faldaprevir (BI201335) / Boehringer Ingelheim - LARVOL DELTA

Safety, tolerability, and pharmacokinetics of faldaprevir after single increasing doses in healthy subjects. (PubMed, Front Pharmacol) - "In conclusion, at single doses of 4-1,200 mg in healthy male subjects, FDV showed dose-dependent pharmacokinetics and was generally considered safe and well tolerated. Food had no clinically relevant effect on the rBA of FDV."

Journal • PK/PD data • Hepatitis C • Infectious Disease • Inflammation

Pharmacokinetics and Pharmacodynamics of Faldaprevir Following Multiple Oral Rising Doses in Healthy Volunteers and Subjects with Gilbert's Syndrome. (PubMed, Clin Pharmacol Drug Dev) - "Total bilirubin increased dose-dependently, with higher indirect bilirubin in GS subjects. FDV exhibited non-linear, time-dependent PK and was generally well tolerated up to 240 mg/day in subjects with or without GS."

Clinical • Journal • PK/PD data • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Beyond Barriers, Big Crystallization Hurdles: Atropisomerism in Beyond Rule of Five Compounds Explored by Computational and NMR Studies. (PubMed, Mol Pharm) - "In this study, we explore the intricate interplay between atropisomerism and crystallization using two model bRo5 compounds, namely, ACBI1 and BI201335, both violating three of four Lipinski's rules. This comprehensive analysis highlights the significance of understanding stereochemical phenomena such as atropisomerism in designing and developing bRo5 compounds. By integrating advanced analytical techniques and crystallization strategies, this work provides novel insights into tailoring pharmaceutical properties for next-generation therapeutics."

Journal

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

Interdisciplinary in silico studies to understand in-depth molecular level mechanism of drug resistance involving NS3-4A protease of HCV. (PubMed, J Biomol Struct Dyn) - "The observations are also true in case of other Faldaprevir-like peptidomimetic inhibitors. Understanding this binding mechanism would be significant for the development of novel inhibitors with less susceptibility towards drug resistance."

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

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro. (PubMed, Antimicrob Agents Chemother) - "Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among macrocyclic PI, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir in between. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively...Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19."

Journal • Preclinical • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Lung Cancer • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Effect of itraconazole on the pharmacokinetics of faldaprevir in healthy subjects. (PubMed, Pharmazie) - "Co-administration with ICZ, however, resulted in an approximately two-fold increase in FDV steady-state exposure. Furthermore, FDV required no dosage adjustment when co-administered with ICZ."

Clinical • Journal • PK/PD data • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. (PubMed, Sci Rep) - "Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CL inhibitors. We recommend further experimental investigation of these compounds."

Journal • Infectious Disease • Novel Coronavirus Disease

Drug Drug Interaction Study Between BI 201335 and BI 207127 in Chronic Hepatitis C Infected Patients (clinicaltrials.gov) - P1; N=72; Active, not recruiting; Sponsor: Boehringer Ingelheim; N=102 -> 72

Enrollment change • Biosimilar • Hepatitis C Virus • Immunology

"#Researchers, the excellent preclinical properties of our HCV protease inhibitor faldaprevir make it an excellent choice for advancing science against #InfectiousDiseases. Now on #opnMe" (@Boehringer)

Preclinical • Hepatitis C Virus • Infectious Disease

[Late breaking abstract] Rapid and consistent virologic responses in a phase 2 trial of a new all-oral combination of faldaprevir, deleobuvir, and PPI-668, with and without ribavirin, in patients with HCV genotype-1a infection (AASLD 2013) - Presentation time: Mon, Nov 04, 2013; 8:00 AM - 5:30 PM; P2, N=36; NCT01859962; Sponsor: Presidio; "...oral combination regimen of faldaprevir + deleobuvir + PPI-668 +/- RBV has consistently produced rapid virologic responses, with 28/29 (97%) patients to date achieving HCV RNA <25 IU/mL...and with 13/13 (100%) patients exhibiting non-detectable HCV RNA...at end of treatment (week 12). SVR4 data will be available at the meeting."

P2 data • Hepatitis C Virus

Rapid and consistent virologic responses in a phase 2 trial of a new all-oral combination of faldaprevir, deleobuvir, and PPI-668 (HepDART 2013) - Abstract 100; P2a, N=36; NCT01859962; Sponsor: Presidio Pharmaceuticals; "Of 29 patients with at least 4 weeks of treatment, 28 achieved HCV RNA <25 IU/mL (<LLOQ). Two of these patients had potentially meaningful pre-existing NS5A resistance substitutions and 9 had NS5B Thumb 1 polymorphic substitution A421V....Adverse events were mild to moderate, with rashes and gastrointestinal side effects similar to previous faldaprevir and deleobuvir trials." 

P2 data • Hepatitis C Virus

High rate of sustained virologic response in patients with HCV genotype-1a infection: A phase 2 trial of faldaprevir, deleobuvir and PPI-668, with and without ribavirin (EASL 2014) - Presentation time: 11.04.2014, 16:00-18:00; Abstract #O65; P2, N=36; NCT01859962; Sponsor: Presidio; “27/28 (96%) patients had HCV RNA levels below lower limit of detection (< LLOD) at EOT. 19/20 (95%) patients who reached 4 weeks post-treatment have achieved SVR4 (1 relapse), and 12/12 (100%) have achieved SVR8…Rash and GI events are similar to previous FDV/DBV trials, with the RBV-free cohort showing fewer AEs.”

P2 data • Hepatitis C Virus

Presidio Pharmaceuticals teams up with Boehringer Ingelheim on hepatitis C drug combo (San Francisco Business Times) - "Presidio's drug PPI-668 will be combined in an oral treatment with Boehringer Ingelheim's two protease inhibitors BI201335 and BI207127...The two companies will test a combination...in a Phase IIa clinical trial over 12 weeks. The tests begin in the second quarter of 2013."

Anticipated new P2a trial • Hepatitis C Virus

Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection (Liver Int) - PMID: 23944720; P2, N=NA; "SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated."

P2 data • Hepatitis C Virus

Drug-drug interaction with BI 201335 and efavirenz (clinicaltrials.gov) - P1, N=29; Recruiting → Active, not recruiting

Enrollment closed • Hepatitis C Virus

Japanese pegylated interferon (PegIFN) alfa-2b/ribavirin (RBV) combination trial (clinicaltrials.gov) - P3, N=131; Recruiting -> Active, not recruiting

Enrollment closed • Hepatitis C Virus

BI 207127 / faldaprevir combination therapy in hepatic impairment (Child-Pugh B) patients with genotype 1b chronic hepatitis C infection: HCVerso3 (clinicaltrials.gov) - P2, N=36 -> 35; Sponsor: Boehringer Ingelheim; Recruiting -> Active, not recruiting.

Enrollment closed • Hepatitis C Virus

This trial evaluates safety, pharmacokinetic profile and anti-viral response of BI 207127 and BI 201335 for patients with chronic hepatitis C (clinicaltrials.gov) - P2, N=25; Sponsor: Boehringer Ingelheim; Active, not recruiting -> Completed.

Trial completion • Hepatitis C Virus

Pharmacokinetics of faldaprevir of soft capsule (clinicaltrials.gov) - P1, N=25; Sponsor: Boehringer Ingelheim; Active, not recruiting -> Completed.

Trial completion • Hepatitis C Virus

Pharmacokinetics and safety of BI 201335 in patients with mild to severe renal impairment (clinicaltrials.gov) - P1, N=28; Recruiting -> Completed; Primary completion date: Dec 2012 -> Jun 2012

Trial completion • Trial completion date • Hepatitis C Virus

Drug-drug interaction with BI 201335 and efavirenz (clinicaltrials.gov) - P1, N=29; Not yet recruiting

Hepatitis C Virus

Drug Drug Interaction Study Between BI 201335 and BI 207127 in Chronic Hepatitis C Infected Patients (clinicaltrials.gov) - P1; N=72; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting -> Completed ; Trial primary completion date: Dec 2013 ->Oct 2014

Trial completion • Trial primary completion date • Biosimilar • Hepatitis C Virus • Immunology • Inflammation

New Boehringer Ingelheim hepatitis C data to be presented at AASLD (Businesswire) - BI will present new HCV data at scientific sessions of 62nd AASLD; Key data presented will include a week 12 interim analysis of SOUND-C2, a P2b study evaluating an interferon-free combination of its protease inhibitor BI 201335 & its polymerase inhibitor BI 207127 – with and without ribavirin in treatment-naïve HCV infected pts; In addition, SILEN-C1 & SILEN-C3 data will further assess efficacy & safety of BI 201335 in treatment-naïve HCV-infected pts, in combination PegIFN/RBV

Anticipated data presentation • Hepatitis C Virus

Investigation of interactions between faldaprevir, itraconazole, atorvastatin and rosuvastatin (clinicaltrials.gov) - P1, N=54; Sponsor: Boehringer Ingelheim; Recruiting; New P1 trial.

New P1 trial • Hepatitis C Virus