alisporivir and Hepatitis-C--Chronic

Alisporivir (ALV) (previously known as Debio 025) is a potent, pangenotypic host-targeting antiviral oral agent acting on cyclophilin A, which is necessary for HCV replication. Areas covered: This article reviews the therapeutic efficacy and safety of ALV for the treatment of HCV infection. Expert opinion: Direct-acting antivirals (DAAs) have revolutionized the HCV antiviral treatment paradigm with success rates well above 95% for all HCV genotypes. However, challenges still remain in certain patient populations such as those who have developed resistance and have experienced multi-DAA failure. To cure HCV infection, a treatment regimen must combine antiviral potency and a high barrier to resistance. ALV fulfills this need as shown by the studies evaluating its clinical efficacy. Nevertheless, ALV missed the chance to be included in the HCV treatment armamentarium after the FDA halted clinical studies following reports of serious side effects (three cases of pancreatitis, one lethal). However, it is possible that ALV could still be considered for HCV-infected non-cirrhotic patients that are infected with a multiresistant virus or with HCV genotype 3, although it must be said that the drug industry would be reluctant to invest in new antivirals if the current clinical need is effectively met.

Topics: Antiviral Agents; Cyclosporine; Hepacivirus; Hepatitis C, Chronic; Humans; Treatment Outcome

Due to the side effect profile of pegylated interferons interferon treatment has become the holy grail of drug development for chronic hepatitis C. The precise role of interferon in treatment of hepatitis C is not fully understood, besides its antiviral effects interferon is an immune modulator. Nevertheless, recent proof of concept studies indicated, that cure of chronic hepatitis C can be achieved without interferon. Various compounds achieved this goal, like the polymerase inhibitor PSI 7977, the combination of NS5a inhibitor (daclatasvir) and a protease inhibitor (asunaprevir) and the cyclophillin antagonist alisporivir. Various other combinations are investigated currently. Providing that phase 3 studies will confirm these exciting data, direct acting antivirals or host targets will replace peginterferon/ribavirin combination therapy.

Topics: Antiviral Agents; Carbamates; Cyclophilins; Cyclosporine; Drug Substitution; Hepatitis C, Chronic; Humans; Imidazoles; Immunologic Factors; Interferon-alpha; Polyethylene Glycols; Pyrrolidines; Recombinant Proteins; Serine Proteinase Inhibitors; Sofosbuvir; Uridine Monophosphate; Valine

Topics: Antiviral Agents; Cyclosporine; Diterpenes; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fatty Alcohols; Female; Fluvastatin; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Male; Metformin; Nitro Compounds; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Silybin; Silymarin; Thiazoles

Several directly acting and host targeting antivirals that inhibit hepatitis C virus replication have entered clinical trials. Among the most advanced of these are RG7128, an inhibitor of the NS5B polymerase; BMS-790052, an inhibitor of NS5A; and alisporivir, an inhibitor of human cyclophilins. These agents have potent antiviral activity in chronic HCV patients, act additively or synergistically with inhibitors of the HCV NS3/4A protease, and improve the rate of virologic response produced by traditional pegylated interferon plus ribavirin therapy. No cross resistance has been observed; moreover, nucleoside NS5B and cyclophilin inhibitors appear to suppress resistance to non-nucleoside NS5B and NS3/4A inhibitors. Several recent reports of virologic responses produced by combinations of agents that inhibit HCV replication in the absence of interferon provide optimism that eradication of HCV will be possible without interferon in the future.

Topics: Animals; Antiviral Agents; Carbamates; Cyclosporine; Deoxycytidine; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Pyrrolidines; Valine; Virus Replication

Debio 025 is a cyclophilin (Cyp) inhibitor without calcineurin-binding properties. The drug inhibits viral replication of genotype 1b and 2a replicons in nanomolar concentrations and shows an additive to synergistic antiviral effect with interferon, ribavirin, and specifically targeted antiviral therapy for hepatitis C (STAT-C) drugs. There is no cross-resistance with protease and polymerase inhibitors. In humans, Debio 025 has shown activity against genotypes 1, 2, 3, and 4, and displays an additive antiviral effect with pegylated interferon (peg-IFN)alpha2a in genotype 1 and 4 patients. The most prominent side effect is reversible hyperbilirubinaemia caused by inhibition of biliary transporters. Debio 025 is a potent anti-HCV drug, with a novel mechanism of action and an efficacy profile that makes it an attractive candidate for combination with current and future HCV treatments.

Topics: Animals; Antiviral Agents; Cyclophilins; Cyclosporine; Hepatitis C, Chronic; Humans

Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of >90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced alisporivir susceptibility, emerged in two subjects in the alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8log10IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the association of alisporivir or interferon treatment with the observed amino acid changes.

Topics: Antiviral Agents; Cyclosporine; Drug Resistance, Viral; Genome, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Phylogeny; Polyethylene Glycols; Recombinant Proteins; Viral Load; Viral Nonstructural Proteins

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents.

Topics: Adult; Aged; Antiviral Agents; Cyclosporine; Double-Blind Method; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Placebos; Ribavirin; Salvage Therapy; Treatment Outcome; Viral Load; Young Adult

Alisporivir is a cyclophilin inhibitor with pan-genotypic anti-hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL-1 study assessed alisporivir as interferon (IFN)-free therapy in treatment-naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once-daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg-IFN); or arm 5, Peg-IFN and RBV. Patients receiving IFN-free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg-IFN from weeks 6 to 24. Overall, 300 patients received ALV-based regimens. In arm 1 to arm 4, the intent-to-treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg-IFN/RBV. Per-protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN-free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg-IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN-free regimens were numerically higher in genotype 3- than in genotype 2-infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN-free ALV treatment showed markedly better safety/tolerability than IFN-containing regimens.. ALV plus RBV represents an effective IFN-free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN-free combination regimens with direct-acting antiviral drugs deserve exploration in future trials.

Topics: Adult; Antiviral Agents; Cyclosporine; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin

Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance.. To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection.. Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy.. A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension.. Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Cyclosporine; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Treatment Outcome; United States; Young Adult

The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-alpha2a (PEG IFN-alpha2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-alpha2a 180 microg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 microg/week PEG IFN-alpha2a. In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments induced a continuous decay in viral load that reached -4.61 +/- 1.88 and -4.75 +/- 2.19 log(10) IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by -5.91 +/- 1.11 and -5.89 +/- 0.43 log(10) IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-alpha2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day).. These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-alpha2a.

Topics: Adult; Aged; Antiviral Agents; Cyclosporine; Double-Blind Method; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Viral Load; Young Adult

Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin.

Topics: Adult; Age Factors; Antiviral Agents; Asian People; Blood Glucose; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclosporine; Diabetes Mellitus, Type 2; Female; Hepatitis C, Chronic; Humans; Interferons; Logistic Models; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Ribavirin; Risk Factors; Sex Factors; Treatment Outcome

Alisporivir (ALV), a cyclophilin inhibitor, is a host-targeting antiviral (HTA) with multigenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. Recent advances have supported the concept of interferon (IFN)-free regimens to treat chronic hepatitis C. As the most advanced oral HTA, ALV with direct-acting antivirals (DAAs) represents an attractive drug combination for IFN-free therapy. In this study, we investigated whether particular DAAs exhibit additive, synergistic, or antagonistic effects when combined with ALV. Drug combinations of ALV with NS3 protease, NS5B polymerase, and NS5A inhibitors were investigated in HCV replicons from genotypes 1a, 1b, 2a, 3, and 4a (GT1a to -4a). Combinations of ALV with DAAs exerted an additive effect on GT1 and -4. A significant and specific synergistic effect was observed with ALV-NS5A inhibitor combination on GT2 and -3. Furthermore, ALV was fully active against DAA-resistant variants, and ALV-resistant variants were fully susceptible to DAAs. ALV blocks the contact between cyclophilin A and domain II of NS5A, and NS5A inhibitors target domain I of NS5A; our data suggest a molecular basis for the use of these two classes of inhibitors acting on two distinct domains of NS5A. These results provide in vitro evidence that ALV with NS5A inhibitor combination represents an attractive strategy and a potentially effective IFN-free regimen for treatment of patients with chronic hepatitis C. Due to its high barrier and lack of cross-resistance, ALV could be a cornerstone drug partner for DAAs.

Topics: Antiviral Agents; Cyclophilin A; Cyclophilins; Cyclosporine; Drug Resistance, Viral; Drug Synergism; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Replicon; Viral Nonstructural Proteins; Virus Replication

Topics: Antiviral Agents; Cyclosporine; Hepacivirus; Hepatitis C, Chronic; Humans; Protease Inhibitors; RNA-Dependent RNA Polymerase