Item 1. Business
ITEM 1. BUSINESS
Overview
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.
The U.S. 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"). 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. 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 expect that trial to begin in 2024.
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.
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Our Pipeline
The following table summarizes our current drug candidates and their respective stages of development:
Our Strategy
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. 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.
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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"). We expect that trial to begin in 2024.
• 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 .
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). 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. The onset of T1D is not believed to be affected by diet or lifestyle.
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. 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.
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
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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”).
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. 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. 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.
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. Moreover, a clinically meaningful decrease (40%) in the frequency of severe and symptomatic hypoglycemia was observed in patients taking cadisegliatin when compared to those taking placebo.
Mechanistic study
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.
Consistent with previous clinical studies of cadisegliatin , the drug was well tolerated with fewer subjects reporting treatment-emergent adverse events in the group taking cadisegliatin than in the placebo group. Importantly, patients taking cadisegliatin reported no events of hypoglycemia, while four events of hypoglycemia were reported in the placebo group.
ADME study
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.
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.
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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. We expect that trial to begin in 2024.
Preclinical Development Plan
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.
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.
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. Following the expiration of a lock up period, from the period May 31, 2022 until December 31, 2024, or if earlier, the date of receipt of FDA approval in the United States for cadisegliatin (the “FDA Approval”), the Company has granted to G42 Investments certain shelf and piggyback registration rights with respect to those shares of Class A common stock issued to G42 Investments pursuant to the G42 Purchase Agreement, including the ability to conduct an underwritten offering to resell such shares under certain circumstances. The registration rights include customary cooperation, cut-back, expense reimbursement, and indemnification provisions.
Contemporaneously with the G42 Purchase Agreement, effective on May 31, 2022, the Company entered into a collaboration and license agreement (the “Cogna Agreement”) with Cogna Technology Solutions LLC, an affiliate of G42 Investments (“Cogna”), which requires Cogna to work with the Company in performing clinical trials for the Company’s compound cadisegliatin (the “Licensed Product”) as well as jointly creating a global development plan to develop, market, and commercialize cadisegliatin in certain countries in the Middle East, Africa, and Central Asia (the “Partner Territory”). Under the terms of the Cogna Agreement, Cogna will obtain a license under certain intellectual property controlled by the Company to enable it to fulfill its obligations and exercise its rights under the Cogna Agreement, including to develop and commercialize the Licensed Product in the Partner Territory, but will not have access to the various intellectual property related to the license and cadisegliatin . Specifically, the Company will share various protocols with Cogna related to conducting the clinical trials and will provide the patient dosages and placebo of cadisegliatin needed to conduct the trials.
Under the Cogna Agreement, Cogna has the right to develop and commercialize the Licensed Product in the Partner Territory at its own cost once restrictions on the use of the IP have been lifted by the Company. The Cogna Agreement determined which specific countries in the Partner Territory that Cogna may pursue development and commercialization and provides the Company with the ability to determine when Cogna can benefit from this IP through the powers granted to the Company to approve the global development plan. Further, the Company may supply at cost, or Cogna may manufacture, cadisegliatin for commercial sale under terms to be agreed upon by the parties at a later date.
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 . 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. As a result of the novation, all references to Cogna herein shall be deemed to refer to G42 Healthcare.
The G42 Purchase Agreement also provides for, following the receipt of the FDA Approval of the Licensed Product, at the option of G42 Investments, either (a) the issuance of the Company’s Class A common stock (the “Milestone Shares”) having an aggregate value equal to $30.0 million or (b) the payment by the Company of $30.0 million in cash (the “Milestone Cash Payment”). The issuance of the Milestone Shares or the payment of the Milestone Cash Payment, as applicable, are conditioned upon receipt of the FDA Approval and subject to certain limitations and conditions set forth in the G42 Purchase Agreement. There can be no assurance that the FDA Approval will be granted or as to the timing thereof.
Once commercialization takes place in the Partner Territory, the Company will receive royalties in the single digits from Cogna on the net sales of the Licensed Product for a period of at least ten years after the first commercial sale of the Licensed Product in the Partner Territory.
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On February 28, 2023, the Company and G42 Investments amended the G42 Purchase Agreement and modified the G42 Promissory Note to accelerate the payment due under the note. Pursuant to the amendment, on February 28, 2023, the Company received $12.0 million, which reflected the original amount due under the G42 Promissory Note less a 3.75% discount, in full satisfaction of the note. On February 27, 2024, the Company and G42 Investments further amended the G42 Purchase Agreement in connection with the Private Placement.
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. The Company, CinPax and CinRx subsequently amended the CinRx Purchase Agreement on February 27, 2024, in connection with the Private Placement. The CinRx Purchase Agreement provides CinPax the right for two years following the Closing to designate a board observer, which has been subsequently approved by the Company’s board.
The CinRx Purchase Agreement also provides CinRx warrants to purchase up to 30,000 shares of Class A common stock at an initial exercise of price of approximately $28.80 per share (the “CinRx Warrants”). The CinRx Warrants will become exercisable by CinRx only if (i) the Company receives FDA approval to market and distribute the pharmaceutical product containing the Company’s proprietary candidate, cadisegliatin , or (ii) the Company is acquired by a third party, sells all or substantially all of its assets related to cadisegliatin to a third party or grants a third party an exclusive license to develop, commercialize and manufacture cadisegliatin in the United States. If neither of these events happen within five years of the date of the issuance of the CinRx Warrants, the CinRx Warrants will expire and will not be exercisable by CinRx. The exercise price of the CinRx Warrants and the number of shares issuable upon exercise of the CinRx Warrants are subject to adjustments in accordance with the terms of the CinRx Warrants.
Additionally, in conjunction with the CinRx Purchase Agreement the Company and CinRx entered into a Master Service Agreement whereby CinRx provides the Company with consulting, preclinical and clinical trial services, as enumerated in project proposals negotiated between the Company and CinRx from time to time.
Our Pipeline Programs
TTP273 - GLP-1r Agonist
Overview
Glucagon-like peptide (GLP-1) is a naturally occurring hormone ligand for the GLP-1 receptor (GLP-1R) that has been associated with improved metabolism and decreased inflammation, as well as cardio and neuroprotective effects. Glucagon-like peptide 1 receptor agonists (GLP-1RA) are effective therapies in lowering glycosylated hemoglobin (HbA1c), providing cardio protective benefits and lowering weight. 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.
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TTP273
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. Unlike some other GLP-1RAs, TTP273 exhibits biased increase of cyclic adenosine monophosphate ("cAMP") signaling but does not activate the extracellular signal-regulated kinase ("ERK")/β-arrestin pathway significantly at clinically relevant concentrations which may improve efficacy and tolerability. 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 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.
HPP3033 - Nrf2/Bach1 Modulator
Our candidate, HPP3033 , represents a novel, non-electrophilic therapeutic approach to activating the nuclear factor erythroid 2–related factor 2 ("Nrf2") pathway that has the potential to be used in the treatment of chronic diseases associated with oxidative stress.
The Role of Nrf2/Bach1 Modulators
Chronic, unresolved inflammation, oxidative stress, and resulting fibrosis are key features of many diseases. Inflammation is an integral component of the normal immune response that occurs when cells encounter harmful stimuli, such as invading pathogens, damaged cells, or irritants. During inflammation, cells activate inflammatory processes and complexes that increase the production of cytokines, which are proteins that recruit and activate immune cells.
Inflammation and mitochondrial metabolism are closely associated. The mitochondria are often called the “powerhouses” of the cell as they produce the energy that the cell needs to function. This energy is produced by converting fatty acids and glucose into adenosine triphosphate (ATP) by a process called oxidative phosphorylation. During inflammation, mitochondrial metabolism is temporarily reprogrammed to suppress oxidative phosphorylation. Instead of primarily making ATP, the mitochondria divert fatty acids and glucose to increase the production of proinflammatory mediators. During this reprogramming, the mitochondria release chemically reactive molecules called reactive oxygen species (ROS) that can directly attack pathogens and amplify the production of cytokines.
In a normal immune response, the resolution of inflammation begins after the harmful stimuli have been eliminated. Nrf2 is a protein that plays a key role in the resolution of inflammation by regulating the expression of specific genes involved in mitochondrial metabolism, redox balance, and cytokine production. When activated, Nrf2 promotes the resolution of inflammation by normalizing mitochondrial metabolism, restoring redox balance, and suppressing cytokine production.
In many chronic and genetic diseases, Nrf2 activity is suppressed, and the resolution of inflammation fails to occur or is inadequate, leading to persistent mitochondrial dysfunction, excess production of ROS, and production of cytokines. These processes cause chronic inflammation, which can ultimately lead to tissue damage and loss of organ function.
To date, FDA-approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are nonspecific alkylating agents relying on reactive, electrophilic biological targets that present safety and tolerability issues. Non-electrophilic activation of the Nrf2 pathway via targeting the transcription factor BTB and CNC homology 1 ("Bach1") transcriptional repressor provides an alternative mechanism by which to increase the activation of Nrf2 to reduce the oxidative stress and inflammation associated with many acute and chronic diseases.
Bach1 is a transcriptional repressor that controls the expression of certain genes involved in the body’s antioxidant response processes. Genetic knock-out models of Bach1 have shown increased expression of multiple antioxidant proteins such as heme oxygenase-1 (HMOX1), leading to a significant level of cellular, tissue and organ protection in a wide variety of mouse models. Hemin and the hemin mimetic cobalt protoporphyrin IX (“CoPP”) are Bach1 ligands that have served as useful tool compounds to investigate the role of Bach1 inhibition in a variety of disease settings. Both molecules have been shown to have beneficial effects on oxidative stress and inflammatory-mediated pathologies in several animal models.
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Further, the ubiquity of the response suggests that the observed tissue protective effects are not related to the underlying causes of a particular disease, but instead are an intrinsic outcome of Bach1 modulation along with Nrf2 activation.
HPP3033
Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson’s disease (PD). In a model of Parkinson's disease, oral administration of HPP3033 attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ("MPTP") neurotoxicity in pre- and post-treatment paradigms. Bach1 inhibitor-induced neuroprotection was associated with the up regulation of Bach1 targeted pathways in concurrence with the results from Bach knock-out ("KO") mice. Nrf2 activators are known to exert protection in the pre-treatment paradigm, but the benefits of pharmacological Nrf2 activation are rarely observed in post-treatment models. Therefore, the results obtained with HPP3033 in this study hold promise for the future development of this compound.
HPP737 - PDE4 Inhibitor
Psoriasis Overview
Psoriasis is a chronic autoimmune inflammatory disease in which the growth cycle of skin is accelerated due to an imbalance in proinflammatory and anti-inflammatory cytokines. This results in the proliferation of skin cells and the development of raised, red, silvery scale plaques (i.e., plaque psoriasis, psoriasis vulgaris) that have not only medical implications but an impact on a patient’s quality of life. While the specific inciting events for this proinflammatory process are unknown, psoriasis may be caused by autoimmunity and genetic predisposition. Events such as trauma to the skin, stress, illness, or infection that triggers the immune systems, obesity, and weather have been identified as triggers for flare ups.
Current Treatment for Psoriasis and Their Limitations
Topical therapies, including glucocorticoids and vitamin D analogs, are the mainstay of treatment for mild psoriasis. The continuous long-term use of glucocorticoids is limited by the risk of skin thinning and/or atrophy and the potential for systemic absorption. Vitamin D analogs are often added to glucocorticoids to improve glucocorticoid efficacy while allowing for reduction in glucocorticoid dose. Moderate to severe disease is treated with systemic therapies including oral phosphodiesterase-4 ("PDE4") inhibition, immunosuppressants, retinoids, and biologics (e.g., anti-tumor necrosis factor ("anti-TNF") agents, interleukin-17 ("IL-17") inhibitors, and interleukin-23 ("IL-23") inhibitors). Biologics, while realizing high efficacy rates in treating psoriasis, are associated with administration by injection, high cost, need for laboratory monitoring and increased risk of infection.
Inhibitors of PDE4 act by increasing intracellular concentrations of cyclic adenosine monophosphate (“cAMP”), which has a broad range of anti-inflammatory effects. PDE4 activity is increased in the skin of patients with psoriasis leading to up-regulation of immune modulatory, proinflammatory genes and cytokines, including IL-17, IL-23, and tumor necrosis factor-alpha (TNF-α). Treatments for psoriasis are aimed at reducing proinflammatory cytokine activity. The therapeutic potential of oral PDE4 inhibitors has been limited by dose limiting adverse events such as nausea, vomiting, diarrhea, and headache.
HPP737
HPP737 is an orally administered, potent and selective, non-central nervous system ("non-CNS") penetrant PDE4 inhibitor that addresses inflammatory diseases and offers the potential for an improved tolerability profile and efficacy over commercially available PDE4 inhibitors. HPP737 has shown potent inhibition of IL-17a and TNF-α production in in vitro studies and activity in several animal models of inflammation. HPP737 has completed Phase 1 single-ascending dose and initial multiple-ascending dose studies, in which it was well tolerated at all doses tested in healthy volunteers. Clinical data generated to date supports achieving target engagement (reduction in ex vivo lipopolysaccharide ("LPS") stimulated TNF-α) at HPP737 plasma concentrations predicted to be efficacious from preclinical models.
In September 2021, we announced the results of a multiple ascending dose Phase 1 study of HPP737 to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of HPP737 in healthy volunteers as part of our psoriasis development program. 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
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or tolerability findings observed. There were no serious adverse events and no discontinuations due to treatment emergent adverse events.
Partnered Development Programs
PDE4 and Newsoara Biopharma
On May 31, 2018, we entered into a license agreement with Newsoara (the “Newsoara License Agreement”), under which Newsoara obtained an exclusive and sublicensable license to develop and commercialize our PDE4 program, including the compound HPP737 , in China and other Pacific Rim territories (collectively, the “Newsoara License Territory”). Additionally, under the Newsoara License Agreement, we obtained a non-exclusive, sublicensable, royalty-free license to develop and commercialize certain Newsoara patent rights and know-how related to our PDE4 program for therapeutic uses in humans outside of the Newsoara License Territory.
Under the terms of the Newsoara License Agreement, as amended, Newsoara paid us an upfront cash payment of $2.0 million. We are eligible to receive additional potential development, regulatory and sales-based milestone payments totaling up to $58.5 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.
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.
The Newsoara License Agreement, unless terminated earlier, will continue until expiration of all royalty obligations of Newsoara to us. Either party may terminate the Newsoara License Agreement for the other party’s uncured material breach. Newsoara may terminate the Newsoara License Agreement at will upon prior written notice. 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.
Azeliragon and Cantex Pharmaceuticals, Inc.
On June 22, 2021, vTv Therapeutics Inc. and Cantex Pharmaceuticals, Inc. (“Cantex”) entered into a licensing agreement under which Cantex obtained exclusive worldwide rights to develop and commercialize azeliragon , vTv’s novel antagonist of RAGE (the receptor for advanced glycation end products).
Under the terms of the agreement, Cantex will be responsible for the development and commercialization of azeliragon, and the companies will allocate downstream profits under a tiered arrangement.
On January 9, 2023, Cantex announced that the FDA has granted Orphan Drug Designation to azeliragon for the treatment of glioblastoma. In addition, a Phase 2 trial of azeliragon is in progress in women receiving “neoadjuvant chemotherapy” of breast cancer, which is chemotherapy to prevent cancer from returning after initial potentially curative treatment. 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. 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, we have received common stock and certain participation rights representing a minority interest in Reneo’s outstanding equity.
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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 .
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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.
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.
Novo Nordisk
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. As part of this license grant, we obtained certain worldwide rights to Novo Nordisk’s GKA program, including rights to preclinical and clinical compounds such as cadisegliatin . This agreement was amended in May 2019 to create milestone payments applicable to certain specific and non-specific areas of therapeutic use. Under the terms of the Novo License Agreement, the Company has additional potential developmental and regulatory milestone payments totaling up to $9.0 million for approval of a product for the treatment of type 1 diabetes, $50.5 million for approval of a product for the treatment of type 2 diabetes, or $115.0 million for approval of a product in any other indication. 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
We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We currently rely, and expect to continue to rely, on third parties to manufacture clinical supplies of our drug candidates and for our other research and discovery programs. We do not have multiple sources of supply for the components used in our drug candidates.
Intellectual Property
Patents
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. The issued U.S. patent covering cadisegliatin as a composition of matter will expire no earlier than 2025,
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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. 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
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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.
Trade Secrets
In addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and commercial partners. These agreements are designed to protect our proprietary information and, in the case of the invention assignment agreements, to grant us ownership of technologies that are developed by employees or through a relationship with a third party. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems. While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become publicly known or be independently discovered by competitors. 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.
Competition
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. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all our programs are likely to be their efficacy, safety, convenience, and availability of reimbursement.
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.
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.
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Government Regulation and Product Approvals
Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union (“EU”), extensively regulate, among other things, the research, development, testing, manufacture, pricing, reimbursement, sales, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of biopharmaceutical products. 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.
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. None of our employees are represented by a labor union, and we consider our employee relations to be good.
Our Corporate Information
We were incorporated under the laws of the State of Delaware in 2015. Our principal executive offices are located at 3980 Premier Drive, Suite 310, High Point, NC 27265, and our telephone number is (336) 841-0300. We also maintain a corporate website, www.vtvtherapeutics.com, where stockholders and other interested persons may review, without charge, among other things, corporate governance materials and certain Securities Exchange Commission (SEC) filings, which are generally available on the same business day as the filing date with the SEC on the SEC’s website http://www.sec.gov . The contents of our website are not made a part of this Annual Report on Form 10-K.
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