Friday, April 4, 2014

Hepatitis C - Off-label combinations of antiviral agents

Preparing for the uncertain yet inevitable: Off-label combinations of antiviral agents in hepatitis C virus 

Andrew Aronsohn,1,2 Nancy Reau,1 and Donald Jensen1

Article first published online: 1 MAR 2014
DOI: 10.1002/hep.26903

The next generation of direct-acting antiviral agents (DAAs) will change the landscape of hepatitis C virus (HCV) therapy. Approval of complimentary oral agents will also introduce new opportunities for off-label treatment. Off-label therapy in HCV will include (1) combinations of approved drugs, used for the approved indication in an unapproved combination, such as combining two DAAs in an interferon (IFN)-sparing regimen, and (2) combinations of approved drugs used in an unapproved combination for an unapproved indication, such as using two available DAAs to treat patients post-LT (liver transplantation). Both providers and patients might find off-label combinations attractive; however, there may be limited data to support safety and efficacy. These treatment choices may also go against the recommendations published in therapeutic guidelines.

This article will address anticipated issues regarding off-label use of HCV medications, including the role of the U.S. Food and Drug Administration (FDA), consumer pressure, medical society guidelines, and third-party payers. Off-label issues specific to the United States will be described; however, many concepts, such as uncertainties of cost, label regulation, and reimbursement, can be applied to health care systems globally.

The FDA Regulation of Off-Label Use

The FDA regulates market entry for all new prescription drugs in the United States. Once approved, physicians are not bound to prescribe according to the label-in many cases, off-label prescriptions may be part of best practice or standard of care. Off-label prescribing is legal and has been shown to occur in over one fifth of office-based prescriptions.[1] Upcoming generations of DAAs represent robust therapeutic innovation, which will likely outpace the breadth and capacity of the FDA-approved label. Prescribing already approved agents in an off-label combination may be desired to improve efficacy. In addition, safety may also be improved using these combinations by potentially eliminating drugs with toxicity, such as IFN. FDA approval for these combinations would require a new and unique application for the combined regimen, which would be costly and would require partnership between separate manufacturers. As a result, although the FDA will not regulate a provider's ability to prescribe off-label HCV treatment as they see fit, appropriate applications of use may be ambiguous because they will ultimately be based on a combination of opinion and potentially limited available data.

Defining the Need for Off-Label Combinations

Over 185 million people are infected with HCV worldwide.[2] It has surpassed human immunodeficiency virus (HIV) as a cause for mortality and has been linked to higher all-cause mortality and diminished quality of life.[3, 4] Despite data showing that sustained viral response (SVR) reduces mortality, relatively few patients have undergone successful treatment.[5] Historically, suboptimal efficacy and toxicity of IFN-based therapy has limited therapeutic options for many; however, opportunity is on the horizon. Multiple agents are in the late stages of development. These drugs will target various aspects of the HCV life cycle, making combinations of these agents a natural strategy to more effectively treat HCV and eliminate intolerable side effects or adverse events. Data involving various combinations of DAAs, often from different manufacturers, is rapidly becoming available; however, many of these studies are performed as proof of concept and are unlikely to progress to FDA-approved combinations. Combining DAAs based on these data in an off-label manner may be an attractive option for patients unwilling to undergo IFN-based therapy in addition to patients with comorbidites that have previously disqualified candidacy for standard-of-care therapy. This strategy is not without risk. Insurers may be unwilling to pay for off-label therapy,[6] and these combinations may have inadequate supporting safety and efficacy data.

Recent Centers for Disease Control and Prevention and U.S. Preventive Services Task Force guidelines to screen all patients born between 1945 and 1965 will help identify many patients who have been infected for decades and are at risk for developing complications of chronic liver disease. Although most of these patients are candidates for standard-of-care therapy, with anticipated rates of SVR reaching 75%,[7, 8] many patients and providers have chosen to defer therapy in anticipation for IFN-free regimens. Deferring therapy comes with risk, which includes progression of disease, change in health status, which may make future treatment impossible, possibility of infecting others, and change in patient insurance status, making therapy unaffordable. Although FDA-approved IFN combinations will likely be available in upcoming years, patients and providers may begin to feel restless, deferring therapy, and opt for a readily available off-label IFN-free combination. This patient population will likely represent a short-term utilization of off-label DAA combinations, which will diminish as IFN-free regimens come to market.

Alternatively, there are many subsets of individuals with HCV that that are in need of DAA-based treatment, but will be excluded from upcoming FDA labels because of limitations in supporting data. These patients include those with decompensated cirrhosis, first-generation protease inhibitor failures, chronic kidney disease, pediatric populations, HIV coinfection, and post-LT. Because many of these populations represent relatively small numbers of patients with HCV, it may be difficult to accumulate requisite data and possibly cost prohibitive for manufacturers to apply for FDA approval. These patients may represent longer-term utilization of off-label treatment.

Is There Precedent for Off-Label Use of Therapy?

The Human Immunodeficiency Virus Paradigm
Acquired immune deficiency syndrome (AIDS) was identified in 1981; however, zidovudine was not available until 1987. Between 1987 and 2008, 25 anti-HIV (human immunodeficiency virus) compounds were licensed for use. Similar to HCV, these agents directly target various aspects of the HIV life cycle. As single agents were approved, there was pressure by clinicians and advocates to find off-label combinations that would prevent emergence of viral resistance. By 1996, combination regimens were widely accepted, although the first regimen, Combivir (zidovudine and lamivudine), was not FDA approved until September 26, 1997.[9] The turning point in therapeutics began in 1996, when data presented at the 11th International Conference on AIDS in Vancouver, British Columbia, Canada, represented HIV as a highly efficient virus, producing 10 billion virions per day. Several key publications followed, illustrating the substantial benefit of three agent-based highly active antiretroviral therapies.[10] Although multiagent therapy was quickly incorporated into clinical practice and eventually established as the standard of care, this principle was first supported by expert opinion and guidelines-not necessarily the package insert. In most instances, payers reimbursed these off-label combinations and the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act provided support. A loud and vocal advocacy campaign provided the necessary impetus for this outcome.

Experience With Hepatitis B

Before the approval of entecavir and tenofovir for hepatitis B virus (HBV), the combination of adefovir and lamivudine was used to control HBV resistant to monotherapy, as well as to prevent the development of resistance in those considered at high risk. Tenofovir, commercially available as an approved drug for HIV, was used off label in the management of hepatitis B well before the FDA approved the drug for this indication. Truvada (tenofovir in combination with emtracitabine) continues to be used off label in the management of HBV. Clinical guidelines advocate for off-label combinations of these medications to manage resistant HBV.[11]

HCV Therapy May Be Different

Although there is precedent for off-label therapy in many diseases, HCV has unique considerations. First, unlike HIV, in patients without advanced fibrosis there is often no urgency to initiate therapy. Progression to clinically significant disease in HCV often takes decades, and patients and providers may be less willing to take on the risk of off-label treatment when an approved regimen is only months to years away. Second, for many patients, the current standard-of-care HCV treatment is safe and offers high rates of SVR. Alternatively, drug-resistant HBV, HIV, and many cancers may have limited, if any, FDA-approved treatments, making an off-label therapy the only option. Finally, there is not the same intensity of HCV advocacy as there had been for HIV, a pivotal factor in swaying third-party reimbursement.

Practical Considerations in Off-Label Use of DAAs

How Much Supporting Data Will Be Required?
Off-label use of upcoming DAAs will certainly occur; however, the degree of utilization will rely on availability of safety and efficacy data. One emerging source of data may come from prospective observational studies, such as HCV TARGET and CUPIC. These multicenter studies enroll large numbers of patients undergoing HCV therapy and have the potential to capture vast amounts of off-label therapeutic data. If a high level of evidence from observational studies or well-controlled clinical trials is available, it is possible that off-label combinations may be advocated by authoritative guidelines from well-respected academic associations. More likely, especially in understudied populations, robust data will not be available. In these cases, providers and patients will have to determine their minimal threshold of safety and efficacy data to initiate off-label therapy without the assistance of guidelines or a package insert. Treatment based on limited data will require extensive communication and understanding of therapeutic options between the patient and provider.

What Will Be the Role of Industry and How Will It Be Regulated?

Although prescribing practices are unregulated, industry promotion of off-label use is highly restricted. Pharmaceutical companies are required to submit final promotional materials to the FDA for review at the time of public dissemination. Off-label promotion in these materials is strictly prohibited and is subject to FDA regulatory action. In contrast, the FDA has taken a more lenient position on activities that fall under the safe harbor of scientific exchange of information. Recent guidelines allow for industry dissemination of scientific literature of non-FDA-approved drug use, provided it is in an unabridged form, published in a peer-reviewed journal, and accompanied by a clear statement that indicates the study involves off-label use of a given therapy.[12] Another potential outlet for marketing will be industry-sponsored continuing medical education activities, which may include nonpromotional discussion of off-label use of a therapy. Both of these practices are already highly utilized in the HCV therapy market and will likely increase in volume as new agents prepare to come to market and are approved. Providers who treat HCV will encounter vast amounts of data presented in these formats that are unregulated by the FDA and will be required to critically evaluate the quality and utility of these data before integrating it into clinical practice.

Reimbursement of Off-Label Therapy

Opportunities for off-label HCV treatment with newer DAAs will only be realized if payers reimburse drug costs. Because most health plans rarely publicize policy regarding off-label reimbursement, there tends to be heterogeneity among plans with regard to reimbursement procedures. In general, the likelihood of reimbursement can be thought of as a continuum in which FDA-approved use has the highest probability of reimbursement; mention of an off-label use in society guidelines, compendia, or peer-reviewed literature are less likely to be reimbursed, and expert opinions of off-label use, including data presented in non-peer-reviewed abstract form being least likely to be reimbursed. This continuum is affected by both cost of drug and availability of therapeutic alternatives. In 2009, 34 third-party payers representing approximately one quarter of Medicare and Medicaid beneficiaries nationwide were surveyed regarding practices in off-label reimbursement.[13] Approximately 25% of these payers refused payment for off-label therapy of any kind. Of those who did reimburse off-label therapy, data sources that were felt to be very important in determining eligibility for reimbursement included peer-reviewed literature (74%), clinical practice guidelines (53%), and cost-effectiveness data (21%). In instances where off-label reimbursement was allowed, restrictions of use were reported to be imposed 85% of the time. Examples of restrictions included requirement for previous authorization, step therapy (i.e., failing less costly treatment first), and quantity limits.

Off-label uses of therapies supported by high-quality evidence and seen as standard of care are more likely to be reimbursed by payers. The competitive development of HCV therapy is unique and may uncover exceptions to this rule. First, the rapid progress of the HCV therapeutic pipeline combined with the chronic nature of HCV and a highly effective standard-of-care therapy may deincentivize payers to reimburse off-label treatment when similar FDA-approved therapeutic regimens are projected to be only months away. For example, payers may be reluctant to allow for payment for both simeprevir and sofosbuvir based on the COSMOS trial when IFN-free regimens, offering similar safety and efficacy data, are under consideration for FDA approval in the near future.[14]In addition, as newer agents continue to minimize toxicity and optimize efficacy, payers will be less likely to reimburse potentially costly off-label regimens that offer only incremental benefits of efficacy, safety, or duration of therapy. Finally, because price will be independently negotiated on a per-drug basis, mixing different agents may skew cost/efficacy ratios and threaten to increase financial burden to payers.

Off-label HCV therapy will offer a unique opportunity for providers to use innovative combinations of drugs to treat patients in need; however, this treatment will come at a cost. To mitigate this cost, we can expect increasing payer requirements to justify off-label use. Ironically, third-party payers may become a de facto regulatory body by making decisions on which off-label regimens will be allowed.


The availability of new DAAs will provide unprecedented opportunities for off-label HCV therapies in many patients. These patients will include those who are unwilling to take, or intolerant of, IFN and those in need of HCV therapy with no other treatment options. For many, this will ultimately be tempered by FDA-approved all-oral options, but until that time, patients, prescribers, and payers will struggle in an environment where more questions exist than answers. There are no rules, and thus there will be little consistency. Historical precedent only serves as proof of concept. Hepatitis C therapy is not offered under the Ryan White CARE Act rules, and as a consequence, HCV treatment will certainly become polarized. No standard for the minimal amount of safety and efficacy data exists, and in many cases, providers will make treatment decisions without the support of the FDA or treatment guidelines. Patient communication, critical evaluation of available evidence, and meticulous management of off-label treatment recipients will be of paramount importance as we enter into the next era of on- and off-label DAA therapy.


Wednesday, April 2, 2014

Watch-Recent FDA approval of sofosbuvir and simeprevir- Implications for current HCV treatment

Clinical Liver Disease
Volume 3, Issue 3
Pages 43–68


Recent FDA approval of sofosbuvir and simeprevir. Implications for current HCV treatment

Authors M. Valerie Lin M.D., Raymond Chung M.D.

Hepatitis C Drug Trials to Take Spotlight at Liver Congress

Medscape Medical News from the
European Association for the Study of the Liver (EASL) International Liver Congress 2014

This coverage is not sanctioned by, nor a part of, the European Association for the Study of the Liver.
Medscape Medical News > Conference News

Hepatitis C Drug Trials to Take Spotlight at Liver Congress

Miriam E. Tucker
April 02, 2014

New all-oral interferon-free treatment regimens for hepatitis C will take center stage at the European Association for the Study of the Liver (EASL) International Liver Congress 2014, with an unprecedented number of phase 3 trials demonstrating cure rates of up to 100%.
The congress will take place April 9 to 13 in London, United Kingdom.

"There are a lot of very important things being discussed, but I think what really stands out are the remarkable results achieved in several trials on the treatment of hepatitis C, particularly genotype 1, which is the most difficult to treat," explained Giorgina Mieli-Vergani, MD, who is honorary president of the EASL.

 Dr. Markus Peck-Radosavljevic

"Hepatitis C is a major killer in the world, and doctors have been trying for a long time to find the best way of treating it. Now we are very close to being able to treat it very effectively — this is a major, major thing coming out of this congress," Dr. Mieli-Vergani told Medscape Medical News.
In fact, "we've never had this many phase 3 studies in one conference before, said Markus Peck-Radosavljevic, MD, secretary-general of the EASL. "They will be changing clinical practice."

The studies will show that "without interferon, by combining 2 or 3 drugs, you can cure hepatitis C in 95% and 99% of cases, which means essentially you can cure everybody with very little side effect," said Dr. Peck-Radosavljevic told Medscape Medical News.

Moving "Very, Very Fast"
Some of the most highly anticipated phase 3 results are from the SAPPHIRE trials, which evaluated 12-week regimens of ribavirin plus ABT-450/r, ABT-267, and ABT-333, under development by AbbVie, in patients with genotype 1 hepatitis C. SAPPHIRE I involves treatment-naïve patients and SAPPHIRE II involves treatment-experienced patients.
Also anticipated are results from the ION-2 study, which evaluated the fixed-dose combination of sofosbuvir plus ledipasvir (Gilead Sciences), with and without ribavirin, in treatment-naïve and treatment-experienced patients with genotype 1 hepatitis C.

Dr. Giorgina Mieli-Vergani
The once-daily sofosbuvir/ledipasvir pill appears to work in a short period of time in the most difficult-to-treat patients, and with far fewer adverse effects than regimens containing pegylated interferon. Dr. Mieli-Vergani called the results "amazing."

"I am a pediatrician, and this is exceedingly exciting for me," she told Medscape Medical News. "The current oral drug regimens require up to 12 pills a day, which is impossible for a child. There are no trials in children yet, but they will follow." Although hepatitis C is much less common in children than in adults, 6% to 7% of infected mothers pass along the infection to their infants, she explained.

New treatment guidelines for hepatitis C from the World Health Organization — primarily addressing the developing world — will be presented at the meeting.

Also presented will be EASL guidelines on hepatitis C. Although they were published online in December 2013, they are already outdated, Dr. Peck-Radosavljevic told Medscape Medical News (J Hepatol. 2014;60:392-420).

"Things are moving very, very fast. We will definitely need to update again within a year," he said. The organization will probably stop printing the guidelines on paper and only house them online so that they can be continually updated, he said.

Hallway Conversation
Not officially on the agenda but sure to be discussed is the high cost of new drugs for hepatitis C. "How all people who need it are going to be able to have it, I don't know," said Dr. Mieli-Vergani.
Dr. Peck-Radosavljevic pointed out that "companies have to recover their cost of development and satisfy their investors." But, he added, "you have a drug curing a deadly disease in 100% of patients. If you put that into perspective, the pricing is not outrageous."

Both he and Dr. Mieli-Vergani predict that the prices will eventually drop, as was the case with the HIV drugs.

Beyond Hepatitis C
Beyond hepatitis C, new information on numerous liver disease-related topics, including hepatitis B and D, nonalcoholic fatty liver disease, hepatocellular carcinogenesis, liver regeneration, and noninvasive assessment of liver disease, will be featured, and beginner and advanced sonography workshops will be offered.

Of note, phase 3 data will be presented on the use of obeticholic acid (Intercept Pharmaceuticals) for the treatment of primary biliary cirrhosis.

"This is a new type of drug. It's very interesting because it's the first time in many years we will have a new drug that works in primary biliary cirrhosis," said Dr. Peck-Radosavljevic.
The current treatment, ursodeoxycholic acid, has been on the market for about 40 years. "It helps, but doesn't work for all patients, so it is really quite important to have something new here," he said.
Primary biliary cirrhosis is an autoimmune liver disease of major interest to Dr. Mieli-Vergani. She is looking forward to meeting with 40 to 50 fellow members of an international ad hoc autoimmune hepatitis interest group that meets every year at the EASL and major liver meetings, she told Medscape Medical News.

"Autoimmune liver disease is a small part of the meeting, but a very intense and important part," she said.

Another "small but important" topic is children with liver disease. They are by and large surviving into adulthood now and transitioning to adult hepatology care, Dr. Mieli-Vergani explained.
"When I started doing pediatric hepatology 40 years ago, 60% of my patients died within 2 years of diagnosis. There were many conditions we didn't understand or know how to treat. Transplantation didn't exist. Nowadays, it's about 5%," she reported.

It is challenging for adult hepatologists, she said, because these patients are very different from those who develop liver disease in adulthood. In the United Kingdom, efforts have been made to ease the transition by having pediatric, adolescent, and adult specialists coordinate care for the patient during a transition period.

"Pediatrics is a very small part of the meeting, but the fact that they have me as the honorary president is a very nice sign," she told Medscape Medical News.

Dr. Mieli-Vergani reports receiving research funding from Roche, and being a consultant for Roche, Bristol Myers Squibb, and Novartis. Dr. Peck-Radosavljevic reports consulting for or receiving speaker honoraria from BMS, AbbVie, Gilead, Merck, Roche, Lilly, Bayer, Boehringer, and GlaxoSmithKline.

Gilead Announces Results From Phase 3 Study of Sofosbuvir Among Hepatitis C Patients in Japan

Gilead Announces Results From Phase 3 Study of Sofosbuvir Among Hepatitis C Patients in Japan

– Results Confirm Efficacy and Safety of All-Oral Sofosbuvir-Based Regimen for Genotype 2 HCV Patients –

– Japanese Regulatory Filing Planned for Mid-Year –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Apr. 2, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced topline results from a Phase 3 clinical trial (Study GS-US-334-0118) in Japan evaluating the once-daily nucleotide analog polymerase inhibitor sofosbuvir in combination with ribavirin (RBV) for the treatment of genotype 2 chronic hepatitis C virus (HCV) infection. The study met its primary efficacy endpoint of superiority compared to a predefined historical control sustained virologic response (SVR) rate. In the study, 97 percent (n=148/153) of genotype 2 HCV-infected patients receiving 12 weeks of an all-oral regimen of sofosbuvir plus RBV achieved a sustained virologic response 12 weeks after completing therapy (SVR12). SVR12 rates among treatment-naïve and treatment-experienced patients were 98 percent (n=88/90) and 95 percent (n=60/63), respectively. Of the 153 patients who received treatment, 11 percent (n=17) had documented cirrhosis.

Japan has one of the highest rates of liver cancer of any industrialized country, and the majority of cases are due to chronic HCV infection. An estimated two million people in Japan are living with HCV infection, and approximately 20-30 percent have the genotype 2 strain of the virus. Current treatment options for genotype 2 HCV infection in Japan involve up to 48 weeks of therapy with pegylated interferon injections, which may not be suitable for certain patients.

In Study GS-US-334-0118, 153 patients (100%) became HCV undetectable by treatment Week 4 and remained undetectable through the remainder of the 12-week treatment period. Post-treatment relapse accounted for five virologic failures. There were no treatment discontinuations due to adverse events and all patients completed the 12 week post-treatment follow-up visit. The most common side effects observed in the study, consistent with the population and safety profile of RBV, included nasopharyngitis, anemia, headache, malaise and pruritis. Full study results will be presented at a future scientific meeting.

“This study confirms the high efficacy of all-oral therapy with sofosbuvir among genotype 2 hepatitis C patients in Japan, regardless of whether they are treatment experienced or new to treatment,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “Based on these trial results, Gilead anticipates submitting a New Drug Application for sofosbuvir to the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by mid-2014.”

Gilead established operations in Japan with the formation of Gilead K.K. in Tokyo in September 2013. If approved by the PMDA, sofosbuvir would be the first product to be launched and marketed by Gilead in Japan.

Gilead is also conducting a Phase 3 study in Japan evaluating the efficacy and safety of a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir 90 mg and sofosbuvir 400 mg with and without ribavirin for the treatment of patients with genotype 1 chronic HCV infection, the most common strain of HCV in Japan. SVR12 results are expected in the second half of 2014.

Sofosbuvir is an investigational product in Japan and its safety and efficacy has not yet been established. The compound has been approved by regulatory authorities in the United States, European Union and Canada and is commercialized under the tradename Sovaldi®. The ledipasvir/sofosbuvir fixed-dose combination is an investigational product and its safety and efficacy has not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable results from additional clinical trials involving sofosbuvir or the ledipasvir/sofosbuvir fixed-dose combination in Japan, and the possibility we may not file for regulatory approval of sofosbuvir in Japan in the currently anticipated timelines. Further, the PMDA may not approve these products in Japan, and any marketing approvals, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at

Sovaldi is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Phase 3 Trials evaluating Simeprevir and Sofosbuvir have been initiated

Press Release 2 April 2014
Two phase III trials evaluating once-daily Simeprevir and Sofosbuvir in hepatitis C infected patients have been initiated

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that two phase III trials are recruiting patients to examine the efficacy and safety of the NS3/4A protease inhibitor simeprevir in combination with the nucleotide inhibitor sofosbuvir for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection in treatment-naïve and treatment-experienced patients with and without cirrhosis.

“Positive safety and efficacy results have previously been demonstrated in genotype 1 HCV infected patients with the interferon- and ribavirin free combination of simeprevir and sofosbuvir in the phase II COSMOS study. The OPTIMIST trials aim to further consolidate these data and to explore a shorter treatment duration of eight weeks to potentially further simplify this promising treatment option,” says Charlotte Edenius, EVP Development, Medivir AB

Study design
The first trial, called OPTIMIST-1 or TMC435HPC3017, is a phase III, open-label, randomized study investigating the efficacy and safety of simeprevir 150 mg in combination with sofosbuvir 400 mg.
The combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naïve or treatment experienced. This study will enroll approximately 300 patients in the U.S. and Canada.

The second trial, called OPTIMIST-2 or TMC435HPC3018, is a phase III, open-label, single-arm study investigating the efficacy and safety of simeprevir 150 mg in combination with sofosbuvir 400 mg.

The combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naïve or treatment experienced. This study will enroll approximately 100 patients in the U.S. and Canada.

Ribavirin will not be administered in the OPTIMIST trials. The primary efficacy endpoint in each study is the proportion of patients achieving sustained virologic response 12 weeks after the end of treatment (SVR12).

For additional information, including inclusion and exclusion criteria for these trials, please visit

COSMOS study
The combination of simeprevir and sofosbuvir was previously evaluated in the phase II COSMOS trial.

The final cohort 1 study results (SVR12) in patients without fibrosis or cirrhosis (METAVIR score of F0-2) and the interim cohort 2 study results (SVR4) in patients with fibrosis or cirrhosis (METAVIR score of F3-4) from the COSMOS study were presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting 2013 in Washington, D.C.

Final cohort 2 results (SVR12) have been accepted for presentation at the European Association for the Study of the Liver (EASL) International Liver Congress 2014 on April 12.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.00 CET on 2 April 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB will retain marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. The treatment was approved for the treatment of genotype 1 hepatitis C in September 2013 in Japan and in November 2013 in Canada and the U.S. and in March 2014 in Russia. The Committee for Medicinal Products for Human Use (CHMP) recently recommended Marketing Authorisation in the European Union for the use of Simeprevir in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients. An approval is expected during Q2-2014.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

Tuesday, April 1, 2014

Gastroenterologists Would Prescribe Sovaldi/Daclatasvir plus Ribavirin to 60 Percent of Genotype-3 Patients

Gastroenterologists Would Prescribe Sovaldi plus Daclatasvir plus Ribavirin to 60 Percent of Their Genotype-3 Patients, According to Findings from Decision Resources Group

BURLINGTON, Mass., April 1, 2014 /PRNewswire/ -- Decision Resources Group finds that surveyed gastroenterologists in the United States and Europe agree that the percentage of hepatitis C virus (HCV) genotype-3 infected patients with cirrhosis of the liver achieving a sustained virologic response (SVR) is one of the attributes that most influences their prescribing decisions. Clinical data and interviewed experts indicate that interferon-free regimens containing Gilead's Sovaldi (sofosbuvir) and Bristol-Myers Squibb's NS5A inhibitor daclatasvir have convenience and efficacy advantages over currently available regimens for HCV genotype-3 infections. However, competition from other NS5A inhibitors, such as Gilead's GS-5816, may constrain uptake of daclatasvir.

Other key findings from the DecisionBase report entitled Hepatitis C Virus Genotype 3: What Untapped Opportunities Remain for Treatment of Genotype-3 Infections:

Payer receptivity to new HCV genotype-3 therapies: Almost half of surveyed U.S. managed care organization pharmacy directors would not reimburse a new HCV genotype-3 therapy offering a 6-week duration if priced at $100,000 per course, with a notable share citing price and insufficient clinical benefit as the reasons. This suggests that, assuming comparable efficacy, payers are unwilling to accept a premium for a shorter course of therapy.

The importance of cost in treatment decisions for HCV genotype-3 infections: Conjoint analysis of drug attributes influencing prescribing behavior revealed that surveyed gastroenterologists perceive the cost of treatment as important as SVR rate in treatment decisions for HCV genotype-3 infected patients. This suggests that the cost of sofosbuvir plus ribavirin is a key barrier to prescribing and that physicians and payers will favor a lower-cost alternative with comparable efficacy and safety.

Estimated prescribing of the sofosbuvir and daclatasvir combination: Surveyed U.S. gastroenterologists indicated that they would prescribe sofosbuvir and daclatasvir plus ribavirin to 60 percent of their HCV genotype-3 patients.

Comments from Decision Resources Group Analyst Seamus Levine-Wilkinson, Ph.D.:
"Gilead's interim phase two data for their pangenotypic interferon- and ribavirin-free combination of Sovaldi and the NS5A inhibitor GS-5816 indicates that up to 100 percent of genotype-3 infected patients achieved SVR4. If these impressive results are confirmed in planned phase three studies, likely including evaluation of a coformulated sofosbuvir and GS-5816 one-pill, once-daily regimen, then this combination will provide a highly effective, safe, pangenotypic, and convenient single-tablet regimen for HCV infections. In other words, this could be one pill to rule them all."

"Cost of HCV therapies is a serious concern among both payers and physicians. Given the high price for a 24-week course of Sovaldi, the new standard of care for HCV genotype-3 infections, it is likely that payers and physicians will be very skeptical of any new HCV genotype-3 therapy priced at a premium to Sovaldi. Conversely, a drug developer that is able to offer a lower-cost interferon- and ribavirin-free regimen for HCV genotype-3 that achieves high SVR rates, will be very well positioned to compete in this market segment."

About Decision Resources Group

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WSJ Live - $1,000-a-Day Hepatitis C Drug Is a Blockbuster

WSJ Live

$1,000-a-Day Hepatitis C Drug Is a Blockbuster
Runaway demand for a life-saving hepatitis C treatment that costs $1,000 a day could send insurers' earnings per share down by double-digit percentages this year. Jonathan Rockoff reports on Lunch Break.

Karen Hoyt: Your Best Friends Guide To Hepatitis C

HCV Advocate Karen Hoyt

Meet the creator of; Your Best Friends Guide To Hepatitis C, Karen Hoyt, an inspirational woman, HCV advocate, and author who is living with hepatitis C and cirrhosis. Karen embraces life with an infectious spirit she generously shares online with you, her friends. With her blog Karen has created a safe haven for anyone living with this sometimes cruel and unpredictable illness. Exuding pure devotion Karen gently guides us through each HCV test, symptom, and every emotion this disease has to offer.

In addition to her blog,, a series of four exceptional videos appropriately deemed "True Champions" featuring Karen were recently launched by HealthiNation. If you haven't seen them you're in for a treat. 

True Champions: Hepatitis C Videos

In each of these video segments Karen takes us on an incredible journey beginning with her own battle with HCV.  In the video "Advocates" Karen interviews author Lucinda Porter, another loved and respected HCV advocate who has educated our community for over a decade. 

Begin Here........... 

Stay connected with both Karen and Lucinda on Twitter