FDA Grants Orphan Drug Designation to Amezalpat for Advanced HCC

HCC | Image Credit: © Sebastian Kaulitzki – stock.adobe.com

The FDA has granted orphan drug designation (ODD) to the selective peroxisome proliferator-activated receptor alpha (PPAR⍺) antagonist amezalpat (TPST-1120) for the treatment of patients with hepatocellular carcinoma (HCC).¹

This designation was supported by data from the global, randomized phase 1b/2 MORPHEUS-LIVER trial (NCT04524871), which investigated the addition of amezalpat to the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) vs atezolizumab plus bevacizumab alone as first-line therapy for patients with unresectable or metastatic HCC.

Results from the study demonstrated a 6-month improvement in median overall survival (OS) for the amezalpat arm vs the control combination (HR, 0.65).² Patients treated with amezalpat plus atezolizumab and bevacizumab (n = 40) achieved a median OS of 21 months vs 15 months for those given atezolizumab plus bevacizumab alone (n = 30).

Additionally, prior data from a topline analysis of the study showed the objective response rate (ORR) was 30% in the amezalpat arm vs 13.3% in the control arm.

“Receiving orphan drug designation for amezalpat to treat HCC underscores the critical need for new treatment options for patients suffering from this historically hard-to-treat disease,” Sam Whiting, MD, PhD, chief medical officer and head of R&D at Tempest Therapeutics, stated in a news release.¹

MORPHEUS-LIVER is an open-label, multicenter, randomized, 2-stage umbrella study evaluating the addition of various agents to the immuno-oncology–based treatment regimens.³ The study is enrolling patients at least 18 years of age with histologically or cytologically confirmed locally advanced or metastatic and/or unresectable HCC that was not amenable to curative surgical or locoregional therapies; prior systemic treatment for HCC is not allowed.

Other key inclusion criteria consist of an ECOG performance status of 0 or 1 within 7 days of randomization; Child-Pugh class A status within 7 days of randomization; a life expectancy of at least 3 months; measurable disease per RECIST 1.1 criteria; and adequate hematologic and end-organ function.

During the amezalpat portion of the study in stage 1, patients were randomly assigned to receive either 1200 mg of oral amezalpat once per day in combination with 1200 mg of intravenous (IV) atezolizumab on day 1 and 15 mg/kg of IV bevacizumab on day 1 of each 21-day cycle, or atezolizumab and bevacizumab alone.

ORR is serving as the trial’s primary end point. Secondary end points include progression-free survival, OS, landmark OS, duration of response, disease control rate, and safety.

Notably, the OS benefit of amezalpat was preserved in key subgroups, including patients with PD-L1–negative tumors and those harboring β-catenin mutations.¹ This finding was consistent with amezalpat’s proposed dual mechanism of action, which is intended to target tumor cells directly and modulate the immune response to enhance antitumor activity.

In terms of safety, the addition of amezalpat was well tolerated, with no new or unexpected adverse effects (AEs) reported compared with atezolizumab plus bevacizumab alone. Most treatment-related AEs were manageable and did not lead to significant treatment discontinuation.

“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, the team continues to prepare for a pivotal phase 3 study for amezalpat in [patients with] first-line HCC,” Whiting added in the news release.¹

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. January 6, 2025. Accessed January 8, 2025. https://ir.tempesttx.com/news-releases/news-release-details/tempest-receives-orphan-drug-designation-us-food-and-drug
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. June 20, 2024. Accessed January 8, 2025. https://ir.tempesttx.com/news-releases/news-release-details/tempest-unveils-new-survival-data-amezalpat-tpst-1120-randomized
3. A study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with advanced liver cancers (Morpheus-Liver). ClinicalTrials.gov. Updated September 21, 2023. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT04524871