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

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 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Liver Cancer • Oncology • Solid Tumor • PD-L1

A phase 1 study of TPST-1120 as a single agent and in combination with nivolumab in subjects with advanced solid tumors. (ASCO 2022) - P1 | "TPST-1120 is a novel therapy designed to inhibit tumor proliferation and angiogenesis and stimulate anti-cancer immunity through inhibition of PPARα, a key regulator of FAO. The drug is well tolerated as a single agent and in combination with nivolumab. Promising objective responses have been observed in combination with nivolumab in subjects previously refractory to anti-PD-1 therapy, including 2/2 responders in late-line RCC, and a subject with heavily pretreated CCA, a tumor type generally not responsive to anti-PD-1 alone."

Clinical • Combination therapy • IO biomarker • Biliary Cancer • Cholangiocarcinoma • Fatigue • Gastrointestinal Cancer • Hypertension • Musculoskeletal Pain • Oncology • Renal Cell Carcinoma • Solid Tumor • PPARA • THBS1 • TPST1

Pharmacodynamics and gene expression analysis of patients with renal cell carcinoma treated with combination nivolumab and TPST-1120 in a phase I clinical trial (NCT03829436). (ASCO-GU 2024) - P1 | "There is a paucity of treatment options for patients with stage IV RCC post anti-PD1 and anti-VEGF therapies. Novel therapies on this clinical scenario are needed. On this abstract we showed radiographic and pharmacodynamic data on patients with RCC who achieved a clinical partial response by RECIST on the phase I clinical trial TPST1120-001."

Clinical • IO biomarker • PK/PD data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ACSL3 • FABP1 • 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. (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

GO42216: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients with Advanced Liver Cancers (Morpheus-Liver) (clinicaltrialsregister.eu) - P1/2 | N=29 | Recruiting | Sponsor: F. Hoffmann-La Roche AG | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • PD-L1

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: Dec 2027 ➔ Sep 2027 | Trial primary completion date: Dec 2027 ➔ Jul 2027

Trial completion date • Trial primary completion date • 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

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

USP47 alleviates metabolic-associated fatty liver disease by activating the PPARα signaling pathway through the stabilization of SIRT1. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "USP47 inhibits the ubiquitination and degradation of SIRT1 and stabilizes its expression. SIRT1, in turn, increases PPARα expression through deacetylation, thereby promoting lipid metabolism and alleviating MAFLD."

Journal • Hepatology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Targeted Protein Degradation • PPARA • USP47

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

Strategic Priorities (GlobeNewswire) - "Amezalpat remains Phase 3-ready in first-line hepatocellular carcinoma ('HCC'), supported by global regulatory alignment and positive randomized Phase 2 data. Tempest plans to pursue business development discussions to advance pivotal development...Tempest plans to progress additional dual-targeting CAR-T programs that broaden the platform across modalities and indications, including: TPST-3003: an allogeneic dual-targeting CD19/BCMA CAR-T; TPST-2206: a dual-targeting CD70/CD70 CAR-T; TPST-3206: an allogeneic dual-targeting CD70/CD70 CAR-T."

New P3 trial • Pipeline update • Hematological Malignancies • Hepatocellular Cancer • Immunology • Lupus • Renal Cell Carcinoma

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: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2026 ➔ Dec 2027

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

Tempest Announces Strategic Acquisition of New Dual-CAR T Programs from Factor with Simultaneous Runway Extension Projected to Mid 2027 (GlobeNewswire) - "Acquisition will expand existing advanced clinical-stage pipeline of amezalpat (PPAR⍺ Antagonist, Phase 3-ready) and TPST-1495 (Dual Ep2/4 Antagonist, Phase 2 start expected near term)...The Proposed Transaction will expand and further diversify Tempest’s existing clinical-stage pipeline, with the acquisition of the first clinical-stage CD19/BCMA parallel structured dual-CAR T specifically designed to target patients with extramedullary disease (EMD), which we are referring to as TPST-2003...Tempest plans to pursue business development discussions or an additional financing to advance the pivotal development of amezalpat (TPST-1120) in first-line liver cancer ('HCC')....Plan to continue the development of additional new preclinical and research-stage pipeline programs: TPST-2206: dual-targeting CD70/CD70 CAR-T for renal cell carcinoma; TPST-3003: allogeneic dual-targeting CD19/BCMA; TPST-3206: allogeneic dual-targeting CD70/CD70."

M&A • Genetic Disorders • Hepatocellular Cancer • Multiple Myeloma • Renal Cell Carcinoma • Systemic Lupus Erythematosus

PROSPERO: 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 | Trial completion date: Dec 2029 ➔ Jul 2030 | Initiation date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Mar 2028 ➔ Dec 2028

Trial completion date • Trial initiation date • Trial primary completion date • Hepatocellular Cancer • Oncology • Solid Tumor

Financial Results (The Globe and Mail) - "Tempest ended the quarter with $14.3 million in cash and cash equivalents, compared to $30.3 million on December 31, 2024...Cash used in operating activities for the six months ended June 30, 2025 was $16.5 million...Research and development expenses for the six months ended June 30, 2025 were $11.5 million, compared to $10.2 million for the same period in 2024. The $1.3 million increase was primarily due to an increase in costs incurred from contract research and manufacturing organizations in preparation for the company’s pivotal Phase 3 trial of amezalpat for the treatment of first-line HCC."

Commercial • Hepatocellular Cancer

Tempest Receives Clearance to Proceed with Pivotal Trial of Amezalpat Combination Therapy for First-Line HCC in China (GlobeNewswire) - "Tempest Therapeutics, Inc...announced that the company received approval from the National Medical Products Administration (NMPA) in China to proceed with a pivotal trial to evaluate amezalpat (TPST-1120) in combination with atezolizumab and bevacizumab, the current standard of care, versus the standard of care alone in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma...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 has also received agreement from the FDA and EMA on its Phase 3 study design, dose of amezalpat, and the statistical plan, including a pre-specified efficacy analysis that could shorten the time to primary analysis."

Trial status • Hepatocellular Cancer

Peroxisome proliferator-activated receptor antagonists as emerging therapeutics in cancer treatment. (PubMed, Bioorg Chem) - "PPARα antagonists, such as N-(2-bromophenyl)-2-[[(3-chlorophenyl)amino]thioxomethyl]acetamide (GW6471) and TPST-1120, impair tumor metabolism and angiogenesis, reducing cancer progression...This review provides a comprehensive analysis of the medicinal chemistry, molecular mechanisms, and pharmacological development of PPAR antagonists, highlighting their potential clinical applications. Future efforts should refine drug design, develop personalized treatments, and conduct well-designed clinical trials to unlock their role in precision oncology."

Journal • Review • Metabolic Disorders • Oncology • CTNNB1 • PPARA

Tempest Receives Orphan Drug Designation from the European Medicines Agency for Amezalpat for the Treatment of Patients with HCC (GlobeNewswire) - "Tempest Therapeutics...announced that the European Medicines Agency (EMA) 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).....The company announced earlier this year that the FDA had granted both ODD and Fast Track Designation (FTD) to amezalpat to treat patients with HCC. These three designations follow positive data across multiple key study efficacy and safety endpoints from 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 • Hepatocellular Cancer

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 | "Interim analyses for futility (30% OS events) and efficacy (70% OS events) are planned. Findings of this pivotal study will inform the efficacy and safety profile of amezalpat added to AB vs AB alone in pts with unresectable or mHCC not previously treated with systemic therapy."

Clinical • Combination therapy • IO biomarker • Metastases • Biliary Cancer • Cholangiocarcinoma • Hepatocellular Cancer • Oncology • Sarcoma • Solid Tumor • AFP • PPARA

Tempest Reports First Quarter 2025 Financial Results and Provides Business Update (GlobeNewswire) - "Research and development expenses for the quarter were $7.6 million compared to $4.3 million for the same period in 2024. The $3.3 million increase was primarily due to an increase in costs incurred from engaging contract research and manufacturing organizations in preparation for our pivotal Phase 3 trial of amezalpat for the treatment of first-line HCC."

Commercial • Hepatocellular Cancer

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