapies for various conditions.

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Generics and Biosimilars: Many older CNS drugs have lost patent protection, leading to the availability of generic and biosimilar versions. This has intensified competition, particularly in the treatment of common conditions like depression and anxiety.

●
R&D Investment: Companies invest heavily in research and development to discover and develop new CNS drugs. Advancements in neuroscience are driving innovative therapies, including novel mechanisms of action and targeted treatments.

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Regulatory Challenges: Developing CNS drugs can be challenging due to the complexity of the brain and the potential for side effects. Companies must navigate stringent regulatory processes to gain approvals from agencies like the FDA and EMA.

●
Biologics and Gene Therapies: Emerging treatments, such as gene therapies and biologics, are becoming more prevalent in the CNS market. These advanced therapies often come with high costs and complex manufacturing processes.

●
Market Access and Pricing: Reimbursement and pricing challenges exist, and companies must demonstrate cost-effectiveness to secure market access, especially for novel, high-cost treatments.

Global Brain Tumor Drug Market:

The competitive conditions in this market are:

●
Tumor Type Variability: The market for brain tumor drugs is highly diverse due to the various types of brain tumors, including glioblastoma multiforme (GBM), meningioma, and astrocytoma, each requiring different treatment approaches.

●
Surgery and Radiation Therapy: Brain tumors often require a combination of surgery and radiation therapy. Competition can be intense among medical device manufacturers and radiation therapy providers, as well as pharmaceutical companies offering adjuvant therapies.

●
Targeted Therapies: Developing targeted therapies that focus on specific genetic mutations or signaling pathways associated with brain tumors is an active area of competition. Personalized medicine approaches are increasingly relevant.

●
Immunotherapy: Immunotherapies are being explored for brain tumors, and competition revolves around developing effective immunotherapeutic strategies to harness the body’s immune system against the tumor.

●
Clinical Trials: Companies often compete based on the strength of their clinical trial results and their ability to bring new drugs to market. The effectiveness and safety of brain tumor drugs are critical factors.

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●
Orphan Drug Designations: Some brain tumor treatments may qualify for orphan drug designations, which can provide certain advantages, including extended exclusivity and incentives for development.

●
Patient Advocacy: Patient advocacy organizations play a significant role in raising awareness and influencing drug development. Collaboration with these groups can enhance a company’s competitive position.

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Research and Innovation: Continuous research and innovation in areas such as drug delivery, biomarker discovery, and imaging technologies contribute to the competitive landscape.

●
Combination Therapies: Companies explore combination therapies that can enhance treatment effectiveness. Combining surgery, radiation, and chemotherapy, for example, is a common approach in brain tumor treatment.

●
Global Expansion: Companies that can navigate international regulatory frameworks and secure approvals in various markets have a competitive edge.

There are numerous other pharmaceutical and biotech companies, as well as academic institutions, involved in brain tumor research and drug development, including:

●
Bristol Myers Squibb (BMS): Makers of Opdivo® (nivolumab) which has been explored for glioblastoma.

●
Merck & Co., Inc.: Their drug, Temozolomide (Temodar® in the US, Temodal® in Europe), is a primary treatment for glioblastoma and anaplastic astrocytoma.

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Roche: They have received accelerated US approval for Avastin® (bevacizumab) for recurrent glioblastoma.

●
Novocure: Developers of the Optune® device, a non-invasive treatment for glioblastoma.

●
AstraZeneca are engaged in various stages of research, development, and commercialization of treatments for brain tumors.

●
Eli Lilly and Company: Conducting research in targeting brain tumors.

●
Pfizer: Involvement in the development of treatments for various types of cancers, including brain tumors.

●
Celldex Therapeutics: Working on drug candidates for glioblastoma.

The competition in this sector extends beyond just drug therapies. Various modalities, including radiation, surgery, and newer non-drug technologies, also vie for market share in the brain tumor treatment domains.

NEO212

NEO212 is a temozolomide conjugate that is given orally. Its main competitive landscape will be standard of care alkylating agents such as temozolomide and lomustine. It is intended that NEO212 will have an oral formulation for primary brain cancers and may also be used for metastatic brain cancers. These cancers are treated currently by surgery or radiosurgery only.

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Future Growth Drivers

We anticipate several goals and plans that may potentially support our long-term growth, with some supported by additional high-growth global markets:

●
Potential commercial launch of NEO100 following FDA market approval.

●
Possible clinical trials & FDA approval of other POH compounds in our product pipeline.

●
Exploration of NEO100 pediatric indication.

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We are currently investigating several additional proprietary chemotherapy agents that have shown preliminary positive effects in laboratory tests on various types of cancers, i.e., NEO212 oral and intranasal delivery for primary and metastatic brain cancer.

●
Treatments for other CNS diseases and disorders based on our POH technology, such as Alzheimer’s, Parkinson’s and Epilepsy.

Manufacturing

We do not own or operate manufacturing facilities for the production of NEO100 nor do we plan to develop our own manufacturing operations in the foreseeable future. We currently depend on third party contract manufacturers for all of our required raw materials, active pharmaceutical ingredient and finished products for our preclinical and clinical trials.

Manufacturers of our products are required to comply with applicable FDA manufacturing requirements contained in the FDA’s current good manufacturing practice standards (“cGMP”) regulations. cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation. Pharmaceutical product manufacturers and other entities involved in the manufacture and distribution of approved pharmaceutical products are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved NDA/NDA, including withdrawal of the product from the market. In addition, changes to the manufacturing process generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

Intellectual Property

We have exclusively licensed a large worldwide patent portfolio from USC consisting of both issued patents and pending patent applications related to NEO100, NEO212 and other products from the NeOnc patent family for multiple uses, including oncological and neurological conditions. In the United States, the Company has exclusive rights to 28 issued patents and 14 pending patent applications. Internationally, we have 65 patents issued and 28 patents applications pending.

The patent families of our product candidates are briefly described in the table below. All patents are owned by USC and exclusively licensed to us from USC. Patent Term Extension (PTE) may be available on certain patents after product approval.

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Product Candidate
Title [description]
US Application #
US Patent
Expiration Date
Foreign Counterparts

NEO100

Pharmaceutical Compositions Comprising Monoterpenes

[Ultra Pure]

13/040,059

13/939,834

14/817,286

14/843,097

15/040,002

15/220,135

16/575,587

17/749,293

8,507,7341,2

9,133,0851

9,480,6591

9,498,4481

9,700,5243

10,457,6181

10,899,6911

Pending3

8/29/2031

6/5/2031

3/3/2031

3/3/2031

3/3/2031

3/3/2031

3/3/2031

3/3/2031*

Canada, China, China, EU (France, Germany, United Kingdom, Ireland, and Italy)

NEO212

Pharmaceutical Compositions Comprising POH Derivatives

[POH conjugated to temozolomide (TMZ)]

13/566,731

14/455,371

13/818,972

15/408,866

8,916,5452

9,580,3723

9,499,4611,2,3

10,092,5623

8/26/2031

8/26/2031

8/26/2031

8/26/2031

Brazil, China, EU (Germany, Spain, France, United Kingdom Switzerland, Ireland, Italy, Netherlands, Sweden), Japan, Hong Kong

NEO 214

Pharmaceutical Compositions Comprising POH Derivatives

[POH conjugated to rolipram]

16/123,729

16/388,535

17/306,167

11,077,1043

11,013,8042

pending2,3

8/26/2031

8/26/2031

8/26/2031*

Japan, EU (Spain, France, United Kingdom, Ireland, Italy, Netherlands, Sweden)

NEO 216

Pharmaceutical Compositions Comprising POH Derivatives and Methods of Use

[POH conjugated to valproic acid]

16/606,520

18/150,933

11,559,5082

pending3

11/24/2038

4/18/2038*

China, EU (pending in both)

NEO 218

A Perillyl Alcohol-3-Bromopyruvate Conjugate and Methods of Treating Cancer

[POH conjugated to 3- Bromopyruvate]

16/465,081
10,858,3051,2,3
11/29/2037
China, EU, Japan
(pending in all)

NEO 400

Pharmaceutical Compositions Comprising POH Derivatives

[POH conjugated with linoleic acid (LA)]

17/251,452

17/313,258

17/573,693

pending3

pending3

pending2

8/26/2031*

8/26/2031*

8/26/2031*

China, EU (pending in both)

NEO 412

Pharmaceutical Compositions Comprising Perillyl Alcohol Derivatives

[Triple conjugation of perillyl alcohol, linoleic acid, and temozolomide]

15/041,743

16/126,586

9,522,9181,2

10,696,6803

2/11/2036

2/11/2036

Australia, China, EU (Germany, France, United Kingdom, Ireland), Japan

1
Method of making pharmaceutical composition

2
Pharmaceutical composition

3
Method of using pharmaceutical composition

*
20 years from the earliest filing date, subject to patent term adjustment

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Our commercial success will depend in part on our ability to obtain and maintain patent and other intellectual property protection in the United States and other countries with respect to our technology, including NEO100, NEO212 and our other product candidates. We also rely in part on trade secret, copyright and trademark laws, and confidentiality, licensing and other agreements with employees and third parties, all of which offer only limited protection. We seek to protect our proprietary position by filing and prosecuting patent applications in the United States and abroad related to our technology and product candidates.

The patent positions of biotechnology and pharmaceutical companies generally are highly uncertain, involve complex legal and factual questions and have in recent years been the subject of much litigation. As a result, the issuance, scope, validity, enforceability and commercial value of our licensed patents and any patents we own are highly uncertain. The steps we and our licensor have taken to protect our proprietary rights may not be adequate to preclude misappropriation of our proprietary information or infringement of our intellectual property rights, both inside and outside of the United States.

Further, the examination process may require us to narrow the claims for our licensed pending patent applications, which may limit the scope of patent protection that may be obtained if these applications issue. Our pending licensed and future patent applications may not result in patents being issued that protect our product candidates, in whole or in part, or which prevent others from commercializing competitive product candidates. The scope of a patent may also be reinterpreted after issuance. The rights that may be granted under our issued patents may not provide us with the proprietary protection or competitive advantages we are seeking. Even if patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage. If we are unable to obtain and maintain patent protection for our technology or for NEO100 or our other product candidates, or if the scope of the patent protection obtained is not sufficient, our competitors could develop and commercialize products similar or superior to ours in a non-infringing manner, and our ability to successfully commercialize NEO100 or our other product candidates and future technologies may be adversely affected. It is also possible that we will fail to identify patentable aspects of inventions made in the course of our development and commercialization activities before it is too late to obtain patent protection on them.

In addition, the patent prosecution process is expensive, time-consuming and complex, and we may not be able to file, prosecute, maintain, enforce or license all necessary or desirable patent applications at a reasonable cost or in a timely manner. Although we enter into non-disclosure and confidentiality agreements with parties who have access to confidential or patentable aspects of our research and development output, such as our employees, collaborators, and other third parties, any of these parties may breach the agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection. It is also possible that we will fail to identify patentable aspects of our research and development efforts in time to obtain patent protection.

Our licensed pending applications cannot be enforced against third parties practicing the inventions claimed in such applications unless and until a patent issues from such applications with a claim that covers infringing third-party activity. Because the issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, issued patents that we license from third parties or own in the future may be challenged in the courts or patent offices in the United States and abroad, including through opposition proceedings, derivation proceedings, post-grant review, inter partes review, interference proceedings or litigation. Such proceedings may result in the loss of patent protection, the narrowing of claims in such patents or the invalidity or unenforceability of such patents, which could limit our ability to stop others from using or commercializing similar or identical products, or limit the duration of the patent protection for our technology. Protecting against the unauthorized use of our patented inventions, trademarks and other intellectual property rights is expensive, time consuming, difficult and in some cases may not be possible. In some cases, it may be difficult or impossible to detect third-party infringement or misappropriation of our intellectual property rights, even in relation to issued patent claims, and proving any such infringement may be even more difficult. If we are unable to obtain, maintain, and protect our intellectual property our competitive advantage could be harmed, and it could result in a material adverse effect on our business, financial condition, results of operations, stock price and prospects.

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Exclusive Patent License Agreement between USC and our Company

On March 9, 2009, Nas-Onc, Inc. (k/n/a NeOnc Technologies, Inc). entered into an exclusive, worldwide license agreement with USC, pursuant to which USC granted us a license to use certain patents and patent applications for the treatment and therapies of disease symptoms in mammals (the “USC Agreement”). The license is exclusive except for the rights granted to the US government pursuant to the Bayh-Dole Act and the right of USC and other non-profit academic research institutions to practice and improve the licensed patents for educational and research purposes. Pursuant to the USC Agreement, we (1) paid USC an upfront royalty payment of $20,000, (2) granted USC 117,236 shares of Common Stock, (3) will pay USC an earned royalty of 2% of Net Sales (as that term is defined in the USC Agreement), (4) has paid annual maintenance royalties of: $5,000 due January 1, 2011, $5,000 due January 1, 2012, $10,000 due January 1, 2013, $20,000 due January 1, 2014 through January 1, 2025, and (5) will continue to pay annual maintenance royalties of $20,000 due on January 1 of each year thereafter. Annual maintenance royalties paid to USC are creditable toward earned royalties. We are also responsible for paying all reasonable patent expenses incurred by USC for filing prosecution and maintaining the licensed patents.

Under the USC Agreement, payments will not be due to USC upon reaching certain development milestones. As of December 31, 2025, we have paid USC $20,000 for a patent maintenance fee. In the event of suspected patent infringement, the parties may agree to jointly institute suit, wherein the parties will share equally all costs and any recovery, with control of such lawsuit being by agreement between us and USC. Absent an agreement to jointly institute a suit, USC has the sole right to institute suit, at its option, where USC will bear the cost of such litigation and retain all recovery. In the event that USC does not institute the lawsuit, we may bring suit, at its option, and bear all such costs. Any recovery obtained by us must be shared with USC, after litigation costs reimbursement, as royalties on Net Sales for the remaining recovery. These rights and obligations were changed pursuant to the Amended License Agreement discussed below.

The USC Agreement is sublicensable subject to the same terms, except that (1) sublicensees may not grant sublicenses, (2) the earned royalty may be increased as to sublicensees, (3) the sublicense reverts to USC in the event the USC Agreement is terminated as to us and, (4) additional issue and maintenance fees are owed to USC for each sublicense. These rights and obligations were changed pursuant to the Second Amendment and Restated Agreement discussed below.

We may challenge the licensed patents upon 90 days’ notice and payment of all royalties due. If we are unsuccessful in its challenge, the earned royalty will thereafter be increased by a factor of three. These rights and obligations were changed pursuant to the Restated Agreement discussed below.

The term of the USC Agreement extends until the last to expire of the licensed patents. The Term of the Agreement was changed pursuant to the Restated Agreement discussed below.

The USC Agreement may be terminated by either party upon 30 days’ notice or upon material breach, wherein the breaching party is permitted 30 days to remedy such breach. USC may terminate immediately if (1) we attempt to sublicense, transfer or assign its rights contrary to the terms of the agreement, (2) we do not maintain the required insurance coverage, or (3) we are determined to be insolvent. These rights and obligations were changed pursuant to the Restated Agreement discussed below.

The parties amended the USC Agreement on April 5, 2023 (“Amended License Agreement”). The Amended License Agreement added NeOnc Technologies Holdings, Inc. as a licensee. The Amended License Agreement also added additional patents and patent applications to the prior license grant and requires us to obtain and record fully executed assignments of the added patents/applications demonstrating USC’s ownership in all relevant jurisdictions. Pursuant to the Amended License Agreement, we agreed to issue USC 560,000 additional shares of our Common Stock. The 560,000 shares were issued to USC on October 11, 2023.

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In addition, the Amended License Agreement provides for an 4% earned royalty on Net Sales on licensed products protected by the newly added patents on a country by-country basis. In the event that a licensed product is protected by patents from both the USC Agreement and the Amended License Agreement, the higher royalty will apply. The Amended License Agreement also recognizes a Royalty Credit, in the event that we must obtain additional licenses from third parties in order to sell the licensed products. The Amended License Agreement also grants us control the prosecution of any patent application and maintenance of any patent included within Licensed Patents. We continue to be responsible for all costs associated with the prosecution and maintenance of the licensed patents. The Amendment also changed the parties enforcement obligations. Specifically, we shall have the first right, following consultation with USC, at our sole expense, to file suit against any alleged infringer or in defense of any Third Party claim. Any recovery or settlement in excess of litigation costs paid to us will be shared with USC as if it were Sublicense Revenue as defined in the USC Agreement. USC must consent to any settlement that is detrimental to USC or USC’s intellectual property rights. If we elect not to file suit against an alleged infringer, then upon such election, we will be deemed to have assigned to USC all rights, causes of action, and damages resulting from the alleged infringement. USC then has the sole right to institute suit, at its option.

The parties further amended the USC Agreement on May 30, 2023 (“Second Amendment”). The Second Amendment revised the license agreement to permit sublicensees to sublicense the patents pursuant to specific terms.

On November 19, 2023, the Company and USC entered into an Amended and Restated Exclusive License Agreement (the “Restated Agreement”). The Restated Agreement addressed and clarified certain reporting obligations of the Company under the USC Agreement and addressed certain financial and other obligations, defaults, and deficiencies in connection with the Company’s performance under the USC Agreement. In satisfaction prior unpaid sublicense issue royalties and annual maintenance royalties due for sublicensees, the Company must pay USC $230,000 by March 31, 2024. On July 17, 2024, the restated agreement was amended to extend the payment date of the $230,000 to the earlier of September 1, 2025 or withing five days of a public offering. In connection with the Restated Agreement, the Company recorded the settlement amount of $230,000 in the accompanying consolidated statement of operations for the year ended December 31, 2023, and is included in accounts payable – related parties to USC in the accompanying consolidated balance sheets as of December 31, 2025 and 2024.

The Restated Agreement provides for the same annual maintenance royalties of $20,000 per year above as well as the earned royalty of 2% or 4% on Net Sales on Licensed Products based on patent coverage (with the higher royalty applied when the Licensed Product is protected by patents from both the USC Agreement and the Amended License Agreement) and on a country-by-country basis. As above, the Restated Agreement recognizes the Royalty Credit.

In the event that we, or our sublicensee (other than OEP (discussed below)), challenges a Licensed Patent the annual maintenance royalty, milestone payments and the earned royalty percentage rated will be doubled during the pendency of such challenge. At the conclusion of such challenge, if a Valid Claim that covers the Licensed Product, Licensed Service or Licensed Process is held valid and enforceable then such ongoing royalty payments will be tripled. We must also reimburse USC for all costs incurred in connection with such challenge. Further, we must provide USC at least 180 day’s written notice prior to our, or our sublicensee (excluding OEP) challenging a Licensed Patent. The notice is required to contain the prior art and a description of the facts and arguments that support the invalidity or unenforceability contention. We are required to discuss same with USC in an attempt to resolve the issues.

As above, we may grant sublicenses and our sublicensees may further grant licenses through one tier. By way of reference, on November 8, 2013, we entered into a collaboration agreement (“OEP Agreement”) with OEP, pursuant to which NeOnc licensed to OEP the right to commercialize NEO100 in those territories specified in the OEP Agreement. As to the OEP Agreement, the Restated Agreement waives any prior breach by us of the USC Agreement and permits the OEP sublicense despite inconsistencies with certain terms of the Restated Agreement. On February 20, 2024, OEP and the Company entered into a settlement agreement whereby the Company and OEP terminated the OEP Agreement in exchange for a payment in the amount of $4,000,000 payable by the Company to OEP within ten days of the close of the Company’s initial public offering. The Company has a litigation settlement payable of $4,000,000 in the accompanying consolidated balance sheets as of December 31, 2025 and 2024.

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As above, pursuant to the Restated Agreement we maintain us sole control the prosecution of any patent application and maintenance of any patent included within licensed patents. We continue to be responsible for all costs associated with the prosecution and maintenance of the licensed patents. In addition, the parties enforcement obligations as described in the Amended License Agreement remain unchanged. Specifically, we have the first right, following consultation with USC, at our sole expense, to file suit against any alleged infringer or in defense of any Third Party claim. Any recovery or settlement in excess of litigation costs paid to us will be shared with USC as if it were sublicense revenue. USC must consent to any settlement that is detrimental to USC or USC’s intellectual property rights. If we elect not to file suit against an alleged infringer, then upon such election, we will be deemed to have assigned to USC all rights, causes of action, and damages resulting from the alleged infringement. USC then has the sole right to institute suit, at its option.

The Restated Agreement changes the Term of the license. Specifically, the term is now tied to our royalty obligations under the Restated Agreement. We are obligated to pay royalties as to each Licensed Product, Licensed Service or Licensed Process on a country-by-country basis until (a) the last to expire Licensed Patent covering such product/service/process or (b) for 15 years after the date of first commercial sale of such product/service/process where such product/service/process is not covered by a Valid Claim of a Licensed Patent but such product/service/process was developed or made using any Licensed Process. The Term of the license ends when no further royalty obligations are due.

Last, as to termination, the Restated Agreement provides that the parties may mutually agree to terminate. Further, USC may immediately terminate if (a) we do not make payments when due and fail to cure, (b) we default on our indemnification or insurance obligations, (c) we are determined to be insolvent, (d) if any of our officers, directors or employees are convicted of a felony related to the development, manufacture use, marketing, distribution or sale of the Licensed Product, (e) if an audit shows an underpayment by us or a sublicensee of 15% or more for any 12 month period, or (f) we default in the performance of our other obligations in the agreement, and in each case fail to cure. We may terminate the license by giving 180 days advance written notice.

Upon any termination of the license (other than expiration of the Term), then the Restated Agreement grants to USC a non-exclusive worldwide fully paid license, with the right to sublicense to the Licensed Product Data, which includes all pre-clinical, clinical and other regulatory data generated by or on behalf of the Company relating to the Licensed Product and generated after the effective date of the USC Agreement.

Transforming CNS Drug Development: NTHI’s AI and 3D Bioprinting Platforms for Precision Oncology and Beyond

NTHI has strategically acquired and integrated two proprietary technology platforms that materially enhance its drug development capabilities and competitive positioning in the central nervous system (CNS) therapeutics space: (1) an artificial intelligence (AI)-powered compound modeling and sonodynamic therapy (SDT) optimization platform, and (2) a patented magnetic-field-guided 3D bioprinting technology for the generation of tumor spheroids and organoids.

1.
Artificial Intelligence for Drug Discovery and Personalized Sonodynamic Therapy

NTHI has acquired and operationalized an AI-driven computational drug modeling platform designed to support the rational development of sonosensitizers, including the Company’s lead assets, NEO100 and NEO212. This proprietary platform enables predictive modeling of blood-brain barrier (BBB) permeability, reactive oxygen species (ROS) generation, and drug-tumor interactions across heterogeneous CNS tumor environments, including glioblastoma, meningioma, diffuse intrinsic pontine glioma (DIPG), and brain metastases.

Key capabilities include:

●
Simulation of compound behavior, BBB penetration, and cytotoxicity (e.g., NEO100, NEO212 vs. temozolomide) across tumor types and microenvironments.

●
AI-guided optimization of ultrasound activation parameters to enhance SDT precision and efficacy.

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●
In silico design of next-generation analogs and combinatorial therapeutic regimens with immuno-oncology and targeted agents.

●
Reduction in preclinical costs and cycle times by replacing low-throughput assays with high-fidelity computational predictions.

●
Personalization of treatment strategies based on patient-specific tumor biology and anatomical characteristics.

The platform significantly accelerates drug discovery and improves translational predictability, offering a scalable foundation for expanding NTHI’s CNS oncology pipeline and clinical trial design.

2.
3D Bioprinting Platform for Tumor and Disease Modeling

NTHI acquired exclusive rights to a patented 3D bioprinting platform developed at McMaster University (U.S. Patent No. 11,788,057 B2). This technology utilizes magnetic field manipulation to generate highly structured and reproducible tumor spheroids and organoids that accurately replicate the tumor microenvironment and neural architecture. This advancement resolves longstanding challenges of conventional 2D cultures and many 3D systems in terms of scalability, fidelity, and biological relevance.

Applications and strategic impact include:

●
High-throughput modeling of brain tumors (e.g., GBM, DIPG, meningioma) for drug screening and mechanism-of-action studies.

●
Expansion into neurodegenerative disease models (e.g., Alzheimer’s, Parkinson’s) and non-CNS organoid systems (e.g., liver, lung, gut).

●
Alignment with NIH and international mandates to reduce reliance on animal models, positioning NTHI at the forefront of ethical, next-generation research tools.

●
Potential for licensing and strategic collaborations with academic institutions, biotech firms (e.g., Stemcell Technologies), and global pharmaceutical CROs.

Together, these platforms provide a synergistic and vertically integrated framework that supports NTHI’s mission to deliver innovative, non-invasive CNS therapies, while opening parallel revenue opportunities in drug discovery tools, precision oncology, and disease modeling.

Settlement Agreements with Licensees

On July 1, 2022, NeOnc Technologies, Inc. and Fox Infused, LLC, a Delaware limited liability company (“Fox Infused”), entered into an Intellectual Property License and Supply Agreement effective July 1, 2022 (the “Agreement”) whereby NeOnc agreed to supply certain products to Fox Infused and license certain of our patents. We terminated the Agreement with Fox Infused on April 25, 2023. On June 6, 2023, Fox Infused filed a complaint against NeOnc in the Central District of California alleging that the termination was improper (Civil Action No. 2:23-04431). Fox Infused also filed an ex parte application for a temporary restraining order and an order to show cause on a preliminary injunction against us seeking to have the court stop the termination of the contract. Fox Infused’s temporary restraining order application was denied and the case dismissed without prejudice. Fox Infused refiled the case in arbitration before the American Arbitration Association (Case No. 01-23-0002-5020). The parties engaged in settlement discussions, and agreed to settle the dispute for a $600,000 payment by us to Fox Infused within 5 business days of the closing date of the Company’s initial public offering or March 31, 2024. The Company was in default under the terms of such settlement agreement as of the end of 2025 and subject to accumulated interest at an annual rate of 10.0%. Fox Infused initiated default proceedings against the Company which resulted in direct and indirect costs to us in defending and responding to such proceedings. In March 2026, the Company satisfied this obligation by paying the settlement amount plus accrued interest of $737,929.

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On June 14, 2023, the Company terminated its collaboration agreement with Orient EuroPharma Co., Ltd. (“OEP”). OEP retained counsel, who informed the Company that it believed that the collaboration agreement was improperly terminated by the Company and intended to take legal action in connection therewith. The parties engaged in a mediation on August 29, 2023. The Company withdrew its termination notice on October 31, 2023. The Company believed this would resolve the matter. However, on February 5, 2024, OEP initiated an arbitration claiming that the Company’s termination notice was invalid, the collaboration agreement remained binding and the Company breached representations in that agreement. The Company was prepared to defend the claims and assert counterclaims. Instead, the Company and OEP negotiated a settlement that resulted in the termination of the collaboration agreement and all of OEP’s license rights and resolved all disputes between the parties. Pursuant to the settlement agreement, the Company will pay OEP $4.0 million within ten days of the closing date of the Company’s initial public offering. As the Company believes its Direct Listing is not an initial public offering, the Company does not intend to make payment to OEP. OEP recently informed the Company that it believes the Company is currently obligated to pay such amount; while the Company does not agree with this assertion, there is a risk that OEP could institute additional proceedings against us which could result in direct and indirect costs to us in defending and responding to such proceedings and could result in operational disruptions that could harm our reputation, brand and result of operations, any of which may affect the Company’s ability to raise additional proceeds from the sale of its securities.

Government Regulation and Product Approval

In the United States, the FDA regulates pharmaceutical products under the Federal Food, Drug, and Cosmetic Act, or the FDCA, the PHSA, and regulations and guidance documents implementing these laws. The FDCA, PHSA and their corresponding regulations govern, among other things, the testing, manufacturing, safety, purity, potency, labeling, packaging, storage, record keeping, distribution, reporting, advertising and other promotional practices involving pharmaceutical products. Consent from the FDA is required before conducting human clinical testing of drug products. FDA approval of a new drug application (NDA) or a biologics license application (BLA) also must be obtained before marketing a new drug or biological product. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the continued expenditure of substantial time and financial resources.

U.S. Small Molecule New Drug Product Development Process

Any new drug product must be approved by the FDA before it may be legally marketed in the United States. FDA approval is also required before marketing an approved drug product for a new indication or condition of use. The process required by the FDA before a new drug product candidate may be marketed in the United States generally involves the following:

●
Completion of preclinical laboratory tests and in vivo studies in accordance with the FDA’s Good Laboratory Practice (GLP) regulations and applicable requirements for the humane use of laboratory animals or other applicable regulations;

●
Submission to the FDA of an investigational new drug (IND) application, which allows human clinical trials to begin unless FDA objects (issues a “clinical hold”) within 30 calendar days;

●
Approval by an independent institutional review board (IRB), reviewing each proposed clinical trial and clinical site before each clinical trial may be initiated;

●
Performance of adequate and well-controlled human clinical trials in accordance with the protocol contained in the approved IND and in accordance with the FDA’s Good Clinical Practice (GCP) regulations, and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed product candidate for its intended use;

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●
Preparation and submission to the FDA of a new drug application (NDA) for marketing approval that includes substantial evidence of safety and efficacy from results of nonclinical testing and clinical trials;

●
Review of the product by an FDA advisory committee, if applicable;

●
Satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the product candidate is produced to assess compliance with current Good Manufacturing Practice (cGMP) requirements and to assure that the facilities, methods and controls are adequate to preserve the product candidate’s identity, safety, strength, quality, potency and purity;

●
Potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the NDA; and

●
Payment of user fees and FDA review and approval of the NDA.

The testing and approval process of product candidates requires substantial time, effort, and financial resources. Satisfaction of the FDA’s pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity, and novelty of the product or disease. Before testing any product candidate in humans, the product candidate must undergo preclinical testing. Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as in vivo animal studies to assess the potential safety and activity of the product candidate and to establish a rationale for therapeutic use. The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs.

Concurrent with clinical trials, companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the drug in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final drug product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

A clinical trial sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. Some preclinical testing may continue even after the IND is submitted. The IND automatically becomes active 30 calendar days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to a proposed clinical trial, including concerns that human research subjects will be exposed to unreasonable health risks, and places the clinical trial on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The FDA also may impose partial or full clinical holds on a product candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, trials may not begin, or recommence without FDA authorization and then only under terms authorized by the FDA. Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that, once begun, that issues arise that partially or fully suspend or terminate such studies.

Human Clinical Trials Under an IND

Clinical trials involve the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators which generally are physicians not employed by, or under, the control of the trial sponsor. Clinical trials must be conducted under written study protocols detailing, among other things, the objectives of the trial, subject selection and exclusion, the trial procedures, the parameters to be used in monitoring safety, the criteria to be evaluated, and a statistical analysis plan. Each protocol and any amendments to the protocol must be submitted to the FDA as part of the IND.

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Further, clinical trials must be conducted in accordance with federal regulations and GCP requirements, which include the requirements that all research subjects provide their informed consent in writing for their participation in any clinical trial, as well as review and approval by an IRB at each study site participating in the clinical trial or a central IRB. An IRB is charged with protecting the welfare and rights of trial participants and considers items such as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject, or their legal representative, reviews and approves the study protocol, and must monitor the clinical trial until completed.

Human clinical trials typically are conducted in three sequential phases that may overlap or be combined:

●
Phase I. The product candidate initially is introduced into a small number of healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early understanding of its value in treating patients. In the case of some product candidates for severe or life-threatening diseases, especially when the product candidate may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

●
Phase II. The product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.

●
Phase III. Phase III clinical trials are commonly referred to as “pivotal” or “registrational” studies, which typically denotes a study which presents the data that the FDA or other relevant regulatory agency will use to determine whether or not to approve a product. In Phase III studies, the product candidate is administered to an expanded patient population, generally at multiple geographically dispersed clinical trial sites in adequate and well-controlled clinical trials to generate sufficient data to statistically demonstrate the efficacy and safety of the product for approval. These clinical trials are intended to establish the overall risk/benefit ratio of the product candidate and provide an adequate basis for product labeling.

Post-approval clinical trials, sometimes referred to as Phase IV clinical trials, may be required by FDA, or may be voluntarily conducted after initial approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up.

During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA.

Written IND safety reports must be promptly submitted to the FDA and the investigators for: serious and unexpected adverse events; any findings from other studies, in vivo laboratory tests or in vitro testing that suggest a significant risk for human subjects; or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Relevant additional information obtained by the sponsor that pertains to a previously submitted IND safety report must be submitted as a follow-up IND safety report. Such report should be submitted within 15 calendar days after the sponsor receives the information.

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Information about certain clinical trials, including a description of the study and, in some cases, study results, must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on their clinicaltrials.gov website. Manufacturers or distributors of investigational products for the diagnosis, monitoring, or treatment of one or more serious or life-threatening diseases or conditions where no other comparable or satisfactory therapeutic options exist must also have a publicly available policy on evaluating and responding to requests for expanded access, sometimes called “compassionate use,” requests.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor that regularly reviews accumulated data and advises the study sponsor regarding the continuing safety of the trial. This group, known as a Data and Safety Monitoring Board (DSMB) or Data and Safety Monitoring Committee (DSMC), may also review interim data to assess the continuing validity and scientific merit of the clinical trial. This group receives special access to unblinded data during the clinical trial and may advise the sponsor to halt the clinical trial if it determined there is an unacceptable safety risk for subjects or on other grounds, such as no demonstration of efficacy.

The FDA may order the temporary, or permanent, discontinuation of a clinical trial at any time, or impose other sanctions, if it believes that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial patients. An IRB may also require the clinical trial at the site to be halted, either temporarily or permanently, for failure to comply with the IRB’s requirements or if the trial poses an unexpected serious harm to subjects. The FDA or an IRB may also impose conditions on the conduct of a clinical trial. Clinical trial sponsors may also choose to discontinue clinical trials as a result of risks to subjects, a lack of favorable results, or changing business priorities.

Compliance with Current Good Manufacturing Practices (cGMP) Requirements

Manufacturers of pharmaceutical products must comply with applicable cGMP regulations, including quality control and quality assurance and maintenance of records and documentation. Manufacturers and others involved in the manufacture and distribution of such products also must register their establishments with the FDA and certain state agencies. Both domestic and foreign manufacturing establishments must register and provide additional information to the FDA upon their initial participation in the manufacturing process. Establishments may be subject to periodic, unannounced inspections by government authorities to ensure compliance with cGMP requirements and other laws. Discovery of problems may result in a government entity placing restrictions on a product, manufacturer or holder of an approved NDA, and may extend to requiring withdrawal of the product from the market. The FDA will not approve a NDA unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specification.

Concurrent with clinical trials, companies usually complete additional preclinical studies and must also develop additional information about the physical characteristics of the product candidate as well as finalize a process for manufacturing the product candidate in commercial quantities in accordance with cGMP requirements. To help reduce the risk of the introduction of adventitious agents or of causing other adverse events with the use of small molecule products, the PHSA emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other requirements, the sponsor must develop methods for testing the identity, strength, quality, potency and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

In relation to the clinical trials that may be conducted in other countries with a view to obtaining a marketing authorization, there are comparable cGMP requirements and other regulatory rules that are implemented nationally.

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U.S. FDA Review and Approval Process

Assuming successful completion of the required clinical and preclinical testing, the results of the preclinical tests and clinical trials together with detailed information relating to the product’s CMC, including negative or ambiguous results as well as positive findings, and proposed labeling, among other things, are submitted to the FDA for NDA (new drug application) approval to market the product for one or more indications.

Under the Prescription Drug User Fee Act (PDUFA), as amended, each NDA must be accompanied by a significant user fee. The FDA adjusts the PDUFA user fees on an annual basis. The PDUFA also imposes an annual program fee for approved therapeutic products. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for product candidates designated as orphan drugs, unless the product candidate also includes a non-orphan indication.

In addition, under the Pediatric Research Equity Act (PREA), an NDA for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and potential of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe. Also, applications for product candidates intended for the treatment of adult cancer which are directed at molecular targets that the FDA determines to be substantially relevant to the growth or progression of pediatric cancer, in place of the PREA investigations, sponsors must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric study data, using appropriate formulations, to inform potential pediatric labeling. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. Orphan products are also exempt from the PREA requirements.

The FDA reviews a NDA within 60 days of submission to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In that event, the NDA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth, substantive review of the NDA.

The FDA reviews the NDA to determine, among other things, whether the proposed product candidate is safe and effective for its intended use, has an acceptable purity profile and whether the product candidate is being manufactured in accordance with cGMP to assure and preserve the product candidate’s identity, safety, strength, quality, potency and purity. The FDA may refer applications for novel therapeutic products or therapeutic products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions. During the product approval process, the FDA also will determine whether a risk evaluation and mitigation strategy, (REMS) is necessary to assure the safe use of the product candidate. REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity. A REMS could include medication guides, physician communication plans and elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS; the FDA will not approve the NDA without a REMS, if required.

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Before approving a NDA, the FDA will inspect the facilities at which the product candidate is manufactured. The FDA will not approve the product candidate if it determines that the manufacturing processes and facilities are not in compliance with cGMP requirements or otherwise are not adequate to assure consistent production of the product candidate within required specifications. Additionally, before approving a NDA, the FDA typically will inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND trial requirements and GCP requirements.

On the basis of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications. A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application. If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.

If a product candidate receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling. The FDA may impose restrictions and conditions on product distribution, prescribing or dispensing in the form of a REMS, or otherwise limit the scope of any approval. The FDA may also require post-marketing clinical trials, sometimes referred to as Phase IV clinical trials, designed to further assess a product’s safety, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.

Every five years, the FDA agrees to specified performance goals in the review of NDAs under the PDUFA. One such current goal is to review standard NDAs in ten months after the FDA accepts the NDA for filing, and priority NDAs in six months, whereupon a review decision is to be made. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs and its review goals are subject to change from time to time. The review process and the PDUFA goal date may be extended by three months if the FDA requests or the NDA sponsor otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date.

Expedited Development and Review Programs

The FDA has a Fast Track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet certain criteria. Specifically, new drugs and biologics are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast Track designation applies to both the product and the specific indication for which it is being studied. The sponsor can request the FDA to designate the product for Fast Track status any time before receiving NDA approval, but ideally no later than the pre-NDA or pre-BLA meeting.

Any product submitted to the FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. A product may be eligible for priority review if it is intended to treat a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies.

A Fast Track product may also be eligible for rolling review, where the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

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A product may also be eligible for accelerated approval if it is intended to treat a serious or life-threatening condition and generally provide a meaningful advantage over available therapies. In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM), which is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials. If the FDA concludes that a drug shown to be effective can be safely used only if distribution or use is restricted, it may require such post-marketing restrictions as it deems necessary to assure safe use of the product.

Additionally, a drug may be eligible for designation as a Breakthrough Therapy if the product is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints. The benefits of Breakthrough Therapy designation include the same benefits as Fast Track designation, plus intensive guidance from the FDA to ensure an efficient drug development program. Fast Track designation, priority review, accelerated approval and Breakthrough Therapy designation do not change the standards for approval, but may expedite the development or approval process.

Post-Approval Requirements

After approval, there also are continuing annual program user fee requirements for approved products, excluding, under certain circumstances, orphan products.

Rigorous and extensive FDA regulation of pharmaceutical products continues after approval, particularly with respect to cGMP requirements. Manufacturers are required to comply with applicable requirements in the cGMP regulations, including quality control and quality assurance and maintenance of records and documentation. To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined. The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the United States and between states.

Other post-approval requirements applicable to pharmaceutical products include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information and complying with electronic record and signature requirements. In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, and potency of pharmacological products.

In addition, manufacturers and other entities involved in the manufacture and distribution of approved pharmaceuticals are required to register their establishments with the FDA and certain state agencies, list their products, and are subject to periodic announced and unannounced inspections by the FDA and these state agencies for compliance with current cGMP and other requirements, which impose certain procedural and documentation requirements upon us and third-party manufacturers. Manufacturers must continue to expend time, money, and effort in the areas of production and quality-control to maintain compliance with current cGMPs. Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered. In addition, changes to the manufacturing process or facility generally require prior FDA approval or notification before being implemented, and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

Moreover, the Drug Quality and Security Act imposes obligations on manufacturers of pharmaceutical products related to product tracking and tracing.

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Adverse event reporting and submission of periodic reports, including annual reports and deviation reports, are required following FDA approval of a NDA. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in significant regulatory actions. Such actions may include refusal to approve pending applications, license suspension or revocation, imposition of a partial or full clinical hold or termination of clinical trials, warning letters, untitled letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and result in adverse publicity, among other adverse consequences.

A sponsor also must comply with the FDA’s advertising and promotion requirements, such as the prohibition on promoting products for uses or in patient populations that are inconsistent with the product’s approved labeling (known as “off-label use”). The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability. Violations relating to the promotion of off-label uses may lead to investigations alleging violations of federal and state healthcare fraud and abuse and other laws, as well as state consumer protection laws. Companies, however, may generally share truthful and non-misleading information that is otherwise consistent with a product’s FDA approved labeling. Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.

Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant or manufacturer to administrative or judicial civil or criminal actions and adverse publicity. These actions could include refusal to approve pending applications or supplemental applications, withdrawal of an approval, clinical hold, suspension or termination of a clinical trial by an IRB, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines or other monetary penalties, refusals of government contracts, mandated corrective advertising or communications with healthcare providers, debarment, restitution, disgorgement of profits or other civil or criminal penalties.

Broadly equivalent requirements and controls typically apply in other countries to the submission of marketing authorization applications and, post-approval, to the holding of such marketing authorizations.

The Hatch-Waxman Amendments and Generic Competition

Orange Book Listing

Once a drug product is approved under an NDA, the product is listed in the FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations,” commonly known as the Orange Book. An NDA-approved drug product will be designated in the Orange Book as a Reference Listed Drug (RLD). Sponsors of approved NDAs are required to list with the FDA patents whose claims cover the product’s active ingredient, formulation, or an approved method of using the drug.

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Patent Term Extensions

Depending upon the timing, duration and specifics of FDA approval of the use of our therapeutic candidates, some of our United States patents may be eligible for limited patent term extension under the Hatch-Waxman Amendments to the FDCA (Hatch-Waxman”). Hatch-Waxman permits a patent restoration term of up to five years as compensation for patent term lost during drug product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product or therapeutic candidate’s approval date. The patent term restoration period is generally one half of the time between the effective date of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved product or therapeutic candidate is eligible for the extension and the application for extension must be made prior to expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we intend to apply for restorations of patent term for some of our currently owned or licensed patents to add patent life beyond their current expiration date, depending on the expected length of clinical trials and other factors involved in the submission of the relevant NDA(s).

ANDA Approval Process for Generic Drugs

Hatch-Waxman also established an abbreviated FDA approval process for generic drugs that are shown to be pharmaceutically equivalent and bioequivalent to drugs previously approved by the FDA through the NDA process. Approval to market and distribute these drugs is obtained by filing an abbreviated new drug application, or ANDA, with the FDA. An ANDA provides for marketing of a drug product that has the same active ingredients in the same strengths and dosage form as the listed drug and has been shown to be bioequivalent to the listed drug. An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical ingredient, drug product formulation, specifications and stability of the generic drug, as well as analytical methods, manufacturing process validation data and quality control procedures. ANDAs are termed abbreviated because they generally do not include preclinical and clinical data to demonstrate safety and effectiveness. Instead, a generic applicant must demonstrate that its product is bioequivalent to the innovator drug. In some cases involving drugs with no or limited systemic absorption, an ANDA must include clinical endpoint (efficacy) studies in order to demonstrate bioequivalence. Drugs approved in this way are commonly referred to as “generic equivalents” to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.

Section 505(b)(2) NDA Approval Process

As an alternative path to FDA approval for modifications to formulations or uses of products previously approved by the FDA under a “full” NDA, an applicant may submit an NDA under Section 505(b)(2) of the FDCA. Section 505(b)(2) was enacted as part of the Hatch-Waxman Amendments and enables the applicant to rely, in part, on the FDA’s previous approval of a similar product, and/or published literature, in support of the safety and/or efficacy of its drug product. Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference. If the Section 505(b)(2) applicant can establish that reliance on FDA’s previous findings of safety and effectiveness is scientifically appropriate, it may eliminate the need to conduct certain preclinical studies or clinical trials of the new product. The FDA may also require companies to perform additional studies or measurements, including clinical trials, to support the change from the approved reference drug. The FDA may then approve the new product candidate for all, or some, of the label indications for which the reference drug has been approved or for any new indication sought by the Section 505(b)(2) applicant.

ANDA and 505(b)(2) products may be significantly less costly to bring to market than the reference listed drug, and companies that produce generic products are generally able to offer them at lower prices. Moreover, generic versions of RLDs are often automatically substituted for the RLD by pharmacies when dispensing a prescription written for the RLD. Thus, following the introduction of a generic drug, a significant percentage of the sales of any branded product or reference listed drug is typically lost to the generic product.

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ANDA and 505(b)(2) NDA Patent Certification Requirements

Any applicant who files an ANDA seeking approval of a generic equivalent version of a drug listed in the Orange Book or a Section 505(b)(2) NDA referencing a drug listed in the Orange Book must certify to the FDA, as applicable, that (1) no patent information on the drug product that is the subject of the application has been submitted to the FDA; (2) such patent has expired; (3) the date on which such patent expires; or (4) such patent is, in the applicant’s opinion, invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. This last certification is known as a paragraph IV certification. If an ANDA or 505(b)(2) NDA is submitted to FDA with a Paragraph IV Certification, the applicant must also provide a “Paragraph IV Notification” to the holder of the NDA for the RLD and to the owner of the listed patent(s) being challenged by the applicant, providing a detailed written statement of the bases for the applicant’s position that the relevant patent(s) is invalid or would not be infringed. If the patent owner brings a patent infringement lawsuit against the applicant within 45 days of the Paragraph IV Notification, FDA approval of the ANDA or 505(b)(2) NDA will be automatically stayed for 30 months, or until 7-1/2 years after the RLD’s NDA approval date if the ANDA or 505(b)(2) NDA was filed between 4 years and 5 years after the NDA approval. Any such stay will be terminated earlier if the court rules that the patent is invalid or would not be infringed. The applicant may, in certain circumstances, elect to submit a “section viii” statement with respect to a listed method of use patent, certifying that the proposed ANDA or 505(b)(2) product’s labeling does not contain (or carves out) any language that would infringe a method of use patented listed in the Orange Book for the RLD.

The ANDA or 505(b)(2) application also will not be approved until any applicable non-patent exclusivity listed in the Orange Book for the reference drug has expired as described in further detail below.

Regulatory Exclusivities

New Chemical Entity Exclusivity

The Hatch-Waxman Amendments provide a period of five years of non-patent marketing exclusivity for the first approved drug containing a new chemical entity (“NCE”) as an active ingredient. An NCE is an active moiety that has not been approved by the FDA in any other NDA. A fixed combination drug product may receive NCE exclusivity if one of its active ingredients is an NCE, but not if all of its active ingredients have previously been approved. An “active moiety” is defined as the molecule or ion responsible for the drug substance’s physiological or pharmacologic action. During the five-year exclusivity period, the FDA cannot accept for filing any ANDA or 505(b)(2) NDA seeking approval of a product that contains the same active moiety, except that the FDA may accept such an application for filing after four years if the application includes a paragraph IV certification to a listed patent. In the case of such applications accepted for filing between four and five years after approval of the reference drug, the 30-Month Stay of approval triggered by a timely patent infringement lawsuit is extended by the amount of time necessary to extend the stay until 7-1/2 years after the approval of the reference drug NDA.

New Clinical Trial (3-Year) Exclusivity

A drug, including one approved under Section 505(b)(2), may obtain a three-year period of exclusivity for a particular indication or condition of approval, or change to a marketed product, such as a new formulation for a previously approved product, if one or more new clinical trials (other than bioavailability studies) was essential to the approval of the application or supplemental application and was conducted/sponsored by the applicant. Should this occur, the FDA would be precluded from approving any ANDA or Section 505(b)(2) application for the protected modification until after that three-year exclusivity period has run. However, unlike NCE exclusivity, the FDA can accept an application and begin the review process during the 3-year exclusivity period.

Orphan Drug Designation and Orphan Exclusivity Under the Orphan Drug Act

The FDA may grant orphan designation to a drug product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States but for which there is no reasonable expectation that the cost of developing and making the product available in the United States for this type of disease or condition will be recovered from sales of the product.

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Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care or in instances of drug supply issues. However, competitors may receive approval of either a different product for the same indication or the same product for a different indication but that could be used off-label in the orphan indication. Orphan drug exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval before we do for the same product, as defined by the FDA, for the same indication we are seeking approval, or if a product candidate is determined to be contained within the scope of the competitor’s product for the same indication or disease. If one of our products is designated as an orphan drug and receives marketing approval for an indication broader than that which is designated, it may not be entitled to orphan drug exclusivity. Orphan drug status in the European Union has similar, but not identical, requirements and benefits.

Pediatric Exclusivity

Pediatric exclusivity is another type of non-patent marketing exclusivity available in the United States and, if granted, it provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity or listed patents. Under the Best Pharmaceuticals for Children Act, or BPCA, certain therapeutic candidates may obtain an additional six months of exclusivity if the sponsor conducts pediatric research and submits new clinical information requested in writing by the FDA, referred to as a Written Request, relating to the use of the active moiety of the product or therapeutic candidate in children. The data do not need to support a label change for pediatric use; rather, the additional protection is granted if the pediatric clinical trial is deemed to have fairly responded to the FDA’s Written Request. Although the FDA may issue a Written Request for studies on either approved or unapproved indications, it may only do so where it determines that information relating to that use of a product or therapeutic candidate in a pediatric population, or part of the pediatric population, may produce health benefits in that population. The issuance of a Written Request does not require the sponsor to undertake the described trials. This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another application.

Other Healthcare Laws and Regulations

Our business activities, including but not limited to, research, sales, promotion, distribution, medical education, and other activities following product approval will be subject to regulation by numerous federal and state regulatory and law enforcement authorities in the United States in addition to the FDA, including potentially the Department of Justice, the Department of Health and Human Services (HHS) and its various divisions, including the Office of Inspector General, the Centers for Medicare & Medicaid Services (CMS) and the Health Resources and Services Administration, the Department of Veterans Affairs, the Department of Defense, and state and local governments. Healthcare providers and third-party payors play a primary role in the recommendation and use of pharmaceutical products that are granted marketing approval. Arrangements with third-party payors, existing or potential customers and referral sources, including healthcare providers, are subject to broadly applicable fraud and abuse laws and regulations, and these laws and regulations may constrain the business or financial arrangements and relationships through which manufacturers conduct clinical research, market, sell and distribute the products for which they obtain marketing approval. Such restrictions under applicable federal and state healthcare laws and regulations include the following:

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The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in cash or kind, in exchange for, or to induce, either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs. This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers, on the one hand, and prescribers, purchasers, formulary managers and other individuals and entities on the other. The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the ACA) amended the intent requirement of the federal Anti-Kickback Statute such that a person or entity no longer needs to have actual knowledge of this statute or specific intent to violate it in order to commit a violation;

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The federal civil and criminal false claims, including the civil FCA, and Civil Monetary Penalties Laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid or other third-party payors that are false or fraudulent, or making a false statement to avoid, decrease, or conceal an obligation to pay money to the federal government. Certain marketing practices, including off-label promotion, also may implicate the FCA. In addition, the ACA codified case law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA;

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The federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, therapeutic products and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or the CMS, information related to payments and other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and other healthcare providers and their immediate family members;

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Health Insurance Portability and Accountability Act of 1996 (HIPAA) prohibits knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, a healthcare benefit program, regardless of whether the payor is public or private, in connection with the delivery or payment for health care benefits, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters. Additionally, the ACA amended the intent requirement of certain of these criminal statutes under HIPAA so that a person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation; and

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State and foreign law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers and drug pricing and/or marketing expenditures; and state and local laws requiring the registration of pharmaceutical sales representatives and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Further, we may be subject to data privacy and security regulation by both the federal government and the states and foreign jurisdictions in which we conduct our business. HIPAA, as amended by the Health Information Technology for Clinical Health Act of 2009 (HITECH), and its respective implementing regulations imposes certain requirements, including mandatory contractual terms, on covered entities, business associates and their covered subcontractors relating to the privacy, security, and transmission of certain individually identifiable health information known as protected health information. Among other things, HITECH, through its implementing regulations, makes HIPAA’s security standards and certain privacy standards directly applicable to business associates, defined as a person or organization, other than a member of a covered entity’s workforce, that creates, receives, maintains, or transmits protected health information on behalf of a covered entity for a function or activity regulated by HIPAA. HITECH also strengthened the civil and criminal penalties that may be imposed against covered entities, business associates, subcontractors, and individuals, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, other federal and state laws may govern the privacy and security of health and other information in certain circumstances, many of which differ from each other in significant ways and may not be pre-empted by HIPAA, thus complicating compliance efforts.

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To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or transfers of value to healthcare professionals.

In the EU, the data privacy laws are generally perceived to be stricter than those which apply in the United States and include specific requirements for the transfer of personal data outside the EU to the United States to ensure that EU standards of data privacy will be applied to such data.

Violation of the laws described above or any other governmental laws and regulations may result in significant penalties, including administrative, civil and criminal penalties, damages, fines, the curtailment or restructuring of operations, the exclusion from participation in federal and state healthcare programs, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, imprisonment, and additional reporting requirements and oversight if a person becomes subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws. Furthermore, efforts to ensure that business activities and business arrangements comply with applicable healthcare laws and regulations can be costly for manufacturers of branded prescription products.

Coverage and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any products for which we may obtain regulatory approval. In the United States, sales of any product candidates for which regulatory approval for commercial sale is obtained will depend in part on the availability of coverage and adequate reimbursement from third-party payors. Third-party payors include government authorities and health programs in the United States such as Medicare and Medicaid, managed care providers, private health insurers and other organizations. These third-party payors are increasingly reducing reimbursements for medical products and services. The process for determining whether a payor will provide coverage for a drug product may be separate from the process for setting the reimbursement rate that the payor will pay for the drug product. Third-party payors may limit coverage to specific drug products on an approved list, or formulary, which might not include all of FDA-approved drugs for a particular indication. Additionally, the containment of healthcare costs has become a priority of federal and state governments, and the prices of drugs have been a focus in this effort. The U.S. government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results.

A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, coverage and reimbursement for drug products can differ significantly from payor to payor. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

Third-party payors are increasingly challenging the price and examining the medical necessity and cost of medical products and services, in addition to their safety and efficacy. New metrics frequently are used as the basis for reimbursement rates, such as average sales price, average manufacturer price and actual acquisition cost. In order to obtain coverage and reimbursement for any product that might be approved for sale, it may be necessary to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and rational of the cost of the products, in addition to the costs required to obtain regulatory approvals. If third-party payors do not consider a product to be cost saving when compared to other available therapies, they may not cover the product after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow a company to sell its products at a profit.

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The marketability of any product candidates for which we or our collaborators receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care in the United States has increased and we expect will continue to increase the pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we or our collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future. The cost containment measures that healthcare payors and providers are instituting and any healthcare reform could significantly reduce our revenues from the sale of any approved product candidates. We cannot provide any assurances that we will be able to obtain and maintain third-party coverage or adequate reimbursement for our product candidates in whole or in part.

In the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost of a particular product candidate to currently available therapies. EU member states may approve a specific price for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market. Other member states allow companies to fix their own prices for products, but monitor and control company profits. The downward pressure on health care costs has become intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country. Any country that has price controls or reimbursement limitations may not allow favorable reimbursement and pricing arrangements.

Health Reform

The United States and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our products profitably. Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by federal and state legislative initiatives, including those designed to limit the pricing, coverage, and reimbursement of pharmaceutical products, especially under government-funded health care programs, and increased governmental control of drug pricing.

By way of example, in March 2010, the ACA was signed into law, intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add transparency requirements for the healthcare and health insurance industries, impose taxes and fees on the healthcare industry and impose additional health policy reforms. Among the provisions of the ACA of importance to our business are:

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An annual, non-deductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs;

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An increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13.0% of the average manufacturer price for branded and generic drugs, respectively;

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A methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

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Extension of a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

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Expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

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A Medicare Part D coverage gap discount program, in which manufacturers must now agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for a manufacturer’s outpatient drugs to be covered under Medicare Part D;

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Expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; and

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A Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical research, along with funding for such research.

There have been executive, judicial and Congressional challenges to certain aspects of the ACA. For example, on June 17, 2021 the U.S. Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress. Thus, the ACA will remain in effect in its current form. Further, prior to the U.S. Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace. The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, re-examining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. In addition, in August 2022, President Biden signed the Inflation Reduction Act of 2022 (the IRA) into law, which among other things, extends enhanced subsidies for individuals purchasing coverage in ACA marketplaces through plan year 2025. The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost through a newly established manufacturer discount program.

Other legislative changes have been proposed and adopted in the United States since the ACA. For example, through the process created by the Budget Control Act of 2011, there are automatic reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013 and, following passage of the BBA and the Infrastructure Investment and Jobs Act, will remain in effect until 2031 unless additional Congressional action is taken.

The heightened governmental scrutiny
in the United States of pharmaceutical pricing practices in light of the rising cost of prescription drugs and biologics, also has resulted
in executive orders, congressional inquiries and proposed and enacted federal and state legislation designed to, among other things,
bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government
program reimbursement methodologies for products. At the federal level, President Trump used several means to propose or implement drug
pricing reform, including through federal budget proposals, executive orders, and policy initiatives. For example, on July 24, 2020
and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing that attempt
to implement several of the administration’s proposals. The FDA concurrently released a final rule and guidance in September 2020
implementing a portion of the importation executive order providing pathways for states to build and submit importation plans for drugs
from Canada. Further, on November 20, 2020, the HHS finalized a regulation removing safe harbor protection for price reductions
from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price
reduction is required by law. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as
a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers. The implementation of the rule
has been delayed until 2032. Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law,
which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single
source and innovator multiple source drugs, beginning January 1, 2024. In July 2021,

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the Biden administration
released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at
prescription drugs. In response to Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for
Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative
policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles. In
addition, the IRA directs the Secretary of HHS to establish a Drug Price Negotiation Program (the Program) to lower prices for
certain single-source prescription drugs and biologics covered under Medicare Parts B and D, based on criteria established under the
IRA. Under the Program, the Secretary of HHS will publish a list of “selected drugs,” and will then negotiate maximum
fair prices (MFP) with their manufacturers. Beginning in 2026, the first year of the Program, the number will be limited to 10 Part
D drugs and biologics. By 2029, and in subsequent years thereafter, the number will increase to 20 drugs and biologics covered under
Part D and Part B. Agreements between HHS and manufacturers will remain in place until a drug or biologic is no longer considered a
“selected drug” for negotiation purposes. Manufacturers who do not comply with the negotiated prices set under the
Program will be subject to an excise tax based on a percentage of total sales of a “selected drug” up to 95% and the
potential of civil monetary penalties. Further, the IRA imposes rebates under Medicare Part B and Medicare Part D to penalize price
increases that outpace inflation. In addition, the Biden administration released an additional executive order on October 14,
2022, directing HHS to submit a report within ninety (90) days on how the Center for Medicare and Medicaid Innovation can be further
leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

At the state level, individual states in the United States have increasingly passed legislation and implemented regulations designed to control pharmaceutical and therapeutic product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. Some third-party payors also require pre-approval of coverage for new or innovative devices or therapies before they will reimburse healthcare providers that use such therapies.

We expect that these initiatives, as well as other healthcare reform measures that may be adopted in the future, as well as the trend toward managed healthcare and increasing influence of managed care organizations, may result in more rigorous coverage criteria and lower reimbursement, and in additional downward pressure on the price that we receive for any approved product. It is also possible that additional governmental action is taken in response to the COVID-19 pandemic. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors. The implementation of current and future cost containment measures or other healthcare reforms may adversely affect our operations and prevent us from being able to generate revenue, attain profitability or commercialize our product candidates.

Data Privacy and Security

In the ordinary course of our business, we collect, process and store confidential and sensitive information, including personal information, intellectual property, trade secrets, and proprietary information owned or controlled by ourselves or other third parties. We, and third parties upon whom we rely, use sophisticated information technology, software and services to process, store, use, generate, transfer and disclose information, as well as other sensitive information controlled by ourselves or other third parties.

We may also be subject to federal, state, and foreign data privacy and security laws and regulations. In the United States, numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws and regulations (e.g., Section 5 of the FTC Act), govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners, vendors, or other third parties on whom we rely. The legislative and regulatory framework related to the collection, use, retention, safeguarding, disclosure, sharing, transfer, security and other processing of personal data worldwide is rapidly evolving. The number and scope of data protection laws and regulations is changing, subject to differing applications and interpretations, and may be inconsistent among jurisdictions, or in conflict with other rules, laws or other data processing obligations. Efforts to ensure that our current and future business arrangements, including our relationship with our CROs or other vendors who process data on our behalf, comply with applicable data privacy and data security laws and regulations will involve substantial costs.

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For example, HIPAA, as amended by HITECH, and its implementing regulations, impose requirements relating to the privacy, security and transmission of individually identifiable health information on certain health care providers, health plans and health care clearinghouses, known as covered entities, as well as their business associates and covered subcontractors that perform certain services that involve creating, receiving, maintaining or transmitting individually identifiable health information for or on behalf of such covered entities. Entities that are found to be in violation of HIPAA as the result of a breach of unsecured protected health information, a complaint about privacy practices or an audit by HHS, may be subject to significant civil, criminal and administrative fines and penalties and/or additional reporting and oversight obligations if required to enter into a resolution agreement and corrective action plan with HHS to settle allegations of HIPAA non-compliance. Further, entities that knowingly obtain, use, or disclose individually identifiable health information maintained by a HIPAA covered entity in a manner that is not authorized or permitted by HIPAA may be subject to civil and criminal penalties. Even when HIPAA does not apply, according to the FTC, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure may constitute unfair acts or practices in or affecting commerce in violation of Section 5 of the FTC Act. The FTC expects a company’s data security measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities. Individually identifiable health information is considered sensitive data that merits stronger safeguards.

Likewise, we expect that there will continue to be new proposed laws, regulations and industry standards relating to privacy and data protection in the United States, the EU and other jurisdictions, such as the California Consumer Privacy Act of 2018 (CCPA), which has been characterized as the first “GDPR-like” privacy statute to be enacted in the United States. Although the CCPA exempts certain data processed in the context of clinical trials, the CCPA, to the extent applicable to our business and operations, may increase our compliance costs and potential liability with respect to the personal information we maintain about California residents. The CCPA among other effects, creates individual privacy rights for California consumers (as defined in the law), places increased privacy and security obligations on entities handling certain personal data of consumers or households, requires covered companies to provide disclosures to consumers regarding data collection, use and sharing practices, requires covered companies to allow users to opt-out of certain sales or transfers of personal information, and provides consumers with a private right of action for certain data breaches. The CCPA became effective on January 1, 2020, and the California Attorney General’s authority to begin bringing enforcement actions began July 1, 2020. As currently written, the CCPA may impact our business activities and exemplifies the vulnerability of our business to the evolving regulatory environment related to personal data and protected health information. Further, the California Privacy Rights Act (CPRA) was recently voted into law by California residents. The CPRA significantly amends the CCPA, and imposes additional data protection obligations on covered companies doing business in California, including additional consumer rights processes and opt outs for certain uses of sensitive data. It also creates a new California data protection agency specifically tasked to enforce the law, which would likely result in increased regulatory scrutiny of California businesses in the areas of data protection and security. The substantive requirements for businesses subject to the CPRA went into effect on January 1, 2023, and become enforceable on July 1, 2023. A similar law, the Consumer Data Protection Act (CDPA), was recently passed in Virginia and went into effect on January 1, 2023.

We also are or will become subject
to privacy laws in the jurisdictions in which we are established or in which we sell or market our products or run clinical trials. For
example, in the EU, we are subject to Regulation (EU) 2016/679, the GDPR, in relation to our collection, control, processing, and other
use of personal data (i.e. data relating to an identified or identifiable living individual). We process personal data in relation to
participants in our clinical trials in the European Economic Area (EEA), including the health and medical information of these participants.
The GDPR is directly applicable in each EU and EEA Member State, however, it provides that EU and EEA Member States may introduce further
conditions, including limitations which could limit our ability to collect, use and share personal data (including health and medical
information), or could cause our compliance costs to increase, ultimately having an adverse impact on our business. As noted above, the
GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing
and implement policies as part of its mandated privacy governance framework. It also requires data controllers to be transparent and
disclose to data subjects (in a concise, intelligible and easily accessible form) how their personal information is to be used, imposes
limitations on retention of personal data; defines for the first time pseudonymized (i.e., key-coded) data; introduces mandatory data
breach notification requirements; and sets higher standards for data controllers to demonstrate that they have obtained valid consent
for certain data processing activities. We are also subject to EEA rules with respect to cross-border transfers of personal data out
of the EEA. As noted above, recent legal developments in the EU have created complexity and uncertainty regarding transfers of personal
data from the EEA to the United States, e.g. on July 16, 2020, the Court of Justice of the European Union (CJEU),

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invalidated the EU-U.S. Privacy Shield Framework, or the Privacy Shield, under which personal data could be transferred from the EEA to U.S. entities who had self-certified under the Privacy Shield scheme. While the CJEU upheld the adequacy of the standard contractual clauses (a standard form of contract approved by the European Commission as an adequate personal data transfer mechanism, and potential alternative to the Privacy Shield), it made clear that reliance on them alone may not necessarily be sufficient in all circumstances. Use of the standard contractual clauses must now be assessed on a case-by-case basis taking into account the legal regime applicable in the destination country, in particular applicable surveillance laws and rights of individuals and additional measures and/or contractual provisions may need to be put in place, however, the nature of these additional measures is currently uncertain. On June 4, 2021, the European Commission adopted new standard contractual clauses under the GDPR for data transfers from entities that are subject to the GDPR to transfer personal data outside of the EEA. The new standard contractual clauses impose additional obligations, including the obligation to conduct a transfer impact assessment and, depending on a party’s role in the transfer, to implement additional security measures and to update internal privacy practices. If we elect to rely on the standard contractual clauses for data transfers, we may be required to incur significant time and resources to update our contractual arrangements and to comply with new obligations. Additionally, on September 8, 2020, the Swiss Data Protection Authority (the Federal Data Protection and Information Commissioner) concluded that the Swiss-U.S. Privacy Shield does not provide an adequate level of protection for personal data transfer from Switzerland to the U.S. pursuant to the Swiss Federal Act on Data Protection. As supervisory authorities issue further guidance on personal data export mechanisms, including circumstances where the standard contractual clauses cannot be used, and/or start taking enforcement action, we could suffer additional costs, complaints and/or regulatory investigations or fines, and/or if we are otherwise unable to transfer personal data between and among countries and regions in which we operate, it could affect the manner in which we provide our services, the geographical location or segregation of our relevant systems and operations, and could adversely affect our financial results.

We are subject to the supervision of local data protection authorities in those EU jurisdictions where we are established or otherwise subject to the GDPR. Fines for certain breaches of the GDPR are significant: up to the greater of €20.0 million or 4% of total global annual turnover. Further, following the withdrawal of the United Kingdom from the EU on January 31, 2020, pursuant to the transitional arrangements agreed between the United Kingdom and the EU, we will have to comply with the GDPR and separately the GDPR as implemented in the United Kingdom, each regime having the ability to fine up to the greater of €20 million / £17 million or 4% of global turnover. Following December 31, 2020, and the expiry of the post-Brexit transitional arrangements between the United Kingdom and EU, although it is likely that the data protection obligations of the GDPR will continue to apply to UK-related processing of personal data in substantially unvaried form and fashion, for at least the short term thereafter, the relationship between the United Kingdom and the EU in relation to certain aspects of data protection law remains unclear. For example, it is not yet clear whether the United Kingdom will be the subject of a so-called adequacy decision of the European Commission, and it is therefore unclear how data transfers between EU/EEA Member States and the United Kingdom will be treated. Any changes relating to the UK and EU position regarding aspects of data protection law may lead to additional compliance costs and could increase our overall risk. In addition to the foregoing, a breach of the GDPR or other applicable privacy and data protection laws and regulations could result in regulatory investigations, reputational damage, orders to cease/change our use of data, enforcement notices, an inability to process personal data or to operate in certain jurisdictions, or potential civil claims including class action type litigation.

Moreover, we use third-party service providers and subprocessors to help us operate our business and engage in processing on our behalf. If we, our service providers, partners, or other relevant third-parties have experienced, or in the future experience, any security incident(s) that result in any data loss, deletion or destruction, unauthorized access to, loss of, unauthorized acquisition or disclosure of, or inadvertent exposure or disclosure of sensitive information, or compromise related to the security, confidentiality, integrity of our (or their) information technology, software, services, communications or data, it may result in a material adverse impact, including without limitation, regulatory investigations or enforcement actions, litigation, or an inability to process data in some jurisdictions. Furthermore, applicable data protection laws, privacy policies and data protection obligations may require us to notify relevant stakeholders of security breaches, including affected individuals, customers, and regulators. Such disclosures are costly, and the disclosure or the failure to comply with such requirements, could result in a material adverse impact, including without limitation, regulatory investigations or enforcement actions.

For more information on the potential impact of the GDPR, and associated EEA data protection laws, on our business, see the section titled “Risk Factors-Failure to comply with health and data protection laws and regulations could lead to government enforcement actions (which could include civil or criminal penalties), private litigation and/or adverse publicity and could negatively affect our operating results and business.”

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Additional Regulation

In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservation and Recovery Act and the Toxic Substances Control Act, affect our business. These and other laws govern the use, handling and disposal of various biologic, chemical and radioactive substances used in, and wastes generated by, operations. If our operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines. Equivalent laws have been adopted in other countries that impose similar obligations.

U.S. Foreign Corrupt Practices Act

The U.S. Foreign Corrupt Practices Act (FCPA) prohibits U.S. corporations and individuals from engaging in certain activities to obtain or retain business abroad or to influence a person working in an official capacity. It is illegal to pay, offer to pay or authorize the payment of anything of value, directly or indirectly, to any foreign government official, government staff member, official or employee of a public international organization, or a political party or political candidate for the purpose of influencing any act or decision of the foreign entity in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity. The scope of the FCPA includes interactions with healthcare professionals of foreign state-owned or affiliated hospitals, universities, or research institutions. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations. Activities that violate the FCPA, even if they occur wholly outside the United States, can result in criminal and civil fines, imprisonment, disgorgement, oversight, and suspension and debarment from government contracts, and refusal of orders under existing government contracts.

Equivalent laws have been adopted in other foreign countries that impose similar or arguably broader obligations.

Employees

As of March 30, 2026, we had 5 full-time employees. There are also four PhD professionals and one lab technician who are paid by USC which is then reimbursed by us. None of our employees are subject to a collective bargaining agreement or represented by a trade or labor union. We consider our relationship with our employees to be good.

Corporate Information

NeOnc Technologies Holdings, Inc. (“NeOnc” or the “Company”) was incorporated in the State of Delaware. The Company was formed as a holding company in connection with a share exchange transaction completed on April 7, 2023, pursuant to which all of the common stockholders of NeOnc Technologies, Inc. (“NTI”), the Company’s wholly owned operating subsidiary, exchanged their shares in NTI for shares of common stock of the Company. NTI was originally incorporated in California in 2008 under the name NAS-ONC, Inc. and subsequently redomiciled and renamed NeOnc Technologies, Inc. Following the share exchange, NTI became a wholly owned subsidiary of the Company, which conducts all of the Company’s research and development and clinical operations.

Our principal executive office is located at 23975 Park Sorrento, Suite 205, Calabasas, CA 91302.

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Available Information

We file electronically with the SEC our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). The SEC maintains an Internet site that contains reports, proxy information, information statements, and other information regarding issuers that file electronically with the SEC. The address of that website is www.sec.gov. All reports we file with the SEC are available free of charge via EDGAR through the SEC website.

Financial and other information about our company is available on our website at https://www.neonc.com. Our investor relations website includes a section through which we make available, free of charge, our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, Proxy Statements and Forms 3, 4, and 5 filed on behalf of directors and executive officers, as well as any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC. Except as specifically incorporated by reference into this Annual Report, information on these websites is not part of this filing.

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