FDA Grants Fast Track Designation to Amezalpat Combination in HCC

Amezalpat plus atezolizumab and bevacizumab achieved a 6-month increase for OS compared with atezolizumab and bevacizumab alone in patients with HCC.

Amezalpat (TPST-1120), an oral, small molecule, selective PPAR⍺ antagonist, has been granted fast track designation by the FDA in the treatment of patients with hepatocellular carcinoma (HCC), according to a press release from the developer, Tempest Therapeutics.¹

Previously, in January 2025, amezalpat received the orphan drug designation in patients with HCC.²

The fast track designation follows positive results from cohort 1 of the open-label, randomized umbrella phase 1b/2 MORPHEUS-LIVER trial (NCT04524871) evaluating the efficacy and safety of first-line amezalpat plus standard-of-care atezolizumab (Tecentriq) and bevacizumab (Avastin; n = 40) vs atezolizumab and bevacizumab alone (n = 30) in patients with unresectable or metastatic HCC.

At the data cutoff of February 14, 2024, treatment with amezalpat plus atezolizumab and bevacizumab yielded a median overall survival (OS) of 21 months compared with 15 months in the group that received only atezolizumab and bevacizumab (HR, 0.65).³ Key subpopulations such as those with PD-L1–negative disease also experienced a survival benefit with the amezalpat combination treatment.¹

“We are thrilled to receive fast track designation from the FDA. This designation, following the orphan drug designation granted last month, reinforces the promise of amezalpat as a potential treatment option for patients [with] HCC,” Sam Whiting, MD, PhD, chief medical officer and head of Research and Development at Tempest, stated in the press release.¹ “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.”

During stage 1 of the trial, eligible patients were initially randomly assigned to one of several treatment arms including agents such as tiragolumab, tocilizumab (Actemra), tobemstomig, ADG126, and IO-108.⁴ Those who experience a loss of clinical benefit or unacceptable toxicity during stage 1 will be allowed to receive a different treatment combination in stage 2.

Amezalpat was administered orally at 1200 mg daily during each 21-day cycle, atezolizumab at 1200 mg intravenously on day 1 of each 21-day cycle, and bevacizumab at 15 mg/kg via intravenous infusion on day 1 of each 21-day cycle.⁴

Eligible patients had histologically or cytologically confirmed locally advanced or metastatic and/or unresectable HCC; an ECOG performance of status of 0 or 1 within 7 days of randomization; Child-Pugh class A status within 7 days of randomization; disease that was not amenable to curative surgical or locoregional therapies; no prior systemic treatment of HCC; and a life expectancy of 3 or more months.

Patients were not permitted to have prior treatment with investigational therapy or locoregional therapy to the liver within 28 days of treatment initiation; untreated or incompletely treated esophageal or gastric varices at high risk for bleeding; inadequately controlled hypertension; history of hypertensive crisis or hypertensive encephalopathy; significant vascular disease; and metastatic disease involving major airways or blood vessels, or centrally located mediastinal tumor masses of a large volume.

The primary trial end point was objective response rate (ORR). Secondary end points were progression-free survival, OS, duration of response, disease control, and percentage of patients with adverse events during stage 1 and 2.

Earlier data analysis, at a data cutoff of April 20, 2023, demonstrated a confirmed ORR of 30% and 13.3% in the experimental and the control arm, respectively.³ In PD-L1–negative tumors, the confirmed ORR was 27% for the group who received the amezalpat combination vs 7% in the control arm.

The treatment with amezalpat was well tolerated and consistent with phase 1 data.

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, Inc. February 10, 2025. Accessed February 11, 2025. https://tinyurl.com/e2yxaxwc
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, Inc. January 6, 2025. Accessed February 11, 2025. https://tinyurl.com/2a4jtkwe
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, Inc. June 20, 2024. Accessed February 11, 2025. https://tinyurl.com/4jv3ackw
4. A study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with advanced liver cancers (Morpheus-Liver) (MORPHEUS-LIVER). ClinicalTrials.gov. Updated February 10, 2025. Accessed February 11, 2025. https://tinyurl.com/2wvaa6b6