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

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

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

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 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

A Study of CPI-613 for Patients With Relapsed or Refractory Burkitt Lymphoma/Leukemia or High-Grade B-Cell Lymphoma With High-Risk Translocations (clinicaltrials.gov) - P2 | N=24 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Dec 2026 ➔ Aug 2026 | Trial primary completion date: Dec 2026 ➔ Aug 2026

Trial completion • Trial completion date • Trial primary completion date • B Cell Lymphoma • Burkitt Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • MYC

CPI-613 (Devimistat) in Combination with Chemoradiation in Patients with Pancreatic Ductal Adenocarcinoma (PDAC): Results of the Phase I Clinical Trial (ASTRO 2026) - No abstract available

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

Combination of lonidamine with devimistat induces synergistic antitumor effects in lung cancer via multifaceted disruption of cellular energy metabolism. (PubMed, Oncol Rep) - "Furthermore, combining these two metabolic inhibitors could induce the production of ROS, reduce the generation of ATP, impair mitochondrial morphology and function, and ultimately activate apoptosis in tumor cells through metabolic regulation, facilitating antitumor treatment. The findings underscore the necessity and effectiveness of targeting tumor energy metabolism for lung cancer therapy, providing reliable evidence that metabolic therapies can effectively participate in cancer treatment."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Hyperpolarized [2-13C]Pyruvate Identifies a Mitochondria-Active Hepatocellular Carcinoma Phenotype With Vulnerability to Mitochondrial Inhibition. (PubMed, NMR Biomed) - "Cell viability following treatment with the glutaminase inhibitor BPTES and the mitochondrial metabolic inhibitor CPI-613 was assessed by MTT assay, and metabolic changes following CPI-613 treatment were further evaluated using HP [2-13C]pyruvate...These findings demonstrate that HP [2-13C]pyruvate enables functional identification of a mitochondria-active HCC phenotype characterized by enhanced pyruvate-to-glutamate conversion. This approach may facilitate metabolic subtype classification, help identify tumors susceptible to mitochondrial metabolic inhibition, and enable non-invasive monitoring of treatment-induced metabolic adaptation."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Inhibition of PGC1β-dependent mitochondrial biogenesis enhances EGFR-targeted therapy in lung cancer. (PubMed, EMBO Mol Med) - "Moreover, combining osimertinib with the mitochondria-targeting agent CPI-613 synergistically suppresses mitochondrial biogenesis, induces apoptosis, and inhibits the growth of osimertinib-resistant cells and tumors. Collectively, these findings identify PGC1β-dependent mitochondrial biogenesis as a critical determinant of therapeutic response to osimertinib and suggest co-targeting mitochondrial metabolism as a potential strategy to overcome acquired resistance in EGFRm NSCLC."

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

Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma. (PubMed, Cell Death Dis) - "Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression...Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level."

Journal • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • HIF1A • MYC

Ketogenic diet as a metabolic vehicle enhancing the therapeutic efficacy of mebendazole and devimistat in juvenile syngeneic high-grade glioma. (PubMed, Cell Rep Med) - "MBZ inhibited glycolysis and glutaminolysis in VM-M3 cells and reduced proliferation and viability of SF-188 cells. KD-enabled combination therapy allowed lower drug dosing, reduced toxicity, and improved survival, supporting further investigation of metabolically informed diet-drug strategies for pediatric gliomas."

Journal • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor

ATAD3A Limits Aortic Dissection via Mito-Lysosome Contacts and Lipoylation. (PubMed, Circ Res) - "Pharmacological modulation was performed with the copper chelator tetrathiomolybdate and the lipoylation inhibitor devimistat...ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca2+ influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD."

Journal • Cardiovascular • FDX1 • LIAS

MechAInistic: An LLM-guided Multi-Agent System for Reasoning over Genome-Scale Constraint-Based Metabolic Models. (PubMed, bioRxiv) - "For rheumatoid arthritis/healthy Naive B models, it identified mitochondrial metabolic rewiring and nominated Devimistat/CPI-613 as an investigational OGDH-centered hypothesis. In CD4+ Th17 multiple sclerosis/healthy models, the workflow identified NADP-dependent isocitrate dehydrogenase as the optimal target and proposed Ivosidenib as an FDA-approved repurposing candidate."

Journal • CNS Disorders • Immunology • Inflammatory Arthritis • Multiple Sclerosis • Rheumatoid Arthritis • Rheumatology • CD4

OGDH primes macrophage for M1-like polarization and ferroptosis in sepsis associated acute lung injury. (PubMed, Respir Res) - "Overall, our study reveals that OGDH is a key immunometabolism regulator and a novel biomarker in S-ALI, and its inhibitor CPI-613 may represent a potential therapeutic target for this condition."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock

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

Mitochondrial inhibition enhances the sensitivity of pancreatic ductal adenocarcinoma cells to oncolytic adenovirus. (PubMed, Mol Ther Oncol) - "We demonstrated the cytopathic activity of telomerase-specific, replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against PDAC cells. Our results suggest that non-glycolytic PDAC cells are refractory to oncolytic adenoviruses. CPI-613 is a promising reagent for overcoming virotherapy resistance in PDAC tumors."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • 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

Repurposing nebivolol with dasatinib and CPI-613: A synergistic strategy to combat triple-negative breast cancer (AACR 2025) - "These findings highlight the potential of NEB in combination with DAS or CPI as a promising therapeutic strategy for TNBC. Ongoing in vivo studies using a TNBC mouse model aim to validate these findings and further explore the clinical potential of these combinations to improve TNBC patient outcomes."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

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 • Solid Tumor

A Study of CPI-613 for Patients With Relapsed or Refractory Burkitt Lymphoma/Leukemia or High-Grade B-Cell Lymphoma With High-Risk Translocations (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • B Cell Lymphoma • Burkitt Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • MYC

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

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