Amezalpat Gains FDA Orphan Drug Status in HCC

• The FDA has granted amezalpat (TPST-1120) orphan drug designation for the treatment of patients with hepatocellular carcinoma (HCC).
• Amezalpat is an investigational PPAR⍺ antagonist.
• The agent, which is being investigated in a phase 1b/2 study (NCT04524871), has shown safety and efficacy benefits when given in combination with atezolizumab (Tecentriq) and bevacizumab (Avastin) in patients with metastatic or unresectable HCC.

The FDA has granted amezalpat (TPST-1120), an investigational PPAR⍺ antagonist, orphan drug designation for the potential treatment of patients with hepatocellular carcinoma (HCC).¹

Data from a phase 1b/2 study (NCT04524871) support this designation, showing that when given in combination with atezolizumab and bevacizumab, amezalpat demonstrated potential efficacy and safety benefits as a frontline treatment for patients with metastatic or unresectable HCC.² A total of 40 patients were randomized in the study to receive the combination with amezalpat, and 30 patients were randomized to the control arm.³

At a data cutoff date of February 14, 2024, the median overall survival (OS) was 21 months for those treated with the amezalpat combination vs 15 months for those given atezolizumab and bevacizumab alone (HR, 0.65).² Further, 20 patients treated with the amezalpat combination remained in survival follow-up at the time of analysis compared with 9 patients in the control arm.

“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,” said Sam Whiting, MD, PhD, chief medical officer and head of Research and Development at Tempest, in a 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.”

3D illustration of human liver: © PIC4U - stock.adobe.com

Earlier findings from the trial showed that at a data cutoff date of April 20, 2023, and at median follow-ups of 9.2 and 9.9 months, respectively, the confirmed objective response rate (ORR) in the amezalpat arm was 30% vs 13.3% in the control arm. The duration of response (DOR) was not yet reached.

Seven patients (21%) in the study had b-catenin activating mutations. The confirmed ORR for this patient population was 43% and the disease control rate (DCR) was 100% for those treated with amezalpat. For both PD-L1–positive and –negative tumors, the amezalpat arm was consistently active with a confirmed ORR of 27% among patients treated with the TPST-1120 triplet vs 7% for the control arm.

For safety, the agent remains well-tolerated and data were comparable between the 2 arms.

About Amezalpat

Amezalpat is an oral, small-molecule antagonist targeting PPAR⍺. Research has shown that the agent may combat cancer by acting directly on tumor cells, as well as by modulating immune-suppressive cells and reducing angiogenesis within the tumor environment.¹

In August 2024, the FDA approved the design for a phase 3 study of amezalpat as a first-line option for patients with unresectable or metastatic HCC. Tempest and the FDA aligned on the dosage of amezalpat and statistical plan, which includes a prespecified efficacy analysis that could expedite the primary analysis.⁴ Preparations are underway to initiate the phase 3 trial in the first quarter of 2025.

Then in November 2024, the FDA has issued a “Study May Proceed” letter for evaluating the combination of amezalpat, atezolizumab, and bevacizumab as a first-line option for patients with unresectable or metastatic HCC in a pivotal phase 3 randomized trial.

The study is planned to be a phase 3, international, double-blind, 1:1 randomized trial that will compare the amezalpat-containing regimen with a placebo plus atezolizumab and bevacizumab regimen, the current SOC, in this patient population.⁵

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 8, 2025. https://tinyurl.com/4u2t9wdk

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 8, 2025. https://tinyurl.com/ywrzfdud

3. TPST-1120 as monotherapy and in combination with nivolumab in subjects with advanced cancers. ClinicalTrials.gov. Updated July 3, 2023. Accessed January 8, 2025. https://clinicaltrials.gov/ct2/show/NCT03829436

4. 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 8, 2025. https://tinyurl.com/yc8df39h

5. Tempest receives FDA study may proceed for pivotal phase 3 trial of amezalpat combination therapy for the treatment of first-line hepatocellular carcinoma. News release. Tempest Therapeutics, Inc. November 12, 2024. Accessed January 8, 2025. https://tinyurl.com/mwhvfph6