amezalpat (TPST-1120) / Tempest Therap - LARVOL DELTA

PROSPERO: A phase 3 randomized, placebo (Pbo)-controlled study of amezalpat (TPST-1120), a peroxisome proliferator-activated receptor a (PPARα) inhibitor, in combination with atezolizumab + bevacizumab (AB) for patients (pts) with unresectable or metastatic hepatocellular carcinoma (mHCC) not previously treated with systemic therapy. (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT06680258 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Combination therapy • Metastases • Hepatocellular Cancer • Oncology • Solid Tumor • PPARA

Amezalpat, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist, inhibits suppressive macrophage development, activation and function (AACR 2025) - "Finally, in co-cultures of M2 macrophages with autologous activated CD8+ T cells and HCC tumor cells (SNU-449), amezalpat induced tumor cell cytotoxicity and M2 cell death commensurate with cell-type specific expression levels of its target PPARα. Together, these data suggest amezalpat modulates suppressive macrophage development and function and supports the contribution of an immune-mediated mechanism to anti-tumor activity reported in clinical studies."

Oncology • CD163 • CD8 • IL10 • MRC1 • PPARA • TGFB1

Tumor extracellular vesicles trigger a dendritic cell stress response to promote immune evasion and immunotherapy resistance (AACR 2025) - "Indeed, a PPARalpha antagonist, TPST-1120, overcomes resistance to anti-PD-1 immunotherapy in a poorly immunogenic autochthonous melanoma model while suppressing DC lipid stores and DC FAO in situ. Together, this work suggests that pharmacologic targeting of pathways elicited by tumor-derived ECVs can reverse DC tolerization in the TME and overcome immunotherapy resistance in select tumors. Understanding which tumors rely on ECVs to suppress anti-tumor immunity will be a critical step in prospectively developing targeted therapeutics to block these immune evasive pathways and enhance the efficacy of checkpoint inhibitor immunotherapy."

Breast Cancer • Melanoma • Oncology • Solid Tumor • CD8 • CD81 • XBP1

Tempest hits funding block for Phase III liver cancer drug-in-waiting (Pharmaceutical Technology) - "Tempest Therapeutics is eyeing a strategic partner to continue amezalpat’s development amid ‘unavailable capital markets'....The US biotech’s clinical asset, amezalpat, has already demonstrated positive Phase II data, though the step to Phase III looks more difficult."

Commercial • Hepatocellular Cancer

Tempest Reports Year End 2024 Financial Results and Provides Business Update (GlobeNewswire) - "Amezalpat (TPST-1120) (clinical PPARα antagonist): Plan to advance amezalpat into a registrational study in first-line liver cancer patients, subject to obtaining additional resources."

New trial • Hepatocellular Cancer

Tempest Announces Amezalpat Poster Presentation at the 2025 American Association for Cancer Research (AACR) Annual Meeting (GlobeNewswire) - "Tempest Therapeutics...announced that an abstract highlighting data supporting the immune component of amezalpat’s purported mechanism of action has been accepted for poster presentation at the 2025 American Association for Cancer Research (AACR) Annual Meeting...Clinical data supporting mechanism of action reinforce potential as a novel cancer treatment."

Clinical data • Oncology

Tempest Granted Fast Track Designation from the U.S. Food and Drug Administration for Amezalpat to Treat Patients with Hepatocellular Carcinoma (GlobeNewswire) - "Tempest Therapeutics, Inc...today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to amezalpat (TPST-1120), an oral, small molecule, selective PPAR⍺ antagonist for the treatment of patients with hepatocellular carcinoma (HCC)."

Fast track • Hepatocellular Cancer

Tempest Receives Orphan Drug Designation from the U.S. Food and Drug Administration for Amezalpat to Treat Patients with Hepatocellular Carcinoma (HCC) (GlobeNewswire) - "Tempest Therapeutics, Inc...today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to amezalpat (TPST-1120), an oral, small molecule, selective PPAR⍺ antagonist for the treatment of patients with hepatocellular carcinoma (HCC)....This important regulatory designation follows positive data across multiple key study efficacy and safety endpoints in a global randomized Phase 1b/2 clinical study evaluating amezalpat plus standard-of-care atezolizumab and bevacizumab versus atezolizumab and bevacizumab alone in the first-line treatment of patients with unresectable or metastatic HCC."

Orphan drug • Gastrointestinal Cancer • Hepatocellular Cancer

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (clinicaltrials.gov) - P1/2 | N=518 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Aug 2026 ➔ Dec 2026 | Trial primary completion date: Aug 2026 ➔ Dec 2026

Metastases • Trial completion date • Trial primary completion date • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • PD-L1

A Study of TPST-1120 With Atezolizumab Plus Bevacizumab in Patients With Unresectable or Metastatic HCC Not Previously Treated With Systemic Therapy (clinicaltrials.gov) - P3 | N=740 | Not yet recruiting | Sponsor: Tempest Therapeutics

Combination therapy • Metastases • New P3 trial • Hepatocellular Cancer • Oncology • Solid Tumor

Tempest Receives FDA Study May Proceed for Pivotal Phase 3 Trial of Amezalpat Combination Therapy for the Treatment of First-Line Hepatocellular Carcinoma (GlobeNewswire) - "The planned Phase 3 study is a global, blinded, 1:1 randomized study of amezalpat plus atezolizumab and bevacizumab versus placebo plus atezolizumab and bevacizumab, the standard of care, for the first-line treatment of patients with unresectable or metastatic HCC....The company is working to enable a Phase 3 study to start in the first quarter of 2025."

IND • Trial status • Hepatocellular Cancer

Tempest Announces Agreement with Roche to Support Advancement of Amezalpat Combination Therapy into First-Line Hepatocellular Carcinoma Pivotal Trial (GlobeNewswire) - "Tempest Therapeutics, Inc...today announced an agreement with Roche to advance the evaluation of amezalpat (TPST-1120) in combination with atezolizumab (Tecentriq) and bevacizumab, the current standard of care for unresectable or metastatic hepatocellular carcinoma (HCC), into a pivotal Phase 3 trial for the first-line treatment of unresectable or metastatic hepatocellular carcinoma...Under the agreement, Roche will supply atezolizumab globally and Tempest will sponsor and lead the pivotal study....The company is preparing for the Phase 3 study start in the first quarter of 2025."

Commercial • New P3 trial • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Tempest Reports Second Quarter 2024 Financial Results and Provides Business Update (GlobeNewswire) - "Potential Future Milestones: (i) Amezalpat (TPST-1120) (clinical PPARα antagonist): Plan to advance amezalpat into a registrational Phase 3 study in first-line HCC patients, subject to obtaining feedback from the FDA; (ii) TPST-1495 (clinical dual EP2/4 prostaglandin receptor antagonist):...Expect to report data from the combination arm at the two highest TPST-1495 doses in patients with advanced endometrial cancer, where prostaglandin signaling is implicated, in 2024."

New P3 trial • P1 data • Endometrial Cancer • Hepatocellular Cancer

Tempest Announces Successful End-of-Phase 2 Meeting with FDA for Amezalpat (TPST-1120) to Treat First-Line Hepatocellular Carcinoma (GlobeNewswire) - "Tempest Therapeutics, Inc...today announced positive feedback from its end-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) for amezalpat (TPST-1120) in combination with atezolizumab and bevacizumab to treat first-line unresectable or metastatic hepatocellular carcinoma (HCC)...Key outcomes of the FDA meeting include: Agreement on Phase 3 study design, including the standard-of-care control arm and the primary and secondary study endpoints; Agreement on appropriateness of the current amezalpat dose and schedule for the Phase 3 study; Agreement on the Phase 3 statistical plan including a pre-specified early efficacy analysis that the company currently estimates could shorten the time to primary analysis by up to 8 months...The company is preparing for the Phase 3 study start in the first quarter of 2025."

FDA event • New P3 trial • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Tempest Unveils New Survival Data for Amezalpat (TPST-1120) in Randomized First-Line HCC Study Demonstrating a Six-Month Improvement over Control Arm (GlobeNewswire) - P1/2 | N=506 | Morpheus-Liver (NCT04524871) | Sponsor: Hoffmann-La Roche | "At the cutoff date of February 14, 2024, the new data from 40 patients randomized to the amezalpat arm and 30 patients randomized to the control arm show: 21 month median OS for the amezalpat arm versus 15 month for the control arm, a six-month survival advantage; 20/40 patients remain in survival follow up in the amezalpat arm, compared to 9/30 patients in the control arm; 0.65 hazard ratio ('HR') for OS, revealing a stable HR since the top-line analysis 10 months earlier when the HR was 0.59; Manageable safety profile consistent with Phase 1 data...The earlier top-line data analysis, dated April 20, 2023, had a median follow up of 9.2 and 9.9 months for the amezalpat and control arms, respectively, and showed: Confirmed objective response rate...of 30% for the amezalpat arm versus 13.3% for the control arm...Amezalpat remains well tolerated, with safety data comparable between the two arms..."

P1/2 data • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Tempest to Report New Data from Global Randomized Combination Study of Amezalpat (TPST-1120) in First-Line Hepatocellular Carcinoma (GlobeNewswire) - "Tempest Therapeutics, Inc...today announced the company plans to report new data from the global randomized Phase 1b/2 combination study of amezalpat (TPST-1120) with atezolizumab and bevacizumab in first-line treatment of hepatocellular carcinoma (HCC) in a premarket press release followed by a webcasted conference call with associated slide presentation on Thursday, June 20, 2024 at 8:30 a.m. ET."

P1/2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (clinicaltrials.gov) - P1/2 | N=506 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2025 ➔ Aug 2026 | Trial primary completion date: Dec 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • PD-L1

PPAR-α antagonist enhances immunotherapy and anti-angiogenic therapy to inhibit murine renal cancer (AACR 2024) - "Importantly, we demonstrate that TPST-1120 can reverse an immunosuppressive class of immune cells to promote anti-tumor immunity and anti-angiogenesis in kidney cancer in the absence of overt toxicity. These data support advancement of TPST-1120 into RCC."

Preclinical • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD8 • MBD4 • MED1 • PPARA

Tempest Reports New Preclinical Data for TPST-1120 in RCC at the AACR Annual Meeting (GlobeNewswire) - "Preclinical data presented at AACR showed that TPST-1120 increases infiltrating cytotoxic CD8+ T cells in the tumor microenvironment, consistent with modulation of the tumor microenvironment to a more immune responsive environment that allows for the influx of tumor specific CD8+ T cells....In preclinical models of renal cell carcinoma (RCC), treatment with TPST-1120 reduced tumor growth by 52%-56% as monotherapy. Additional improvement in anti-cancer activity was demonstrated in combination treatment with standard first-line RCC cabozantinib or anti-PD1 therapy, where tumor inhibition was 81% and 74%, respectively."

Preclinical • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Tempest Announces Publication of Positive Data from Phase 1 Trial of TPST-1120 in Patients with Advanced Solid Tumors in Journal of Cancer Research Communications (GlobeNewswire) - P1 | N=38 | NCT03829436 | Sponsor: Tempest Therapeutics | "Based on subsequent positive randomized data, Company preparing to move TPST-1120 into pivotal Phase 3 trial in HCC....The data showed that TPST-1120 demonstrated clinical activity, including tumor shrinkage, even in PD-1 inhibitor refractory and immune compromised cancers, and was well tolerated both as monotherapy and in combination with nivolumab....We believe there is tremendous potential for TPST-1120 to make a meaningful impact for patients and we look forward to providing updated data this year."

New P3 trial • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

First-in-Human Phase I Trial of TPST-1120, an inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors. (PubMed, Cancer Res Commun) - P1 | "TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers."

Combination therapy • Journal • Metastases • Monotherapy • Biliary Cancer • Cholangiocarcinoma • Fatigue • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PPARA • TPST1

First-in-Human Phase I Trial of TPST-1120, an inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors (Cancer Res Commun) - P1 | N=38 | NCT03829436 | Sponsor: Tempest Therapeutics | "39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAEs) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 RCC patients, both of whom had previously progressed on anti-PD-1 therapy, and one patient with late-line CCA."

P1 data • Cholangiocarcinoma • Renal Cell Carcinoma

Tempest Reports Year End 2023 Financial Results and Provides Business Update (GlobeNewswire) - "Potential Future Milestones: TPST-1120 (clinical PPARα antagonist)...Expect to announce updated data from the ongoing randomized study in first-line liver cancer patients in 2024; Plan to advance TPST-1120 into a registrational study in first-line liver cancer patients, subject to obtaining feedback from the FDA."

New trial • P1 data • Hepatocellular Cancer

Our study showed association between fatty acid genomic and pharmacodynamic modulation with clinical response in patients with ccRCC treated with the PPAR alpha antagonist TPST-1120 @ASCO #GU24 #RCC #Cancer

Tempest Presents New Data at the SITC 2024 Spring Scientific Meeting Supporting Potent Anti-tumor Activity of TPST-1120 in Multiple Cancer Types (GlobeNewswire) - P1 | N=38 | NCT03829436 | Sponsor: Tempest Therapeutics | "In addition, biomarker results from the Phase 1 clinical trial of TPST-1120 in multiple solid tumor indications showed statistically significant, exposure-dependent elevations in expression levels of multiple immune-related genes, and patients exhibiting objective responses displayed increased circulating free fatty acids (FFA), both of which are in-line with the proposed TPST-1120 mechanism of action. Clinical response and biomarker findings support that inhibition of PPARα may be an effective therapeutic strategy for the treatment of cancer."

Biomarker • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor