Tuesday, March 24, 2015

Drugs in Clinical Pipeline: Ravidasvir | NS5A Inhibitor | Treatment for Hepatitis C | IFN free Regimen

Ravidasvir [Methyl N-[(1S)-1-({(2S)-2-[5-(6-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]- 3- methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}naphthalen-2-yl) -1H- benzimidazol- 2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate] is an Nonstructural protein 5A (NS5A) inhibitor.

Ravidasvir: 2D and 3D Structure

It is an antiviral agent that is being developed as a potential treatment for hepatitis C virus infection. Ravidasvir has 50% inhibitory concentrations (EC50 's) values of 0.02-1.3 nM in replicon assays for HCV genotypes 1-7 (gt1-gt7). 
Ravidasvir was developed by Presidio Pharmaceuticals Inc, later Ascletis licensed it. Ravidasvir is in Phase II clinical trials proving interferon (IFN)-free regimen to treat chronic hepatitis C (CHC). Ascletis is now the first Chinese company to file clinical trial applications in China for an IFN-free regimen. 
IUPAC Name: Methyl N-[(1S)-1-({(2S)-2-[5-(6-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}naphthalen-2-yl) -1H- benzimidazol- 2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate
Common Name: PPI-668; BI 238630; ASC16
Originator: Presidio Pharmaceuticals Inc/Ascletis

One striking thing about this name, Ravidasvir (Ravidas+vir):
Ravidas was a North Indian Guru mystic of the bhakti movement He was active in the 15th century CE. He is often given the honorific title of Bhagat or Sant. He was a socio-religious reformer, a thinker, a theosophist, a humanist, a poet, a traveller, a pacifist and a spiritual figure. 
Hepatitis C virus infection is a major health problem worldwide and no vaccine has yet been developed against this virus. The standard therapy of pegylated-interferon and ribavirin induces serious side effects and provides viral eradication in less than 50% of patients. Combination therapy of HCV including ribavirin and interferon are currently is the approved therapy for HCV. Unfortunately, such combination therapy also produces side effects and is often poorly tolerated, resulting in major clinical challenges in a significant proportion of patients. The combination of direct acting agents can also result in drug-drug interactions. To date, no HCV therapy has been approved which is interferon free. There is therefore a need for new combination therapies which have reduced side effects, and interferon free, have a reduced emergence of resistance, reduced treatment periods and/or and enhanced cure rates.
Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. 
A number of direct-acting antiviral agents (DAAs) are under development for the treatment of chronic HCV infection. These agents block viral production by directly inhibiting one of several steps of the HCV lifecycle. several viral proteins involved in the HCV lifecycle, such as the non-structural (NS)3/4A serine protease, the NS5B RNA-dependent RNA polymerase (RdRp), and the NS5A protein, have been targeted for drug development. Two NS3/4A protease inhibitors already approved for clinical use, numerous other protease inhibitors are being developed as well as inhibitors of viral replication, including nucleoside/nucleotide analogue inhibitors of HCV RdRp, non-nucleoside inhibitors of RdRp, cyclophilin inhibitors, and NS5A inhibitors. 
Inhibition of NS5A at picomolar concentrations has been associated with significant reductions in HCV RNA levels in cell culture-based models, which makes these agents among the most potent antiviral molecules yet developed.

1H NMR (Estimated) for Ravidasvir

This NS5A inhibitor has been shown to possess high efficacy against HCV genotype 1, with up to 3.7 log10 mean HCV RNA reductions, in a Phase Ib clinical trial. Activity was demonstrated against variants harbouring the L31M substitution. In an added genotype-2/3 cohort, the first 2 patients achieved mean 3.0 log10 RNA level reductions [1].
Results from the Phase IIa study involving a combination therapy with Faldaprevir and Deleobuvir plus Ravidasvir came with positive news where the said combination cured 92 percent of those with genotype 1a of hepatitis C virus (HCV) when given with ribavirin.  The results presented at the 49th annual meeting of the European Association for the Study of the Liver (EASL) in London [2, 3].
The 36 study participants were randomly dived into three even cohorts of 12 each: The first received 600 mg of Deleobuvir twice a day as well as once-daily doses of Faldaprevir (120 mg), Ravidasvir and Ribavirin. The second group received the same regimen except the Faldaprevir dose was 400 mg. The third group took the regimen with the higher dose of Faldaprevir, but without Ribavirin. All participants were treated for 12 weeks with follow up for next 24 weeks.
Ninety-two percent of the first and second cohorts (11 out of 12 in both cases) achieved a sustained virologic response 12 weeks after completing therapy (SVR12, considered a cure). In the end, 14 participants were required for the third cohort, because one was incarcerated early on during treatment and another experienced viral rebound at week eight as a result of not adhering to the treatment regimen. Of the other 12 participants, eight, or two-thirds, have achieved an SVR12, while one more participant stopped taking the therapy at week eight but has since achieved an SVR8. 
1. Lalezari, J. P.; et. al. PPI-668, a potent new pan-genotypic HCV NS5A inhibitor: phase 1 efficacy and safety. Hepatology 2012, 56, 1065A-1066A.
2. ClinicalTrials.gov A Study of the Efficacy and Safety of PPI-668 (NS5A Inhibitor) Plus Sofosbuvir, With or Without Ribavirin, in Patients With Chronic Hepatitis C Genotype-4. NCT02371408 (retrieved on 24-03-2015)
3. ClinicalTrials.gov Study of PPI-668, BI 207127 and Faldaprevir, With and Without Ribavirin, in the Treatment of Chronic Hepatitis C. NCT01859962 (retrieved on 15-09-2015)
4. Lalezari, J.; et. al. 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-The International Liver Congress 2014 - 49th Annual Meeting of the European  Association for the Study of the Liver London, United Kingdom  April 9-13 (article here)