FDA Grants Orphan Drug Designation to Amezalpat in Hepatocellular Carcinoma

The orphan drug designation follows reports from a phase 1b/2 study (NCT04524871) demonstrating the potential efficacy and safety benefits of amezalpat in combination with atezolizumab and bevacizumab as frontline therapy for those with metastatic or unresectable HCC.

The FDA has granted orphan drug designation to the investigational PPAR⍺ antagonist amezalpat (TPST-1120) as a treatment for patients with hepatocellular carcinoma (HCC), according to a press release from the developer, Tempest Therapeutics, Inc.¹

The orphan drug designation follows reports from a phase 1b/2 study (NCT04524871) demonstrating the potential efficacy and safety benefits of amezalpat in combination with atezolizumab (Tecentriq) and bevacizumab (Avastin) as frontline therapy for those with metastatic or unresectable HCC. Investigators previously highlighted data from this international randomized trial in June 2024.²

With a data cutoff of February 14, 2024, findings highlighted a median overall survival (OS) of 21 months among patients who received the amezalpat-based triplet (n = 40) vs 15 months among those who received atezolizumab/bevacizumab alone (n = 30; HR, 0.65). Additionally, 20 patients in the experimental arm remained in survival follow-up at the time of analysis compared with 9 of those in the control arm. Investigators also reported a manageable safety profile that was comparable with phase 1 data.

Based on an earlier data analysis with a cutoff of April 20, 2023, the amezalpat combination yielded a confirmed objective response rate (ORR) of 30% compared with 13.3% using atezolizumab and bevacizumab alone. The confirmed ORR and disease control rate (DCR) were 43% and 100%, respectively, among patients with b-catenin activating mutations (n = 7) who received amezalpat. Of those with PD-L1–negative tumors, the confirmed ORR was 27% and 7% in the experimental and control arms, respectively.

“Receiving orphan drug designation for amezalpat to treat HCC underscores the critical need for new treatment options for patients [with] this historically hard-to-treat disease,” Sam Whiting, MD, PhD, chief medical officer and head of Research and Development at Tempest, stated in the press release.¹ “Tempest is dedicated to developing groundbreaking cancer treatments that will improve patients’ lives, and with broad agreement in hand from both the FDA and European Medicines Agency [EMA], the team continues to prepare for a pivotal phase 3 study [NCT06680258] for amezalpat in [patients with] first-line HCC.”

Developers designed amezalpat as an orally available, small molecule PPAR⍺ antagonist that may directly target tumor cells and regulate suppressive cells and angiogenesis in the tumor microenvironment.

In August 2024, the FDA gave positive feedback in an end-of-phase 2 meeting with developers regarding the next steps for researching amezalpat plus atezolizumab/bevacizumab for patients with frontline unresectable or metastatic HCC.³

During the meeting, both parties aligned on the phase 3 study design, which included the standard-of-care control arm and the primary and secondary end points. The agency also agreed with developers on the appropriateness of the amezalpat dosing schedule and a statistical plan—including a pre-specified early efficacy analysis that may reduce the time to primary analysis by up to 8 months—as part of the phase 3 design.

“We are thrilled with the positive outcome of our end-of-phase 2 meeting with the FDA. Tempest and the FDA are in broad agreement on all major aspects of the proposed pivotal phase 3 clinical trial for amezalpat in patients with [HCC] in the first-line setting,” Whiting said in a press release regarding the meeting.³ “This planned phase 3 study closely mirrors the randomized phase 2 study and the strongly favorable hazard ratio for [OS] observed at top-line analysis of the phase 2 [study], confirmed at the latest survival follow-up, give us confidence in the potential success of the phase 3 [study].”

References

1. Tempest receives orphan drug designation from the U.S. Food and Drug Administration for amezalpat to treat patients with hepatocellular carcinoma (HCC). News release. Tempest Therapeutics, Inc. January 6, 2025. Accessed January 7, 2025. https://tinyurl.com/2a4jtkwe
2. Tempest unveils new survival data for amezalpat (TPST-1120) in randomized first-line HCC study demonstrating a six-month improvement over control arm. News release. Tempest Therapeutics, Inc. June 20, 2024. Accessed January 7, 2025. https://tinyurl.com/ywrzfdud
3. Tempest announces successful end-of-phase 2 meeting with FDA for amezalpat (TPST-1120) to treat first-line hepatocellular carcinoma. News release. Tempest Therapeutics, Inc. August 15, 2024. Accessed January 7, 2025. https://tinyurl.com/3sdyx24r