Denifanstat – Our Lead Product Candidate in Multiple Indications
Denifanstat, our lead product candidate, is an oral, once daily pill and inhibitor of fatty acid synthase (FASN), the key enzyme in the de novo lipogenesis (DNL) pathway that converts metabolites of dietary sugars such as fructose into palmitate, a saturated fatty acid.
Denifanstat was selected from our library of over 1,200 internally-discovered and wholly owned FASN inhibitors that were identified through a rigorous medicinal chemistry and preclinical development effort. We received Fast-Track designation for denifanstat from the FDA for the treatment of MASH, formerly known as nonalcoholic steatohepatitis (NASH), in March 2021, has been studied in more than 740 subjects, including healthy volunteers and patients with MASH, acne and solid tumors.
Metabolic Dysfunction-Associated Steatohepatitis (MASH)
MASH is an aggressive form of fatty liver disease characterized by an abnormal build-up of excess fat in the liver, inflammation and fibrosis along with systemic metabolic changes including dyslipidemia and insulin resistance. Left untreated, the liver becomes cirrhotic and even cancerous with time. The damage can also exacerbate a spectrum of other health problems including cardiovascular diseases, obesity, type 2 diabetes and metabolic syndrome. MASH is a growing epidemic that affected more than 265 million people worldwide in 2019. Currently, there are no approved treatments in the United States or Europe.
We believe that denifanstat is differentiated among drug candidates in development for MASH due to its ability to directly target hepatocytes, inflammatory cells and stellate cells in the liver.
We announced positive topline results from FASCINATE-2, a Phase 2b clinical trial of denifanstat in MASH with liver biopsy-based primary endpoints, in January 2024. FASCINATE-2 was a Phase 2b clinical trial of denifanstat in biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) patients with moderate to advanced fibrosis (F2/F3) at week 52. In this trial, denifanstat, an oral, selective FASN inhibitor, showed statistically significant improvements relative to placebo on both of the primary endpoints of MASH resolution without worsening of fibrosis with ≥2-point reduction in NAS, and ≥2-point reduction in NAS without worsening of fibrosis. Denifanstat-treated patients also showed statistically significant fibrosis improvement by ≥ 1 stage with no worsening of MASH, and a greater proportion of MRI-derived proton density fat fraction (MRI-PDFF) ≥30% responders relative to placebo.
Combination Potential and Other MASH Indications
Based on its proposed mechanism of action, oral administration and tolerability profile to date, we believe denifanstat has the potential to be a backbone monotherapy as well as improve clinical activity in combination with a broad set of other drugs. We believe combination therapy has the potential to play a meaningful role in the MASH treatment paradigm to effectively address all patient segments.
Given the disease complexity as well as the heterogeneity and large size of the MASH patient population, we intend to study denifanstat in other MASH indications such as cirrhotic (F4) MASH and pediatric MASH to maximize its full clinical and commercial potential.
TVB-3567
TVB-3567 showed potent FASN inhibitory activity based on inhibition of palmitate synthesis in human, rat, mouse, and dog cell lines; a single dose of TVB-3567 inhibited palmitate synthesis in a rat model. These studies include the standard suite of IND-enabling, GLP-compliant safety pharmacology and genotoxicity studies, and GLP-compliant general toxicology studies of up to four weeks treatment duration in rats and dogs. We plan to initiate a TVB-3567 clinical development program in the U.S. for the treatment of acne. We are evaluating the timing to file an IND with the FDA to conduct a first-in-human Phase 1 clinical trial as a basis for further clinical development in acne.
Acne – Ongoing Phase 2 Clinical Trial
Acne is the most common skin condition in the United States, affecting up to 50 million Americans annually. Acne is a promising therapeutic area for application of FASN inhibitors because FASN is required for sebum production, which is upregulated in acne and leads to exacerbation of acne lesions including development of nodules and cysts. In two Phase 1 clinical studies, denifanstat reduced overall sebum production, including palmitate and sapienic acid lipids.
In May 2023, our license partner, Ascletis, announced positive topline results with the achievement of primary and key secondary endpoints in a Phase 2 randomized, double-blind, placebo-controlled clinical trial in 179 patients with moderate to severe acne vulgaris in China. Denifanstat is currently being tested by Ascletis in a Phase 3 clinical trial in China for moderate to severe acne vulgaris.
Based on these results, we are evaluating options to move forward with our own acne program in the US, Europe, and other markets.
FASN’s role in acne
Oncology
Dysregulation of lipid metabolism is a hallmark of certain cancers. Increased expression of FASN has been associated with poor prognosis and reduced survival in tumor cell types. Several cancer types have been shown to upregulate FASN to rewire lipid metabolism and change the nature of the tumor cell membrane making these cells resistant to traditional cancer drugs. FASN inhibition can also potentially address the enormous challenge of resistance to cancer therapies.
We completed a Phase 1 clinical trial with denifanstat in 136 patients with advanced, heavily pretreated and mostly metastatic solid tumors, which demonstrated clinical activity in defined patient populations and provides the foundation for future clinical development.
Our strategy is to evaluate denifanstat either alone or in combination with other classes of oncology drugs in specific subsets of solid tumors that are FASN-dependent.
These include:
- Glioblastoma – Denifanstat is currently being tested in a Phase 3 clinical trial in glioblastoma (GBM), by Ascletis, our license partner in China. In September 2023, Ascletis announced the enrollment of 120 recurrent GBM patients in its Phase 3 GBM trial, which it expects will provide a sufficient basis for its planned interim analysis of the Phase 3 trial. If the results of this study are positive, we will explore with regulatory authorities initiating our own registrational trial with denifanstat for the treatment of recurrent GBM.
- Metastatic castration resistant prostate cancer, FASN-dependent – Planning underway for investigator-sponsored Phase 1 clinical trial of denifanstat combination therapy
- Hepatocellular carcinoma FASN-dependent – Translational studies ongoing
- Non-small cell lung cancer/KRAS mutation – Additional preclinical work ongoing; encouraging results observed in patients with NSCLC KRASM tumors enrolled in a Phase 1 clinical trial in patients with solid tumors.
