Boehringer Ingelheim presents interferon-free SOUND-C2 data at EASL...

Today (Saturday, April 21, 2012) is the big day all us HCV drug development nerds (I'd use 'wonks', but that sounds even worse) are waiting for in regards to the late-breaker presentations from EASL and any additional nuggets of info.  One of those presentations will  on the SOUND-C2 trial, featuring the interferon-free combination of Boehringer Ingelheim's HCV PI BI 201335 and polymerase inhibitor BI 207127 both with  ribavirin. According to the press release below, the interim results of the combo show a 68% SVR12 overall in genotype 1 patients in the 28 week arm regardless of IL-28B status. In the 16 week arm, SVR12 was achieved in 59% of patients.  As one might suspect, those subjects that were genotype 1a and non-CC IL-28B status experienced higher relapse and breakthrough rates than those who were G1b and CC.  It was also found that without the benefit of ribavirin, the subjects did substantially worse with only at 39% SVR12.  


Details are still coming, but it appears that this will be a 28 week option and the G1a non-CC patients may either need to go longer (there is a 40 week arm of this study that awaits presentation) or the addition of interferon. Ribavirin will clearly be needed in this combination as well. The odds of dosing confusion are a bit higher, with the PI boasting QD dosing and the polymerase inhibitor BID dosing.


A sub-analysis looking at the efficacy of the combination in the compensated cirrhotic was also presented in poster format. Although the numbers are small and clearly the G1b subjects respond better to the combo, it's encouraging to see any sort of SVR12 in this extremely difficult to treat population, especially without the aid of interferon.

Phase 2b Study of Boehringer Ingelheim’s Interferon-Free Hepatitis C Treatment Shows Undetectable Virus in HCV Genotype-1 Patients 12 Weeks After Treatment Ended (SVR12)

Barcelona, Spain and Ridgefield, CT, April 19, 2012 – New data from a pre-specified interim analysis of the Phase 2b SOUND-C2 study show that 68 percent of genotype-1 (GT1) hepatitis C virus (HCV) patients achieved sustained viral response 12 weeks after the end of treatment (SVR12) with Boehringer Ingelheim’s investigational direct-acting antiviral compounds – the protease inhibitor BI 201335 and polymerase inhibitor BI 207127 – plus ribavirin (RBV), without interferon. SVR12 has been highly correlated with SVR24, which is a recognized indicator of viral cure. These patients received combination therapy with BI 201335 once-daily (QD), BI 207127 twice-daily (BID) and RBV for 28 weeks. The SOUND-C2 study investigated interferon-free treatment in HCV GT1 patients, the most difficult genotype to treat, regardless of IL-28B status. Among study participants, 10 percent had compensated liver cirrhosis.

“Eliminating interferon from HCV treatment is an urgent need,” said Stefan Zeuzem, M.D., Chief of the Department of Medicine and Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and lead investigator of the study. “The antiviral activity of BI's all oral direct-acting antiviral compounds in the SOUND-C2 study demonstrates the potential for an interferon-free cure for HCV.”

Furthermore, a separate arm of the SOUND-C2 study showed that after 16 weeks of interferon-free treatment, SVR12 was achieved in 59 percent of patients. Investigators presented relapse data broken out by genotype and IL-28B status. The rate of relapse in the treatment arms ranged between 2 and 10 percent for GT1b and GT1a-CC patients. There was a higher rate of relapse in GT1a non-CC patients, with relapse ranging from 0 to 40 percent. The full results from this interim analysis of SOUND-C2 are being presented on Saturday, April 21, at the International Liver Congress, the 47th Annual Meeting of the European Association of the Study of the Liver (EASL 2012) in Barcelona, Spain (Abstract #101). These results supplement the abstract findings highlighted today during an official EASL press conference.

“We are looking forward to the final results from this study, that we hope will be a significant step towards an interferon-free future for patients with HCV,” said Peter Piliero, M.D., Vice President, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “We are committed to the millions of people around the world who are chronically infected with HCV. Through our clinical trial program HCVersoTM, we are working with experts worldwide to ask the difficult questions that remain in HCV to find answers to the challenges that these patients face.”

Planning of the interferon-free Phase 3 clinical trial program is underway.

SOUND-C2 Pre-Specified Interim Analysis
In this open-label Phase 2b study, 362 treatment-naïve GT1 HCV patients were randomized into five interferon-free treatment groups, each with 120 mg BI 201335 QD, but with different dosing of BI 207127 and treatment durations. The randomization was stratified by HCV genotype (1a or 1b) and patient IL-28B genotype, with 41 percent of patients being GT1a and 75 percent being IL-28B CT or TT.

Investigators reported breakthrough broken out by genotype and IL-28B status. In GT1b and GT1a-CC patients, breakthrough occurred in 7 percent of patients in Arm A, 11 percent of patients in Arm B, 19 percent of patients in Arm C, 9 percent of patients in Arm D, and 29 percent of patients in Arm E (no RBV arm). In GT1a non-CC patients, breakthrough occurred in 40 percent of patients in Arm A, 50 percent of patients in Arm B, 25 percent of patients in Arm C, 64 percent of patients in Arm D, and 91 percent of patients in Arm E (no RBV arm).

In this study, the most common adverse events (AEs) were skin (photosensitivity, rash), gastrointestinal (GI) disorders (vomiting, diarrhea), and jaundice due to unconjugated hyperbilirubinemia. Treatment discontinuations due to AEs correlated with increased dosing frequency and treatment duration, with discontinuations ranging from 4.9 percent in Arm A (16 weeks) to 24.7 percent in Arm C (40 weeks). In the arm with BID dosing of BI 207127 (Arm D), discontinuations were 7.7 percent. BID dosing of BI 207127 is planned for Phase 3 investigation.

Boehringer Ingelheim enrolls final patient in BI 210335 HCV protease inhibitor phase III trial....

The race for the 2nd generation of HCV Direct Acting Antivirals continues to be too close to call, with BI's BI 210335 HCV protease inhibitor finalizing it's last patient for it's phase III trial. The asute observer of the HCV marketplace will recall the interim results of BI's SOUND-C2 trial looking at the interferon-free combo of BI 201335 and BI's BI 207127 polymerase inhibitor in genotype 1 tx-naive patients. At week 12, 76% of patients had VR with a respectable 63% of patients achieved SVR12.


From Medical News Today

Boehringer Ingelheim Completes Patient Entry For Phase III Trial Program In Hepatitis C
12 Dec 2011

According to Boehringer Ingelheim's announcement, the company's large-scale Phase III clinical trial program for BI210335, an investigational, oral protease inhibitor for the treatment of chronic hepatitis C virus (HCV) has randomized the final patient for treatment.

Their current extensive trial program is conducted in 15 countries, with key regions in the E.U., Japan, the U.S., Canada, Korea, Taiwan and Russia at over 350 sites and involves almost 2,000 treatment-experienced and treatment-naïve patients overall.

The program's three Phase III trials will be carried out to assess BI 201335 combined with the golden standard treatment of pegylated interferon (pegIFN) and ribavirin (RBV) in patients with chronic genotype-1 HCV. The majority of HCV patients infected with the genotype 1 virus are amongst the most difficult patient groups to treat. The study program's primary clinical endpoint is the assessment of "sustained viral response" (SVR), considered to be a viral cure, with results from the Phase III trials expected in the first half of 2013.

The complete BI 201335 program was awarded a Fast Track designation by the FDA. The U.S. Food and Drug Administration has designed the Fast Track process to enable the development and review process of important new drugs to treat serious diseases more rapidly than usual to fill an unmet medical need.

Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim said: "We are progressing our BI 201335 program with a high priority to leverage its potential to improve cure rates in HCV treatment. We believe our HCV-pipeline may become an important tool to fight a chronic disease that affects over 170 million people worldwide."

Last month at the American Association for the Study of Liver Diseases (AASLD) 2011 Liver Meeting in San Francisco, USA, Boehringer Ingelheim presented findings of their Phase IIb trial, which demonstrated that the interferon-free combination of BI 201335, with their polymerase inhibitor BI 207127 (SOUND-C2) resulting in 76% of patients achieving a virological response at week 12 and 63% of patients achieved SVR12, an undetectable virus 12 weeks after treatment, at week 16.

In addition to their BI 201335 results, the company also presented their SILEN-C1 and SILEN-C3 study results at the AASLD, demonstrating that BI 201335/ PegIFN/RBV's potentially shortens the time of treatment and improves the likelihood of viral cure (SVR). These Phase IIb results provide a strong case for further development, whilst BI 201335 continues its progress through Phase III.

Written by: Grace Rattue

Boehringer Ingelheim BI 201335 and BI 207127 data to be presented at AASLD...

BI releases it's oral and poster presentation coverage for AASLD. Hot on the list will be SOUND-C2, a phase IIb study looking at an interferon-free combo regimen of BI's polymerase inhibitor BI 2071287 and protease inhibitor BI 201335 both with and without ribavirin.


Boehringer Ingelheim announces new data from hepatitis C virus portfolio

Published on October 22, 2011 at 12:58 AM

Boehringer Ingelheim announced today that new data from its hepatitis C virus (HCV) portfolio will be presented in scientific sessions at The Liver Meeting® 2011, the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place November 4 - November 8 in San Francisco, CA. The abstracts are published online at www.aasld.org.

Key data presented will include a week 12 interim analysis of SOUND-C2, a Phase IIb study evaluating an interferon-free combination of its protease inhibitor BI 201335 and its polymerase inhibitor BI 207127 - with and without ribavirin in treatment-naïve HCV infected patients. In addition, SILEN-C1 and SILEN-C3 data will further assess the efficacy and safety of BI 201335 in treatment-naïve HCV-infected patients, in combination with pegylated interferon alfa-2a and ribavirin (PegIFN/RBV).

SOUND-C2
In SOUND-C2, 362 treatment-naïve patients with chronic genotype-1 HCV infections were randomised into five interferon-free treatment arms, each with 120mg BI 201335 once daily (QD) but with different dosings of BI 207127 and ribavirin as follows:
• 120 mg QD BI 201335 combined with 600 mg TID (thrice daily) BI 207127 and RBV for 16 weeks
• 120 mg QD BI 201335 combined with 600 mg TID BI 207127 and RBV for 28 weeks
• 120 mg QD BI 201335 combined with 600 mg TID BI 207127 and RBV for 40 weeks
• 120 mg QD BI 201335 combined with 600 mg BID (twice daily) BI 207127 and RBV for 28 weeks
• 120 mg QD BI 201335 combined with 600 mg TID BI 207127 for 28 weeks (no RBV)
The interim results will provide early virological response rates for all treatment arms of the novel interferon-free combination of BI 201335/BI 207127/ribavirin and are due to be presented by Stefan Zeuzem, M.D., Chief of the Department of Medicine and Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany and lead investigator of the study.

SILEN-C1
In SILEN-C1, 429 treatment-naïve patients with chronic genotype-1 HCV infections were randomised to the following treatment groups:
• Placebo
• BI 201335 120 mg QD with 3 days lead-in (LI) of PegIFN/RBV
• BI 201335 240 mg QD/LI
• BI 201335 240 mg QD without LI
In each arm, BI 201335 or placebo were given for 24 weeks together with PegIFN/RBV for 24 or 48 weeks. Results presented at AASLD will include an analysis of sustained virological response across different baseline factors, including difficult to treat HCV cases.

SILEN-C3
In SILEN-C3, 159 treatment-naïve genotype-1 patients were randomised to the following treatment groups:
• BI 201335 120mg QD for 12 weeks with 3 days lead-in of PegIFN/RBV
• BI 201335 120mg QD for 24 weeks with 3 days lead-in of PegIFN/RBV
In each arm, PegIFN/RBV was given for 24 or 48 weeks. Results presented at AASLD will provide an analysis of 12 versus 24 weeks of treatment with BI 201335.
Titles for accepted abstracts are below and full results and conclusions for these abstracts will be shared at AASLD at the times specified.
• Virologic response to an interferon-free regimen of BI 201335 and BI 207127, with and without ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Week 12 interim results of the SOUND-C2 study
(Poster LB-15. Zeuzem, et al. November 7, 8:00 a.m. - 5:30 p.m. PT)

Oral presentations
• SILEN-C3: Treatment for 12 or 24 weeks with BI 201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype-1 HCV infection
(Abstract 39. D. Dieterich, et al. November 6, 4:15 p.m. - 4:30 p.m. PT)
• Treatment with the second generation HCV protease inhibitor BI 201335 results in high and consistent SVR rates - results from SILEN-C1 in treatment-naïve patients across different baseline factors
(Abstract 226. M.S. Sulkowski, et al. November 8, 8:45 a.m. - 9:00 a.m. PT)
• High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI 201335, polymerase inhibitor BI 207127 and ribavirin, followed by BI 201335 and PegIFN/ribavirin - the SOUND-C1 study
(Abstract 249. S. Zeuzem, et al. November 8, 11:15 a.m. - 11:30 a.m. PT)

Poster presentation
• Characterization of HCV NS3 variants that emerged during virologic breakthrough and relapse from BI 201335 phase 2 SILEN-C1 study
(Poster 1339. G. Kukolj, et al., November 7, 8:00 a.m. - 5:30 p.m. PT)
The results from the HCV portfolio at AASLD underscore the promise of the company's pipeline as Boehringer Ingelheim continues to focus on the real-world challenges faced by HCV patients globally.
Boehringer Ingelheim is continuing its long heritage in virology and is dedicated to developing new medicines for HCV patients. BI 201335 and BI 207127 are being investigated with the goal of improving cure rates for more HCV patients, including those traditionally difficult to treat.

A bit more info on Novartis' cyclophilin inhibitor...

An article appearing on Pharmiweb about the approval of Telaprevir and Boceprevir, but also comments on alisporivir, also known as DEB025 which Novartis licensed from fellow Swiss firm Debiopharm in February 2009.

THE Food and Drug Administration (FDA) has approved Vertex Pharmaceuticals Inc.'s (VRTX) hepatitis C drug telaprevir and Merck’s hepatitis C drug, boceprevir.

Both drugs are protease inhibitors (PIs) and are designed to block an enzyme that helps the hepatitis C virus replicate. Hepatitis C is a liver disease caused by infection with the hepatitis C virus, which is transmitted through contaminated blood. The infection can cause liver failure and liver cancer.

The move follows the presentation and publication of new data on the drugs at the recent annual meeting of the European Association for the Study of Liver Disease (EASL) held in Berlin. Also presented at the meeting was data on Novartis' novel investigational oral agent alisporivir. This data was described as “fantastic” by EASL vice secretary Mark Thursz, professor of hepatology at Imperial College, London, while Robert Flisiak from the Medical University of Bialystok, Poland, told the congress as he presented the data: “This novel agent has the potential to be an important component of future hepatitis C treatment.” The availability of novel agents such as alisporivir and the protease inhibitors marks a new era in the treatment of hepatitis C infection. More than 30 potential hepatitis C agents are currently in R&D pipelines. Professor Thursz said that the new PIs offered unprecedented levels of sustained virological response and would be used initially with the current standard of care, pegylated interferon-alpha plus ribavirin. However, with so many potential novel treatments for hepatitis C on the horizon, he envisaged a time when standard of care for hepatitis C would be an interferon-free regimen. Boehringer’s HCV polymerase inhibitor BI 207127 has been fast-tracked by the FDA in combination whilst Bristol-Myers Squibb is trialling its PI, BMS 650032, in combination with the NS5A inhibitor BMS 790052.

Novartis’ alisporivir shows significant promise if its phase II data from the ESSENTIAL study, presented at EASL, is repeated in a phase III trial, which is now underway. The ESSENTIAL study involved 300 previously untreated patients infected with genotype 1 HCV. Of those treated with alisporivir, plus standard of care (pegylated-interferon alfa 2a/ribavirin), 76% achieved superior viral cure compared to 55% of patients on standard care alone 24 weeks after stopping treatment.

The study’s principal investigator, Stefan Zeuzem from Goethe University Hospital in Frankfurt, said: “Hepatitis C is difficult to treat and current therapies are effective only in about half of patients with the most prevalent genotype. These results are exciting because a large majority of patients achieved sustained viral response with alisporivir.”

Alisporivir is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the hepatitis C virus directly, alispirovir, targets host proteins that the hepatitis C virus uses for replication. A Phase IIb trial looking at the potential of the agent in HCV patients with genotypes 2 and 3 is also underway. The host proteins are needed for replication in all types of HCV infection so there is potential for the agent to have broad activity; there are six variations of HCV.

An international Phase III study is evaluating the efficacy and safety of alisporivir combined with standard care in previously untreated HCV G1 patients. The Phase II study showed that serious adverse events occurred in 6.9% of patients treated with alispirovir and standard care compared to 5.5% of patients treated with standard care alone. Prof Flisiak reported a higher rate of bilirubin (32.9% versus 1.4% in the alisporivir-treated group compared to standard care alone) but this was transient and reversible and associated with the initial loading dose. Final data from the Phase III ESSENTIAL-2 is expected in March 2013.

Novartis medical director Nikolai Naoumov said: “The data is very encouraging because it has produced a significant response in the most common form of HCV which can be very difficult to treat and with a reasonable safety profile. If the results of Phase III and other studies are also encouraging, this agent could offer a paradigm shift in clinical practice by being able to treat a number of genotypes and patients who have not responded to standard care.” Novartis in-licensed alisporivir, also known as DEB025, from fellow Swiss firm Debiopharm in February 2009.

Read more: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=40176#ixzz1Lo0stbq3

Original article here: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=40176

Boehringer Ingelheim starts STAT-C combination study...

According to Clinical Trails.gov, Boehringer Ingelheim has initiated a STAT-C combination study looking at their compounds BI 207127 (Non-nucleoside polymerase inhibitor) and BI 201335 (Protease inhibitor) plus Ribavirin. This study does not have an interferon component.

They are recruiting 302 naive patients who will be randomized to the following arms:
4 weeks of high dose TID BI 207127 + QD BI 201335 (protease inhibitor) + RBV
4 weeks of low dose TID BI 207127 and QD BI 201335 + RBV
24 or 48 weeks of high dose TID BI 207127 and QD BI 201335 + RBV
24 or 48 weeks of high dose BID BI 207127 and QD BI 201335 + RBV
24 or 48 weeks of high dose TID BI 207127 and QD BI 201335

The primary outcome measures are RVR and SVR. All sites are in the EU

http://clinicaltrials.gov/ct2/show/NCT01132313?term=hepatitis+OR+hep+OR+HCV&lup_s=05%2F01%2F2010&lup_d=30