Incivek (telaprevir) / J&J, Vertex, Mitsubishi Tanabe - LARVOL DELTA

The chaperone DnaK promotes the emergence and accumulation of antibiotic-resistant clones through its ATPase activity in Riemerella anatipestifer. (PubMed, Poult Sci) - "Importantly, it was indicated that the broad DnaK molecular chaperone inhibitor, telaprevir (TP), effectively decreases the frequency of antibiotics resistant (FOR) in R. anatipestifer through inhibiting the ATPase activation of the DnaK molecular chaperone. Taken together, this study suggested that the chaperone DnaK can be used as a target for drug design to control the emergence and accumulation of antibiotic-resistant clones in R. anatipestifer and reduce the risk of antibiotic resistance in clinical treatment."

Journal

Assessment of drug induced hyperuricemia and gout risk using the FDA adverse event reporting system. (PubMed, Sci Rep) - "Among the hyperuricemia-related reports, telaprevir was the most frequently implicated drug, whereas lenalidomide ranked highest in the gout-related reports...Specifically, peginterferon alfa-2b was found to be an independent risk factor for drug-induced hyperuricemia, while 20 drugs-including pegloticase, febuxostat, allopurinol, rofecoxib, and furosemide-were identified as independent risk factors for drug-induced gout...Furthermore, key independent risk factors-including sex, age, and specific drugs-were identified through machine learning and multivariate analysis. These findings provide valuable insights for pharmacovigilance and clinical medication management."

Adverse events • Journal • Gout • Inflammatory Arthritis • Rheumatology

Telaprevir attenuates caspase-11-dependent pyroptosis in mouse heart following ischemia/reperfusion via inhibition of MALT1/TRAF6 pathway. (PubMed, Toxicol Appl Pharmacol) - "Mechanistically, telaprevir inhibited the recruitment of TRAF6 by MALT1, concomitant with the reduced recruitment of caspase-11 by TRAF6, and in turn, attenuated caspase-11 K63 poly-ubiquitination and activation, which was further confirmed by knockdown of TRAF6. Based on these results, we concluded that telaprevir could protect mouse heart against I/R injury by reducing caspase-11-dependent pyroptosis through inhibition of MALT1/TRAF6 pathway."

Journal • Preclinical • Cardiovascular • Extranodal Marginal Zone Lymphoma • Hematological Malignancies • Hepatitis C • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Myocardial Infarction • Oncology • Reperfusion Injury • Targeted Protein Degradation • MALT1 • TNFA • TRAF6

Advancing high-throughput anti-HCV drug screening: a novel dual-reporter HCV replicon model with real-time monitoring. (PubMed, Res Pharm Sci) - "Furthermore, the replicon system demonstrated a concentration-dependent response to anti-HCV pharmaceutical agents including telaprevir and sofosbuvir. These compelling results underscored the potential utility of the proposed HCV replicon system as an innovative model for the expeditious high-throughput screening of prospective anti-HCV agents within a short timeframe."

Journal • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Oncology • Solid Tumor

A Comprehensive Review of Antiviral Therapy for Hepatitis C: The Long Journey from Interferon to Pan-Genotypic Direct-Acting Antivirals (DAAs). (PubMed, Viruses) - "When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone...Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally."

Journal • Review • CNS Disorders • Depression • Hematological Disorders • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Psychiatry

Enterovirus D68 2A protease causes nuclear pore complex dysfunction and motor neuron toxicity. (PubMed, bioRxiv) - "We further show that 2A pro is toxic to induced pluripotent stem cell derived motor neurons by demonstrating a rescue of toxicity with 2A pro inhibitor telaprevir at concentrations that are insufficient to inhibit viral replication. This study expands our understanding of EV-D68 neuropathogenesis and provides a rationale for targeting the NPC or 2A pro therapeutically in AFM."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Infectious Disease • NUP98 • POM121

EARLY NONINVASIVE EVALUATION OF LIVER FIBROSIS AFTER HEPATITIS C TREATMENT: THE IMPACT OF INFLAMMATION. (PubMed, Arq Gastroenterol) - "The evaluation of hepatic elastography by the ARFI method before and after (6 - 9 months) successive treatment of hepatitis C in responders and non-responders led to the conclusion that the reduction of elastography parameters seems to be related to a decrease in hepatic inflammation rather than a reduction in fibrosis per se."

Journal • Fibrosis • Gastroenterology • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis

Pyrrolidine SS13 Induces Oxidative Stress and Autophagy-Mediated Cell Death in Colorectal Cancer Cells. (PubMed, Eur J Pharm Sci) - "Moreover, many medicinal drugs contain pyrrolidine moiety such as sunitinib (anticancer drug), telaprevir and ombitasvir (antiviral drugs) or ramipril (antihypertensive drug)...Finally, chloroquine, an inhibitor of autophagy, enhanced cell survival and suppressed the cytotoxic effect of SS13 in HCT116 and Caco-2 cells, indicating that SS13 contributes to autophagy-mediated cell death. Taken together, our results suggest that oxidative stress and autophagy participate in the antiproliferative effect of pyrrolidine SS13 on colorectal cancer cells. Further research using primary cell cultures obtained from different animal tissues as well as performing in vivo experiments is needed to understand these processes in detail and to investigate the potential therapeutic application of new pyrrolidine derivatives."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ATG7 • SOD2

Targeting inhibition of T3JAM reduces brain cell ferroptosis in rat following ischemia/reperfusion via a mechanism involving prevention of TLR4-mediated iron overload. (PubMed, Arch Biochem Biophys) - "Moreover, Telaprevir, an anti-hepatitis C virus (HCV) drug, could also provide beneficial effect on alleviating ischemic brain injury via inhibition of T3JAM. Based on these observations, we conclud that inhibition of T3JAM can reduce I/R-induced brain cell ferroptosis through downregulating TLR4 and that T3JAM could be a potential target for identifying novel or existing drugs (such as Telaprevir) to treat cerebral I/R injury."

Journal • Preclinical • Cardiovascular • CNS Disorders • Hematological Disorders • Hepatitis C • Hepatology • Infectious Disease • Oncology • Reperfusion Injury • Vascular Neurology • GPX4 • TFRC • TLR4 • TNFA

Research and development expenditure for CFTR modulators versus revenues after marketing: Striking the balance? (NACFC 2024) - " Cumulative R&D expenditures from 2001 until the marketing of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019 were $18.6 billion...More than 93% of the company's total sales revenues are derived from modulators, with the remainder from telaprevir... Cumulative CFTR modulator revenues are $52.8 billion, and pre-ETI R&D expenditures were $32 billion (including cost of capital), with total sales potentially passing $190 billion by patent expiry. Vertex's limited portfolio of marketed products allows meaningful direct comparison of R&D spending and product revenues. This methodology accounts for cost of Figure 1 (abstract 421): Cumulative annual inflation-adjusted R&D expenditure (without of USD."

Focusing on non-responders to infliximab with ulcerative colitis, what can we do first and next? (PubMed, Int Immunopharmacol) - "This study developed a novel prediction model for pre-assessing the efficacy of IFX in patients with UC, as the first step towards personalized therapy. Meanwhile, drugs and non-coding RNAs were provided as potential candidates to develop the next-step precise treatment for the predicted non-responders. In particular, Defeasirox appears to hold promise as an adjuvant or alternative to IFX for the optimization of UC therapy."

Journal • Colorectal Cancer • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CYP24A1

Disruption of bacterial DnaK synergizes with protein translation inhibitors (ACS-Fall 2024) - "Recently, we identified telaprevir, a peptidomimetic drug, as a micromolar inhibitor of DnaK ATPase activity and refolding ability in vitro...Biochemical and mass spectrometry assays indicate that DnaK interacts directly with these mistranslated clients. This work highlights the importance of chaperone function in handling proteins containing amino acid errors and presents a new mechanism to disable pathogenic bacteria, which will fuel the development of new small molecule chaperone inhibitors."

Infectious Disease • Respiratory Diseases • Targeted Protein Degradation • Tuberculosis

Desymmetric Hydrogenation of meso-Dicarboxylic Acids. (PubMed, J Am Chem Soc) - "This method provides a straightforward approach to produce chiral lactone intermediates for the manufacture of biotin, telaprevir, and other antivirus drugs. Both experimental and computational investigations were carried out, revealing a novel neighboring group coordination mechanism in the catalytic cycle."

Journal

Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors. (PubMed, J Med Chem) - "These efforts led to the discovery of 2A inhibitors with improved antiviral activity than telaprevir. These compounds represent promising lead compounds for further development as EV-D68 antivirals."

Journal • Respiratory Diseases

Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. (PubMed, Diagnostics (Basel)) - "L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant...The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Structure-based virtual screening of natural compounds against wild and mutant (R1155K, A1156T and D1168A) NS3-4A protease of Hepatitis C virus. (PubMed, J Biomol Struct Dyn) - "Telaprevir, a widely used protease inhibitor, was recruited as the control drug...Stable associations between the top compounds and the target protease were confirmed by the formation of hydrogen bonds in the binding pocket involving residues: His1057, Gly1137, Ser1139, and Ala1157. These findings suggest the potential of these compounds for further validation through biological evaluation.Communicated by Ramaswamy H. Sarma."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Telaprevir Improves Memory and Cognition in Mice Suffering Ischemic Stroke via Targeting MALT1-Mediated Calcium Overload and Necroptosis. (PubMed, ACS Chem Neurosci) - "According to these results, it can be concluded that telaprevir alleviates neuronal brain injury in stroke mice via restraining GluN2B activation and suppresses the receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway through inhibiting MALT1. Thus, telaprevir might have a novel indication for treating patients with ischemic stroke."

Journal • Preclinical • Cardiovascular • CNS Disorders • Hematological Malignancies • Hepatitis C • Hepatology • Infectious Disease • Ischemic stroke • Lymphoma • Marginal Zone Lymphoma • Oncology • Vascular Neurology • GRIN2B • MALT1 • RIPK1

Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways. (PubMed, Cell Metab) - "Using high-throughput screening assays, we identified telaprevir as a potent PE inhibitor that can increase human and rodent β cell viability in vitro and in vivo and improve glucose tolerance in insulin-resistant mice. Phospho-antibody microarrays and single-cell RNA sequencing analysis identified PAR2 and mechano-signaling pathways as potential mediators of PE. Taken together, our work highlights PE as a potential regulator of acinar-β cell crosstalk that acts to limit β cell viability, leading to T2D."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • ELANE

Utilization, Reimbursements and Prices Trends of Hepatitis C Virus Drugs in the US Medicaid Programs from 2001 to 2021 (ISPOR 2023) - "The study evaluated all medications authorized for HCV treatment in the US, such as ribavirin (RBV), pegylated interferon alfa-2a (PEG-INFA2a), and DAA brand and generics (e.g., Boceprevir, Telaprevir, Simeprevir, Sofosbuvir, Ledipasvir/Sofosbuvir, Elbasvir/Grazoprevir, Daclatasvir, Sofosbuvir/Velpatasvir, and Glecaprevir/Pibrentasvir). Despite the introduction of multiple DAAs agents, the drug prices remained high and unchanged during the study period. The increase in HCV incidence cases in recent years indicates accessibility issues for costly and effective DAAs medications."

Medicaid • Reimbursement • US reimbursement • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Telaprevir Treatment Reduces Paralysis in a Mouse Model of Enterovirus D68 Acute Flaccid Myelitis. (PubMed, J Virol) - "This study improves understanding of EV-D68 pathogenesis in the mouse model of AFM. This study serves as a proof of principle for the first FDA-approved drug that has been shown to improve AFM outcomes and have in vivo efficacy against EV-D68 as well as underlines the importance of the continued development of EV-D68 antivirals."

Journal • Preclinical • CNS Disorders • Infectious Disease • Pediatrics

Interventions for dialysis patients with hepatitis C virus (HCV) infection. (PubMed, Cochrane Database Syst Rev) - "In dialysis patients with HCV infection grazoprevir plus elbasvir probably improves ETR. There is no difference in ETR or SVR for combinations of telaprevir, ribavirin and PEG interferon given for different durations and doses. Though no longer in use, PEG interferon was more effective than standard interferon for ETR but not SVR. Increasing doses of PEG interferon did not improve responses. The addition of ribavirin to PEG interferon may result in fewer relapses, higher SVR, and higher numbers with adverse events."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Nephrology • Renal Disease • Transplantation

Development of FRET and Stress Granule Dual-Based System to Screen for Viral 3C Protease Inhibitors. (PubMed, Molecules) - "Moreover, Telaprevir and Trifluridine also modulated 3Cpro-mediated physiological processes, including the cleavage of host proteins, inhibition of the innate immune response, and consequent facilitation of viral replication. Taken together, the FRET and SG dual-based system exhibits a promising potential in the screening for inhibitors of viral proteases that cleave G3BP1."

Journal • Infectious Disease • Novel Coronavirus Disease • G3BP1

TIG3: Telaprevir in Genotype 3 HCV (clinicaltrials.gov) - P4 | N=14 | Completed | Sponsor: Queen Mary University of London | Unknown status ➔ Completed | N=30 ➔ 14

Enrollment change • Trial completion • Hepatitis C • Hepatology • Infectious Disease • Inflammation

An in-silico pharmacophore-based molecular docking study to evaluate the inhibitory potentials of novel fungal triterpenoid Astrakurkurone analogues against a hypothetical mutated main protease of SARS-CoV-2 virus. (PubMed, Comput Biol Med) - "To conclude, Astrakurkurone analogues ZINC89341287 and ZINC12128321 can be potential therapeutic agents against the highly infectious SARS-CoV-2 virus."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Clinical and economic value of sofosbuvir-based regimens in the treatment of chronic hepatitis C in Spain. (PubMed, PLoS One) - "For Spain, SOF-based regimens offer value for HCV patients in terms of lowering HCV-related liver disease burden and generating significant cost savings for the health system, contributing to the WHO goal."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Oncology • Solid Tumor • Transplantation