Delving into the Latest Updates on Faldaprevir with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

Faldaprevir-sodium, 福达瑞韦

+ [4]

Target

NS3/NS4A

Mechanism

NS3/NS4A inhibitors(Hepatitis C virus serine protease, NS3/NS4A inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System DisordersImmune System Diseases+ [4]

Active Indication-

Inactive Indication

Chronic hepatitis C genotype 1Chronic hepatitis C genotype 1bCompensated cirrhosis+ [5]

Originator Organization

Boehringer Ingelheim GmbH

Active Organization-

Inactive Organization

Boehringer Ingelheim GmbH

Trek Therapeutics PBCStartupBoehringer Ingelheim International GmbH

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC40H49BrN6O9S

InChIKeyLLGDPTDZOVKFDU-XUHJSTDZSA-N

CAS Registry801283-95-4

To investigate the potential of Faldaprevir to induce skin phototoxicity, immediate or delayed type, to UV light and visible light in healthy male and female subjects. To investigate the degree, wavelength dependency, severity, pigmentation and morphology of the phototoxic effects. The persistence of the phototoxic susceptibility will be explored following cessation of study medication. Within a sunscreen sub-study, the efficacy of commercially available high factor sunscreen will also be assessed in terms of its potential to prevent any phototoxic skin responses seen. The safety and tolerability of Faldaprevir will also be assessed.

Start Date01 Apr 2014

Sponsor / Collaborator

Boehringer Ingelheim GmbH

100 Clinical Results associated with Faldaprevir

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100 Translational Medicine associated with Faldaprevir

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100 Patents (Medical) associated with Faldaprevir

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91

Literatures (Medical) associated with Faldaprevir

30 Sep 2023·Diagnostics (Basel, Switzerland)

Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections.

Article

Author: Izhari, Mohammad Asrar

Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), n = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n = 9) and genotype 5 (n = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. 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.

22 Sep 2023·Journal of Biomolecular Structure and Dynamics

Interdisciplinaryin silicostudies to understand in-depth molecular level mechanism of drug resistance involving NS3-4A protease of HCV

Article

Author: Hazra, Mousumi ; Dubey, Ramesh Chandra

Hepatitis C virus (HCV) causes hepatitis, a life-threatening disease responsible for liver cirrhosis. Urgent measures have been taken to develop therapeutics against this deadly pathogen. NS3/4A protease is an extremely important target. A series of inhibitors have been developed against this viral protease including Faldaprevir. Unfortunately, the error-prone viral RNA polymerase causes the emergence of resistance, thereby causing reduced effectiveness of those peptidomimetic inhibitors. Among the drug resistant variants, three single amino acid residues (R155, A156 and D168) are notable for their presence in clinical isolates and also their effectivity against most of the known inhibitors in clinical development. Therefore, it is crucial to understand the mechanistic role of those drug resistant variants while designing potent novel inhibitors. In this communication, we have deeply analyzed through using in silico studies to understand the molecular mechanism of alteration of inhibitor binding between wild type and its R155K, A156V and D168V variants. Principal component analysis was carried to identify the backbone fluctuations of important residues in HCV NS3/4A responsible for the inhibitor binding and maintaining drug resistance. Free energy landscape as a function of the principal components has been used to identify the stability and conformation of the key residues that regulate inhibitor binding and their impact in developing drug resistance. Our findings are consistent with the trend of experimental results. 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.Communicated by Ramaswamy H. Sarma.

01 May 2021·Die PharmazieQ4 · MEDICINE

Effect of itraconazole on the pharmacokinetics of faldaprevir in healthy subjects.

Q4 · MEDICINE

Article

Author: Koenen, R ; Elgadi, M ; Huang, F ; Kammerer, K P ; Strelkowa, N ; Marzin, K ; Haertter, S

Faldaprevir (FDV), a substrate of CYP3A/P-glycoprotein (P-gp), is a selective inhibitor of the hepatitis C virus (HCV) NS3/4 protease. FDV is currently under clinical development for application in interferon-free treatment regimens for patients with chronic HCV infection. Understanding the drug-drug interaction potential of FDV is critical, as certain drug combinations may facilitate the more rapid achievement of steady-state-that is, the ideal drug concentration and balanced metabolic cycle of absorption and elimination that optimize drug efficacy. We thus conducted this study to investigate the effect of itraconazole (ICZ), a strong inhibitor of CYP3A and a moderate inhibitor of P-gp, on the pharmacokinetics (PK) of FDV. Eighteen healthy male and female volunteers participated in this open-label, fixed-sequence study. FDV 120 mg twice daily (BID) was administered on Day 1, followed by 120 mg once daily (QD) from Day 2 until the end of the 10-day study; after 6 days of FDV alone, ICZ 200 mg was added to FDV for an additional 4 days (BID on Day 7 and QD from Day 8 to Day 10). Intensive PK sampling was performed after 6 days of FDV treatment and again after 4 days of combined FDV/ICZ treatment. The adjusted geometric mean (gMean) ratios (%) of area under the concentration curve over dosing interval at steady-state (AUC_{τ, ss}) and maximal concentration at steady-state (C_{max, ss}) for combined FDV/ICZ treatment vs. FDV treatment alone were 198.6% and 180.6%, respectively, with 90% confidence intervals (CIs) of 182.4-216.1 and 165.7-196.9. Administration of FDV alone or in combination with ICZ was observed to be safe and well-tolerated. 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.

100 Deals associated with Faldaprevir

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Faldaprevir	J05AP04	DB11808

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic hepatitis C genotype 1	Phase 3	JP	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	KR	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	AT	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	JP	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	KR	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	ES	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	AT	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	ES	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	DE	Boehringer Ingelheim GmbH	01 Apr 2011
Chronic hepatitis C genotype 1	Phase 3	DE	Boehringer Ingelheim GmbH	01 Apr 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01579474 (Pubmed \| Hepatol Res)	Phase 3	Chronic hepatitis C genotype 1	131	faldaprevir 120 mg	(fvhfnblhdw) = moetlxhabj nfvdzrsrcc (alrpbxewyg )	-	01 Mar 2017
				faldaprevir 240 mg 12 weeks	(fvhfnblhdw) = zboozsovxy nfvdzrsrcc (alrpbxewyg )
NCT01830127 (HCVerso3, Pubmed \| J Biol Chem) Manual	Phase 2	Fibrosis \| Hepatitis C	35	Faldaprevir+Deleobuvir+Ribavirin (moderate hepatic impairment（Child-Pugh B [CPB]）)	(qwbgpqucgw) = omaxykerdi bdfhdesnrx (egfdivhssl, 29.2 - 76.7) View more	Positive	28 Dec 2016
				Faldaprevir+Deleobuvir+Ribavirin (mild hepatic impairment（Child-Pugh A [CPA]）)	(qwbgpqucgw) = xdmsksayxi bdfhdesnrx (egfdivhssl, 38.6 - 83.6) View more
NCT01525628 (CTgov)	Phase 1	Chronic hepatitis C genotype 1	72	BI 207127+pegylated interferon+BI 201335+tolbutamide+midazolam+caffeine+ribavirin (Group A)	ruytbofpef(hmjlwfmzjm) = bsrwvdwrlw jtmjtyemch (jhieuomqyk, bbmuryflee - yapbyloaub) View more	-	10 Jun 2016
				BI 207127+pegylated interferon+BI 201335+tolbutamide+midazolam+caffeine+ribavirin (Group B)	ruytbofpef(hmjlwfmzjm) = dbofcsqydl jtmjtyemch (jhieuomqyk, ahvytkufdw - ashquugxxs) View more
NCT01965431 (CTgov)	Phase 1	-	48	BI 207127+Faldaprevir (BI 207127+ Faldaprevir)	llmqwrlwel(uyvdasdnrj) = eyhgdxvovn sxbjtjextp (gddkuldurn, xsigolroky - xutsdjvuzz) View more	-	14 Apr 2016
				Placebo+BI 207127+Faldaprevir (Placebo to BI 207127 + Placebo to Faldaprevir)	llmqwrlwel(uyvdasdnrj) = atrjfffgmf sxbjtjextp (gddkuldurn, tjhfzkdtux - gfqczsvdpa) View more
NCT01528735 (CTgov)	Phase 2	Hepatitis C, Chronic	25	Deleobuvir+Faldaprevir (600mg Deleobuvir and 80mg Faldaprevir)	qeyftqfvdq(ewomftkjhr) = wevmqvpbba bslyexhrcb (zmihvomweo, prtijdvfux - surdqlknqh) View more	-	13 Apr 2016
				Deleobuvir+Faldaprevir (600mg Deleobuvir and 120mg Faldaprevir)	qeyftqfvdq(ewomftkjhr) = oplrheepqz bslyexhrcb (zmihvomweo, jdkxjssjnj - hqgaqqkwcj) View more
NCT01957657 (CTgov)	Phase 1	Renal Insufficiency	4	Deleobuvir+Faldaprevir	uwgvuztwaf(dfvcaxngpp) = zhatdcqfvc kawhuyzjeb (yigeitmklf, nrduvwwjva - rjrdskonys) View more	-	11 Apr 2016
NCT01941615 (CTgov)	Phase 1	-	18	Deleobuvir+Faldaprevir+Microgynon	zeackqfvck(buvkbkzapz) = akjpjeqhka hleicwfski (negmkqmepk, lhmdjietfq - rruaznjzut) View more	-	11 Apr 2016
NCT01737996 (CTgov)	Phase 1	-	32	Deleobuvir (400 mg Deleobuvir)	qzslecrpwq(itmgpjeoqj) = zyzwxsfftu qnwtoypvjg (hkapecetlp, ggbrqxntps - nubxqryzbx) View more	-	08 Apr 2016
				Deleobuvir (600 mg Deleobuvir)	qzslecrpwq(itmgpjeoqj) = dfsrfwuixv qnwtoypvjg (hkapecetlp, ugvknekgrg - laktwgugop) View more
NCT01528735 (Pubmed \| Hepatol Res) Manual	Phase 2	Chronic hepatitis C genotype 1 First line	25	deleobuvir+ribavirin+peginterferon-α-2a+faldaprevir 80mg	(kknebpriuo) = xwxpaxxvzy rkzvoicenh (hceuaaswyv ) View more	Positive	01 Mar 2016
				deleobuvir+ribavirin+peginterferon-α-2a+faldaprevir 120mg	(kknebpriuo) = vfmqcoigbd rkzvoicenh (hceuaaswyv ) View more
NCT01330316 (Pubmed \| J Viral Hepat) Manual	Phase 3	Hepatitis C	118	peginterferon+ribavirin+faldaprevir (prior relapsers)	(bararzobhg) = nycdmwxsua fwxoqcwxom (tythicugqf, 89.1 - 100.0) View more	Positive	01 Mar 2016
				peginterferon+ribavirin+faldaprevir (prior nonresponders (null responders, partial responders and patients with breakthrough))	(bararzobhg) = ahkupkibcs fwxoqcwxom (tythicugqf, 43.4 - 65.9) View more