INX 189 / BMS - LARVOL DELTA

Cardiotoxicity risk assessment of anti-cancer drugs and future perspectives (PubMed, Nihon Yakurigaku Zasshi) - "BMS-986094, which failed in clinical trials due to the occurrence of heart failure, was used as a positive compound...Doxorubicin was observed to decrease cytotoxicity and both contraction and relaxation velocities in hiPSC-CMs. We are currently further evaluating other anti-cancer drugs with different mode-of-actions using hiPSC-CMs and assess the predictivity and utility of contractile assessment using hiPSC-CMs by comparing with real-world data. Here, we introduce our novel method to assess the chronic contractility of hiPSC-CMs by imaging analysis and discuss the future perspectives for assessing the anti-cancer drug-induced cardiotoxicity."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Heart Failure • Hypertension • Oncology

Prediction of Cardiac Toxicity by Anti-cancer Drugs Using iPSC Cardiomyocytes (PubMed, Yakugaku Zasshi) - "The compound BMS-986094, which was withdrawn from clinical trials, inhibited contractility velocity and relaxation velocity in hiPSC-CMs. Currently, we are trying to investigate the predictability of the contractility assay by comparing the hiPSC-CM data with adverse events reports from real-world database. In this review, we would like to introduce the novel imaging-based contractility method using hiPSC-CMs and future perspectives in anti-cancer drug-induced cardiotoxicity."

Journal • Atrial Fibrillation • Cardiovascular • Oncology

Evaluation of chronic drug-induced electrophysiological and cytotoxic effects using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). (PubMed, Front Pharmacol) - " To assess this platform, we tested tyrosine-kinase inhibitors with high-cardiac risk profile (sunitinib, vandetanib and nilotinib) and low-cardiac risk (erlotinib), as well as known classic cardiac toxic drugs (doxorubicin and BMS-986094), ion-channel trafficking inhibitors (pentamidine, probucol and arsenic trioxide) and compounds without known clinical cardiotoxicity (amoxicillin, cetirizine, captopril and aspirin). Of note, some cardiotoxic effects could not be identified at acute time points (<2 h) but were clearly detected after 24 h, reinforcing the importance of chronic drug evaluation. In conclusion, the evaluation of chronic drug-induced cardiotoxicity using a hiPSC-CMs in vitro assay can contribute to the early de-risking of compounds and help optimize the drug development process."

Journal • Atrial Fibrillation • Cardiovascular

Preclinical Drug Testing in Scalable 3D Engineered Muscle Tissues. (PubMed, J Vis Exp) - "Here, we show data from cardiac muscle EMTs under acute and chronic dosing with known toxicants, including a drug (BMS-986094) that was pulled from clinical trials after patient fatalities due to unanticipated cardiotoxicity. Altered skeletal muscle function in engineered tissues in response to treatment with a myosin inhibitor is also presented. This platform enables the researcher to integrate complex, information-rich bioengineered model systems into their drug discovery workflow with minimal additional training or skills required."

Journal • Preclinical • Cardiovascular

Modeling Contractile Diseases Using Scalable 3D Engineered Heart Tissues For Drug Discovery (BCVS 2022) - "We will present data from a drug (BMS-986094) that failed clinical trials due to unanticipated cardiotoxicity. We go on to show both the acute and chronic effects of doxorubicin in cardiac EMTs...A repeat bolus, however, irreversibly abolished contraction, suggesting that repeat dosing may have a cardiotoxic effect on the muscle. These data demonstrate a first-and-only commercial platform for high-throughput assessment of 3D cardiac muscle contraction with potential for widespread adoption within the drug development field."

Cardiovascular • Heart Failure

Drug repurposing based on a quantum-inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2. (PubMed, PLoS Comput Biol) - "We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device...While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best...While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Assessing Contractility of 3D iPSC-derived Muscle Models for Safety and Discovery Using a Novel, High-throughput, and Label-free Instrumentation Platform. (PubMed, FASEB J) - "We will present data showing acute effects of drugs measured minutes after EMT dosing and chronic effects of structural cardiotoxicants like doxorubicin, sunitinib, and BMS-986094 on EMTs. We have designed a novel system that can leverage the complexity of 3D cellular models in a scalable format and can be tailored for specific applications, including personalized medicine or disease modeling. The Mantarray platform will provide a stand-alone tool capable of screening significant numbers of compounds for the rapid safety evaluation of drug candidates thereby accelerating drug discovery and development."

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes. (PubMed, J Toxicol Sci) - "Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings."

Journal • Cardiovascular • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Intracellular metabolism and potential cardiotoxicity of a β-D-2'-C-methyl-2,6-diaminopurine ribonucleoside phosphoramidate that inhibits hepatitis C virus replication. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "Imaging data of drug treated human cardiomyocytes was found to be most useful in determining toxicity potential as no obvious beating rate change was observed for IDX-184 up to 50 µM up at 48 h. However, with BMS-986094 and DAPN-PD at 10 µM changes to both beat rate and rhythm were noted."

Journal • Hepatitis C Virus • Hepatology • Infectious Disease

The synthesis of 2'-Me, 6-methoxyl guanosine from the parent ribonucleoside Guanosine. (PubMed, J Org Chem) - "A short and efficient synthesis of the nucleoside fragment contained in the NS5B nucleoside inhibitor BMS-986094 was achieved in 23% overall yield on a gram scale. The synthesis uses the widely available starting material guanosine, via a short sequence ending in a Mukaiyama hydration reaction to establish the key tertiary alcohol moiety and set the C-2' methyl stereogenic center. This work resulted in a robust and scalable approach to this complex nucleoside."

Journal

Inhibitex to Present at Two Upcoming Investor Conferences (Businesswire) - Inhibitex will present an overview of the company & its pipeline of differentiated antiviral compounds at two investor conferences in May

Hepatitis C Virus

Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189. (PubMed) - Org Lett - "This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated."

Journal • Biosimilar

Study of the safety & PK of INX-08189 in chronically-infected HCV, treatment-naïve subjects (clinicaltrials.gov) - P1, N=70; Completed; Design: No of Arms NA -> 7

Clinical protocol • Hepatitis C Virus