Hepatitis C: Phase III data show Boehringer Ingelheim’s faldaprevir* is effective even in patients with common drug-resistant viral variant

16 December 2013

Summary: Naturally occurring mutations in the hepatitis C virus (HCV) are common and many lead to reduced efficacy of antiviral treatments. Faldaprevir* has now been shown to be effective even in patients with the common HCV Q80K variant,¹ which affects an estimated 700,000^2,3,4 patients in the USA alone. Faldaprevir* is being studied in combinations both with and without interferon. The EMA recently granted accelerated assessment for faldaprevir* as part of an interferon-based regimen and a decision on marketing authorisation is anticipated next year.^5,6

For media outside of the US, the UK & Canada only

INGELHEIM, 16 December, 2013 – Data show that Boehringer Ingelheim’s second-generation protease inhibitor faldaprevir*, when used in combination with pegylated interferon and ribavirin, was effective even with the presence of naturally-occurring mutant variants of the hepatitis C virus (HCV), such as the NS3 Q80K polymorphism. The Q80K mutant was detected in 23% (49/127, STARTVerso™1) and 40% (159/398, STARTVerso™2) of genotype-1a infected patients. Its presence was found to have no effect on the chances of viral cure (SVR12) in genotype-1 infected hepatitis C patients treated with faldaprevir* plus pegylated interferon and ribavirin.¹ These data were presented last week at HEP DART 2013, taking place in Big Island, Hawaii.

"These data are encouraging as they demonstrate that HCV genotype-1 infected patients irrespective of the presence of the common HCV Q80K variant may benefit from faldaprevir," said Christoph Sarrazin, M.D., Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. "In some parts of the world, the Q80K mutation is present in almost 50% of genotype-1a infected patients, who will potentially require additional screening prior to using some HCV protease inhibitors. With faldaprevir’s* efficacy against HCV Q80K, physicians should be able to avoid screening for this mutation prior to treatment of genotype-1a infected patients."

The HCV NS3/4A protease is essential for viral replication and is a key target for direct acting antiviral (DAA) treatments such as faldaprevir*. The NS3 Q80K variant is the most commonly observed NS3 polymorphism in genotype-1a HCV and has been reported in up to 47% of genotype-1a infected patients. The variation in frequency is influenced by the geography, with the prevalence of Q80K being particularly high in the USA.⁴

Faldaprevir* is the core component of Boehringer Ingelheim’s investigational hepatitis C pipeline and is being studied in combinations both with and without interferon. Faldaprevir* was recently granted accelerated assessment by the European Medicines Agency. If approved by the European Commission, faldaprevir* could be available for marketing in the EU in the second half of 2014 as part of an interferon-based regimen. In addition, Boehringer Ingelheim aims to deliver one of the first interferon-free regimens for the treatment of hepatitis C infection. Pivotal Phase III HCVerso® data for the interferon-free regimen of faldaprevir*, deleobuvir* and ribavirin will be available in 2014.

Additional data from Boehringer Ingelheim at HEP DART
Data presented last week as part of the ‘oral abstract session II’ show a high rate of virologic response in patients treated with a 12 week all-oral combination of Boehringer Ingelheim’s faldaprevir* and deleobuvir* and Presidio’s PPI-668* with and without ribavirin.⁷ Results from the ongoing Phase II trial were recently presented at the 64^th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

NOTES TO EDITORS

The Boehringer Ingelheim NewsHome: An innovative resource for journalists
The Boehringer Ingelheim hepatitis C www.newshome.com is the one-stop-shop for clear, concise and easy to understand information about hepatitis C for media.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

*Faldaprevir, deleobuvir and PPI-668 are investigational compounds and not yet approved.Their safety and efficacy have not yet been fully established.

References
1. Sarrazin et al. NS3/4A baseline polymorphisms and treatment-emergent variants in HCV genotype-1 infected, treatment-naïve patients from the Phase III STARTVerso1 and 2 clinical studies of faldaprevir plus pegylated interferon a-2A and ribavirin. Presented at HEP DART 2013.
2. Centers for Disease Control and Prevention. Hepatitis C FAQs for health professionals. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm [last accessed 03/12/13]
3. Theodore Sy, M. Mazen Jamal. Epidemiology of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006; 3(2):41-46.
4. Berger et al. Baseline HCV NS3 Polymorphisms and their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir. Antimicrob Agents Chemother. 2013 Nov 11.
5. Boehringer Ingelheim Data on file. European Medicines Agency, Human Medicines Evaluation Division. (Faldaprevir Boehringer Ingelheim, Boehringer Ingelheim International GmbH). Submission validation, 21 November, 2013
6. Boehringer Ingelheim Data on file. European Medicines Agency, Human Medicines Evaluation Division. (Faldaprevir Boehringer Ingelheim, Boehringer Ingelheim International GmbH). Accelerated assessment acceptance, 12 November, 2013
7. Lalezari, et al. 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. Presented at HEP DART 2013

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LabCorp Announces the Availability of Hepatitis C Virus Q80k Polymorphism Screening for the Newly Approved Drug OLYSIO(TM) (simeprevir)

BURLINGTON, N.C.--(BUSINESS WIRE)--December 03, 2013--

Laboratory Corporation of America(R) Holdings (LabCorp(R) ) (NYSE: LH) announced today the immediate availability of an enhanced version of its HCV GenoSure(R) NS3/4, a drug resistance test that screens for the Q80K polymorphism. Q80K is a naturally occurring polymorphism that develops in certain strains of HCV, making the virus less susceptible to Janssen Therapeutics' OLYSIO(TM) (simeprevir), which was recently approved by the U.S. Food and Drug Administration for the treatment of certain adult patients diagnosed with genotype 1chronic hepatitis C (HCV). In clinical trials, patients with HCV genotype 1 containing the Q80K polymorphism demonstrated significantly lower response rates to treatment with OLYSIO. Approximately one-third of HCV patients have virus with Q80K polymorphism. Given the high frequency of the Q80K polymorphism and its significant impact on OLYSIO's success rate, it is recommended that patients be screened for the Q80K polymorphism prior to treatment.

LabCorp and Monogram Biosciences, Inc., a member of the LabCorp Specialty Testing Group, were the first to launch an HCV drug resistance test for NS3/4A protease inhibitors. In addition to OLYSIO, LabCorp's HCVGenoSure NS3/4A test also provides resistance information for the drugs VICTRELIS(R) (boceprevir) and INCIVEK(R) (telaprevir). With the inclusion of all three FDA approved protease inhibitors, HCV GenoSure NS3/4A enables healthcare providers to select the most appropriate therapy regimen for their patients.

An estimated 3.2 million people in the U.S. (and 170 million worldwide) are chronically infected with HCV, which if left undiagnosed and untreated can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. The Centers for Disease Control and Prevention (CDC) estimates that nearly half of the U.S. HCV population is currently undiagnosed, and the slow and often silent onset of HCV disease presentation has prompted more aggressive efforts to proactively diagnose and treat HCV infection. "We are proud to be a leader in the growing effort to screen and monitor individuals with HCV and to support physicians in treatment decisions to improve patient outcomes," said David P. King, Chairman and CEO.

About LabCorp(R)

Laboratory Corporation of America(R) Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.7 billion in 2012, over 34,000 employees worldwide, and more than 220,000 clients, LabCorp offers more than 4,000 tests ranging from routine blood analyses to reproductive genetics to companion diagnostics. LabCorp furthers its scientific expertise and innovative clinical testing technology through its LabCorp Specialty Testing Group: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc, The Center for Esoteric Testing, Litholink Corporation, Integrated Genetics, Integrated Oncology, Dianon Pathology, Monogram Biosciences, Inc, Colorado Coagulation, Cellmark Forensics, MedTox, and Endocrine Sciences. LabCorp conducts clinical trials testing through its LabCorp Clinical Trials division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our website at: www.labcorp.com.

OLYSIO is a trademark of Janssen Therapeutics, Division of Janssen Products, LP.

VICTRELIS is a registered trademark of Schering Corp., a subsidiary of Merck & Co., Inc.

INCIVEK is a registered trademark of Vertex Pharmaceuticals Incorporated.

This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2012, and subsequent SEC filings.

CONTACT: Laboratory Corporation of America(R) Holdings
Stephen Anderson, 336-436-5076
www.labcorp.com

SOURCE: Laboratory Corporation of America Holdings
Copyright Business Wire 2013

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New Hepatitis C Drug Approved: Janssen’s Hepatitis C Drug Simeprevir Now Available

Provided by Liver Specialists of Texas

The Blog of Dr. Joseph S. Galati
Discussions about the liver and everything else related to health and wellness.

by DR. JOE GALATI on 11/29/2013

This past week, the FDA gave approval to Janssen’s new drug to treat hepatitis C. Simeprevir, commercially know as OLYSIO, is the first new hepatitis C drug since the release of telapravir (Incevik) and boceprevir (Victrelis) in 2011. Simeprevir is a  NS3/4A protease inhibitor, used in combination with interferon and ribavirin.

The release of simeprevir marks the beginning of a new wave of direct acting antiviral agents against the hepatitis C virus. Additional drugs are set for FDA approval, including the Gilead drug sofosbuvir in early December 2013.

Most of the new hepatitis C drugs will have a number of features in common. These include:

• Very high cure rate, in the 80-90% range – lower in null and non-responders
• Less side effects
• Shorter duration of treatment
• Less pills to take each day
• Cirrhosis reduces response rates
• Less drug-drug interactions
• Genotype 1 subtype differences exist

Looking at the dosing of simeprevir, I have attached the official product insert that describes how the drug will be doses. Several points to consider:

• This is an interferon/ribavirin based therapy
• Patients with genotype 1 need additional screening for the NS3 Q80K polymorphism
• Those with this variant have a decreased response rate to the therapy, and should be considered for an alternative therapy
• The initial dosing is 12 weeks of simeprevir with interferon and ribavirin, followed by an additional 12 or 36 weeks of interferon and ribavirin combination therapy.
• There are drug-drug interaction which have to be monitored closely
• FDA approval is for genotype 1 patients only

While the release of simeprevir is welcomed, it has not provided the proverbial “home-run” we have been looking for in our quest to cure hepatitis C. In well selected patients, achieving a better than 80% cure rate is available. The concerns I have relate to the Q80K polymorphism noted above. This will be an additional step required in screening our patients. Additionally, in patients with prior non-response or null responders, as well as those with cirrhosis, these patients will still require a full 48 week of interferon and ribavirin. One of the goals of the next generation of hepatitis C therapies is reduced interferon exposure, or complete elimination. Simeprevir does not fully meet this goal.

In the days to come, I will post additional information on sofosbuvir. For now, these are the highlights to consider (refer to this FDA document for additional details):

• Sofosbuvir will likely receive FDA approval for Genotype 1,2,3, and 4 patients with hepatitis C
• Interferon-free treatment in genotype 2 and 3 for 12 weeks
• Sofosbuvir combined with interferon and ribavirin in genotype 1 and 4 for 12 to 16 weeks

This treatment strategy is far different than the simeprevir treatment noted above.

Looking further, we will eventually have all interferon-free protocols. It is anticipated that as additional new drugs are approved, they will be combined (example sofosbuvir and simeprevir), allowing us to treat a wide range of patients, safely, and with a cure rate many of us may have never envisioned 20 years ago.

For a consultation to see if you are a candidate for these new drugs, contact Lexa at our office at 713-794-0700 and visit our webpage for additional information.

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OLYSIO™ (simeprevir): Quick Facts -- What You Need to Know

November 24, 2013
By Patricia Emory

OLYSIO™ (simeprevir) was approved in the United States November 22, 2013 by the FDA for the treatment of hepatitis C patients in conjunction with pegylated interferon and ribavirin in adult patients (treatment-naive and treatment-experienced) with genotype 1 including those with compensated cirrhosis.

OLYSIO™ (simeprevir) is a “2nd generation”  NS3/4A protease inhibitor which acts by blocking the protease enzyme that enables the virus to replicate.

Dosing and Duration of treatment

Dosing: Fixed dose of 150mg once a day

Duration of Treatment:

Treatment-naïve and prior-relapsers: 12 weeks of Simeprevir in combination with 24 weeks of pegylated interferon and ribavirin

Partial and null-responders: 12 weeks of Simeprevir in combination with 48 weeks of pegylated interferon and ribavirin

Adverse Effects

The most common adverse effects of Simeprevir are rash and sensitivity to sunlight (most common in the first 4 weeks of treatment) as well as those associated with pegylated interferon and ribavirin.

Q80K polymorphism

Q80K polymorphism is found in 56.7% of genotype 1a patients in the US. The Q80K polymorphism  greatly reduces treatment response. It is suggested that all patients being considered for treatment using Simeprevir be screened for the Q80K polymorphism.

Financial Assistance

According to the OLYSIO™ website:

“Information on financial assistance through OLYSIO^™ Support will be available soon. In the meantime, please call1-800-JANSSEN (1-800-526-7736) for information.”

Further Information

OLYSIO™ (simeprevir) website 

OLYSIO™ (simeprevir) Receives FDA Approval for Combination Treatment of Chronic Hepatitis C – Janssen Press Release

FDA approves new treatment for hepatitis C virus – FDA Press Release

FDA Antiviral Drugs Advisory Committee Meeting Briefing Document

Baseline HCV NS3 Polymorphisms and their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

Antimicrob Agents Chemother. 2013 Nov 11. [Epub ahead of print]

Berger KL, Triki I, Cartier M, Marquis M, Massariol MJ, Böcher WO, Datsenko Y, Steinmann G, Scherer J, Stern JO, Kukolj G.

Boehringer Ingelheim Canada Ltd. R&D, Laval, QC, Canada.

Abstract

A challenge to the treatment of chronic hepatitis C with direct acting antivirals is the emergence of hepatitis C virus (HCV) drug-resistant variants. HCV with pre-existing polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b; 437 genotype 1a). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (< 1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naïve patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment-experienced (17% vs 26%; P = 0.47) or treatment-naïve (62% vs 66%; P = 0.72).

PMID: 24217701 [PubMed - as supplied by publisher]

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Why Gilead's Sofosbuvir Is Better Than J&J's Simeprevir

Provided by The Motley Fool

By Todd Campbell | More Articles
October 28, 2013

Johnson & Johnson's simeprevir Achilles' heel is Q80K. Coming out of the FDA's Antiviral Drugs Advisory Committee Meeting on Oct. 24, your takeaway should be that simeprevir is a very good drug with a smaller than hoped addressable market.

When data from J&J's two phase 3 trials were pooled together, patients with the Q80K polymorphism didn't benefit from simeprevir. The sustained viral response over 12 weeks, or SVR12, for Q80K patients was a statistically insignificant 58% versus 55% for the control arm.

"Most striking in the subgroup analysis was the substantial impact of the Q80K baseline HCV GT1a polymorphism on the efficacy of simeprevir. In subjects with the Q80K polymorphism at baseline, no statistically significant difference in SVR12 rates was observed when comparing the simeprevir group to the Control group," according to the advisory committee meeting materials.

Looking at the pooled non-Q80K patients, the SVR12 rate jumps to 84% for simeprevir patients versus just 43% for placebo. This means it's unlikely simprevir will get prescribed for patients with Q80K. That's unfortunate for J&J because Q80K was identified in 48% of HCV genotype 1a patients in J&J's phase 3 trials.

The high prevalence of Q80K in genotype 1 patients is important because in a U.S. study of HCV patients, 56.7% were classified as genotype 1a, 17% as 1b, 3.5% as 2a, 11.4% as 2b, 7.4% as 3a, 0.9% as 4, 3.2% as type 6.

"Given the high frequency of the Q80K polymorphism in the U.S. population and its significant impact on rates of SVR12, DAVP is recommending that all GT1a patients be screened for the Q80K polymorphism. Alternative treatment options should be considered for patients found to be infected with this polymorphic variant," the advisory committee materials went on to say.

The findings give Gilead's sofosbuvir an edge
That opens up an advantage for Gilead Sciences sofosbuvir, because sofosbuvir doesn't have the same reason for pause as simeprevir in Q80K patients. Sofosbuvir got the advisory panel's unanimous nod of recommendation two days after it recommended simeprevir.

But, Q80K isn't the only advantage sofosbuvir may have over J&J's simprevir. The holy grail of hepatitis C treatments remains discarding prior generation therapies peg-interferon and ribavirin, which are saddled with side effects.

While simprevir will be dosed as part of combination therapy including peg-interferon injections and ribavirin, the panel recommended sofosbuvir dosed with only ribavirin in HCV2 and HCV3 populations as part of an all-oral therapy. In Gilead's phase 3 POSITRON study of patients unwilling or unable to take interferon, SVR12 was 78% versus 0% for placebo.

That two-drug combination provided better outcomes and shorter treatment periods than any of the current standard treatments available. Importantly, the absence of peg-interferon injections marks a big step forward in removing significant hurdles faced by patients who are either unwilling, or unable to tolerate interferon.

Those with the more common HCV1 and HCV4 genotypes will still need to be dosed with peg interferon, but treatment duration drops to 12 weeks, helping limit some of the side effects compared to existing treatment protocols. However, that leaves Gilead on equal footing with J&J in those patients.

You should also know that across Gilead's trials, 12-week dosing didn't have nearly as robust a rate of success in patients with genotype 3 as those with genotype 2. However, in Gilead's FUSION phase 3 trial, extending treatment to 16 weeks produced a much better outcome. In FUSION, the SVR jumped to 62% at week 16 from 38% at week 12. As a result, it's likely protocol for HCV3 patients treated with sofosbuvir will be for the longer treatment period.

The Foolish final take
The market for hepatitis C is big. The World Health Organization estimates around 170 million are infected worldwide with 2.7 million chronic cases in the U.S. Roughly 20,000 to 30,000 new cases are diagnosed in the U.S. each year.

Both drugs will likely win approval by the FDA, given its common to follow the advice of the advisory panels. But, sofosbuvir likely stands to benefit more than simeprivir when commercialized. However, it's not all bad for J&J.

In a phase 2a study called COSMOS, treating HCV1 patients who had previously failed on peg-interferon and ribavirin therapy with a combination of simeprivir and sofosbuvir without interferon or ribavirin, showed promising results, with SVR8 of 93%. That suggests while simeprevir isn't likely to win the script battle head to head with sofosbuvir, it may find itself part of a later combination therapy with the drug.

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Todd Campbell owns shares of Gilead Sciences. Todd owns E.B. Capital Markets, an institutional research firm serving money managers. E.B. Capital's clients may or may not have positions in the companies mentioned. Todd also owns Gundalow Advisors, LLC, a high net worth advisory firm. Gundalow's clients do not own shares in the companies mentioned. The Motley Fool recommends Gilead Sciences and Johnson & Johnson. The Motley Fool owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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FDA Panel Recommends Approval of Simeprevir for Hepatitis C – Excellent Summary from Medscape

Medscape Medical News

Troy Brown, RN
October 24, 2013

An advisory committee to the US Food and Drug Administration (FDA) unanimously recommended simeprevir (Janssen) for the treatment of chronic hepatitis C virus (HCV) genotype 1 (GT1) infection, combined with peginterferon alfa and ribavirin in adults with compensated liver disease (including cirrhosis) who are treatment naïve or who have failed previous interferon therapy with or without ribavirin.

Simeprevir is an HCV protease inhibitor, and if approved it will be the third HCV protease inhibitor approved in the US. Boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals, Inc) were approved in 2011, according to background information provided by the FDA. The proposed dose is 150 mg once daily, in combination with peginterferon alfa and ribavirin.

"We clearly need better drugs, and the evidence is strong that this is a better drug than we have," voting member Curt H. Hagedorn, MD, Chief, Medicine Service, at Central Arkansas Veterans Healthcare Service, in Little Rock, Arkansas, noted.

The vote follows a discussion of data from 3 phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in patients with chronic HCV GT1. Patients in the treatment groups (N = 781) were given simeprevir 150 mg daily for 12 weeks plus peginterferon and ribavirin (PR) for 12 weeks, followed by PR only for either 12 or 36 weeks based on the individual's virologic response to therapy. Patients in the control groups (N = 397) were given placebo for 12 weeks combined with PR for 48 weeks.

Those in trials C208 and C216 were treatment-naïve, and those in HPC3007 had received 24 weeks or more of a pegylated interferon-based treatment and had relapsed within 1 year after the last medication dose. Efficacy data from C208 and C216 were pooled because the studies were nearly identical in design.

Efficacy

The trials' primary endpoint was sustained virologic response 12 weeks after the anticipated end of treatment (SVR12), which was defined as an undetectable HCV RNA at treatment end and HCV RNA < 25 IU/mL 12 weeks after the anticipated end of treatment.

The pooled results from C208 and C216 showed an SVR12 rate of 80% in the treatment group and 50% in the control group. For the relapsed patients in HPC3007, the SVR12 rate was 79% in the treatment group and 36% in the control group.

Secondary endpoints for all 3 trials included SVR24 and SVR 72. Both endpoints correlated well with the primary endpoint of SVR12, but data were incomplete at the week 60 data cut-off.

SVR rates were lower in patients with a high baseline viral load, advanced disease on liver histology (bridging fibrosis and cirrhosis), older age, African American ethnicity, and absence of the IL28B CC genetic polymorphism.

The presence of the Q80K HCV GT1a polymorphism (commonly found in GT1a patients in the US) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. In HPC3007, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group.

In those without the Q80K polymorphism, the SVR12 rates were 84% in the treatment groups vs 43% in the control group for the 2 pooled trials, and 78% in the treatment group vs 24% in the control group for the relapser trial. The committee recommends screening all patients with GT1a infection for the Q80K viral polymorphisms before initiating simeprevir (combined with pegylated interferon and ribavirin) and considering alternative treatment options for those with this polymorphism.

SVR12 rates were significantly higher in the simeprevir arm compared with the placebo arm in all other subgroup analyses.

Mean simeprevir area under the concentration-time curve 24-h postdose (AUC_24h) values were 2.4 and 5.2-fold higher, respectively, in HCV-uninfected subjects with moderate or severe hepatic dysfunction, compared to healthy controls. Mean simeprevir AUC_24h values were also approximately 3.4-fold higher in HCV infected patients of East Asian ancestry, compared with the pooled Phase 3 population which was about 91% Caucasian. For this reason, the committee would like to see additional studies in patients of East Asian origin.

Safety

A total of 4 deaths occurred in the treatment groups, and they were judged to be unrelated to treatment.

In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, versus 3% of those in the control group during the initial 12 weeks. A total of 3 patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; 1 patient experienced major depression and 2 patients experienced photosensitivity reactions.

Other common adverse events were rash (218 [28%] treatment groups; 79 [20%] control groups), influenza like illness (203 [26%] treatment groups; 84 [21%] control groups), pruritis (168 [22%] treatment groups; 58 [15%] control groups), and nausea (173 [22%] treatment groups; 70 [18%] control groups).

"I think this is a great opportunity at treating more HCV infected patients," said voting member Amanda H. Corbett, PharmD, BCPS, FCCP, a clinical associate professor at the University of North Carolina at Chapel Hill's Eshelman School of Pharmacy.

"Efficacy was clearly demonstrated and the safety profile is clearly favorable," explained voting member Thomas P. Giordano, MD, MPH, an associate professor of medicine at Baylor College of Medicine, medical director of HIV services at Harris Health System, and a research scientist at HSR&D Center of Excellence, Michael E. DeBakey VA Medical Center, in Houston, Texas.

Several committee members remarked on the need for postmarketing studies in racial and ethnic minorities, patients coinfected with HIV, and other underrepresented populations. A number of members suggested that the FDA should be more proactive with the pharmaceutical industry at the beginning of the clinical trial process to ensure a more diverse study population that more accurately represents the clinical population being studied.

The committee members have disclosed no relevant financial relationships.

US Food and Drug Administration (FDA)-Antiviral Drugs Advisory Committee Meeting. FDA Briefing, Janssen Briefing

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FDA panel unanimously approves simeprevir for HCV genotype 1

Provided by Healio

October 24, 2013

The FDA’s Antiviral Drugs Advisory Committee today voted that available data overwhelmingly supports approval of simeprevir in combination with pegylated interferon and ribavirin for treatment of hepatitis C genotype 1 infections.

The panel voted 19-0 with no abstentions after researchers presented study results demonstrating the once-daily protease inhibitor pill manufactured by Janssen Pharmaceuticals, a Johnson & Johnson company, was superior to placebo in achieving a sustained virologic response (SVR) in treatment-naive patients with HCV and those who relapsed after prior pegylated interferon and ribavirin (PR) therapy.

“I thought the evidence was pretty overwhelming,” committee member Dean Follmann, PhD, chief, biostatistics research branch, National Institute of Allergy and Infectious Diseases, said. “It was probably the easiest vote I ever had.”

Presenters provided safety and efficacy details from four double-blind, placebo-controlled studies — two phase 3 studies on treatment-naive patients, one phase 3 study on prior relapsers and one phase 2b study on prior relapsers and nonresponders.

The studies demonstrated positive SVR results in most cases, but a subpopulation of HCV patients — those with genotype 1a and a Q80K polymorphism — responded similarly to controls in naive or relapse trials.

Due to the reduction in efficacy apparent in these subjects, the FDA’s Division of Antiviral Products stated it intends to recommend screening all genotype 1a subjects for the Q80K viral polymorphism before beginning simeprevir with PR therapy in order to potentially consider alternative treatment options.

During discussion of the proposal, the panel voiced questions over whether it was enough to suggest physicians “consider” alternative treatment as opposed to “recommending” another treatment.

The panel also discussed aspects of simeprevir’s safety profile and agreed without a vote that a recommendation for sun-protection measures should be included with the warnings and precautions section of simeprevir’s prescribing information because of photosensitivity reactions during clinical trials.

Additional skin reactions during clinical trials also prompted discussions of whether skin rash should be included in the warnings and precautions section. The question arose because of apparent differences between presentation and management strategy for rash and photosensitivity.

“There are varying opinions about what should be on the label in what sections,” Committee Chairman Yoshihiko Murata, MD, PhD, division of infectious diseases, University of Rochester School of Medicine and Dentistry, said in summarizing the discussion. No final vote was conducted on the discussion point.

The panel also advised that further postmarketing studies should be conducted to better define potential risks to several portions of the population and means to optimize use of simeprevir.

A final decision by the FDA is expected next month.

On Friday, the panel will hear details regarding sofosbuvir (Gilead Sciences).

An FDA background report on sofosbuvir concluded that adding the medication to standard drug therapy cured 90% of those with HCV genotypes 1, 4, 5 and 6 during a 12-week period.

Healio.com/Hepatology will cover the meeting.

Source

J&J-Medivir Hepatitis C Pills Wins U.S. Panel Backing

Provided by Bloomberg

By Anna Edney - Oct 24, 2013 4:00 PM ET

Johnson & Johnson (JNJ) and Medivir’s experimental hepatitis C treatment should be approved, advisers to the U.S. government said, propelling the companies into a position to enter a competitive market for new drugs.

The Food and Drug Administration’s 19-member advisory panel unanimously recommended the therapy, known as simeprevir, be used in combination with other medicines for the most common form of hepatitis C. The FDA, which doesn’t have to follow the panel’s advice, is expected to decide on the drug by Nov. 27.

J&J, Medivir, Gilead Sciences Inc. (GILD) and AbbVie Inc. (ABBV) are among companies developing new pills for hepatitis C to alleviate the burden of current treatments, including interferon injections, which can cause flu-like symptoms. The market for hepatitis C drugs may reach more than $100 billion over a decade, according to Bloomberg Industries. Advisers tomorrow will consider a hepatitis C therapy from Gilead.

“As someone who treats patients with chronic hepatitis C every day, I think this regimen represents a much safer one and a much simpler one than what’s currently existing,” Marc Ghany, a panel member and physician in the liver diseases branch of the National Institute of Diabetes, Digestive and Kidney Diseases, said after the vote.

The panel discussed a recommendation made by FDA staff and supported by J&J, based in New Brunswick, New Jersey, to screen potential simeprevir patients for a genetic mutation called Q80K polymorphism that renders the drug ineffective.

Genetic Defect

The Q80K polymorphism was found in 48 percent of U.S. patients with a genotype 1a hepatitis C infection in clinical trials compared with 19 percent of patients in Europe, J&J said. The mutation is almost nonexistent in those with a genotype 1b infection.

A study of an all-oral combination of simeprevir with Gilead’s sofosbuvir has shown that the regimen mitigates the effect Q80K has on simeprevir, Gaston Picchio, hepatitis disease area leader at J&J’s Janssen unit, said during the meeting.

Data from the study is expected to be released in November at the American Association for the Study of Liver Diseases’ annual conference in Washington.

J&J, the world’s biggest seller of health-care products, and Medivir, based in Huddinge, Sweden, are seeking approval for their once-daily pill to treat chronic hepatitis C patients with the genotype 1 infection. About 70 percent of U.S. patients have the genotype 1 form of the disease. Hepatitis C is divided into 6 genotypes.

Patient Population

About 4 million Americans have the disease, which can cause liver cirrhosis, according to the National Institutes of Health. Hepatitis C can be passed through infected blood or body fluids, most commonly through needle-sharing by drug users.

Treatment for patients now includes interferon and a pill called ribavirin. Most patients take the combination with Merck& Co.’s Victrelis or Vertex Pharmaceuticals Inc. (VRTX)’s Incivek for as long as 48 weeks. Simeprevir is in a class of drugs called protease inhibitors that also include Victrelis and Incivek.

Clinical trials found simeprevir can reduce treatment time in half to 24 weeks. The medicine cured about 80 percent of patients who hadn’t been treated before compared with 50 percent of those who took pegylated interferon and ribavirin. Seventy-nine percent of simeprevir users who failed other treatments were cured compared with 37 percent who took only the older drugs, according to J&J.

The most common major side effects of simeprevir were rash and photosensitivity. Panel members agreed with the FDA that the prescribing information for the drug should include a recommendation for patients to use sun protection and avoid tanning beds.

The drug from Foster City, California-based Gilead that advisers will weigh tomorrow, sofosbuvir, may be the first to market in a new class of drugs called nucleotide polymerase inhibitors. Sofosbuvir is effective across all genotypes and can shrink treatment time to 12 weeks.

To contact the reporter on this story: Anna Edney in Washington at aedney@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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FDA Advisory Committee Recommends Approval of Simeprevir for Combination Treatment of Genotype 1 Chronic Hepatitis C in Adult Patients

RARITAN, N.J., Oct. 24, 2013 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen) announced today that the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) voted unanimously (19 to 0) to recommend approval of the investigational protease inhibitor simeprevir (TMC435) administered once daily as a 150 mg capsule with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis. The Advisory Committee recommended the approval of simeprevir based on analyses of data from clinical trials in patients who are treatment-naive or who have failed previous interferon-based therapy.

"We are pleased with the positive recommendation from the Advisory Committee for simeprevir and appreciate the rigorous review of our data," said Katia Boven, M.D., Medical Department Head, Infectious Diseases and Vaccines, Janssen. "It is our hope that the FDA will consider this recommendation and, upon completion of its review process, make simeprevir available to patients with genotype 1 chronic hepatitis C."

The FDA granted a Priority Review designation in May to the New Drug Application (NDA) filed by Janssen for simeprevir. Recommendations and findings from the Advisory Committee are based in part on efficacy and safety data from an extensive clinical development program for simeprevir and will be considered by the FDA in its review of the NDA for simeprevir, but the FDA is not required to follow them.  

The regulatory submission for simeprevir is supported in part by data from three pivotal Phase 3 studies – QUEST-1 and QUEST-2 in treatment-naive patients and PROMISE in patients who have relapsed after prior interferon-based treatment – as well as data from the Phase 2b ASPIRE study in prior non-responder patients. Janssen R&D Ireland presented data from the QUEST-1 and QUEST-2 studies earlier this year at the 48^th Annual Meeting of the European Association for the Study of the Liver (EASL) in Amsterdam, The Netherlands, and presented data from PROMISE at Digestive Disease Week 2013 (DDW) in Orlando, Florida. Data from ASPIRE were presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in 2012.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide – including approximately 3.2 million people in the United States – and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Simeprevir
Simeprevir (TMC435) is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and its affiliated companies and Medivir AB for the treatment of genotype 1 and genotype 4 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis. Simeprevir works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells.

Janssen is responsible for the global clinical development of simeprevir and has acquired exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB will retain marketing rights for simeprevir in Nordic countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved on September 27, 2013 in Japan for the treatment of genotype 1 hepatitis C and a Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

For additional information about simeprevir clinical trials, please visit www.clinicaltrials.gov.

About Janssen Research & Development, LLC

Janssen Research & Development, LLC is headquartered in Raritan, N.J. and has affiliated facilities in Europe, the United States and Asia. Janssen Research & Development is leveraging a combination of internal and external innovation to discover and develop novel medicines and solutions in five distinct therapeutic areas: Neuroscience, Oncology, Immunology, Infectious Diseases and Vaccines, and Cardiovascular and Metabolism. For more information about Janssen Research & Development, LLC visit www.janssenrnd.com.

Janssen Research & Development, LLC is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

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