FDA Grants Fast Track Designation to Amezalpat for Hepatocellular Carcinoma

The FDA has granted fast track designation to the oral, small molecule, selective PPAR⍺ antagonist amezalpat (TPST-1120) as a potential therapeutic option for patients with hepatocellular carcinoma (HCC).1

In January 2025, the regulatory agency also granted orphan drug designation to amezalpat for patients with HCC.2

Data from phase 1b/2 MORPHEUS-LIVER trial (NCT04524871) reported in June 2024 showed that patients with HCC randomly assigned to receive amezalpat in combination with atezolizumab (Tecentriq) and bevacizumab (Avastin; n = 30) achieved a median overall survival (OS) of 21 months compared with 15 months for those given atezolizumab plus bevacizumab alone (n = 30; HR, 0.65).3

Previous topline data reported in 2023 demonstrated that patients in the experimental arm experienced a confirmed overall response rate (ORR) of 30% compared with 13.3% for the control arm.

“We are thrilled to receive fast track designation from the FDA,” Sam Whiting, MD, PhD, chief medical officer and head of R&D of Tempest Therapeutics, stated in a news release.1 “This designation, following the orphan drug designation granted last month, reinforces the promise of amezalpat as a potential treatment option for patients affected by HCC. We look forward to working closely with the FDA and foreign regulatory agencies to develop amezalpat with the goal of bringing this promising therapy to patients.”

The ongoing MORPHEUS-LIVER trial is evaluating immunotherapy-based combinations in patients with advanced liver cancer.4 The open-label, multicenter, randomized, umbrella study is enrolling patients at least 18 years of age with histologically, cytologically, or clinically confirmed locally advanced or metastatic and/or unresectable HCC that is not amenable to curative surgical and/or locoregional therapies and not previously treated with systemic therapy. Other key inclusion criteria consist of an ECOG performance status of 0 or 1; liver diseases criteria in patients with cirrhosis; a Child-Pugh class A score; and a life expectancy of at least 3 months. Measurable disease per RECIST 1.1 criteria and adequate hematologic and end-organ function are both required in stages 1 and 2 of the trial.

Key exclusion criteria for stage 1 of the trial include prior treatment with anti-CD137 agonists, immune checkpoint blockade therapies, or HIF-2α inhibitors; treatment with investigational therapy within 28 days prior to the start of study treatment; treatment with locoregional therapy to the liver within 28 days of enrollment; untreated or incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding; and prior bleeding due to esophageal and/or gastric varices within 6 months of study enrollment.

Patients are being excluded from both stages of the study if they have fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; a history of hepatic encephalopathy; symptomatic, untreated, or actively progressing central nervous system metastases; or a history of leptomeningeal disease.

During stage 1, several novel agents are being evaluated with the atezolizumab-plus-bevacizumab backbone, including tiragolumab (MTIG7192A), tocilizumab (Actema), amezalpat, ADG126, and NKT2152. Tobemstomig is also being evaluated in combination with bevacizumab.

In the amezalpat arm, patients received 1200 mg of amezalpat per day on days 1 to 21 in combination with 1200 mg of atezolizumab on day 1 and 15 mg/kg of bevacizumab on day 1 of each 21-day cycle. In the control arm, patients received atezolizumab plus bevacizumab alone following the same dosing schedule. Treatment continued in both arms until unacceptable toxicity or loss of clinical benefit. Patients who discontinue treatment during stage 1 may be eligible to receive a different combination in stage 2.

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

References

1. Tempest granted fast track designation from the U.S. Food and Drug Administration for amezalpat to treat patients with hepatocellular carcinoma. News release. Tempest Therapeutics. February 10, 2025. Accessed February 10, 2025. https://ir.tempesttx.com/news-releases/news-release-details/tempest-granted-fast-track-designation-us-food-and-drug
2. 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 February 10, 2025. https://ir.tempesttx.com/news-releases/news-release-details/tempest-receives-orphan-drug-designation-us-food-and-drug
3. 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 February 10, 2025. https://ir.tempesttx.com/news-releases/news-release-details/tempest-unveils-new-survival-data-amezalpat-tpst-1120-randomized
4. A study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with advanced liver cancers (MORPHEUS-LIVER). ClinicalTrials.gov. Updated January 13, 2025. Accessed February 10, 2025. https://clinicaltrials.gov/study/NCT04524871