Bylantra (devimistat) / Cornerstone Pharma 
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  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Preclinical, Journal:  In vitro and in vivo metabolism of a novel antimitochondrial cancer metabolism agent, CPI-613, in rats and human. (Pubmed Central) -  Apr 5, 2022   
    Significance Statement This work highlights the clearance mechanism of CPI-613 via β‑oxidation, species differences in their ability to carry out β‑oxidation and subsequent elimination routes. Structural limitations for completion of terminal cycle of β‑oxidation is discussed against the backdrop of its endogenous counterpart lipoic acid.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma, Ono Pharma
    Trial primary completion date, Combination therapy, Metastases:  CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer (clinicaltrials.gov) -  Mar 17, 2022   
    P1/2,  N=33, Recruiting, 
    Taken together, our study revealed devimistat as a promising candidate in CRC therapy by synergizing with established antineoplastic drugs in vitro and in vivo. Trial primary completion date: Dec 2021 --> Jun 2023
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Inhibition of glutaminolysis overcomes metabolic adaptation to devimistat treatment (Section 6) -  Mar 9, 2022 - Abstract #AACR2022AACR_5578;    
    Most importantly, the addition of a GLS1 inhibitor CB-839 to devimistat treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. These novel and significant findings could lay a scientific foundation for developing more effective treatments targeting the metabolic requirements of HNSCC.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Clinical, Journal:  Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer. (Pubmed Central) -  Mar 1, 2022   
    These novel and significant findings could lay a scientific foundation for developing more effective treatments targeting the metabolic requirements of HNSCC. These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition. (Pubmed Central) -  Jan 28, 2022   
    In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively...In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Preclinical, Journal:  An integrated in vivo and in silico analysis of the metabolism disrupting effects of CPI-613 on embryo-larval zebrafish (Danio rerio). (Pubmed Central) -  Dec 25, 2021   
    These results show that the targeted disruption of KGDH may also impact oxidative phosphorylation (ATP synthesis) and fatty acid metabolism (β-oxidation), in turn influencing cellular bioenergetics and the observed reduction in whole-organism O consumption rate. The results of this study provide an integrated in vivo and in silico framework to study the impacts of metabolic disruption on organismal physiology.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal, Heterogeneity:  DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer. (Pubmed Central) -  Dec 22, 2021   
    Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy. (Pubmed Central) -  Nov 29, 2021   
    The results of in vitro antitumor activity and cell apoptosis revealed that the IC values of TTCI NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM TTCI NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma, Ono Pharma
    Enrollment change, Trial completion date, Trial termination, Trial primary completion date, Combination therapy:  Efficacy/Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. in Older Patients With R/R AML (clinicaltrials.gov) -  Nov 9, 2021   
    P3,  N=194, Terminated, 
    Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2023 N=500 --> 194 | Trial completion date: Mar 2023 --> Aug 2021 | Recruiting --> Terminated | Trial primary completion date: Oct 2022 --> Aug 2021; Futile
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment. (Pubmed Central) -  Oct 27, 2021   
    Simultaneous cell treatment with tetracycline, an inhibitor of the mitochondrial proteosynthesis, further enhances the cytotoxic effect of CPI-613 under acidosis and in tumor spheroids. While there have been numerous attempts to treat cancer by neutralizing the pH of the tumor microenvironment, we alternatively suggest considering tumor acidosis as the Achilles' heel of cancer as it enables selective therapeutic induction of lethal oxidative stress.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma, Ono Pharma
    Trial completion date, Trial primary completion date, Combination therapy, Metastases:  CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer (clinicaltrials.gov) -  Oct 7, 2021   
    P1/2,  N=33, Recruiting, 
    Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells. Trial completion date: May 2021 --> Dec 2023 | Trial primary completion date: May 2021 --> Dec 2021
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma, Ono Pharma
    Trial completion date, Trial initiation date, Trial primary completion date:  APOLLO 613: To Evaluate Maximally Tolerated Dose (MTD), Safety and Efficacy of CPI-613 (clinicaltrials.gov) -  Sep 21, 2021   
    P1/2,  N=47, Not yet recruiting, 
    Not yet recruiting --> Recruiting Trial completion date: Nov 2022 --> Nov 2024 | Initiation date: Dec 2020 --> Oct 2021 | Trial primary completion date: Aug 2022 --> Aug 2023
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Combination therapy, Metastases:  CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) -  Aug 18, 2021   
    P1,  N=21, Active, not recruiting, 
    Trial completion date: Nov 2022 --> Nov 2024 | Initiation date: Dec 2020 --> Oct 2021 | Trial primary completion date: Aug 2022 --> Aug 2023 Trial completion date: Jul 2021 --> Dec 2021
  • ||||||||||  telaglenastat (CB-839) / Calithera, Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    [VIRTUAL] Therapeutic targeting of glutaminolysis and mitochondrial TCA cycle in head and neck cancer () -  Aug 3, 2021 - Abstract #AHNS2021AHNS_337;    
    Moreover, pharmacological blockade of the glutaminolysis pathway by GLS1 inhibitor CB-839 not only decreased cancer cell viability dependent on glutaminolysis, but also improved the therapeutic effectiveness of CPI-613 in cell culture and animal models. These findings provide novel evidence that alternative pathways of metabolism endowed cancer cells with metabolic stress, and suppressing the related compensatory pathways might achieve synergistic anticancer outcomes.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma. (Pubmed Central) -  Jul 10, 2021   
    Furthermore, CPI-613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex-associated metabolic vulnerability.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Combination therapy, Metastases:  CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) -  Apr 22, 2021   
    P1,  N=21, Active, not recruiting, 
    To date, 5 of planned 20 pts enrolled on the phase 1b portion are without dose limiting toxicity. Trial completion date: Mar 2021 --> Jul 2021
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts. (Pubmed Central) -  Apr 10, 2021   
    Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation...A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.