Bylantra (devimistat) / Cornerstone Pharma, Ono Pharmaceutical - LARVOL DELTA

Inhibition of PGC1b/mitochondrial biogenesis as a critical event in mediating therapeutic response of EGFR mutant NSCLC to third generation EGFR inhibitors (AACR 2026) - "Moreover, osimertinib combined with a mitochondria-targeting agent such as CPI-613 synergistically decreased cell survival with enhanced suppression of mitochondrial biogenesis and induction of apoptosis in osimertinib-resistant cells and effectively inhibited the growth of osimertinib-resistant tumors. Hence, it is apparent that the modulation of PGC1β/mitochondrial biogenesis critically impacts the therapeutic outcomes of osimertinib in the treatment of EGFRm NSCLC. Our findings not only reveal a novel mechanism underlying osimertinib acquired resistance, but also suggest a potential therapeutic strategy for overcoming acquired resistance to osimertinib via co-targeting PGC1β, particularly mitochondrial biogenesis."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FOSL1 • PPARGC1A • PPARGC1B

Repurposing nebivolol with CPI-613 for triple-negative breast cancer: Linking in-vitro synergy to in-vivo exposure (AACR 2026) - "NEB and CPI inhibited TNBC growth, but the combination did not outperform single agents. Sub-synergistic, ratio-mismatched tumor exposure may underlie this outcome; upcoming tumor PK studies will determine whether the synergistic ratio is reached within the dosing interval to guide dose optimization."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR

Devimistat Results in a Low Complete Remission Rate in Heavily Pre-Treated Burkitt Lymphoma (ASH 2024) - P2 | "The first CR patient was 40 years old, HIV positive with a viral load of 23 copies/mL, and 4 previous lines of therapy (CODOX-M/R-IVAC, R-ICE, pembrolizumab+acalabrutinib, R-methotrexate cytarabine) before receiving 11 cycles of devimistat...The second CR patient was 21 years old, HIV negative, received 6 previous lines of therapy (R-CHOP, DA-R-EPOCH, R-HCVAD/R-MA and IT MTX, R-Hyper cyclophosphamide, axi-cel, allogeneic SCT)...(Manji, ASH,2021) Despite few treatment options, it was difficult to enroll pts who were often ineligible due to poor performance status, CNS disease or logistical constraints, leading to study closure. Considering the dismal prognosis with the current standard of care, efforts should be made to improve the outcome of those with high-risk BL with their first line of therapy."

Clinical • Burkitt Lymphoma • CNS Disorders • Hematological Disorders • Hematological Malignancies • Hepatology • High-grade B-cell lymphoma • Human Immunodeficiency Virus • Infectious Disease • Lymphoma • Neutropenia • Oncology • Thrombocytopenia • CD4

Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers. (PubMed, Adv Sci (Weinh)) - "We find that bedaquiline (ATP synthase inhibitor) outperforms oligomycin A in specificity, VLX600 (electron transport chain inhibitor) shows superior selectivity to rotenone/metformin, and CPI-613 (tricarboxylic acid cycle blocker) surpasses other glutaminase inhibitors. MitoATP-nFCM establishes a quantitative single-organelle platform that profiles elevated mitoATP levels in cancer cells and enables precision screening of OXPHOS-targeting inhibitors."

Journal • Oncology • HK2

Phase 3, multicenter, randomized study of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) as first-line therapy for patients with metastatic adenocarcinoma of the pancreas (AVENGER500). (ASCO 2022) - P3 | "The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively... The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration."

Clinical • P3 data • Anemia • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Thrombocytopenia

A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic ductal adenocarcinoma (AACR 2024) - P1 | "CPI-613 combined with gem-RT was safe and well tolerated at a dose of 500 mg/m2. Recruitment to the study is ongoing to determine the MTD of CPI-613 in combination with gem-RT. Table 1."

Clinical • Combination therapy • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study. (PubMed, J Clin Oncol) - P3 | "Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat."

Journal • Metastases • P3 data • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Thrombocytopenia

Multi-institutional retrospective study of IDH2-mutated cholangiocarcinoma. (ASCO-GI 2026) - "Of 33 pts with advanced stage, 1L therapy was gemcitabine/platinum +/- devimistat or durvalumab in 84.9%. Most pts with IDH2 mutation had advanced ds with median survival similar to those with IDH1 mutated advanced cholangiocarcinoma. Off label enasidenib had modest benefit in this rare subset of pts and should be investigated further."

Retrospective data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • ARID1A • BAP1 • CDKN2A • FGFR2 • IDH1 • IDH2 • KRAS • PBRM1 • TP53

Gemcitabine and Cisplatin With or Without CPI-613 as First Line Therapy for Patients With Advanced Unresectable Biliary Tract Cancer (BilT-04) (clinicaltrials.gov) - P1/2 | N=75 | Terminated | Sponsor: University of Michigan Rogel Cancer Center | Completed ➔ Terminated; Loss of funding

Trial termination • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Oncology • Solid Tumor

A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in gastric cancer. (PubMed, Nat Commun) - "Based on this insight, we demonstrate that co-targeting this metabolic vulnerability with an inhibitor (devimistat) alongside an anti-TGFβ agent significantly enhances therapeutic efficacy in gastric cancer models. This combination approach presents a promising strategy to overcome the limitations of current therapies."

Journal • Gastric Cancer • Oncology • Solid Tumor • TGFB1

CPI-613 (Devimistat) in Combination With Chemoradiation in Patients With Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1 | N=8 | Terminated | Sponsor: Medical College of Wisconsin | Active, not recruiting ➔ Terminated; The pharmaceutical funder pulled funding and no longer plans to develop the drug further.

Trial termination • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • CEACAM5

Amphiregulin and Epiregulin Confer Radioresistance in Esophageal Squamous Cell Carcinoma Through Oxidative Phosphorylation. (PubMed, Adv Sci (Weinh)) - "Functional experiments demonstrated that radioresistant ESCC cells (KYSE410R) exhibited elevated OXPHOS activity, which is reversed by targeting TCA cycle enzymes (CPI-613 (Devimistat), fumarate hydratase-IN-1 (FH-IN-1), etc.) or Oxidative phosphorylation (OXPHOS) inhibitors (IACS-010759, Rotenone, etc.). Clinically, high Amphiregulin/Epiregulin (AREG/EREG) levels correlated with nCRT resistance and poor prognosis. Collectively, the CEBPB/AREG/EREG axis drives radioresistance by reprogramming OXPHOS, suggesting inhibition of this pathway or OXPHOS itself as a promising strategy to enhance ESCC therapeutic responses."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • AREG • CEBPB • EREG • FH

Management of Burkitt Lymphoma (SOHO 2025) - "Rituximab has been added following a randomized trial...A multi-center phase 2 study of devimistat — an inhibitor of the tricarboxylic acid cycle — had a 1-year overall survival (OS) rate of 15% in all patients and 22% for evaluable relapsed/refractory BL patients who received 4 doses in cycle 1...The trial underscored the difficulty in studying relapsed or refractory BL. We will discuss frontline trials in development that incorporate CD20-CD3 bispecific engagers into a chemotherapy backbone."

Acute Lymphocytic Leukemia • Burkitt Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD20

ACO1 OGDH axis drives mitochondrial immune crosstalk in preeclampsia through systems biology enabling dual target therapy. (PubMed, Sci Rep) - "Drug predictions and docking identified devimistat and acetylcysteine as potential binders...These findings, originating from in silico analyses, require preclinical validation through experimental models. Additionally, the mitochondrial-immune scoring system serves as a candidate tool for PE subtyping."

Biomarker • Journal • Gynecology • Metabolic Disorders • ACO1 • CD8 • KCNQ1OT1 • MIR214 • TFAP2A

CPI-613 (Devimistat) in Combination With Chemoradiation in Patients With Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: Medical College of Wisconsin | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • CEACAM5

Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies. (PubMed, Mol Cell Biochem) - "Clinical trials are ongoing for the mitochondrial enzyme-targeting agents CPI-613 and Gamitrinib, a heat shock protein-targeting agent, which have hence shown great promise for these therapies. With further investigation, mitochondrial-targeted interventions could be promising for preventing or reducing HCC incidence and recurrence, increasing long-term survival, and improving the quality of life of patients with advanced-stage disease."

Journal • Review • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor

Targeting metabolism in pancreatic ductal adenocarcinoma: challenges and insights from the AVENGER 500 trial. (PubMed, J Gastrointest Oncol) - No abstract available

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Novel Devimistat Results in Complete Remissions in Heavily Pre-Treated Burkitt Lymphoma in a phase II trial. (PubMed, Blood Adv) - P2 | "Considering the dismal prognosis of RR MYC-driven aggressive B-cell lymphomas with the current standard of care and low CRR with devimistat, efforts should be made to improve the outcome of these malignancies with their first line of therapy and explore novel therapies in the RR setting. NCT03793140."

Journal • P2 data • B Cell Lymphoma • Burkitt Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pain • Thrombocytopenia • Transplantation

Inhibition of the mitochondrial metabolic enzyme OGDC affects erythroid development (PubMed, Sheng Li Xue Bao) - "Treatment with CPI-613 significantly inhibited the excessive proliferation and differentiation of erythroid progenitor cells of the PV patients. These findings demonstrates the critical role of OGDC in normal erythroid development, suggesting that inhibiting its activity could be a novel therapeutic strategy for treating PV."

Journal • Hematological Disorders • Polycythemia Vera • CD34

NOVEL DEVIMISTAT RESULTS IN COMPLETE REMISSIONS IN HEAVILY PRE-TREATED BURKITT LYMPHOMA (ICML 2025) - P2 | "In our single-arm phase II study, 2 out of 9 patients with RR-BL treated with devimistat, achieved complete remission (ORR and CRR of 22%). By intent to treat this would be only 15%. Considering the dismal prognosis of RR-BL with the current standard of care and low CRR with devimistat, efforts should be made to improve the outcome of those with high-risk BL with their first line of therapy and explore novel therapies in the RR setting."

Clinical • Burkitt Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Oncology

Inhibiting FAT1 Blocks Metabolic Bypass to Enhance Antitumor Efficacy of TCA Cycle Inhibition through Suppressing CPT1A-Dependent Fatty Acid Oxidation. (PubMed, Adv Sci (Weinh)) - "Notably, FAT1-mutant HNSCC cells exhibit resistance to the TCA cycle inhibitor CPI-613 through activation of CPT1A-mediated FAO, whereas genetic ablation of mutant FAT1 restores sensitivity to CPI-613...Collectively, these findings establish that mutant FAT1 drives CPT1A-dependent FAO, facilitating a metabolic bypass that confers resistance to TCA cycle inhibition in HNSCC. This mechanistic insight highlights promising opportunities for combinatorial therapeutic strategies co-targeting genetic and metabolic vulnerabilities in cancer."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ASCL2 • CDH1 • CPT1A • FAT1

Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling. (PubMed, Cancer Res) - "In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC)...These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD36 • CD8 • SCARB1 • THBS2 • XBP1

Phase II open-label multi-cohort study evaluating CPI-613 (devimistat) in combination with hydroxychloroquine and 5-fluorouracil or gemcitabine in patients with advanced chemo-refractory solid tumors (AACR 2025) - P2 | "To date, in all cohorts, CPI-613 + HCQ + (5FU or GEM) did not add new safety signals compared with 5FU or GEM alone. Early efficacy data suggests clinical benefit for certain patients but no ORR's were observed in Cohorts 1 and 2, and they will not continue to Stage 2. Further subgroup efficacy, correlative analysis and updates from ongoing cohort 3 will be presented."

Clinical • Combination therapy • Metastases • P2 data • Oncology • Pancreatic Cancer • Solid Tumor

Preclinical evaluation of pharmacokinetic interactions among nebivolol, dasatinib and devimistat in mice (AACR 2025) - "Co-administration with DAS slowed the NBV elimination, suggesting that NBV accumulation would be considered when used alongside DAS. Additionally, CPI exposure significantly increased in the presence of NBV, indicating that dose adjustments may be necessary in combination therapies."

PK/PD data • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Inhibition of the tumor cell TCA cycle suppresses ER stress-associated THBS2 to selectively potentiate antitumor response of CD36+ effector T cells (AACR 2025) - "This inactivation subsequently triggers the activation of the downstream AKT/mTOR signaling pathway, enhancing the proliferation and cytotoxic potential of CD8+ T cells. These results highlight the immunomodulatory effects of CPI-613 and provide a strong rationale for developing it as a promising treatment strategy for HNSCC."

Tumor cell • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD36 • CD8 • SCARB1 • THBS2