Last updated: December 30, 2024
Introduction
TVB-2640, also known as denifanstat, is a small-molecule inhibitor of the fatty acid synthase (FASN) enzyme, which has been gaining significant attention in the pharmaceutical industry for its potential in treating various diseases, including cancer and nonalcoholic steatohepatitis (NASH). Here, we will delve into the development updates and market projections for this promising drug candidate.
Mechanism of Action and Therapeutic Targets
TVB-2640 is a potent and reversible inhibitor of the ketoacylreductase (KR) enzymatic activity of the FASN enzyme. FASN is crucial for the synthesis of long-chain fatty acids, which are essential for cell membrane formation and energy storage. In cancer cells, FASN is often overexpressed, making it a viable therapeutic target. TVB-2640 has shown efficacy in inhibiting lipogenesis and demonstrating target engagement in clinical studies[3].
Clinical Development in Cancer
Phase I and Phase II Studies
In the first-in-human study, TVB-2640 demonstrated a favorable safety profile with predictable pharmacokinetics and manageable side effects. The study established the recommended phase 2 dose (RP2D) of 100 mg/m². When combined with paclitaxel, TVB-2640 showed a disease control rate (DCR) of 70% and partial response rates in patients with KRAS-mutant non-small cell lung cancer (NSCLC), ovarian cancer, and breast cancer[3].
A phase II study in patients with relapsed high-grade astrocytoma showed that TVB-2640, when combined with bevacizumab, had a well-tolerated safety profile and significant clinical activity. The overall response rate (ORR) was 56%, with a progression-free survival rate at 6 months (PFS6) of 31.4%, which was statistically significant compared to historical bevacizumab monotherapy[1].
Ongoing and Future Studies
TVB-2640 is currently being evaluated in several ongoing clinical trials for various types of cancer, including NSCLC, breast, ovarian, prostate, colon, and pancreatic cancer. The favorable safety profile and response signals from earlier studies support the initiation of larger multicenter trials, including a potential phase III study in astrocytoma[1][3].
Clinical Development in NASH
Phase II Studies
In the context of NASH, TVB-2640 has shown promising results. The FASCINATE-1 phase II trial, a randomized, placebo-controlled study of 99 patients in the United States, demonstrated that TVB-2640 significantly reduced liver fat, with a 61% responder rate in the 50 mg group. Participants also showed improvements in markers of liver function and fibrosis. The drug was well-tolerated, with predominantly grade 1 adverse events and no on-treatment serious adverse events[5].
Bridging Studies and Future Plans
A pharmacokinetic bridging study in China confirmed that TVB-2640 has linear pharmacokinetics and is safe and well-tolerated in Chinese subjects, consistent with findings in the United States. This study supports the global development of TVB-2640 for NASH[5].
Sagimet Biosciences, the developer of TVB-2640, plans to hold an end-of-phase 2 meeting with the FDA and aims to start a phase 3 program in the second half of 2024. Given the positive results, TVB-2640 is expected to be a significant player in the NASH market, which is projected to grow substantially due to the launch of novel therapies[4].
Market Projections
NASH Market
The NASH market is anticipated to experience significant growth, driven by the expected launch of novel emerging therapies. TVB-2640, with its favorable safety profile and efficacy in reducing liver fat and improving liver function, is poised to capture a substantial share of this growing market. The United States is expected to be the largest market for NASH treatments, followed by the EU5 countries and Japan[2].
Cancer Market
In the oncology sector, TVB-2640’s potential in treating various types of cancer, particularly those with KRAS mutations, positions it as a promising candidate. The market for cancer therapies is vast and continuously evolving, with a high demand for effective and safe treatments. TVB-2640’s ability to overcome resistance to existing therapies, such as bevacizumab, makes it an attractive option for patients and healthcare providers[1][3].
Safety and Tolerability
Across various studies, TVB-2640 has consistently demonstrated a favorable safety profile. The most frequently reported adverse events are non-serious and reversible, affecting the skin and eyes. In both cancer and NASH studies, TVB-2640 has shown a benign adverse event profile, predominantly consisting of grade 1 events[1][3][5].
Conclusion
TVB-2640 is a highly selective FASN inhibitor with significant potential in treating both cancer and NASH. Its favorable safety profile, combined with its clinical efficacy, makes it a promising drug candidate. As it progresses through clinical trials and potentially moves towards regulatory approval, TVB-2640 is expected to play a crucial role in the treatment of these diseases, contributing to the growth of the respective markets.
Key Takeaways
- Mechanism of Action: TVB-2640 inhibits the ketoacylreductase activity of the FASN enzyme.
- Cancer Studies: TVB-2640 has shown efficacy in combination with bevacizumab in astrocytoma and in various other cancers.
- NASH Studies: Significant reduction in liver fat and improvement in liver function markers.
- Safety Profile: Well-tolerated with predominantly grade 1 adverse events.
- Market Projections: Expected to capture a substantial share in the growing NASH and cancer therapy markets.
FAQs
Q: What is the primary mechanism of action of TVB-2640?
A: TVB-2640 is a potent inhibitor of the ketoacylreductase (KR) enzymatic activity of the fatty acid synthase (FASN) enzyme.
Q: In which diseases is TVB-2640 being evaluated?
A: TVB-2640 is being evaluated for the treatment of various cancers, including high-grade astrocytoma, NSCLC, breast cancer, ovarian cancer, and nonalcoholic steatohepatitis (NASH).
Q: What were the key findings of the phase II study in astrocytoma?
A: The phase II study showed a well-tolerated safety profile and a significant overall response rate (ORR) of 56% when TVB-2640 was combined with bevacizumab, with a PFS6 of 31.4%[1].
Q: How does TVB-2640 perform in NASH trials?
A: In NASH trials, TVB-2640 significantly reduced liver fat and improved markers of liver function and fibrosis, with a 61% responder rate in the 50 mg group[5].
Q: What are the next steps for TVB-2640 in its clinical development?
A: Sagimet Biosciences plans to hold an end-of-phase 2 meeting with the FDA and aims to start a phase 3 program in the second half of 2024 for NASH, and continue with larger multicenter trials for various cancers[4][5].
Sources
- Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Relapsed High-Grade Astrocytoma. Clinical Cancer Research, 2023.
- Nonalcoholic Steatohepatitis (NASH) Market to Observe Stunning Growth by 2032. Biospace, 2023.
- First-in-human study of the safety, pharmacokinetics, and efficacy of TVB-2640. The Lancet, 2021.
- Sagimet's liver drug impresses in year-long NASH trial. MMM-Online, 2024.
- Bridging Study in China Completed for NASH Drug Candidate ASC40 (TVB-2640). Gannex Pharma, 2020.
