Amezalpat Gains FDA Fast Track and Orphan Drug Designations for Hepatocellular Carcinoma
核心洞察
Amezalpat, a PPARα (搜索) antagonist, receives Fast Track Designation from the FDA, following its prior Orphan Drug Designation for hepatocellular carcinoma (搜索) (HCC (搜索)).
Phase 1b/2 trial data showed a 6-month improvement in median overall survival when amezalpat was added to atezolizumab and bevacizumab for advanced HCC (搜索).
The combination therapy also demonstrated a 30% objective response rate, compared to 13.3% with atezolizumab and bevacizumab alone.
Tempest Therapeutics' amezalpat (TPST-1120), an oral, small molecule, selective PPARα (搜索) antagonist, has been granted Fast Track Designation (FTD) by the FDA for the treatment of hepatocellular carcinoma (搜索) (HCC (搜索)). This follows the Orphan Drug Designation (ODD) granted to amezalpat in January 2025, underscoring its potential to address the unmet need for new treatment options for this aggressive liver cancer. The regulatory decisions are supported by promising data from a Phase 1b/2 clinical trial, suggesting improved outcomes when amezalpat is combined with standard-of-care therapies.
Clinical Trial Results
The Phase 1b/2 MORPHEUS-LIVER trial (NCT04524871) evaluated amezalpat in combination with atezolizumab (Tecentriq) and bevacizumab (Avastin) versus atezolizumab and bevacizumab alone as a first-line treatment for unresectable or metastatic HCC (搜索). The results, with a data cutoff of February 14, 2024, demonstrated a 6-month improvement in median overall survival (OS) for the amezalpat arm (21 months) compared to the control arm (15 months), with a hazard ratio (HR) of 0.65. Furthermore, the objective response rate (ORR) was 30% in the amezalpat arm versus 13.3% in the control arm.
According to Sam Whiting, MD, PhD, chief medical officer and head of R&D of Tempest Therapeutics, "Receiving orphan drug designation for amezalpat to treat HCC (搜索) underscores the critical need for new treatment options for patients suffering from this historically hard-to-treat disease. Tempest is dedicated to developing groundbreaking cancer treatments that will improve patients’ lives, and with broad agreement in hand from both the FDA and EMA, the team continues to prepare for a pivotal phase 3 study for amezalpat in first-line HCC patients."
The survival benefit with amezalpat was observed across key subgroups, including patients with PD-L1-negative tumors and those with β-catenin mutations. This is consistent with amezalpat's proposed dual mechanism of action, targeting tumor cells directly and modulating the immune response to enhance antitumor activity.
Amezalpat's Mechanism of Action
Amezalpat is designed to target tumor cells directly and modulate immune suppressive cells and angiogenesis in the tumor microenvironment. Preclinical data suggests that amezalpat's selective PPARα (搜索) antagonism can disrupt multiple pathways that promote tumor growth and immune evasion.
Regulatory Designations and Next Steps
The FDA's Fast Track designation is intended to expedite the development and review of promising therapies for serious conditions with unmet medical needs. It allows for more frequent interactions with the FDA and potential eligibility for accelerated approval and priority review. The Orphan Drug Designation provides benefits such as tax credits for clinical testing, waiver of FDA application fees, and seven years of market exclusivity upon approval.
Tempest Therapeutics is preparing to initiate a pivotal Phase 3 study of amezalpat in the first quarter of 2025. The study is designed as a global, double-blind, 1:1 randomized trial comparing amezalpat plus atezolizumab and bevacizumab to placebo plus atezolizumab and bevacizumab in patients with unresectable or metastatic HCC (搜索).
Hepatocellular Carcinoma: A Growing Concern
HCC (搜索) is an aggressive cancer with rising mortality rates. It is projected to become the third leading cause of cancer death by 2030. Approximately 900,000 new cases are diagnosed worldwide each year. The incidence and mortality rates are highest in East Asia, but are increasing in parts of Europe and the United States. The majority of HCC cases are associated with chronic liver diseases, including hepatitis B and C, non-alcoholic fatty liver disease (NAFLD), and cirrhosis.