What changed in this filing

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Item 1. Business

2025-03-20 compared with 2024-03-13 · 326 added, 216 removed, 186 unchanged (74% of the section changed)

We are a clinical stage biopharmaceutical company focused on the development of orally administered treatments for metabolic and inflammatory diseases to minimize their long-term complications and improve the lives of patients.

On February 27, 2024, we closed (the “Closing”) a private placement (the “Private Placement”) of our Class A common stock and pre-funded warrants, pursuant to which we received aggregate gross proceeds of approximately $51.0 million, before deducting offering expenses payable by us.

The securities purchase agreement for the Private Placement, among other things, grants the investors the right to purchase up to an additional $30.0 million of Class A common stock 18 months following the Closing.

We anticipate that the financing will enable us to conduct a Phase 3 clinical trial for our lead product candidate, cadisegliatin (TTP399) , an orally administered, small molecule, liver-selective glucokinase activator (“GKA”) that is a potential adjunctive therapy to insulin for the treatment of type 1 diabetes.

Food and Drug Administration ("FDA") granted Breakthrough Therapy designation in 2021 for cadisegliatin as an adjunctive therapy to insulin for the treatment of type 1 diabetes ("T1D").

Our lead product candidate, cadisegliatin (TTP399) , is an orally administered, small molecule, liver-selective glucokinase activator (“GKA”) that is a potential adjunctive therapy to insulin for the treatment of type 1 diabetes ("T1D").

On March 14, 2025, based upon the Company's submission of a complete response letter, the U.S.

Food and Drug Administration ("FDA") lifted the clinical hold that had been placed on the cadisegliatin development program in July 2024.

We plan to resume our Phase 3 trial ("the CATT1 trial") in the second quarter of 2025.

The CATT1 trial is a double-blind, randomized trial to assess the effect of cadisegliatin on reducing the frequency of Level 2 hypoglycemia (blood glucose levels are less than 54 mg/dL or 3 mmol/L, regardless of symptoms) and Level 3 hypoglycemia ("severe" hypoglycemia e.g., requiring assistance of another person).

The CATT1 trial will randomize 150 patients with T1D on a 1:1:1 basis (i.e., 50 patients for each study arm) to receive 800 mg cadisegliatin daily or twice daily or to receive placebo.

A key secondary endpoint is reduction in glycated hemoglobin (HbA1c), a traditional efficacy endpoint in diabetes trials, to assess the potential of cadisegliatin to reduce hyperglycemia.

Although we had planned to conduct the primary assessment of efficacy after 6 months and then continue to retain patients in the CATT1 trial for another 6 months to collect safety data, we plan to amend the protocol of the CATT1 trial to remove the second 6-month period, which will allow us to obtain topline data from the trial sooner and expedite the start of the required pivotal trials.

The FDA granted Breakthrough Therapy designation for cadisegliatin as an adjunctive therapy to insulin for the treatment of T1D in 2021.

The Breakthrough Therapy designation provides a sponsor with added support and the potential to expedite development and review timelines for a promising new investigational medicine.

The Breakthrough Therapy designation for cadisegliatin in T1D was supported by the positive results from the Phase 2 SimpliciT-1 Study, a multi-center, randomized, double-blind, adaptive study assessing the safety and efficacy of cadisegliatin as an adjunct to insulin therapy in adults with T1D.

In this trial, treatment with cadisegliatin resulted in a statistically significant improvement in HbA1c relative to placebo and a clinically meaningful decrease (40%) in the frequency of severe and symptomatic hypoglycemia.

In this trial, treatment with cadisegliatin resulted in a clinically meaningful decrease (40%) in the frequency of sever and symptomatic hypoglycemia and in a statistically significant improvement in HbA1c relative to placebo.

Cadisegliatin demonstrated a favorable safety profile, in which abnormal levels of serum or urine ketones were detected less frequently in patients taking cadisegliatin than those taking placebo.

Moreover, a Phase 1 mechanistic study of cadisegliatin in patients with T1D conducted to determine the impact of cadisegliatin on ketone body formation showed no increased risk of ketoacidosis with cadisegliatin during acute insulin withdrawal in patients with T1D.

We have also completed a Phase 1 study in healthy male subjects to investigate the absorption, metabolism, and excretion of [ 14 C]- cadisegliatin following single dose oral administration.

Ten participants have been dosed and analysis is ongoing.

In May of 2023, the FDA issued new draft guidance on "Diabetes Mellitus:

Efficacy Endpoints for Clinical Trials Investigating Antidiabetic Drugs and Biological Products" which, for the first time, permitted the use of hypoglycemia as an endpoint to support a label claim.

Consistent with this guidance and with input from the FDA, we have initiated a Phase 3 double-blind, controlled trial to assess the effect of cadisegliatin on reducing the frequency of Level 2 hypoglycemia (blood glucose levels are less than 54 mg/dL or 3 mmol/L, regardless of symptoms) and Level 3 hypoglycemia ("severe" hypoglycemia e.g., requiring assistance of another person) in 150 patients with T1D.

Participants in the trial will be randomized to two doses of cadisegliatin or placebo.

Reduction in glycated hemoglobin (HbA1c), a traditional efficacy endpoint in diabetes trials, is a key secondary endpoint to assess the potential of cadisegliatin to reduce hyperglycemia, Following the initial assessment of efficacy after six months of treatment, participants will remain on trial for another six months to assess the durability of potential beneficial effects and safety.

The study protocol was submitted to the FDA on February 29, 2024.

The trial will be conducted in the U.S.

only and is expected to complete enrollment by the fourth quarter in 2024 providing top line 1-year data by the first quarter in 2026.

Concurrently, we will be working on the design for two international registrational studies for cadisegliatin in T1D, which we expect to start in 2026.

In addition, we continue to work with our partner, G42 Investments AI Holding RSC Ltd.

(“G42 Investments”), to initiate a double-blind, randomized, controlled Phase 2 trial in the Middle East region in 450 insulin-using patients with type 2 diabetes ("T2D").

We also completed a Phase 1 study in healthy male subjects to investigate the absorption, metabolism, and excretion of [ 14 C]- cadisegliatin following single dose oral administration (the "ADME study").

The ADME study results included a radiochromatographic signal that, at the time, could not be further characterized, which led the FDA to impose a clinical hold on the cadisegliatin development program.

Based upon extensive testing by two independent laboratories, the Company determined that the radiochromatographic signal identified in the ADME study was an experimental artifact and submitted the results of the investigation to the FDA as part of its complete response.

As previously noted, the FDA lifted the clinical hold on March 14, 2025, allowing the Company to resume its clinical development plan for cadisegliatin .

We continue to work with our partner, G42 Investments AI Holding RSC Ltd.

(“G42 Investments”), to initiate a double-blind, randomized, controlled Phase 2 trial in the Middle East region in patients with type 2 diabetes ("T2D").

The study will randomize 450 patients to assess the potential of cadisegliatin as an adjunct therapy to insulin in patients with T2D.

We expect that trial to begin in 2025.

We also continue to work on the design for additional international registrational studies for cadisegliatin in T1D.

In addition to our clinical development program for cadisegliatin , we continue to further the research and development of our other pipeline candidates through collaborations with academic partners and license agreements.

The following table summarizes our current drug candidates and their respective stages of development:

Our goal is to advance the development of our differentiated pipeline of orally administered, small molecule drug candidates to treat metabolic and inflammatory diseases to minimize their long-term complications and to improve the lives of patients.

In December 2021, the Company announced a strategic decision to prioritize the development of its lead program cadisegliatin , a novel, oral, liver-selective glucokinase activator.

The recent successful closing of the Private Placement will allow us to further advance our lead program for cadisegliatin ( TTP399 ).

We are also actively seeking licensing deals for our other assets.

Our primary goal is to advance the development of our lead program cadisegliatin , a novel, oral, liver-selective glucokinase activator.

In February 2024, we closed (the “Closing”) a private placement (the “Private Placement”) of our Class A common stock and pre-funded warrants, pursuant to which we received aggregate gross proceeds of approximately $51.0 million, before deducting offering expenses payable by us.

The Private Placement will allow us to continue to advance our lead program for cadisegliatin ( TTP399 ).

We are also actively seeking licensing deals for our pipeline assets that are not currently partnered.

As key components of our strategy, we are focused on:

• Continuing to advance cadisegliatin (TTP399) as a potential treatment for type 1 diabetes .

The FDA granted Breakthrough Therapy designation for cadisegliatin as an adjunctive therapy to insulin for the treatment of type 1 diabetes ("T1D") in 2021 which was supported by the positive results from the Phase 2 SimpliciT-1 Study, a multi-center, randomized, double-blind, adaptive study assessing the safety and efficacy of cadisegliatin as an adjunct to insulin therapy in adults with T1D.

Consistent with the May 2023 FDA guidance on efficacy endpoints in clinical trials investigating antidiabetic drugs, and with input from the FDA, we now have initiated a Phase 3 double-blind, controlled trial to assess the effect of cadisegliatin on reducing the frequency of Level 2 hypoglycemia (blood glucose levels are less than 54 mg/dL or 3 mmol/L, regardless of symptoms) and Level 3 hypoglycemia ("severe" hypoglycemia e.g., requiring assistance of another person) in 150 patients with T1D.

Participants in the trial will be randomized to two doses of cadisegliatin or placebo.

Reduction in glycated hemoglobin (HbA1c), a traditional efficacy endpoint in diabetes trials, is a key secondary endpoint to assess the potential of cadisegliatin in reducing hyperglycemia.

Following the initial assessment of efficacy after six months of treatment, participants will remain on trial for another six months to assess durability of potential beneficial effects and safety.

The study protocol was submitted to the FDA on February 29, 2024.

The trial will be conducted in the U.S.

only and is expected to complete enrollment by the fourth quarter in 2024 providing top line 1-year data by the first quarter in 2026.

Concurrently, we will be working on the design for two international registrational studies for cadisegliatin in T1D, which we expect to start in 2026.

In addition, we continue to work with our partner, G42 Investments, to initiate a double-blind randomized controlled Phase 2 trial in the Middle East region in 450 insulin-using patients with type 2 diabetes ("T2D").

The FDA granted Breakthrough Therapy designation for cadisegliatin as an adjunctive therapy to insulin for the treatment of T1D in 2021 which was supported by the positive results from the Phase 2 SimpliciT-1 Study, a multi-center, randomized, double-blind, adaptive study assessing the safety and efficacy of cadisegliatin as an adjunct to insulin therapy in adults with T1D.

Now that the FDA has lifted the clinical hold imposed in July 2024, we plan to reinitiate the CATT1 trial in the second quarter of 2025.

• During 2025, we also will be working on the design and execution of two supportive trials in human volunteers to examine the effects of food on cadisegliatin 's pharmacology and the potential effects of cadisegliatin on cardiac function (thorough QT study) as required by FDA guidance.

We will also start preparing plans for additional international registrational studies for cadisegliatin in T1D.

In addition, we continue to work with our partner, G42 Investments, to initiate a double-blind randomized controlled Phase 2 trial in the Middle East region in 450 insulin-dependent patients with T2D.

We expect that trial to begin in 2025.

• Seeking additional strategic collaborations and additional funding to support the continued development and commercialization of our development programs .

We will continue to seek additional funding to support the further development of our drug candidates.

Such support may come from strategic collaborations with non-profit research funding organizations, such as JDRF International, or from collaboration agreements with other pharmaceutical companies.

We are currently in active discussions with respect to financing, partnering and licensing transactions for the further development of cadisegliatin .

• Seeking additional strategic collaborations and additional funding to support the continued development and commercialization of our pipeline development programs .

We continue to seek additional funding to support the further development of our drug candidates because internal resources are solely focused on the development of cadisegliatin .

Support may come from additional strategic collaborations with other pharmaceutical companies, like our partnerships with Cantex and Newsoara or academic or other research organizations.

We continue to seek financing, partnering and licensing transactions for the further development of the pipeline assets which have not been partnered.

Our Type 1 Diabetes Program – Cadisegliatin (TTP399)

Diabetes Overview

Type 1 diabetes is an autoimmune disease in which a person’s pancreas stops producing insulin (a hormone that enables people to get energy from food).

Type 1 diabetes is an autoimmune disease in which a person’s pancreas stops producing insulin.

T1D results when the body’s immune system attacks and destroys the insulin-producing cells in the pancreas called beta cells.

While the causes of TID are not yet entirely understood, scientists believe that both genetic factors and environmental triggers are involved.

While the causes of T1D are not yet entirely understood, scientists believe that both genetic factors and environmental triggers are involved.

The onset of T1D is not believed to be affected by diet or lifestyle.

An estimated 1.6 million individuals live with T1D in the U.S.

as of 2025, a number which is expected to grow to 2.2 million by 2040.

Globally, an estimated 9.8 million individuals live with T1D as of 2025.

Current Treatments for T1D and Their Limitations

Patients with T1D have difficulty achieving and maintaining consistent glycemic control, defined as HbA1c < 7% as recommended by the American Diabetes Association ("ADA").

In order to maintain appropriate glycemic control, patients with T1D are required to constantly monitor their blood glucose levels, closely manage their diet, and administer insulin via injection in response.

While technology has advanced to help people with T1D manage the burden of this monitoring and insulin administration process, including continuous glucose monitors and insulin pumps, patient outcomes have not improved:

approximately 80% of people with T1D fail to achieve the ADA’s recommended HbA1c levels.

Patients with T1D have difficulty achieving and maintaining glycemic control, defined as HbA1c < 7% as recommended by the American Diabetes Association ("ADA").

To maintain appropriate glycemic control, patients with T1D are required to constantly monitor their blood glucose levels, closely manage their diet, and administer insulin via injection or an insulin pump at meal times and in response to changing blood glucose levels.

While technology including continuous glucose monitors, insulin pumps and automated insulin delivery systems has advanced to help people with T1D manage this burden, approximately 80% of people with T1D still do not achieve the ADA’s recommended HbA1c levels.

Failure to maintain glycemic control results in dangerous excursions into hyperglycemia or hypoglycemia that are potentially fatal.

In addition, the accumulated impact of these glycemic excursions can raise a patient’s risk of potentially serious and life-threatening long-term complications, such as cardiovascular disease, blindness, kidney failure, and nerve damage.

Several existing treatment options for T2D have been investigated to treat T1D, generally without success.

While SGLT-1/2 and SGLT-2 inhibitors were initially approved in Europe and Japan with label restrictions to certain sub-groups of people with T1D, and continue to be approved for patients with T2D, these therapies have since been withdrawn from the European market and never received regulatory approval in the U.S.

for T1D due to safety risks primarily relating to the risk of diabetic ketoacidosis (“DKA”).

Pramlintide (Symlin), an amylin peptide analog approved for meal time injections, has been approved for use in both T1D and T2D since 2005 but has not been adopted widely.

Alternative therapeutic modalities, including monoclonal antibodies, are under clinical investigation and have demonstrated evidence of the potential to delay the onset of T1D.

In 2022, the FDA approved Teplizumab (Tzield), a humanized anti-CD3 monoclonal antibody for the treatment of patients with two or more diabetes-related auto-antibodies to delay onset of full-blown disease, and Donislecel (Lantidra), an allogeneic (donor) pancreatic islet cellular therapy for the treatment of patients with T1D who are in poor glycemic control because of recurrent severe hypoglycemia.

However, Teplizumab does not address the unmet need of existing patients with T1D or those that are eventually at risk to become patients with T1D following any therapeutic delay in disease onset.

The use of Donislecel, on the other hand, is restricted to patients with T1D and recurrent severe hypoglycemic episodes, and requires long-term concurrent immunosuppressive therapy.

Thus, there is a serious unmet medical need to provide people with T1D additional, especially oral, treatment options that can help them to reduce HbA1c and the incidence of hypoglycemia (blood glucose levels below normal) or DKA.

Facing a lack of adjunctive treatments for T1D, several existing treatment options for T2D have been investigated in T1D without success.

SGLT-1/2 and SGLT-2 inhibitors were temporarily approved in Europe and Japan for certain sub-groups of people with T1D;

however, they never received regulatory approval in the U.S.

for T1D and were withdrawn from the European market due to safety risks primarily relating to increased risk of diabetic ketoacidosis (“DKA”).

Pramlintide (Symlin), an amylin peptide analog approved for mealtime injections, was approved for use in both T1D and T2D in 2005 but has not been adopted widely.

In 2022, the FDA approved teplizumab (Tzield ® ), a humanized anti-CD3 monoclonal antibody for the treatment of patients with two or more diabetes-related auto-antibodies to delay onset of Stage 3 T1D, and donislecel (Lantidra™), an allogeneic (donor) pancreatic islet cellular therapy for the treatment of patients with T1D who are in poor glycemic control because of recurrent severe hypoglycemia.

However, teplizumab does not address the unmet need of existing patients with T1D or those that will eventually develop T1D following any therapeutic delay in disease onset.

The use of donislecel is restricted to patients with T1D and recurrent severe hypoglycemic episodes, and requires long-term concurrent immunosuppressive therapy.

Thus, there is a serious unmet medical need to provide people with T1D additional, especially oral, treatment options that can help them to reduce the incidence of hypoglycemia and improve glycemic control (HbA1c) without the risk of DKA or other serious adverse effects.

The Role of Glucokinase Activation in Diabetes

Glucokinase (“GK”) is a key regulator of glucose homeostasis and acts as the physiological glucose sensor, changing its conformation, activity, and/or intracellular location in parallel with changes in glucose concentrations.

GK has two distinctive characteristics that make it a good choice for blood glucose control.

First, its expression is mostly limited to tissues that require glucose-sensing (mainly liver cells and pancreatic β-cells).

Second, GK acts as a biological sensor for changes in serum glucose levels and modulates changes in the liver's uptake or release of glucose and changes in insulin secretion by the β-cells.

GK activation is attractive as a potential therapy for the treatment of T1D because it may improve

overall glucose control and specifically reduce the frequency and severity of low blood glucose (hypoglycemic) episodes through a mechanism of action that is entirely distinct from currently marketed oral anti-diabetic drugs (“OAD”).

Glucokinase (“GK”) is a key regulator of glucose homeostasis and acts as the physiological glucose sensor, changing its conformation, activity, and/or intracellular location commensurate with changes in blood glucose concentrations.

GK has two distinctive characteristics that make it a good choice for a therapeutic target for improving blood glucose control.

First, its expression is mostly limited to glucose-sensing tissues (mainly liver cells and pancreatic β-cells), allowing for a focused therapeutic effect.

Second, GK acts as a biological sensor for changes in serum glucose levels, modulating changes in the liver's uptake or release of glucose and changes in insulin secretion by β-cells.

Activation of GK is attractive as a potential therapy for the treatment of T1D because it may improve overall blood glucose control and specifically reduce the frequency and severity of low blood glucose (hypoglycemic) episodes through a mechanism of action that is entirely distinct from currently marketed oral anti-diabetic drugs (“OAD”).

Cadisegliatin (TTP399)

Cadisegliatin is an orally administered, small molecule, liver-selective GKA in development as an adjunctive therapy to insulin for the treatment of TID.

Cadisegliatin is an orally administered, small molecule, liver-selective GKA in development as an adjunctive therapy to insulin for the treatment of T1D.

C adisegliatin has a novel mechanism of action:

liver-selective activation of GK that seeks to provide improved glycemic control and a reduction in the risk of hypoglycemia.

Our trials for cadisegliatin to date also suggest that our liver-selective approach to GK activation has the potential to avoid the tolerability issues associated with other GKAs, such as stimulation of insulin secretion independent of ambient blood glucose causing hypoglycemia, increased lipids, and liver toxicity.

lipids, and liver toxicity.

Based on data from Phase 1 and 2 trials to date, we believe that cadisegliatin , if approved, has the potential to be a first-in-class OAD due to its liver-selectivity and novel mechanism of action.

We have completed ten Phase 1 and three Phase 2 clinical trials of cadisegliatin in patients with type 1 and type 2 diabetes , one of which was six months in duration.

In these trials, cadisegliatin was well tolerated with negligible incidence of hypoglycemia in the T2D studies and a significant reduction of hypoglycemia observed in the Phase 2 study in TID.

In these trials, cadisegliatin was well tolerated with a significant reduction or hypoglycemia observed in the Phase 2 study in T1D and a negligible incidence of hypoglycemia in the T2D studies .

Positive Phase 2 Simplici-T1 Study

In February 2020, we announced positive results from the Simplici-T1 Study, an adaptive Phase 2 clinical trial of cadisegliatin , assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of cadisegliatin in adult patients with TID over a 12-week period.

The Simplici-T1 Study achieved its primary objective by demonstrating statistically significant improvements in HbA1c for cadisegliatin compared to placebo.

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Mechanistic study

We previously conducted a study to evaluate the impact of liver-selective GK activation on the safety and tolerability of cadisegliatin .

In October 2021, we announced positive results from the mechanistic study indicating no increased risk of ketoacidosis with cadisegliatin during acute insulin withdrawal in patients with T1D.

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In August 2023, we completed an Open-Label Phase 1 Study in Healthy Male Subjects to Investigate the Absorption, Metabolism, and Excretion of [ 14 C]- cadisegliatin (TTP399) Following Single Dose Oral Administration.

Ten participants have been dosed, and analysis is ongoing.

Ten participants were dosed.

The original results indicated the presence of an unexpected radiochromatographic signal which could not be further characterized at the time and led FDA to issue a clinical hold for the cadisegliatin program in July 2024.

vTv initiated a series of studies conducted by two independent laboratories to characterize this signal.

The results from these additional investigations concluded that this signal was an experimental artifact, which resulted in the FDA lifting the clinical hold.

Clinical Development Plan

Based upon the positive results of our Phase 2 Simplici-T1 Study, we requested breakthrough treatment designation (BTD) with the FDA which was granted in April 2021.

Consistent with the new 2023 FDA guidance on efficacy endpoints for anti-diabetic drugs, the Company is planning one supportive small and two larger pivotal, placebo-controlled Phase 3 clinical trials of cadisegliatin in patients with T1D and is engaged with the FDA on the optimal clinical trial designs for these studies.

The FDA confirmed that the effect size of cadisegliatin on events of hypoglycemia as demonstrated in the Phase 2 SimpliciT-1 Study are clinically meaningful and that a reduction in events of hypoglycemia would be an acceptable clinical endpoint for evaluation of an adjunctive therapy for the treatment of T1D.

We now have initiated a Phase 3 double-blind, controlled trial to assess the effect of cadisegliatin on reducing the frequency of Level 2 hypoglycemia (blood glucose levels are less than 54 mg/dL or 3 mmol/L, regardless of symptoms of hypoglycemia) and Level 3 hypoglycemia ("severe" hypoglycemia e.g., requiring assistance of another person) in 150 patients with T1D.

Participants in the trial will be randomized to two doses of cadisegliatin or placebo.

Reduction in glycated hemoglobin (HbA1c), a traditional efficacy endpoint in diabetes trials, is a key secondary endpoint to assess the potential of cadisegliatin in reducing hyperglycemia.

Following the initial assessment of efficacy after six months of treatment, participants will remain on trial for another six months to assess durability of potential beneficial effects and safety.

The study protocol was submitted to the FDA on February 29, 2024.

The trial will be conducted in the U.S.

only and is expected to complete enrollment by the fourth quarter in 2024 providing top line 1-year data by the first quarter in 2026.

Concurrently, we will be working on the design for two international registrational studies for cadisegliatin in T1D, which we expect to start in 2026.

In addition, we continue to work with our partner, G42 Investments, to initiate a double-blind, randomized, controlled Phase 2 trial in the Middle East region in 450 insulin-using patients with T2D.

Based upon the positive results of our Phase 2 Simplici-T1 Study, we requested breakthrough treatment designation (BTD) from th e FDA which was granted in April 2021.

• Based upon the lifting of the clinical hold imposed in July 2024, we plan to resume our Phase 3 CATT1 trial in the second quarter of 2025.

The CATT1 trial will randomize 150 patients with T1D on a 1:1:1 basis (i.e., 50 patients for each study arm) to receive 800 mg cadisegliatin daily or twice daily or to receive placebo.

A key secondary endpoint is reduction in glycated hemoglobin (HbA1c), a traditional efficacy endpoint in diabetes trials, to assess the potential of cadisegliatin to reduce hyperglycemia.

During 2025, we also will be working on the design and execution of two supportive trials in human volunteers to examine the effects of food on cadisegliatin's pharmacokinetics and the potential effects of cadisegliatin on cardiac function (thorough QT study) as required by FDA guidance.

We will also start preparing plans for additional international registrational studies for cadisegliatin in T1D.

We also will continue to work with our partner, G42 Investments to initiate a double-blind, randomized, controlled Phase 2 trial in the Middle East region in patients with T2D.

We expect that trial to begin in 2025.

Preclinical Development Plan

Preclinical Development

Long-term toxicology studies, development and reproductive toxicology studies, have been completed.

Carcinogenicity studies are ongoing and expected to be completed by the second quarter of 2024.

Carcinogenicity studies have been completed in 2024 with no untoward findings.

Collaboration Agreements

G42 Transaction

The Company and G42 Investments, entered into a Common Stock Purchase Agreement (the “G42 Purchase Agreement”) on May 31, 2022, pursuant to which the Company sold to G42 Investments 259,657 shares of the Company’s Class A common stock at a price per share of approximately $96.40, for an aggregate purchase price of $25.0 million, which was paid (i) $12.5 million in cash at the closing and (ii) $12.5 million in the form of a promissory note.

The Company and G42 Investments, entered into a Common Stock Purchase Agreement (the “G42 Purchase Agreement”) on May 31, 2022, pursuant to which the Company sold to G42 Investments 259,657 shares of the Company’s Class A common stock, for an aggregate purchase price of $25.0 million, which was paid (i) $12.5 million in cash at the closing and (ii) $12.5 million in the form of a promissory note.

G42 Investments has agreed to certain transfer restrictions (including restrictions on short sales or similar transactions) and restrictions on further acquisitions of shares, in each case subject to specified exceptions.

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Separately, the Company will conduct its clinical trials for cadisegliatin outside of the Partner Territory, at its own cost.

The results of each party’s clinical trials will be combined by the Company to seek FDA approval in the United States for cadisegliatin .

The results of each party’s clinical trials may be combined by the Company to seek FDA approval in the United States for cadisegliatin .

On December 21, 2022, G42 Healthcare Technology Solutions LLC (formerly known as Cogna Technology Solutions LLC) novated its rights and obligations under the Cogna Agreement to G42 Healthcare Research Technology Projects LLC ("G42 Healthcare"), an affiliate of G42 Investments.

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CinPax and CinRx Transaction

On July 22, 2022, the Company entered into a Common Stock and Warrant Purchase Agreement (as amended, the "CinRx Purchase Agreement") with CinPax, LLC (“CinPax”), a subsidiary of CinRx Pharma, LLC (“CinRx”), pursuant to which the Company sold to CinPax 103,864 shares of the Company’s Class A common stock at a price per share of approximately $96.40, for an aggregate purchase price of $10.0 million, which was paid (i) $6.0 million in cash at the closing of the transaction and (ii) $4.0 million in the form of a non-interest-bearing promissory note with CinPax and was paid to the Company on November 22, 2022.

which the Company sold to CinPax 103,864 shares of the Company’s Class A common stock, for an aggregate purchase price of $10.0 million, which was paid (i) $6.0 million in cash at the closing of the transaction and (ii) $4.0 million in the form of a non-interest-bearing promissory note with CinPax and was paid to the Company on November 22, 2022.

The Company, CinPax and CinRx subsequently amended the CinRx Purchase Agreement on February 27, 2024, in connection with the Private Placement.

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TTP273 is an orally available, small molecule GLP-1RA which has been demonstrated to reduce postprandial glucose excursion in response to an oral glucose test or mixed meal tolerance test in both preclinical and clinical studies.

We are currently exploring options to study the therapeutic potential of TTP273 in patients with cystic fibrosis related diabetes ("CFRD").

Cystic Fibrosis Related Diabetes Overview

Cystic fibrosis related diabetes (“CFRD”) shares some features with both type 1 and type 2 diabetes but is distinct, and is categorized as diabetes due to other causes, specifically a disease of the exocrine pancreas, by the American Diabetes Association.

In people with cystic fibrosis (“CF”), the thick, sticky mucus that is characteristic of the disease causes scarring of the pancreas.

This scarring prevents the pancreas from producing normal amounts of insulin.

The damaged pancreas also responds to insulin signaling in a delayed manner.

The delay and blunting of the insulin response in patients with CFRD results in postprandial hyperglycemia.

The Role of GLP-1r Activation in Cystic Fibrosis Related Diabetes

GLP-1 is released by the gut in response to nutrients and lowers postprandial glucose by promoting insulin secretion.

Abnormally low postprandial stimulation of incretin hormones like GLP-1 has been described in CF patients and improvement in postprandial hyperglycemia has been demonstrated following prandial administration of GLP-1 agonists or dipeptidyl peptidase-4.

Although existing GLP-1 mimetics are available for the treatment of CFRD, their use is limited by the gastrointestinal ("GI") side effects and undesired weight loss associated with these agents.

Therapeutic use of GLP1-RAs overview

GLP-1 RAs were initially developed to treat T2D but have demonstrated effectiveness in promoting weight loss.

The success of GLP-1 RAs in treating obesity has been noteworthy and has positioned GLP-1 RAs as a promising pharmacological intervention for weight management, contributing to improved overall health outcomes for individuals with obesity.

The number of indications for GLP-1 RAs also continues to grow steadily.

Currently, GLP-1RAs have been approved by the FDA for five indications:

T2D, obesity, cardiovascular disease, chronic kidney disease, and sleep apnea.

Additionally, GLP-1 RAs are being investigated in clinical trials for a range of other conditions, including diabetes prevention, heart failure, non-alcoholic steatohepatitis (NASH), and osteoarthritis and recent research has highlighted the potential for GLP-1 RAs to be of benefit in over 100 health outcomes, including in addiction, psychotic disorders, neurocognitive illnesses, and cardiovascular events like myocardial infarction and stroke.

Additionally, in cystic fibrosis related diabetes (“CFRD”) which presents with abnormally low postprandial stimulation of incretin hormones like GLP-1, an improvement in postprandial hyperglycemia has been demonstrated following prandial administration of GLP-1 agonists.

As the indications for GLP-1 RAs expand, the gastrointestinal (GI) side effects associated with many GLP-1 RAs may pose increasing challenges, particularly for those individuals with pre-existing GI conditions or who do not require weight loss (e.g.

Therefore, GLP-1 RAs like TTP273, which in studies has shown to be well tolerated, would be particularly useful for indications where GI issues or excessive weight loss are undesirable or even contraindicated.

TTP273 is an orally available, small molecule GLP-1RA, which has been demonstrated to reduce postprandial glucose excursion in response to an oral glucose test or mixed meal tolerance test in both preclinical and clinical studies.

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We believe that TTP273 could be used to treat postprandial hyperglycemia in CFRD patients and CF patients with abnormal postprandial glucose excursions without inducing hypoglycemia or GI side effects.

An oral therapy such as TTP273 is needed because the current method of treatment of CFRD is injected insulin, which comes with associated risks of hypoglycemia and poses additional burdens on patients.

Other available oral therapies for type 2 diabetes ("T2D") are not recommended for the treatment of CFRD due to side effects, such as hypoglycemia, weight loss, or nausea.

We have completed two Phase 1 clinical trials and one Phase 2 clinical trial of TTP273 .

Additionally, we have completed nine Phase 1 clinical trials and one Phase 2 clinical trial of TTP054 , a predecessor orally administered GLP-1RA.

In our Phase 1 and Phase 2 clinical trials, TTP273 has been demonstrated to be well-tolerated with lower incidences of GI side effects, such as nausea and vomiting, than placebo with minimal weight loss, especially in nonobese patients.

In these trials, TTP273 has been demonstrated to be well-tolerated with lower incidences of GI side effects, such as nausea and vomiting, than placebo with minimal weight loss, especially in nonobese patients.

In a randomized, double-blind Phase 2 trial in patients with T2D treated with metformin only, TTP273 showed clinically relevant reductions of glycated hemoglobin (HbA1c) and systolic blood pressure after 3 months of treatment.

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The trial enrolled 12 subjects in each of two dose cohorts, 15mg and 20mg, randomized to receive HPP737 or placebo (3:1) orally once daily for 14 days.

Dose escalation up to 20mg once per day demonstrated dose proportional increases in exposure, while maintaining a favorable safety and tolerability profile with no dose limiting safety

or tolerability findings observed.

Dose escalation up to 20mg once per day demonstrated dose proportional increases in exposure, while maintaining a favorable safety and tolerability profile with no dose limiting safety or tolerability findings observed.

There were no serious adverse events and no discontinuations due to treatment emergent adverse events.

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We are eligible to receive additional potential development, regulatory and sales-based milestone payments totaling up to $76.5 million.

In addition, Newsoara is obligated to pay us royalty payments at high-single to low-double digit rates, based on tiers of annual net sales of licensed products.

Such royalties will be payable on a licensed product-by-licensed product and country-by-country basis until the latest of expiration of the licensed patents covering a licensed product in a country, expiration of data exclusivity rights for a licensed product in a country or a specified number of years after the first commercial sale of a licensed product in a country.

In addition, Newsoara is obligated to pay the Company royalty payments at mid to upper single digit rates, based on tiers of annual net sales of licensed products.

Such royalties will be payable on a licensed product-by-licensed product and country-by-country basis until the latest of expiration of the licensed patents covering a licensed product in a

country, expiration of data exclusivity rights for a licensed product in a country or a specified number of years after the first commercial sale of a licensed product in a country.

Under the terms of the Newsoara License Agreement, Newsoara will be responsible for the development and commercialization of the licensed products in the Newsoara License Territory, at its cost, and is required to use commercially reasonable efforts with respect to such development and commercialization efforts.

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Upon expiration (but not earlier termination) of the Newsoara License Agreement the licenses granted to Newsoara will survive on a royalty-free basis in perpetuity.

In June 2024, the parties entered into the Second Amendment to License Agreement, which provided that upon Newsoara's payment of the upfront fee of $20.0 million, the Newsoara License Agreement would be expanded to a global license.

The Second Amendment also requires Newsoara to pay vTv LLC up to $41.5 million in development milestones, $35.0 million in sales-related milestones and royalties in the mid to upper single digits depending upon sales volumes.

To date, Newsoara has not paid the upfront fee to expand the license.

Azeliragon and Cantex Pharmaceuticals, Inc.

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In February 2022, Cantex secured a global license from Harvard University to further develop azeliragon as a treatment for inflammatory lung diseases, including COVID-19.

PPAR-δ and Reneo Pharmaceuticals, Inc.

On December 21, 2017, we entered into a License Agreement with Reneo Pharmaceuticals, Inc.

(“Reneo”) (the “Reneo License Agreement”), under which Reneo obtained an exclusive, worldwide, sublicensable license to develop and commercialize our peroxisome proliferation activated receptor delta (PPAR-δ) agonist program, including the compound HPP593 (REN001, mavodelpar ), for therapeutic, prophylactic, or diagnostic application in humans.

Under the terms of the Reneo License Agreement, Reneo paid us an initial license fee of $3.0 million.

We are eligible to receive additional potential development, regulatory and sales-based milestone payments totaling up to $94.5 million.

In addition, Reneo is obligated to pay us royalty payments at mid-single to low-double digit rates, based on tiers of annual net sales of licensed products.

In addition, we have received common stock and certain participation rights representing a minority interest in Reneo’s outstanding equity.

Under the terms of the Reneo License Agreement, Reneo will be responsible for the worldwide development and commercialization of the licensed products, at its cost, and is required to use commercially reasonable efforts with respect to such development and commercialization efforts.

The Reneo License Agreement, unless terminated earlier, will continue until expiration of all royalty obligations of Reneo to us.

Either party may terminate the Reneo License Agreement for the other party’s uncured material breach.

Reneo may terminate the Reneo License Agreement at will upon prior written notice.

Upon expiration (but not earlier termination) of the Reneo License Agreement, the licenses granted to Reneo will survive on a royalty-free basis in perpetuity.

Reneo has continued to progress the development of mavodelpar for primary mitochondrial myopathy (PMM) and long-chain fatty acid oxidation disorders (LC-FAOD).

The Phase 2 study of mavodelpar for glycogen storage disorder type V (McArdle Disease) showed only modest benefits, and Reneo does not plan to proceed further for this indication.

Reneo announced on December 14th, 2023, that its pivotal STRIDE study (NCT04535609) of mavodelpar in adult patients with PMM did not meet its primary efficacy or secondary efficacy endpoint.

The primary efficacy endpoint of the trial was the change from baseline in the distance walked during the 12-minute walk test (12MWT) at week 24.

The secondary efficacy endpoint was the change from baseline in the PROMIS® Short Form Fatigue 13a score.

GLP-1r and Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd.

On December 21, 2017, we entered into a License Agreement with Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd.

(“Huadong”) (the “Huadong License Agreement”), under which Huadong obtained an exclusive and sublicensable license to develop and commercialize our glucagon-like peptide-1 receptor agonist (“GLP-1r”) program, including the compound TTP273 , for therapeutic uses in humans or animals, in China and certain other Pacific Rim territories, including Australia and South Korea (collectively, the “Huadong License Territory”).

Additionally, under the Huadong License Agreement, we obtained a non-exclusive, sublicensable, royalty-free license to develop and commercialize certain Huadong patent rights and know-how related to our GLP-1r program for therapeutic uses in humans or animals outside of the Huadong License Territory.

Under the terms of the Huadong License Agreement, Huadong has paid us an initial license fee of $8.0 million, and we are eligible to receive potential development and regulatory milestone payments totaling up to $22.0 million, as amended in January 2021.

Additionally, we are eligible to receive additional potential regulatory milestone of $20.0 million if Huadong receives regulatory approval for a central nervous system indication.

Further, we are eligible for an additional $50.0 million in potential sales-based milestones, as well as royalty payments ranging from low-single to low-double digit rates, based on tiered sales of licensed products.

Under the original Huadong License Agreement, we had the obligation to conduct a Phase 2 multi-region clinical trial (the “Phase 2 MRCT”), should Huadong require us to do so.

We were also responsible for contributing up to $3.0 million in connection with the Phase 2 MRCT, if it occurs.

However, the Huadong License Agreement was amended in January 2021 to remove these obligations.

The Phase II study in mainland China and Taiwan has achieved Last Patient Out “LPO” on January 11, 2022.

In addition, a milestone was paid in 2022.

Huadong will be responsible for the development and commercialization of the licensed products in the Huadong License Territory, at its cost, and is required to use commercially reasonable efforts with respect to its development efforts.

Further, Huadong is required to use commercially reasonable efforts to develop and commercialize at least one GLP-1r compound in China.

The Huadong License Agreement, unless terminated earlier, will continue on a product-by-product and country-by-country basis until expiration of the royalty obligations Huadong owes to us on such licensed product, which extend until the later of the expiration of certain patent or data exclusivity rights covering such licensed product in such country or eight years after the first commercial sale of such product in such country.

Either party may terminate the Huadong License Agreement for the other party’s uncured material breach.

On December 18, 2023, Huadong notified us of its intent to terminate the Huadong License Agreement.

The termination will not be effective until after both parties negotiate and finalize a termination agreement, which is expected to occur in the first half of 2024.

Nrf2 and Anteris Bio, Inc.

On December 11, 2020, we entered into a license agreement with Anteris Bio, Inc.

(“Anteris”) (the “Anteris License Agreement”), under which Anteris obtained a worldwide, exclusive and sublicensable license to develop and commercialize vTv LLC’s Nrf2 activator, HPP971 .

Under the terms of the Anteris License Agreement, Anteris paid vTv LLC an initial license fee of $2.0 million.

vTv LLC is eligible to receive additional potential development, regulatory, and sales-based milestone payments totaling up to $151.0 million.

Anteris is also obligated to pay vTv royalty payments at a double-digit rate based on annual net sales of licensed products.

Such royalties will be payable on a licensed product-by-licensed product basis until the latest of expiration of the licensed patents covering a licensed product in a country, expiration of data exclusivity rights for a licensed product in a country, or a specified number of years after the first commercial sale of a licensed product in a country.

In addition, vTv LLC received a minority ownership interest in Anteris.

Under the terms of the Anteris License Agreement, Anteris will be responsible for the development and commercialization of the licensed products, at its cost, and is required to use commercially reasonable efforts with respect to such development and commercialization efforts.

The Anteris License Agreement, unless terminated earlier, will continue until expiration of all royalty obligations of Anteris to vTv LLC.

Either party may terminate the Anteris License Agreement for the other party’s uncured material breach.

Anteris may terminate the Anteris License Agreement at will upon prior written notice.

Either party may terminate the Anteris License Agreement for the other party’s insolvency.

On September 25, 2023, Anteris notified the Company that it was terminating the Anteris License Agreement.

The termination became effective on December 24, 2023, and Anteris has since liquidated its assets and ceased doing business.

On May 20, 2024, Cantex announced that the FDA granted Orphan Drug Designation to azeliragon, a well-tolerated once-a-day pill, for the treatment of pancreatic cancer.

Cantex has an ongoing clinical trial studying the safety and efficacy of azeliragon in patients refractory to first-line treatment of metastatic pancreatic cancer.

On December 9, 2024, Cantex announced that the FDA granted Orphan Drug Designation to Cantex’s azeliragon for the treatment of brain metastasis from breast cancer.

Inbound Partnerships

JDRF Agreement

In August 2017, we entered into a research and collaboration agreement with JDRF International (the “JDRF Agreement”) to support the funding of the Simplici-T1 Study, a Phase 2 study to explore the effects of cadisegliatin in patients with type 1 diabetes.

The JDRF Agreement was amended in June 2021 to provide additional funding for the Company’s mechanistic study exploring the effects of cadisegliatin on ketone body formation during a period of insulin withdrawal in people with type 1 diabetes.

According to the terms of the JDRF Agreement, as amended, JDRF provided research funding of $3.4 million based on the achievement of research and development milestones.

Additionally, the Company has the obligation to make certain milestone payments to JDRF upon the commercialization, licensing, sale or transfer of cadisegliatin as a treatment for type 1 diabetes.

In February 2007, we entered into an Agreement Concerning Glucokinase Activator Project with Novo Nordisk A/S (the “Novo License Agreement”) whereby we obtained an exclusive, worldwide, sublicensable license under certain Novo Nordisk intellectual property rights to discover, develop, manufacture, have manufactured, use, and commercialize products for the prevention, treatment, control, mitigation, or palliation of human or animal diseases or conditions.

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The Company may also be obligated to pay an additional $75.0 million in potential sales-based milestones, as well as royalty payments, at mid-single digit royalty rates, based on tiered sales of commercialized licensed products.

During the year ended December 31, 2021, the Company made a payment of $2.0 million related to the satisfaction of the milestone to complete the Phase 2 trials for cadisegliatin under this agreement.

Third-Party Suppliers and Manufacturers

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Intellectual Property

The IP portfolio for cadisegliatin (TTP399) includes issued patents in approximately 35 jurisdictions, including the U.S., over 10 European countries, Japan, Canada, Australia, and China, directed to cadisegliatin as a composition of matter, among other things.

We actively protect our commercially important proprietary technology by, among other methods, obtaining, maintaining, and defending our patent rights.

We have filed numerous patent applications covering our current drug candidates and our other research and discovery programs in the U.S.

and in jurisdictions outside of the U.S., resulting in multiple issued patents.

We pursue patent protection for all inventions and improvements throughout development, including, when possible, compositions of matter, crystal forms (polymorphs), methods of use, dosage regimens, formulations, combination therapies, and manufacturing processes.

Issued patents can provide protection for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance and the legal term of patents in the countries in which they are obtained.

In general, patents issued for applications filed in the U.S.

can provide exclusionary rights for 20 years from the earliest effective non-provisional filing date.

In addition, in certain instances, the term of an issued U.S.

patent that covers or claims an FDA approved product, or its use in treating an approved indication, can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period, which is called patent term extension.

The period of patent term extension in the United States cannot be longer than five years and the total patent term, including the extension period, must not exceed 14 years following FDA approval.

The term of patents outside of the U.S.

varies in accordance with the laws of the foreign jurisdiction, but typically is also 20 years from the earliest effective non-provisional filing date.

However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.

Some countries also provide mechanisms to recapture a portion of the patent term lost during regulatory review, similar to patent term extension in the U.S.

The amount of patent term that can be recaptured depends on the laws of the relevant jurisdictions.

The patent portfolio for cadisegliatin includes multiple patent families directed to crystal forms, salt forms, formulations, combinations, and methods of use for treating diabetes, among other things, that are filed in the U.S.

For example, the patent portfolio for cadisegliatin includes a patent family directed to methods of treating patients with type 1 diabetes using cadisegliatin in combination with insulin.

The issued U.S.

patent covering cadisegliatin as a composition of matter will expire no earlier than 2025,

absent any patent term adjustments or extensions, but may expire as late as 2030 if, after approval by the U.S.

Food and Drug Administration (FDA), we apply for and obtain the maximum possible patent term extension (PTE) that is available under the Drug Price Competition and Patent Term Restoration Act of 1984 (the “Hatch-Waxman Act”).

Only one U.S.

patent applicable to an approved drug may be extended and only those claims covering the approved drug, a method of using it, or a method for manufacturing it may be extended.

Patents covering cadisegliatin as a composition of matter outside the United States will expire no earlier than 2025, absent any patent term adjustments or extensions.

Provisions that are similar to the U.S.

PTE under the Hatch-Waxman Act are available in Europe and some other foreign jurisdictions to extend the term of the patent covering cadisegliatin as a composition of matter.

The IP portfolio for cadisegliatin also includes patent families covering crystal forms, salt forms, and solid formulations of cadisegliatin , among other things.

The issued patents and patent applications, if issued, in these additional patent families would be expected to expire between 2034 and 2041, absent any patent term adjustments or extensions.

The IP portfolio for cadisegliatin further includes additional patent families covering combinations of cadisegliatin with metformin, DPP-4 inhibitors, or GLP-1r agonists, and their use in methods of treatment.

The issued patents and patent applications, if issued, in these additional patent families would be expected to expire between 2031 and 2033, absent any patent term adjustments or extensions.

In addition, the IP portfolio also includes a patent family covering methods of treating patients with type 1 diabetes using cadisegliatin in combination with insulin.

The issued patents and patent applications, if issued in this additional patent family, if issued, would be expected to expire in 2039, absent any patent term adjustments or extensions.

The IP portfolio for HPP737 includes issued patents in the U.S.

patents, as well as U.S.

and foreign patents issuing from pending patent applications, in this patent family would be expected to expire in 2039, absent any patent term adjustments or extensions.

The patent portfolio for cadisegliatin also includes three patent families directed to crystal forms, crystalline salt forms, and solid formulations of cadisegliatin , among other things.

The issued patents and patents issuing from pending patent applications in these patent families are projected to expire between 2034 and 2041, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for cadisegliatin further includes patent families directed to combinations of cadisegliatin with metformin, DPP-4 inhibitors, or GLP-1r agonists, and their use in methods of treatment.

The issued patents and patents issuing from pending patent applications in these additional patent families are projected expected to expire between 2031 and 2033, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for HPP737 includes issued patents in the U.S.

generically covering HPP737 as a composition of matter and methods of use to treat various indications.

The issued U.S.

patent generically covering HPP737 as a composition of matter will expire no earlier than 2029, absent any patent term adjustments or extensions, but may expire as late as 2034 if, after approval by the U.S.

FDA, we apply for and obtain the maximum possible PTE that is available under the Hatch-Waxman Act.

The IP portfolio for HPP737 also includes a patent family specifically covering HPP737 and another patent family covering a crystalline form of HPP737 .

Any patents issuing from these two patent families will expire in 2040, absent any patent term adjustments or extensions.

The IP portfolio for the GLP-1r program includes issued patents in over 25 countries and regions, including the U.S., over 10 European countries, Japan, Canada, Australia, and China, directed to TTP273 as a composition of matter.

The issued U.S.

patent covering TTP273 as a composition of matter will expire no earlier than 2030, absent any patent term adjustments or extensions, but may expire as late as 2035, if after approval by the U.S.

FDA we apply for and obtain the maximum possible PTE that is available under the Hatch-Waxman Act following approval.

Patents covering TTP273 as a composition of matter outside the United States will expire no earlier than 2030, absent any patent term adjustments or extensions.

Provisions that are similar to the U.S.

PTE under the Hatch-Waxman Act are available in Europe and some other foreign jurisdictions to extend the term of the patent covering TTP273 as a composition of matter.

The IP portfolio for TTP273 also includes patent families covering crystalline, non-crystalline, and salt forms, and formulations of TTP273 , synthetic precursors to, and methods of manufacture of TTP273 , as well as combinations of TTP273 and metformin, and their use in methods of treatment, and dosage regimens of TTP273 .

The patent applications in these additional patent families, if issued, would be expected to expire between 2034 and 2042, absent any patent term adjustments or extensions.

The IP portfolio for the Nrf2/Bach1 program includes issued patents in approximately 25 countries and regions, including the U.S., Europe, Japan, Canada, Australia, and China, directed to HPP971 and HPP3033 as compositions of matter, among other things.

The issued U.S.

patent covering HPP971 and HPP3033 as compositions of matter will expire no earlier than 2031, absent any patent term adjustments or extensions.

However, this issued U.S.

patent may expire as late as 2036, if after approval by the U.S.

FDA we apply for and obtain the maximum possible PTE that is available under the Hatch-Waxman Act following approval”), and the patent term adjustments calculated by the USPTO are fully applied.

Patents covering HPP971 and HPP3033 as a composition of matter outside the United States will expire no earlier than 2031, absent any patent term adjustments or extensions.

Provisions that are similar to the U.S.

PTE under the Hatch-Waxman Act are available in Europe and some other foreign jurisdictions to extend the term of the patents covering HPP971 and HPP3033 as a composition of matter.

The IP portfolio for the Nrf2/Bach1 program also includes patent families covering backup compounds, methods of use in combination with other Nrf2 activator compounds such as dimethyl fumarate and bardoxolone, and methods to treat sickle cell diseases, osteoporosis, and refractive ocular disorders.

The patent applications in these additional patent families, if issued, would be expected to expire between 2035 and 2041, absent any patent term adjustments or extensions.

The IP portfolio for azeliragon also includes patent families covering polymorphs, salt forms, metabolites, degradation products and a synthetic precursor of azeliragon , methods of treatment using select dosage regimens of azeliragon , and methods of treating select patient populations, among other things.

The issued patents and patent applications, if issued in these additional patent families, if issued, would be expected to expire between 2028 and 2039.

The issued U.S.

patent covering the polymorph of azeliragon used in clinical development will expire no earlier than 2028, absent any patent term

adjustments or extensions, but may expire as late as 2033 if after approval by the U.S.

FDA we decide to apply for and obtain the maximum PTE under the Hatch-Waxman Act for the U.S.

patent covering the polymorph of azeliragon instead of the U.S.

patent covering azeliragon as a composition of matter.

Only one patent applicable to an approved drug may be extended and only those claims covering the approved drug, a method of using it, or a method for manufacturing it may be extended.

Similar provisions available in Europe and some other foreign jurisdictions to extend the term of a patent that covers an approved drug.

patent generically covering HPP737 as a composition of matter will expire no earlier than 2029, absent any patent term adjustments or extensions.

The patent portfolio for HPP737 also includes a patent family specifically covering HPP737 and another patent family directed to a crystalline form of HPP737 .

Any patents issuing from the pending patent applications in these two patent families will expire in 2040, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for the GLP-1r program includes multiple patent families covering TTP273 directed to composition of matter, crystal forms, non-crystal forms, salt forms, formulations, combinations, and methods of use for treating various indications, among other things.

The GLP-1r IP portfolio includes a patent family directed to TTP273 as a composition of matter.

The issued patents covering TTP273 as a composition of matter will expire no earlier than 2030, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for TTP273 also includes patent families directed to crystalline, non-crystalline, and crystalline salt forms, and formulations of TTP273 , synthetic precursors to, and methods of manufacture of TTP273 , as well as combinations of TTP273 and metformin, and their use in methods of treatment, and dosage regimens of TTP273 .

Patents issuing from pending patent applications in these additional patent families would be expected to expire between 2034 and 2045, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for the Nrf2/Bach1 program includes a patent family directed to HPP971 and HPP3033 as compositions of matter, among other things.

The issued patents in this patent family will expire no earlier than 2031, absent

any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for the Nrf2/Bach1 program also includes patent families directed to methods of use in combination with other Nrf2 activator compounds such as dimethyl fumarate and bardoxolone, and methods to treat sickle cell diseases, osteoporosis, and refractive ocular disorders.

The issued patents and patents issuing from pending patent applications in these additional patent families are projected to expire between 2035 and 2041, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

The patent portfolio for azeliragon also includes patent families covering polymorphs, salt forms, metabolites, degradation products and a synthetic precursor of azeliragon , methods of treatment using select dosage regimens of azeliragon , and methods of treating select patient populations, among other things.

The issued patents and patents issuing from pending patent applications in these patent families, are projected to expire between 2028 and 2039, absent any patent term adjustments or extensions in the U.S.

jurisdictions.

Trade Secrets

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To the extent that our contractors use or incorporate intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

The biopharmaceutical industry is characterized by intense competition and rapid innovation.

Our potential competitors include large pharmaceutical and biotechnology companies, specialty pharmaceutical companies and generic drug companies.

We believe the key competitive factors that will affect the development and commercial success of our drug candidates are efficacy, safety and tolerability profile, mechanism of action, control and predictability, convenience of dosing, price and reimbursement, and availability of comparable alternative therapies.

Many of the companies against which we may compete have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.

Mergers and acquisitions in the pharmaceutical, biotechnology and medical devices industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

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Potential Competing Products – Type 1 Diabetes

If approved, we expect that our type 1 diabetes investigational drug candidate will compete with oral non-insulin agents and new insulin formulations or devices that are currently being developed.

These include the SGLT-1/2 inhibitor sotagliflozin, being developed by Lexicon, and the oral somatostatin type 2 receptor blocker ZT-01 by Zucara Therapeutics.

In addition, Diasome Pharmaceuticals has started a new Phase 2 study in February 2024 to assess the effects of their Hepatic Directed Vesicle (HDV)-based insulin lispro formulation ("HDV Insulin lispro") on the incidence of nocturnal hypoglycemia in patients with T1D.

However, none of these treatments are currently approved or marketed for the treatment of type 1 diabetes.

If approved, we expect that our type 1 diabetes investigational drug candidate will compete with oral or injectable non-insulin agents, new insulin formulations or medical devices that are currently marketed or being developed.

An injectable somatostatin type 2 receptor blocker is being developed by Zucara Therapeutics to treat nocturnal hypoglycemia.

In addition, in 2024 Diasome Pharmaceuticals began a Phase 2b study to assess the effects of their hepatic directed vesicle (HDV)-based insulin lispro formulation on the incidence of nocturnal hypoglycemia in patients with T1D.

In 2023, Carmot Therapeutics has started a phase 2 study of an injectable GLP-1/GIP agonist in overweight or obese patients with T1D to assess its effects on A1c, body weight and continuous glucose monitory ("CGM") metrics including time in hypoglycemia.

REMD Biotherapeutics is developing an injectable glucagon receptor monoclonal antibody, volagedimab, which may help address hyperglycemia in T1D, while Adocia is developing an ultra-rapid insulin with the aim to confer glycemic control benefits by reducing post-prandial hyperglycemia.

None of these therapies are currently approved or marketed for the treatment of type 1 diabetes.

Other therapies in development focus on either delaying the onset of stage 3 T1D or to preserve, regenerate or replace B cells post stage 3 T1D diagnosis.

For example, Teplizumab is an injectable CD-3 targeting immune therapy that was the first disease modifying therapy approved by FDA to delay onset of stage 3 T1D in adults and children while Lantidra is an FDA approved islet cell therapy for patients with T1D who cannot achieve adequate glycemic control because of frequent hypoglycemia.

Because islet cell therapy like Lantidra requires adjunctive immunosuppressive therapy, several companies are developing similar therapies that may not require adjunctive immunosuppressive therapy.

The company Biomea is currently in stage 2 development of an oral covalent menin inhibitor which aims to improve B cell function post stage 3 T1D diagnosis to improve overall glycemic control.

The company TIXiMED recently initiated a phase 1 study of its drug candidate that targets thioredoxin-interacting protein (TXNIP), a detrimental protein that is elevated in diabetes and leads to beta cell death and dysfunction.

Finally, medical devices such as continuous glucose monitors (CGMs), connected smart insulin pens and automated insulin delivery systems, which tie insulin pumps with CGMs through control algorithm software and allow to constantly adjust insulin delivery in response to changing blood glucose levels, continue to evolve and have already shown to improve glucose control and reduce the risk for hypoglycemia.

Collaboration Revenue and Customers

Most of our collaboration revenue for the years ended December 31, 2023, 2022 and 2021 is related to our licenses of certain compounds in the preclinical stage or clinical stage, including the Huadong License Agreement, the Reneo License Agreement, and the Newsoara License Agreement.

Revenue recognized in these periods relates to initial consideration received in the form of upfront payments and equity interests, research activities performed by our personnel, and the achievement of development milestones.

Most of our collaboration revenue for the years ended December 31, 2024, 2023 and 2022 is related to our licenses of certain compounds in the preclinical stage or clinical stage, including the Huadong License Agreement, which was terminated effective September 1, 2024, and the Newsoara License Agreement.

Revenue recognized in these periods relates to the achievement of development milestones.

Government Regulation and Product Approvals

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The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

For a full discussion of the regulatory framework for the approval and regulation of investigational drug candidates, and applicable domestic and foreign healthcare law, please see “Part 1 – Item 1 – Business - Government Regulation and Product Approvals” in our Annual Report on Form 10-K filed on February 21, 2020.

Approval and Regulation of Drugs in the United States

In the United States, drug products are regulated under the Federal Food, Drug and Cosmetic Act (“FDCA”), and applicable implementing regulations and guidance.

The failure of an applicant to comply with the applicable regulatory requirements at any time during the product development process, including non-clinical testing, clinical testing, the approval process or post-approval process, may result in delays to the conduct of a study, regulatory review and approval and/or administrative or judicial sanctions.

These sanctions may include, but are not limited to, the FDA’s refusal to allow an applicant to proceed with clinical trials, refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, warning letters, adverse publicity, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines and civil or criminal investigations and penalties brought by the FDA or Department of Justice (“DOJ”), or other government entities, including state agencies.

An applicant seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be licensed by the FDA:

• preclinical testing including laboratory tests, animal studies and formulation studies, which must be performed in accordance with the FDA’s good laboratory practice (“GLP”), regulations and standards;

• submission to the FDA of an Investigational New Drug Application (“IND”) for human clinical testing, which must become effective before human clinical trials may begin;

• approval by an independent institutional review board (“IRB”), representing each clinical site before each clinical trial may be initiated;

• performance of adequate and well-controlled human clinical trials to establish the safety, potency and efficacy of the product candidate for each proposed indication, in accordance with current good clinical practices (“GCP”);

• preparation and submission to the FDA of a new drug application (“NDA”), for a drug product which includes not only the results of the clinical trials, but also, detailed information on the chemistry, manufacture and quality controls for the product candidate and proposed labelling for one or more proposed indication(s);

• review of the product candidate by an FDA advisory committee, where appropriate or if applicable;

• satisfactory completion of an FDA inspection of the manufacturing facility or facilities, including those of third parties, at which the product candidate or components thereof are manufactured 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’s identity, strength, quality and purity;

• satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCP and the integrity of clinical data in support of the NDA;

• payment of user fees and securing FDA approval of the NDA to allow marketing of the new drug product;

• compliance with any post-approval requirements, including the potential requirement to implement a risk evaluation and mitigation strategy (“REMS”) and the potential requirement to conduct any post-approval studies required by the FDA.

Preclinical Studies

Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.

Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as other studies to evaluate, among other things, the toxicity of the product candidate.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards.

The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and long-term toxicity studies, may continue after the IND is submitted.

The IND and IRB Processes

An IND is an exemption from the FDCA that allows an unapproved product candidate to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer such investigational product to humans.

Such authorization must be secured prior to interstate shipment and administration of any product candidate that is not the subject of an approved NDA.

In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, must be submitted to the FDA as part of an IND.

The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin.

This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks.

At any time during this 30-day period, or thereafter, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold or partial clinical hold.

In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.

Following commencement of a clinical trial under an IND, the FDA may also place a clinical hold or partial clinical hold on that trial.

In July 2024, the FDA placed the cadisegliatin program on clinical hold based upon a radiochromatographic signal that could not be fully characterized at that time.

The FDA subsequently lifted the clinical hold in March 2025, following the Company’s submission of a complete response that demonstrated that the uncharacterized signal was an experimental artifact

A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND.

When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived.

When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval.

Specifically, such studies must be conducted in accordance with GCP, including review and approval by an independent ethics committee (“IEC”), and informed consent from subjects.

The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies, as well as the quality and integrity of the resulting data.

They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.

In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct

continuing review and reapprove the study at least annually.

The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.

An IRB must operate in compliance with FDA regulations.

An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee (“DSMB”).

This group provides authorization as to whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the study.

Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk.

Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.

Information about clinical trials must be submitted within specific timeframes to the National Institutes of Health (“NIH”), for public dissemination on its ClinicalTrials.gov website.

Human Clinical Trials in Support of an NDA

Clinical trials involve the administration of the investigational product candidate to human subjects under the supervision of a qualified investigator in accordance with GCP requirements which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.

Clinical trials are conducted under written clinical trial protocols detailing, among other things, the objectives of the study, inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Human clinical trials are typically conducted in three sequential phases, but the phases may overlap or be combined.

Additional studies may also be required after approval.

Phase 1 clinical trials are initially conducted in a limited population to test the product candidate for safety, including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics in healthy humans or in patients.

During Phase 1 clinical trials, information about the investigational drug product’s pharmacokinetics and pharmacological effects may be obtained to permit the design of well-controlled and scientifically valid Phase 2 clinical trials.

Phase 2 clinical trials are generally conducted in a limited patient population to identify possible adverse effects and safety risks, evaluate the efficacy of the product candidate for specific targeted indications and determine dose tolerance and optimal dosage.

Multiple Phase 2 clinical trials may be conducted by the sponsor to obtain information prior to beginning larger and more costly Phase 3 clinical trials.

Phase 2 clinical trials are well controlled, closely monitored and conducted in a limited patient population.

Phase 3 clinical trials proceed if the Phase 2 clinical trials demonstrate that a dose range of the product candidate is potentially effective and has an acceptable safety profile.

Phase 3 clinical trials are undertaken within an expanded patient population to further evaluate dosage, provide substantial evidence of clinical efficacy and further test for safety in an expanded and diverse patient population at multiple, geographically dispersed clinical trial sites.

A well-controlled, statistically robust Phase 3 clinical trial may be designed to deliver the data that regulatory authorities will use to decide whether or not to approve, and, if approved, how to appropriately label a drug:

such Phase 3 studies are referred to as “pivotal.”

In some cases, the FDA may approve an NDA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval.

Such post-approval trials are typically referred to as Phase 4 clinical trials.

These studies are used to gain additional experience from the treatment of a larger number of patients in the intended treatment group and to further document a clinical benefit in the case of drugs approved under accelerated approval regulations.

Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result in withdrawal of approval for products.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

In addition, IND safety reports must be submitted to the FDA for any of the following:

serious and unexpected suspected adverse reactions;

findings from other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the product;

and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.

Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an

institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product has been associated with unexpected serious harm to patients.

The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Review and Approval of an NDA

In order to obtain approval to market a drug product in the United States, a marketing application must be submitted to the FDA that provides sufficient data establishing the safety, purity and potency of the proposed drug product for its intended indication.

The application includes all relevant data available from pertinent preclinical and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.

Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety, purity and potency of the drug product to the satisfaction of the FDA.

The NDA is a vehicle through which applicants formally propose that the FDA approve a new product for marketing and sale in the United States for one or more indications.

Every new drug product candidate must be the subject of an approved NDA before it may be commercialized in the United States.

Under federal law, the submission of most NDAs is subject to an application user fee and the sponsor of an approved NDA is also subject to an annual program fee.

Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a waiver for certain small businesses.

Following submission of an NDA, the FDA conducts a preliminary review of the application generally within 60 calendar days of its receipt and strives to inform the sponsor by the 74th day after the FDA’s receipt of the submission whether the application is sufficiently complete to permit substantive review.

The FDA may request additional information rather than accept the application for filing.

In this event, the application must be resubmitted with the additional information.

The resubmitted application is also 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.

The FDA has agreed to specified performance goals in the review process of NDAs.

Under that agreement, 90% of applications seeking approval of New Molecular Entities (“NMEs”), are meant to be reviewed within ten months from the date on which the FDA accepts the application for filing, and 90% of applications for NMEs that have been designated for “priority review” are meant to be reviewed within six months of the filing date.

For applications seeking approval of products that are not NMEs, the ten-month and six-month review periods run from the date that the FDA receives the application.

The review process and the Prescription Drug User Fee Act goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.

Before approving an application, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.

These pre-approval inspections may cover all facilities associated with an NDA submission, including component manufacturing, finished product manufacturing and control testing laboratories.

The FDA will not approve an application 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 specifications.

Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

In addition, as a condition of approval, the FDA may require an applicant to develop a REMS.

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.

The FDA may refer an application for a novel product to an advisory committee or explain why such referral was not made.

Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides 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.

Special Expedited Review and Approval Programs

The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life‑threatening disease or condition.

Two such programs are breakthrough therapy designation and priority review designation, regenerative advanced therapy designation and accelerated approval.

Specifically, the FDA may designate a product as a Breakthrough Therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life‑threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The FDA may take certain actions with respect to Breakthrough Therapies, including holding meetings with the sponsor throughout the development process;

providing timely advice to the product sponsor regarding development and approval;

involving more senior staff in the review process;

assigning a cross‑disciplinary project lead for the review team;

and taking other steps to design the clinical trials in an efficient manner.

Cadisegliatin received Breakthrough Therapy designation from FDA in 2021.

The FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

The FDA determines, on a case‑by‑case basis, whether the proposed product represents a significant improvement when compared with other available therapies.

Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment‑limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation.

A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

The FDA’s Decision on an NDA

On the basis of the FDA’s evaluation of the application 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.

The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If the FDA approves a new product, it may limit the approved indications for use of the product.

The agency may also require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, to help ensure that the benefits of the product outweigh the potential risks.

REMS can include medication guides, communication plans for health care professionals, and elements to assure safe use (“ETASU”).

ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring and the use of patent registries.

The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.

After approval, many types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Post-Approval Regulation

If regulatory approval for marketing of a product or new indication for an existing product is obtained, the sponsor will be required to comply with all regular post-approval regulatory requirements as well as any post-approval requirements that the FDA may have imposed as part of the approval process.

The sponsor will be required to report, among other things, certain adverse reactions and manufacturing problems to the FDA, provide updated safety and efficacy information and comply with requirements concerning advertising and promotional labeling requirements.

Manufacturers and certain of their subcontractors 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 ongoing regulatory requirements, including cGMP regulations, which impose certain procedural and documentation requirements upon manufacturers.

Accordingly, the sponsor and its third-party manufacturers must continue to expend time, money and effort in the areas of production and quality control to maintain compliance with cGMP regulations and other regulatory requirements.

A product may also be subject to official lot release, meaning that the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.

If the product is subject to official lot release, the manufacturer must submit samples of each lot, together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot, to the FDA.

The FDA may in addition perform certain confirmatory tests on lots of some products before releasing the lots for distribution.

Finally, the FDA will conduct laboratory research related to the safety, purity, potency and effectiveness of pharmaceutical products.

Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

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 revisions to the approved labeling to add new safety information;

imposition of post-market studies or clinical trials to assess safety risks;

or imposition of distribution or other restrictions under a REMS program.

Other potential consequences include, among other things:

• restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

• fines, warning letters or holds on post-approval clinical trials;

• refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals;

• product seizure or detention, or refusal to permit the import or export of products;

• injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market.

This regulation includes, among other things, standards and regulations for direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, and promotional activities involving the Internet and social media.

Promotional claims about a drug’s safety or effectiveness are prohibited before the drug is approved.

After approval, a drug product generally may not be promoted for uses that are not approved by the FDA, as reflected in the product’s prescribing information.

In the United States, health care professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as off-label uses, because the FDA does not regulate the practice of medicine.

However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses.

It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information.

If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the DOJ, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products.

The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act (“DSCA”), which regulate the distribution and tracing of prescription drug samples at the federal level and set minimum standards for the regulation of distributors by the states.

The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.

Human Capital

As of December 31, 2023, we had sixteen employees (all but seven of whom work in North Carolina), of which at least ten hold graduate degrees (including eight doctorate degrees) and seven are engaged in full-time research and development activities.

As of December 31, 2024, we had twenty-three employees (eight of whom work in North Carolina), of which at least thirteen hold graduate degrees (including ten doctorate degrees).

None of our employees are represented by a labor union, and we consider our employee relations to be good.

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Item 1. Business