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

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 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

Age-induced succinate dysmetabolism promotes Tregulatory cells in Ovarian Cancer. (IMMUNOLOGY 2025) - "Inhibition of succinate synthesis in tumor cells from aged OvCa mice using CPI-613, an alphaketoglutarate dehydrogenase complex inhibitor reversed IL-10 and TGF-β upregulation, restoring CD4+ T cell proliferation. These studies show that an aged microenvironment dysregulates succinate levels, boosting Treg immunosuppressive function and promoting tumor growth in older OvCa mice."

Gynecologic Cancers • Metabolic Disorders • Oncology • Ovarian Cancer • Solid Tumor • CD4 • IL10 • TGFB1

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

Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HK2 • KRAS

The role of pyruvate dehydrogenase in the lifespan determination of daphnids. (PubMed, Nat Commun) - "Inhibition of PDH activity in daphnids by CPI-613 attenuates its ATP supply and locomotor performance but significantly induces longevity...And when the effects of temperature and octopamine on PDH activity are counteracted by inhibitors or agonists, the impact on lifespan becomes ineffective. These results support an important role for PDH in lifespan regulation and locomotor performance in daphnids and provide insights into the metabolic regulation of lifespan."

Journal

Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation. (PubMed, Nat Commun) - "Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • PDHA1

Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair. (PubMed, Sci Adv) - "Inhibiting lipoylation, either through genetic LIPT1 knockout or a lipoylation inhibitor (CPI-613), enhanced tumor control by radiation. Mechanistically, lipoylation inhibition increased 2-hydroxyglutarate, leading to H3K9 trimethylation, disrupting TIP60 recruitment and ataxia telangiectasia mutated (ATM)-mediated DNA damage repair signaling, impairing homologous recombination repair. In summary, our findings reveal a critical role of LIPT1 in regulating DNA damage and chromosome stability and may suggest a means to enhance therapeutic outcomes with DNA-damaging agents."

Journal • Ataxia • Immunology • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Primary Immunodeficiency • Solid Tumor • HRD • LIPT1

Protocol to evaluate fasting metabolism and its relationship to the core circadian clock in mice. (PubMed, STAR Protoc) - "We describe steps for time-course fasting/feeding experiment setup and performing staggered fasting and refeeding for 24 h. We then detail procedures for evaluating oxidative substrate selection and rescuing defective oxidative metabolism through FGF21 and CPI-613 injections. For complete details on the use and execution of this protocol, please refer to Sun et al.1."

Journal • Preclinical • FGF21

Thiamine deficiency aggravates experimental colitis in mice by promoting glycolytic reprogramming in macrophages. (PubMed, Br J Pharmacol) - "Our study provides evidence linking thiamine deficiency with proinflammatory macrophage activation and colitis aggravation, suggesting that monitoring thiamine status and adjusting thiamine intake is necessary to protect against colitis."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis