SVR 24 Two Weeks After a Tripled Dose of Daclatasvir in an HCV Genotype 3 Patient (Case Report)

Case Report

Ann Hepatol. 2018 July - August ,;17(4):661-664. doi: 10.5604/01.3001.0012.0950.

SVR 24 Achievement Two Weeks After a Tripled Dose of Daclatasvir in an HCV Genotype 3 Patient.
Lo Menzo S1, Biagi E1, Di Nuzzo M1, Grilli A1, Contini C1.

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Abstract

Directly-acting antivirals (DAA) have changed the chronic hepatitis C virus (HCV) infection therapeutic scenario allowing virus eradication in more than 95% of patients, independently from the genotype, with 12 to 24-week treatment regimens. We describe a 51-year-old Pakistani man with a chronic HCV-genotype 3 (GT3a) infection with moderate liver fibrosis, who achieved sustained virological response (SVR) 24 after a tripled dose of Daclatasvir (DCV) taken erroneously associated to Sofosbuvir (SOF). The patient had a concomitant intestinal TB infection whose treatment had been delayed in order to firstly eradicate HCV to reduce the liver toxicity of anti-mycobacterial drugs. Thanks to the cultural mediator support, we explained to the patient the correct posology of each drug to take during the day consisting of 12 week SOF (400 mg daily) plus DCV (60 mg daily) regimen. He returned 13 days after for a programmed visit and we were surprised to learn that he had taken 3 pills of DCV (180 mg/daily) instead of one, thus ending DCV assumption after only 9 days while SOF was taken correctly. He complained no symptoms. We immediately performed blood test that showed alteration of lactate dehydrogenase, creatine phosphokinase, and creatin kinase MB activity. At day 15 we stopped SOF closely monitoring the patient. Blood test alterations returned normal after one week of treatment suspension, HCV viremia remained suppressed after 4, 12 and 24 weeks proving HCV eradication. If confirmed, these data could suggest that higher doses of DCV, if tolerated, might be employed in short-time HCV-GT3 treatment.

PMID: 29893709 DOI: 10.5604/01.3001.0012.0950 

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 http://annalsofhepatology.com/revista/numeros/2018/HP184-18-SRV24%20(F_120618m)_PROTEGIDO.pdf

Sofosbuvir-Daclatasvir-Simeprevir Plus Ribavirin in Direct-Acting Antiviral–Experienced Patients With Hepatitis C

Clin Infect Dis (2017) 64 (11): 1615-1618.

DOI:

https://doi.org/10.1093/cid/cix214

Sofosbuvir-Daclatasvir-Simeprevir Plus Ribavirin in Direct-Acting Antiviral–Experienced Patients With Hepatitis C

Christophe Hézode Slim Fourati Stéphane Chevaliez Giovanna Scoazec Alexandre Soulier Anne Varaut Murielle François Isaac Ruiz Françoise Roudot-Thoraval Ariane Mallat Jean-Michel Pawlotsky

Abstract

We assessed the broadly used, off-label combination of sofosbuvir, daclatasvir, simeprevir, and ribavirin in direct-acting antiviral–experienced patients, as recommended in current guidelines despite scarce data. After 24 weeks’ treatment, sustained virological response 12 weeks after the end of treatment was achieved in 6 patients (60%). Two cirrhotic patients relapsed and 2 discontinued treatment due to serious adverse events.

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A Review of Daclatasvir Drug-Drug Interactions

Review article
A Review of Daclatasvir Drug-Drug Interactions.
Garimella T, et al. Adv Ther. 2016

Adv Ther. 2016 Sep 23. [Epub ahead of print]

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Abstract
The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug–drug interactions (DDIs).

Daclatasvir (DCV)—the benchmark pangenotypic nonstructural protein 5A inhibitor—has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir. DCV may be the object of a DDI via the induction or inhibition of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) by the concomitant medication, or the precipitant of a DDI via DCV-based induction/inhibition of CYP 3A4 or inhibition of P-gp, organic anion transporting polypeptide 1B1/B3, and/or breast cancer resistance protein.

This article presents an overview of the drug interaction studies conducted during the clinical development of DCV, the findings of these studies that led to the guidance on concomitant medication use and dosage along with any required DCV dose modifications, and the use of the known metabolic pathway of DCV to guide concomitant dosing where direct drug–drug studies have not been conducted. The robust characterization of the DCV clinical pharmacology program has demonstrated that DCV has few or no clinically relevant DDIs with medications with which it is likely to be co-administered, and the majority of DDIs that do occur can be predicted and easily managed.

Funding: Bristol-Myers Squibb.

KeywordsConcomitant medications Daclatasvir Drug–drug interactions Hepatitis C virus Infectious diseases

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Health Canada Approves DAKLINZA™ (daclatasvir) for Difficult-to-Treat Hepatitis C Patient Populations

Health Canada Approves DAKLINZA™ (daclatasvir) for Difficult-to-Treat Hepatitis C Patient Populations

SOURCE Bristol-Myers Squibb Canada

DAKLINZA™ is approved in Canada in combination with other agents for the treatment of chronic hepatitis C Patients with HIV co-infection, advanced cirrhosis and post-liver transplant HCV recurrence

MONTREAL, May 24, 2016 /CNW/ - Bristol-Myers Squibb Canada today announced Health Canada's approval of DAKLINZA™ (daclatasvir), in combination with sofosbuvir (with or without ribavirin) for 12 weeks in the treatment of chronic hepatitis C (CHC) in adult patients with hepatitis C virus (HCV) genotypes 1, 2 or 3 in three difficult-to-treat populations, including patients with HIV-1 co-infection, patients with compensated or decompensated cirrhosis and patients with HCV recurrence after liver transplantation.1

Both co-infected and post-transplant patient populations, historically, have been difficult to treat, in large part due to potential drug-to-drug interactions between the antiviral therapy regimens for HIV or anti-rejection drugs for post-transplant.2,3

"Chronic hepatitis C patients who have advanced disease, are co-infected with HIV or who have a recurrence of HCV after receiving a new liver pose complex treatment challenges to physicians," said Dr. Curtis Cooper, Director, The Ottawa Hospital and Regional Hepatitis Program. "These new indications for DAKLINZA™ give physicians more treatment options. We can now offer safe and highly curative HCV treatment to even the most complex and medically challenging of patients."

HCV and HIV co-infection is not rare. Approximately 20 per cent of Canadians with HIV have both infections.4 HCV progresses more rapidly to liver damage in people who are co-infected than in those who only have HCV.2 Currently, liver disease related to HCV is the leading cause of death among people with co-infection.2

"As part of our commitment to the HCV community, we have strived to make new treatment options available for patients with different genotypes, including those who are amongst the most difficult-to-treat," said Dr. Nawal Peacock, President and General Manager, Bristol-Myers Squibb Canada. "With this expanded label for DAKLINZA™, we are proud to provide an option that helps bridge what has been a challenging treatment gap for these patients."

The new indications are based on data from the ALLY-1 clinical trial (in post-transplant patients and patients with advanced cirrhosis) and the ALLY-2 clinical trial (in HIV-1 co-infected patients). In ALLY-1, DAKLINZA in combination with sofosbuvir and ribavirin achieved a cure rate of 94 per cent in patients with post-liver transplant and 92 to 94 per cent in patients with advanced cirrhosis.3 In ALLY-2, the DAKLINZA™ plus sofosbuvir combination achieved a 97 per cent cure rate in treatment naive co-infected patients and 98 per cent in treatment experienced co-infected patients.2

"As people in the advanced stages of the disease can attest, HCV can be a devastating illness," Dr. Morris Sherman, hepatologist and chair of the Canadian Liver Foundation, who has treated patients with hepatitis C for more than 20 years. "These patients are in great need of a cure so they can recover and enjoy their life again. The HCV community welcomes each new treatment option that can help to cure this illness, and bring us closer to seeing a day when HCV is gone for good."

DAKLINZA™, a potent, pan-genotypic NS5A replication complex was approved by Health Canada in August 2015 for use in combination with other agents for the treatment of adult patients with HCV genotypes 1, 2, or 3 and compensated liver disease, including cirrhosis.1 In Canada, genotypes 1, 2 and 3 account for 65 per cent, 14 per cent and 20 per cent of HCV infections respectively.5

About Bristol-Myers Squibb Canada Co.
Bristol-Myers Squibb Canada is an indirect wholly-owned subsidiary of Bristol-Myers Squibb Company, a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb global operations, visit www.bms.com. Bristol-Myers Squibb Canada has been delivering innovative medicines for serious diseases to Canadian patients in the areas of cardiovascular health, oncology, neuroscience, immunoscience and virology for over 80 years. Bristol-Myers Squibb Canada employs over 300 people across the country. For more information, please visit www.bmscanada.ca.

Additional Information:

About ALLY-1 Clinical Trial1
In the trial, the DAKLINZA™ plus sofosbuvir and ribavirin regimen demonstrated overall SVR12 in 94 per cent of post-liver transplant patients and 83 per cent of patients in the advanced cirrhosis cohort, including 92 to 94 per cent of patients with compensated cirrhosis (Child-Pugh A or B). In the cirrhosis cohort, four subjects with hepatocellular carcinoma underwent liver transplantation after 1 to 71 days of treatment; three of the four subjects received 12 weeks of post-liver transplant treatment extension and one subject, treated for 23 days before transplantation, did not receive treatment extension. All four subjects achieved SVR12.

In the ALLY 1 trial, the most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue and nausea. Most adverse reactions were mild to moderate in severity. Fifteen (13%) subjects experienced an SAE; all SAEs were considered unrelated to treatment. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs.

About ALLY-2 Clinical Trial1
In ALLY-2, the DAKLINZA™ plus sofosbuvir regimen demonstrated overall SVR12 in 97 per cent in treatment-naive patients and 98 per cent in treatment-experienced patients, including 100 per cent in genotype 3 (n=10). SVR12 rates were high regardless of combination antiretroviral therapy (cART) regimens, including boosted-protease inhibitor-, NNRTI-, and integrase inhibitor-based therapies. In the trial, 2 per cent of subjects experienced SAEs and no discontinuations due to AEs. The most common adverse reaction (=10% or greater) was fatigue (14%).

References
1 Bristol-Myers Squibb Canada DAKLINZA™ Product Monograph. Revised: May 13, 2016.
2 Wyles DL, et al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015;373:714-25.
3 Poordad, F., Schiff, E.R., Vierling, J.M., et al, Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: phase 3 ALLY-1 study. J Hepatol. 2015;62:261.
4 Centre for Communicable Diseases and Infection Control Infectious Disease Prevention and Control Branch Public Health Agency of Canada. Hepatitis C in Canada: 2005-2010 Surveillance Report. 2012. Page 25.
5 RP Myers, RP, Shah KW, Cooper, C, et al. An update on the management of chronic hepatitis C: 2015 consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol 2015.

HCV Next - Impact of Sustained Virologic Response in Hepatitis C Therapy

 

HCV NEXT March Issue

"HCV Next" offers information on a range of topics which include  new HCV combination therapies, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.

The following articles appeared in the March print edition of HCV NEXT, provided online at Healio.

Table of Contents
5 Questions
A Conversation with Adrian J. Dunlop, PhD, MBBS

Cover Story
Narrowing the Gap: Cause for Optimism for Racial Minorities with HCV in the US

Editorial
Medicare Physician Payment: Prepare to ‘MACRA-Mize’ Your Practice

In the Journals
Few Infants Born to Mothers with HCV in Philadelphia Undergo Testing

Simeprevir/Sofosbuvir Yield High SVR Post-Liver Transplant

Faldaprevir Yields High SVR in Relapsers with HCV Genotype 1

Special Series
Global View Series: Sub-Saharan Africa

The Big Picture
Impact of Sustained Virologic Response in Hepatitis C Therapy

Stevan A. Gonzalez, MD, MS
Trend Watch
FDA Grants Priority Review of Supplemental NDA for Viekira Pak

FDA Approves Expanded Label of Daclatasvir for Additional HCV Patients

Sofosbuvir/Velpastasvir Receives Priority Review for All HCV Genotypes

Generic Versions of Daclatasvir - Natco Pharma signs agreement for mfg, sale of hepatitis C drug

Natco Pharma signs agreement for mfg, sale of hepatitis C drug

Natco Pharma has signed a non-exclusive licensing agreement with the Medicines Patent Pool (MPP) and Bristol-Myers Squibb to manufacture and sell generic versions of Daclatasvir, used for the treatment of chronic hepatitis C.

By: PTI | New Delhi | January 21, 2016 1:42 PM

Natco Pharma has signed a non-exclusive licensing agreement with the Medicines Patent Pool (MPP) and Bristol-Myers Squibb to manufacture and sell generic versions of Daclatasvir, used for the treatment of chronic hepatitis C. (Reuters)

Natco Pharma has signed a non-exclusive licensing agreement with the Medicines Patent Pool (MPP) and Bristol-Myers Squibb to manufacture and sell generic versions of Daclatasvir, used for the treatment of chronic hepatitis C.

Natco Pharma, in a BSE filing today said: “It has signed a non-exclusive, royalty free licensing agreement with the Medicines Patent Pool (MPP) and Bristol-Myers Squibb to manufacture and sell generic versions of Bristol-Myers Squibb’s chronic hepatitis C medicine Daclatasvir Dihydrochloride (Daclatasvir).”

Daclatasvir, discovered and developed by Bristol-Myer Squibb, is the first-in-class NS5A inhibitor used in combination with Sofosbuvir to treat patients with chronic hepatitis C virus (HCV) genotype 3 infection.

“Compared to other treatment options, this combination not only increases the cure rate, but is also regarded as a valuable treatment option in some of the difficult-to-treat HCV patient subsets,” it said.

Natco said it will market the drug under its own brand NATDAC, and through its strategic partners in India.

“This agreement allows Natco to expand access to these chronic hepatitis C medicines in 112 developing countries. Under the licence, Natco can set its own price for the generic products it produces,” it said.

Shares of Natco Pharma were trading 4.06 per cent up at Rs 527.50 apiece on BSE.

Source 

http://www.financialexpress.com/article/industry/companies/natco-pharma-signs-agreement-for-mfg-sale-of-hepatitis-c-drug/199531/

Daklinza® (daclatasvir) - Treatment For Welsh Hepatitis C Patients With Advanced Liver Disease

Treatment For Welsh Hepatitis C Patients With Advanced Liver Disease
Friday, June 5th 2015 07:00

Welsh hepatitis C patients with advanced liver disease get NHS access to a new, oral treatment that has been shown to help clear the infection.

All Wales Medicines Strategy Group has recommended Daklinza® (daclatasvir) to be used, in combination with other medicinal products, as an option to treat eligible NHS patients with chronic hepatitis C and advanced liver disease.

Approximately 12,000 people in Wales are thought to have chronic hepatitis C, which can potentially cause liver cancer or liver failure.

The All Wales Medicines Strategy Group (AWMSG) has recommended Daklinza®(daclatasvir) for the treatment of adult patients with chronic hepatitis C virus (HCV) infection.1 The recommendation is specifically for patients with advanced liver disease, for whom treatment options can be limited. Daclatasvir is used in combination with other agents to treat adult patients with chronic HCV genotypes 1, 3 and 4 (which include most of the cases seen in Wales).2,5 This decision could enable some of the most ‘at-risk’ patients in Wales with chronic HCV to access a new, first-in-class treatment which has been shown, when used with other agents, to clear the viral infection in most of these patients after 12 or 24 weeks of therapy.1,2

Commenting on the AWMSG recommendation, Dr. Brendan Healy, Consultant in Microbiology and Infectious Diseases at the University Hospital of Wales, said: “Today’s decision marks an important milestone for patients in Wales with chronic hepatitis C. People living with this virus could go on to develop liver damage and liver cancer. Clearing the virus in these patients is not only good for their health but also for the wider community as it reduces the risk of onward transmission. Daclatasvir is an important addition to our armamentarium against this disease and will help us to treat patients. By doing so, we can help to prevent any further liver damage their hepatitis C may cause.”

Hepatitis C is a preventable and treatable blood-borne viral disease which, if left untreated, can lead to potentially fatal cirrhosis or cancer of the liver.3 Recent estimates indicate that approximately 12,000 people have chronic HCV in Wales.4

“We are at a real turning point in the fight against the virus,” said Charles Gore, Chief Executive of The Hepatitis C Trust. “We must not forget that hepatitis C can cause liver damage without the sufferer even knowing they are carrying the virus. Having access to new tolerable options that can help to treat these patients is really important and we welcome this progressive recommendation by the AWMSG.”

Chronic hepatitis C is usually asymptomatic in the early years, which contributes to the fact that as many as 50% of people living with the disease may be undiagnosed.3 Furthermore, 60% of all those infected will go on to develop some level of damage to their liver.6 Specifically in cirrhotic patients with HCV, it is predicted that up to 8% will develop liver cancer, 1-2% will develop liver failure and liver transplantation will be required in a further 5-10%.6 Less than a sixth of the HCV infected population in Wales is currently being monitored or treated by specialist services.6

Commenting on the recommendation of the AWMSG, Johanna Mercier, General Manager, Bristol-Myers Squibb, UK and Ireland said, “Hepatitis C patients with advanced liver disease have limited treatment options and we are therefore delighted that the AWMSG has taken the decision to recommend daclatasvir-based regimens.”

http://www.swanseasound.co.uk/news/local/treatment-for-welsh-hepatitis-c-patients-with-advanced-liver-disease/

Bristol-Myers Squibb Announces Acceptance of New Drug Application for Investigational Daclatasvir for FDA Review for the Treatment of Hepatitis C Genotype 3

Bristol-Myers Squibb Announces Acceptance of New Drug Application for Investigational Daclatasvir for FDA Review for the Treatment of Hepatitis C Genotype 3
Thu March 12, 2015 3:00 PM|Business Wire

The NDA contains data to support approval for daclatasvir in combination with sofosbuvir; would be the first 12-week regimen specifically for the treatment of hepatitis C genotype 3

The application is based on a Phase III clinical trial which tested a 12-week, ribavirin-free regimen and resulted in sustained virologic response (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced genotype 3 HCV patients

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol-Myers Squibb Company(NYSE:BMY) announced today that the resubmitted new drug application (NDA) for daclatasvir, an investigational NS5A replication complex inhibitor, has been accepted for review by the U.S. Food and Drug Administration (FDA) for use in combination with sofosbuvir for the treatment of chronic hepatitis C (HCV) genotype 3. The original NDA has been amended to include data from the Phase III ALLY-3 trial, which showed high cure rates for the combination, with sustained virologic response 12 weeks after treatment (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced genotype 3 HCV patients. SVR12 rates were higher (96%) in non-cirrhotic genotype 3 patients, regardless of treatment history. The FDA will now review the submission within a six-month timeframe.

The daclatasvir-based NDA seeks to address a high-unmet patient need that still exists despite recent hepatitis C treatment advances. Approximately 9-12% of HCV patients in the U.S. have genotype 3. Thats thousands of individuals in the U.S. who historically have had limited treatment options requiring at least 24 weeks of treatment, said Douglas Manion, M.D., head ofSpecialty Development, Bristol-Myers Squibb. We also are continuing clinical trials to determine the potential of daclatasvir-based regimens in treating a range of other high unmet-need patients, including those coinfected with HIV, HCV patients with decompensated cirrhosis, and HCV recurrence in post-transplant patients.

Genotype 3 is estimated to affect 54.3 million people worldwide, and is the second most common hepatitis C genotype after genotype 1 (83.4 million). The more aggressive nature of genotype 3 lies in the damage it causes to the liver, as it is associated with progressive disease, increased rates of steatosis and a disproportionately increased risk of hepatocellular carcinoma.

In the ALLY-3 study, the daclatasvir and sofosbuvir combination regimen was well tolerated, with no deaths, treatment-related serious adverse events, or discontinuations due to adverse events. The most frequent side effects (e5%) were headache (19.7%), fatigue (19.1%), nausea (11.8%), diarrhea (8.6%), insomnia (5.9%), abdominal pain and arthralgia (both 5.3%). Additionally, there were 17 (11.2%) treatment failures, with 16 relapses post-treatment and 1 rebound at the end of treatment. There were no viral breakthroughs in this ribavirin-free regimen.

About ALLY-3: Study Design

This Phase III open-label clinical trial enrolled 152 genotype 3 HCV patients; 101 treatment-naïve patients and 51 treatment-experienced patients in 2 cohorts each received daclatasvir 60 mg and sofosbuvir 400 mg once daily for 12 weeks, with 24 weeks of follow-up. The primary endpoint was SVR12 rates, defined as HCV RNA < LLOQ target detected or not detected at follow-up week 12 in treatment-naïve and treatment-experienced patients.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Approximately 170 million people worldwide are infected with hepatitis C, with an estimated 2.73.9 million chronically infected in the United States. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 20 percent may progress to liver cancer.

About Bristol-Myers Squibbs HCV Portfolio

Bristol-Myers Squibbs research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, a NS5A complex inhibitor, which continues to be investigated in multiple treatment regimens and in people with co-morbidities.

Daclatasvir was approved in Europe in August 2014, and more recently inBrazil in January 2015, for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Daclatasvir also is approved in Japan in combination with asunaprevir, a NS3/4A protease inhibitor. The daclatasvir+asunaprevir dual regimen is Japans first all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic HCV infection, including those with compensated cirrhosis.

About Bristol-Myers Squibb (BMY)

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that daclatasvir will receive regulatory approval in the United States, or if approved, that it will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Bristol-Myers Squibb Company
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Robert Perry, Office: 609-419-5378
Cell: 407-492-4616
rob.perry@bms.com
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Investors:
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ranya.dajani@bms.com

Source: Bristol-Myers Squibb Company
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Daclatasvir for hepatitis C: Hint of added benefit in genotype 4

Daclatasvir for hepatitis C: Hint of added benefit in genotype 4

Daclatasvir (trade name Daklinza) has been approved since August 2014 for the treatment of adults with chronic hepatitis C (CHC) infection. According to the dossier assessment conducted by the German Institute for Quality and Efficiency in Health Care (IQWiG) in December 2014, no added benefit could be derived for daclatasvir.

In an addendum, the Institute now examined information subsequently submitted by the drug manufacturer in the commenting procedure: According to the findings, there is a hint of an added benefit for treatment-naive patients with genotype 4. The extent is non-quantifiable, however. The study for patients infected with hepatitis C virus (HCV) of genotype 3, which was presented for the first time, is unsuitable to derive an added benefit.

Genotype 4: Additional analyses reinforce advantage of daclatasvir

In the dossier, the manufacturer had analysed one study (AI444042) for treatment-naive HCV genotype 4 patients. Since many patients had discontinued treatment, however, numerous values were missing in the analysis. These missing values had not been considered adequately in the analysis of the study data. The manufacturer dossier last year therefore provided no robust results for the valid surrogate outcome "sustained virologic response (SVR)".

The manufacturer presented further information on the SVR in its comment on IQWiG's dossier assessment. According to the assessment of these data and supplementary analyses by IQWiG, the results on the outcome "SVR" in favour of daclatasvir were shown to be robust: On completion of the treatment, virus particles (HCV RNA) were detectable in more patients in the control arm than in the daclatasvir arm. Overall however, the study results were so uncertain that no more than a hint of an added benefit can be derived from them.

The extent of this added benefit is non-quantifiable, also because it cannot be derived from the results on SVR how many cases of liver cancer can actually be prevented.

HCV genotype 3: uncontrolled study provided no comparator data

In the commenting procedure on the dossier assessment, the manufacturer presented data from a study (ALLY 3) on HCV genotype 3 patients for the first time. This study is unsuitable for conclusions on the added benefit, however: The presentation of study characteristics and results was incomplete, and the analyses were not comprehensible. In addition, the study participants were treated differently than recommended by the Summary of Product Characteristics. Due to the uncontrolled design, the study additionally provided no results on the comparison with the appropriate comparator therapy so that no added benefit can be derived.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the manufacturer's dossier and the IQWiG dossier assessment, the manufacturer submitted additional information in the commenting procedure. The G-BA subsequently commissioned IQWiG to assess the data subsequently submitted. IQWiG now presents this assessment in the form of an addendum. The G-BA conclusively decides on the extent of added benefit.

Explore further: Daclatasvir for hepatitis C: Added benefit not proven

Provided by Institute for Quality and Efficiency in Health Care

Daclatasvir for hepatitis C: Added benefit not proven

Daclatasvir for hepatitis C: Added benefit not proven

The drug daclatasvir (trade name Daklinza) has been available since August 2014 for the treatment of adults with chronic hepatitis C (CHC) infection. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether this new drug offers an added benefit over the appropriate comparator therapy.

The drug manufacturer presented data for patients without cirrhosis of the liver who are infected with hepatitis C virus (HCV) genotype 1, and for patients with HCV genotype 4. However, these data are unsuitable in various aspects to prove an added benefit.

The manufacturer dossier contained no data at all for three further patient groups with HCV genotype 1 infection (pretreated patients, untreated patients with cirrhosis of the liver, and patients with HIV coinfection) as well as for patients with HCV genotype 3 (with compensated cirrhosis and/or treatment-experienced).

Different virus types cause inflammation
Hepatitis C viruses can trigger inflammation in the liver. If this becomes chronic, cirrhosis can develop and organ function progressively deteriorates. Moreover, the risk of liver cancer (hepatocellular carcinoma, HCC) increases. Daclatasvir aims to inhibit the reproduction of HCV by interfering with viral DNA replication. Experts assume that if no viruses are detectable in the blood over a sustained period after treatment (sustained virologic response, SVR), the risk of secondary disease is reduced.

There are six different main types (genotypes) of the hepatitis C virus, which are subdivided into more than 60 subtypes. The effectiveness of different drugs is not the same against all viruses.

Comparison with dual therapy or triple therapy
Depending on the type of virus, the clinical picture and the course of the disease, daclatasvir is used in dual therapy together with the virostatic drug sofosbuvir, in triple therapy with the virostatic drugs sofosbuvir and ribavirin, or in triple therapy with peginterferon alfa to enhance the immune system and ribavirin. According to the approval, treatment duration differs for certain patient groups (12 to 48 weeks).

Depending on patient characteristics, the options for the comparator therapy are dual therapy with peginterferon alfa and ribavirin, or triple therapy consisting of peginterferon alfa and ribavirin plus a protease Inhibitor (boceprevir or telaprevir). The Federal Joint Committee (G-BA) specified a different appropriate comparator therapy for each of six different subindications:

For treatment-naive adults with chronic HCV genotype 1 infection without cirrhosis, and for treatment-experienced patients with HCV genotype 1, the G-BA specified both dual therapy and triple therapy as appropriate comparator therapy.

In four further subindications, daclatasvir was to be compared only with dual therapy: 1) in treatment-naive HCV patients with genotype 1 and cirrhosis, 2) in patients with HCV genotype 1 and additional HIV infection, 3) in patients with HCV genotype 3 infection with compensated cirrhosis and/or treatment-experienced, and 4) in patients with HCV genotype 4 infection.

However, the manufacturer only presented data for treatment-naive adults with chronic HCV genotype 1 infection without cirrhosis and for patients with HCV genotype 4 infection.

Incomplete study pool for HCV genotype 1
Since studies for the direct comparison were lacking, the manufacturer presented an indirect comparison for HCV genotype 1 patients without cirrhosis in its dossier. Using a "historical" comparison of individual arms of different studies, it aimed to derive conclusions on the superiority of daclatasvir versus the triple therapy. The manufacturer did not meet the requirements for the dossier, however: A search in trial registries was not conducted. In addition, the inclusion and exclusion criteria for the choice of studies were unsuitable. At least one relevant study was lacking in the study pool because of this.

The Bayesian Benchmarking Analysis (BBA) additionally cited was used to determine the minimum threshold a study would have to reach in order to show a statistically significant superiority of daclatasvir. The manufacturer did not meet the requirements for the dossier in this analysis either: The search was limited to a period of time up to 2012 and there was no search in trial registries. In addition, the analysis was restricted to the outcome "SVR" without addressing side effects of Treatment.

Genotype 4: unsuitable data due to lacking values
The manufacturer only evaluated one study of the two studies it presented for the direct comparison of daclatasvir in combination with dual therapy versus dual therapy alone in treatment-naive HCV genotype 4 patients. Due to treatment futility, there were treatment discontinuations in both study arms, and hence missing values in the outcome "SVR", the proportions of which differed greatly between the study arms. The imputation strategy for the values was unsuitable because its results were not robust and biased to the disadvantage of the appropriate comparator therapy.

The criteria for discontinuation in the appropriate comparator therapy did not comply with the Summary of Product Characteristics and were also not reasonable because they considerably shorten the treatment duration in a large proportion of patients thus causing a disadvantage for the comparator therapy with regard to the outcome "SVR". In summary, no suitable data were available for treatment-naive HCV genotype 4 patients either.

G-BA decides on the extent of added benefit
The dossier assessment is part of the overall procedure for early benefit assessments according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

Source: Institute for Quality and Efficiency in Health Care

AASLD - BMS Announces High Cure Rates With daclatasvir (DCV) in combination with sofosbuvir (SOF)

BMS Announces High Cure Rates for Hepatitis C Drug
Mon, 11/10/2014 - 10:42am

Bristol-Myers Squibb announced late-breaking data from the landmark ALLY Trial investigating a ribavirin-free 12-week regimen of daclatasvir (DCV) in combination with sofosbuvir (SOF) in genotype 3 hepatitis C (HCV) patients, a patient population that has emerged as one of the most difficult to treat. The results of the study, which showed sustained virologic response 12 weeks after treatment (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced patients, will be presented at The Liver Meeting, the Annual Meeting of The American Association for the Study of Liver Diseases (AASLD), in Boston, MA, November 7 – 11.

“Both treatment naïve and treatment experienced patients in the ALLY-3 study achieved high SVR rates. These results are encouraging given that patients with genotype 3 have emerged as among the hardest to treat,” said David R. Nelson, M.D., professor of Medicine, Molecular Genetics and Microbiology Director, UF Clinical and Translational Science Institute, and assistant Vice President of Research for the University of Florida. “Genotype 3 is associated with a more rapid progression of disease and remains a challenge to the efficacy of even newer regimens. The ALLY-3 results demonstrate the possibility of bringing a cure to genotype 3 patients in an all-oral, 12-week regimen.”

These results build upon the existing body of data on the daclatasvir and sofosbuvir combination. Data from an open-label, randomized study of daclatasvir with sofosbuvir in genotypes 1, 2, and 3 demonstrated that the 24-week regimen of daclatasvir and sofosbuvir achieved SVR12 in 89% of patients with genotype 3. The ALLY study presented at The Liver Meeting investigates the regimen for 12 weeks, halving the previous treatment duration. Other ongoing ALLY studies examine diverse HCV populations across all genotypes: cirrhotic and post-liver transplant patients, as well as treatment-naïve and treatment-experienced patients who are co-infected with HIV.

“HCV is a complex disease, and the treatment community needs multiple options to address the remaining unmet medical needs,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “Daclatasvir has shown pan-genotypic activity in bench research, a factor which is becoming increasingly important as we learn more about the complexity of HCV. Further, daclatasvir’s potential to be combined with many other agents, including sofosbuvir, is significant in continuing to develop additional treatment options that may help patients of all genotypes achieve cure.”

In the ALLY-3 study, the daclatasvir and sofosbuvir combination regimen was well tolerated, with no deaths, treatment-related serious adverse events, or discontinuations due to adverse events. The most frequent side effects were headache (19.7%), fatigue (19.1%), nausea (11.8%), diarrhea (8.6%), insomnia (5.9%), abdominal pain and arthralgia (both 5.3%). Additionally, there were 17 (11.2%) treatment failures, with 16 relapses post-treatment and 1 rebound at the end of treatment. There were no viral breakthroughs in this ribavirin-free regimen.

Source: Bristol-Myers Squibb

AASLD-BMS Daclatasvir TRIO achieves 98% cure rate in treatment-naïve and 93% cure rate in treatment-experienced geno 1 patients w-cirrhosis when used with ribavirin

Phase 3 UNITY Trials Demonstrate High Cure Rates for Investigational, All-Oral Daclatasvir TRIO Fixed-Dose Combination in Genotype 1 Hepatitis C Patients, Including Those with Cirrhosis

Daclatasvir TRIO achieves 98% cure rate in treatment-naïve and 93% cure rate in treatment-experienced genotype 1 patients with cirrhosis when used with ribavirin, as shown in UNITY 2

12-week, all-oral treatment halves current regimen duration for hard-to-manage treatment-experienced genotype 1 patients with cirrhosis

Fixed-dose regimen also demonstrates 91% SVR rates in non-cirrhotic genotype 1 patients without requiring use of ribavirin

November 08, 2014 09:00 AM Eastern Standard Time

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced late-breaking data from the UNITY Trial program investigating a 12-week regimen of its all-oral daclatasvir (DCV) TRIO regimen – a fixed-dose combination of daclatasvir with asunaprevir (ASV) and beclabuvir (BCV) – in a broad range of patients with genotype 1 hepatitis C virus (HCV).

The data will be presented at The Liver Meeting^® 2014, the Annual Meeting of The American Association for the Study of Liver Diseases (AASLD), in Boston, MA, November 7 – 11. The primary endpoint for both studies was the percentage of patients who achieved cure, defined as HCV RNA<LLOQ TD/TND at post-treatment week 12 for treatment-naïve and treatment-experienced patients.

“Even with the most recent HCV treatment advances, genotype 1 patients with cirrhosis remain difficult to treat”

The UNITY-2 study, which evaluated cirrhotic patients in a 12-week regimen of the DCV-TRIO, showed sustained virologic response 12 weeks after treatment (SVR12) among 98% of treatment-naïve and 93% of treatment-experienced cirrhotic patients with ribavirin (RBV) and 93% of treatment-naïve and 87% of treatment-experienced cirrhotic patients without ribavirin.
“Even with the most recent HCV treatment advances, genotype 1 patients with cirrhosis remain difficult to treat,” said Andrew J. Muir, M.D., MHS, Associate Professor of Medicine; Clinical Director, Gastroenterology & Transplant Hepatology, Duke Gastroenterology. “Currently, treatment-experienced cirrhotic patients still require a 24-week regimen to achieve high SVR rates. The data from this clinical trial using the DCV-TRIO regimen showed high cure rates for this population in a 12-week regimen, and has the potential to aid treatment adherence and provide a shorter treatment duration to achieve cure.”

Study Design and Results
The Phase 3 UNITY clinical trial program is an ongoing study investigating 12-week regimens of the DCV-TRIO fixed-dose combination (daclatasvir 30 mg plus asunaprevir 200 mg plus beclabuvir 75 mg) in non-cirrhotic and cirrhotic genotype 1 patients.

The open-label UNITY-1 study evaluated a 12-week regimen of the DCV-TRIO without ribavirin in treatment-naïve and -experienced non-cirrhotic patients. Non-cirrhotic treatment-naïve patients (n=312) and treatment-experienced patients (n=103) received the DCV-TRIO fixed-dose combination in one pill twice daily for 12 weeks, with 24 weeks of follow-up. The majority of the patients (73%) were genotype 1a, and 91% of all patients achieved SVR12. 92% of treatment-naive patients and 89% of treatment-experienced patients achieved cure, without the use of ribavirin.

In the UNITY-2 study, both cirrhotic treatment-naïve and treatment-experienced patients received the DCV-TRIO fixed-dose combination, one arm without ribavirin (n=102) and one with ribavirin (n=100). The study was double-blinded to ribavirin, and the majority of the patients (74%) were genotype 1a. The study showed 96% of all patients who received the DCV-TRIO with ribavirin achieved SVR12, and 90% of those who received the DCV-TRIO without ribavirin achieved SVR12.
“The Phase 3 UNITY results for the daclatasvir TRIO fixed-dose combination are particularly compelling for genotype 1 patients with cirrhosis, whose treatment is often harder to manage than non-cirrhotic patients,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “BMS continues to recognize that HCV is an extremely complicated disease with no ‘one-size-fits-all’ treatment solution, and the UNITY results are especially promising for serving patients with cirrhosis, a specific but significant portion of genotype 1 patients.”

In both UNITY-1 and UNITY-2 there were low rates of adverse events (AEs) leading to discontinuation and of serious adverse events (SAEs) overall. In UNITY-1 there were 7 SAEs, all considered not related to study treatment, and 3 AEs leading to treatment discontinuation. The most common AEs were headache (25.8%) and fatigue (16.6%). In UNITY-2, there were 3 SAEs related to treatment and 4 AEs leading to discontinuation. The most common AEs were headache and fatigue (both 19.8%).
Full abstracts for both presentations are available at The Liver Meeting website.

About Hepatitis C
Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Approximately 170 million people worldwide are infected with hepatitis C, with an estimated 2.7–3.9 million chronically infected in the United States. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 20 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio
Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, a potent pan-genotypic NS5A complex inhibitor (in vitro), which continues to be investigated in multiple treatment regimens and in people with co-morbidities.

Daklinza (daclatasvir) was recently approved in the EU for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Daklinza is also approved in Japan in combination with Sunvepra (asunaprevir), a NS3/4A protease inhibitor. The Daklinza+Sunvepra Dual Regimen is Japan’s first all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic HCV infection, including those with compensated cirrhosis.

In 2013, Bristol-Myers Squibb’s investigational all-oral DCV-TRIO regimen (daclatasvir/asunaprevir/beclabuvir) received Breakthrough Therapy Designation in the U.S., which helped to expedite the start of the ongoing Phase 3 UNITY program. Study populations include non-cirrhotic naïve, cirrhotic naïve and previously treated patients. In addition to UNITY 1 and 2, both the UNITY-3 study among Japanese treatment-naïve and -experienced genotype 1 patients and UNITY-4, which studies the DCV-TRIO regimen without ribavirin in cirrhotic and non-cirrhotic patients in Korea, Russia and Taiwan, are currently ongoing. The DCV-TRIO regimen is being studied as a fixed-dose-combination treatment with twice daily dosing.

Additional studies with daclatasvir in combination with sofosbuvir are being conducted in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients and patients with genotype 3 as part of the ongoing Phase 3 ALLY Program.

About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that daclatasvir or asunaprevir or any other compounds mentioned in this release will receive regulatory approval in the United States, or if approved, that they will become commercially successful products. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2013, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Bristol-Myers Squibb Company
Media:
Carrie Fernandez, Office: 609-419-5448
Cell: 215-859-2605
carrie.fernandez@bms.com
or
Investors:
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MSF responds to BMS commercial strategy for hepatitis C drug daclatasvir in developing countries

Bristol-Myers' 91-country hep C access plan still draws fire from price critics
November 3, 2014 | By Carly Helfand

Bristol-Myers Squibb ($BMY) is taking Gilead's ($GILD) lead when it comes to developing-world access for its hepatitis C drug, offering up a tiered pricing strategy and licensing agreements with generics makers. But according to some critics, that's not enough.

Continue reading @ FiercePharma

Bristol-Myers Plan to Widen Access to its Hep C Drug, But Meets Criticism

By ED SILVERMAN

A Bristol-Myers spokeswoman would not comment on the criticism or the study, but did send a note saying “our prices in developing countries will take into consideration several factors that include economic development and the burden of disease within a country, as well as the commitment of the government to holistically address hepatitis C, including treatment and care. We are currently engaged in discussions with several high disease burden developing-countries on their plans to address hepatitis C, and the role that Bristol-Myers Squibb can potentially play.”

Continue reading @ WSJ

BMS
HCV Developing World Strategy

Bristol-Myers Squibb recognizes the significant public health challenge that hepatitis C (HCV) presents worldwide, including the substantial burden of the disease in the developing world. With more than 80% of the global HCV patient population living in low- and middle-income countries, there is great need for hepatitis C treatment options in these countries. The significant challenges facing many of these countries are not homogeneous, in particular the need for governments, non-governmental organizations, civil society and industry to form coalitions.

As part of our Company-wide commitment to increasing access to medicines for patient populations in need, we have initiated discussions with government health authorities and other stakeholders in a number of developing countries to facilitate access to daclatasvir. Bristol-Myers Squibb’s HCV developing world access approach will utilize tiered pricing, licensing agreements and working in collaboration with other stakeholders who share in our commitment to working toward the eradication of hepatitis C.



Our tiered pricing model for daclatasvir will take into consideration several factors, including countries’ economic development and burden of disease, as well as the commitment of the government to holistically address hepatitis C, including treatment and care. The lowest pricing tier will apply to all low-income and least developed countries. In addition, in 90 countries (see list at right), Bristol-Myers Squibb will work with licensed generic manufacturers to supply licensed versions of daclatasvir. We are eager to leverage our considerable experience in developing world access to our HIV medicines in order to bring daclatasvir to the developing world as soon as possible.

Source

Médecins Sans Frontières (MSF) responds to the news of BMS’s plans on access and licencing for daclatasvir:

MSF responds to BMS commercial strategy for hepatitis C drug daclatasvir in developing countries

Background
Pharmaceutical company Bristol-Myers Squibb (BMS) has recently revealed a restrictive commercial strategy for sales of its new direct-acting antiviral (DAA) hepatitis C drug daclatasvir in developing countries. This new generation of drugs to treat hepatitis C is giving hope to the 185 million people infected with the disease today, as these drugs are expected to improve treatment and provide significantly higher chances of cure.

But the prices of these drugs are of grave cause for concern. Gilead’s sofosbuvir, the first DAA which received USFDA approval, is priced at US$84,000 per three-month treatment course in the United States, and nearly $95,000 per treatment when used in combination with another DAA, ledipasvir. These prices will hinder any attempt to scale up treatment of the disease.

But studies have suggested that the cost to produce these drugs is just a tiny fraction of the price of the drug; sofosbuvir costs just $68 - $136 per treatment to produce. One of these studies, from Liverpool University, suggests daclatasvir could cost as little as $10 - $30 to produce for a 12 week course of treatment. BMS has not yet announced the price for developing countries for daclatasvir, but the company has announced that it will create a tiered pricing strategy for the drug. Tiered pricing is a marketing strategy that sets different prices for different countries, most often based on macroeconomic factors; the effect is that middle-income countries – where nearly three-quarters of the world’s poor, and over 70 percent of people with hepatitis C, live – are required to pay high prices that are unaffordable to treatment providers such as MSF, government health programs, and patients who must pay for medicines out of pocket.

BMS also announced its intention to negotiate voluntary licenses – which allow selected generic manufacturers to market cheaper versions of a drug – but with a geographical coverage of only 90 developing countries. Restrictive licensing terms can prevent generic competition where it is needed most: the BMS policy could mean that many middle-income countries with a significant burden of hepatitis C, including China, Egypt and Ukraine, are excluded from access to more affordable generic versions of daclatasvir and will have to pay higher prices. The ability to produce or import generic versions of daclatasvir will be critical to significantly reduce prices of these drugs, as well as to develop or sell fixed-dose combinations that are expected to provide the best treatment outcomes for patients.

Registration of daclatasvir in all countries will also be key; BMS has indicated that it does not have plans to register the drug worldwide, which will seriously hinder access in those countries where BMS chooses not register the drug.

Finally, BMS has largely decided their plans in secret, sharing very few details on plans for registration, price and access ahead of the announcement, an approach that is reminiscent of industry approaches in the early years of the AIDS epidemic and unacceptable by any standard today. Details shared ahead of the announcement have been purposefully vague and BMS has not yet committed to publishing any licence agreement it signs with generic manufacturers in the future, or its tiered pricing structure for developing countries.

BMS’ secrecy and very restrictive commercial plans for developing countries is of grave concern, given the medical importance of daclatasvir; studies have shown it to have high rates of cure when used in combination with other DAAs. Daclatasvir is also pan-genotypic, showing it is effective for genotype 3, which has proven difficult to treat with other DAAs and is highly prevalent among people living with hepatitis C in India and Pakistan.

Médecins Sans Frontières (MSF) responds to the news of BMS’s plans on access and licencing for daclatasvir:

“Unfortunately, history seems to be repeating itself with BMS, who haven’t learnt from the company’s poor track record responding to the HIV epidemic; it is disappointing that BMS is choosing to lock out millions of people from gaining affordable access to daclatasvir, and will not commit to registering the drug in all countries that have a hepatitis C burden, even those that do not represent a commercial opportunity for BMS.

“Once again, people in middle-income countries – where nearly three-quarters of the world’s poor, and over 70 percent of people with hepatitis C, live – are the ones left empty-handed. Affordable access to daclatasvir has been intentionally blocked from most middle-income countries, with BMS keen to extract as much profit as it possibly can.  MSF hopes that excluded governments will take all relevant measures available under global trade rules and national patent laws to secure access to low-cost generic versions of these medicines.

“BMS’ secrecy portends an unwelcome approach that does not respond to the urgent need for affordable access to hepatitis C drugs for millions of people across the developing world.”

- Rohit Malpani, Director of Policy and Analysis, Médecins Sans Frontières Access Campaign.

Source

Updated November 3, 2014
Reducing the cost of new hepatitis C drugs

Daclatasvir, Harvoni (ledipasvir/sofosbuvir) and Sovaldi.

An index of articles & research weighing the pros and cons over the high price of hepatitis C drugs.

Hepatitis C - Europe: More Direct-Acting Antivirals, More Controversy

Europe: More Direct-Acting Antivirals, More Controversy
By Guest Blogger | Published: September 2, 2014

Source

The storms raging across Europe—and beyond—over the pricing of new hepatitis C treatments have been intensified by the European Union’s approval last week of the latest directly-acting antiviral, Bristol-Myers Squibb’s Daklinza (daclatasvir). Just two months after the European Medicines Agency gave a positive opinion on the drug, the formal authorization was delivered for use in combination for the treatment of chronic infection in adults.

The company will now start negotiations with each of the national pricing and reimbursement authorities in the EU countries where it wants to launch the product—and those negotiations will be conducted amid the turbulence created by arguments over the price for Gilead’s Sovaldi (sofosbuvir).

For the full Applied Clinical Trials article by Peter O’Donnell, click here.

This entry was posted in Europe, Global, Guest Blog, Op-Ed, pricing, Regulatory and tagged Bristol Myers Squibb, Daklinza, directly-acting antiviral, EC, EU, Gilead, Sovaldi. Bookmark the permalink. Trackbacks are closed, but you can post a comment.

More On: Daclatasvir (Daklinza) for Chronic Hepatitis C Cleared in EU

Related News....

Daclatasvir (Daklinza) for Chronic Hepatitis C Cleared in EU

Medscape
The European Commission has approved daclatasvir (Daklinza, Bristol-Myers Squibb) to treat adults with chronic hepatitis C virus (HCV) infection in combination with other drugs, the company announced today.

The approval follows an endorsement in June by the European Medicines Agency Committee for Medicinal Products for Human Use.

Daclatasvir blocks the action of NS5A, a protein essential for HCV replication. It is indicated for adults infected with HCV genotypes 1, 2, 3, and 4.

In a news release, the company notes that oral daclatasvir in combination with oral sofosbuvir provided cure rates of up to 100% in clinical trials, including in patients with advanced liver disease, genotype 3, and those who have previously failed treatment with protease inhibitors.

Daclatasvir is the first NS5A complex inhibitor approved in the European Union (EU) and, in combination with other drugs, provides a "shorter treatment duration (12 or 24 weeks) compared to 48 weeks of treatment with interferon- and ribavirin-based regimens," the company says.

Across clinical studies, daclatasvir-based regimens have been generally well-tolerated, with low discontinuation rates. The most common adverse effects with daclatasvir when used in combination with other drugs are fatigue, headache, and nausea.

The safety of daclatasvir has been demonstrated in diverse patient populations that include elderly patients, patients with advanced liver disease, post–liver transplant recipients, and patients coinfected with HIV, the company says.

"HCV is a challenging virus to overcome," Michael P. Manns, MD, professor and chairman, Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Germany, said in the release. Daclatasvir, when combined with other compounds, "often results in cure among even the hardest-to-treat patients," he added.

Recommended regimens and treatment durations for daclatasvir-based regimens include:

• For HCV genotype 1 or 4 without cirrhosis: daclatasvir plus sofosbuvir for 12 weeks. Consider prolongation to 24 weeks for patients with prior treatment, including a NS3/4A protease inhibitor.
• For genotype 1 or 4 with compensated cirrhosis: daclatasvir plus sofosbuvir for 24 weeks. Consider shortening treatment to 12 weeks for previously untreated patients with cirrhosis and positive prognostic factors such as IL28B CC genotype and/or low baseline viral load. Consider adding ribavirin for patients with very advanced liver disease or with other negative prognostic factors, such as prior treatment experience.
• For genotype 3 with compensated cirrhosis and/or treatment experienced: daclatasvir plus sofosbuvir plus ribavirin for 24 weeks.
• For genotype 4: 24 weeks of daclatasvir plus 24 to 48 weeks of peginterferon alfa and ribavirin. If the patient has HCV RNA undetectable at both treatment weeks 4 and 12, all 3 components of the regimen should be continued for 24 weeks. If the patient achieves undetectable HCV RNA, but not at both treatment weeks 4 and 12, daclatasvir should be discontinued at 24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks.

Daclatasvir monotherapy is not recommended. The Summary of Product Characteristics will be available online. Commercial availability of daclatasvir in the EU will be determined by individual member states.

Bristol-Myers Squibb’s Daklinza (daclatasvir), Approved By European Commission

European Commission Approves Bristol-Myers Squibb’s Daklinza (daclatasvir) Across Multiple Genotypes for the Treatment of Chronic Hepatitis C Infection

Daklinza, when used in combination with sofosbuvir, is an all-oral, once daily regimen that yields cure rates of up to 100%

Daklinza + sofosbuvir offers potential cure for a broad range of EU HCV patients, including those with advanced liver disease, genotype 3 and protease inhibitor failures

R&D News

Wednesday, August 27, 2014 5:00 am EDT

"The eradication of HCV is in sight, and with today’s approval, Daklinza, in combination with other agents, will be an important option to achieve cure across many HCV genotypes and patient types for those in the EU who are in dire need of new treatment choices"

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that the European Commission has approved Daklinza (daclatasvir), a potent, pan-genotypic NS5A replication complex inhibitor (in vitro), for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Daklinza, when used in combination with sofosbuvir, is an all-oral, interferon-free regimen that provided cure rates of up to 100% in clinical trials, including patients with advanced liver disease, genotype 3 and those who have previously failed treatment with protease inhibitors. Daklinza is the first NS5A complex inhibitor approved in the European Union (EU) and will be available for use in combination with other medicinal products, providing a shorter treatment duration (12 or 24 weeks) compared to 48 weeks of treatment with interferon- and ribavirin-based regimens.

Today’s approval allows for the marketing of Daklinza in all 28 Member States of the EU. The marketing authorization for Daklinza follows an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP), a designation that is granted to new medicines of major public health interest.

“HCV is a challenging virus to overcome, requiring multiple modes of attack. With the approval of Daklinza, we have a new class of drug that disrupts the virus in two ways - by inhibiting both viral replication and assembly - and when combined with other compounds often results in cure among even the hardest-to-treat patients,” said Michael P. Manns, MD, Professor and Chairman, Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.

Of the estimated nine million people living with HCV in the EU, genotype 1 is the most common genotype, though distribution varies across the region. The burden of liver disease and other morbidities from HCV infection is significant in Europe, where HCV accounts for 63% of liver transplants among patients with virus-related liver disease. Patient populations with high unmet needs include those with advanced liver disease, protease inhibitor failure, genotype 3, HIV co-infected patients and those who have undergone liver transplant.

“The eradication of HCV is in sight, and with today’s approval, Daklinza, in combination with other agents, will be an important option to achieve cure across many HCV genotypes and patient types for those in the EU who are in dire need of new treatment choices,” said Emmanuel Blin, Head of Worldwide Commercialization, Bristol-Myers Squibb. “We are proud to have discovered, developed and now brought to market this first-in-class NS5A replication complex inhibitor. We look forward to our continued work with EU health authorities to ensure Daklinza-based regimens are available to patients as quickly as possible.”

The approval of Daklinza is supported by data from multiple studies, including an open-label, randomized study of Daklinza with sofosbuvir in genotypes 1, 2, and 3, including patients with no response to prior therapy with telaprevir or boceprevir and patients with fibrosis. Results showed that a regimen of Daklinza with sofosbuvir achieved SVR₁₂ (sustained virologic response 12 weeks after the end of treatment; a functional cure) in 99% of treatment-naïve patients with HCV genotype 1, 100% of patients with genotype 1 who had failed treatment with either telaprevir or boceprevir, 96% of those with genotype 2 and 89% of those with genotype 3.

In addition, the regimen resulted in low rates of discontinuation (<1%) due to adverse events (AEs). The rate of serious adverse events (SAEs) was low (4.7%). The most common adverse events were fatigue, headache and nausea. Across clinical studies, Daklinza-based regimens have been generally well tolerated with low rates of discontinuation across a range of patients. Ongoing and completedDaklinza studies have included more than 5,500 patients in a variety of all-oral regimens and with the current interferon-based standard of care.

The safety of Daklinza for the treatment of hepatitis C has been demonstrated in diverse patient populations that include elderly patients, patients with advanced liver disease, post-liver transplant recipients and patients co-infected with HIV. No unique safety concerns have been identified in patients who were treated withDaklinza across clinical studies and in the early access program. Several of these studies are ongoing.

Recommended regimens and treatment duration for Daklinza combination therapy include:

HCV genotype and patient population			Treatment			Duration
Genotype 1 or 4 without cirrhosis			Daklinza + sofosbuvir			12 weeks Consider prolongation of treatment to 24 weeks for patients with prior treatment including a NS3/4A protease inhibitor (see sections 4.4 and 5.1).
Genotype 1 or 4 with compensated cirrhosis			Daklinza + sofosbuvir			24 weeks Shortening treatment to 12 weeks may be considered for previously untreated patients with cirrhosis and positive prognostic factors such as IL28B CC genotype and/or low baseline viral load. Consider adding ribavirin for patients with very advanced liver disease or with other negative prognostic factors such as prior treatment experience.
Genotype 3 with compensated cirrhosis and/or treatment experienced			Daklinza + sofosbuvir + ribavirin			24 weeks
Genotype 4			Daklinza + peginterferon alfa + ribavirin			24 weeks of Daklinza in combination with 24-48 weeks of peginterferon alfa and ribavirin. If the patient has HCV RNA undetectable at both treatment weeks 4 and 12, all 3 components of the regimen should be continued for a total duration of 24 weeks. If the patient achieves HCV RNA undetectable, but not at both treatment weeks 4 and 12, Daklinza should be discontinued at 24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks.

Daklinza monotherapy is not recommended. The Summary of Product Characteristics will be available at www.ema.europa.eu. Commercial availability of Daklinza in the EU will be determined by individual Member States.

Investment Commentary

Bristol-Myers gets the approval Gilead didn't want: Daklinza + Sovaldi for hep C

And here's where it gets more interesting. We know Gilead will be leaning on its Sovaldi + ledipasvir pill, which is up for FDA approval by Oct. 10. AbbVie's three-drug option is under FDA review for a December decision. Bristol-Myers might want to tout the Daklinza + Sovaldi option when (and if) its FDA nod comes through in November.

But the FDA didn't allow the company to turn in that Sovaldi-Daklinza data with its current app. The approval would be for Daklinza and another BMS drug, Sunvepra (asunaprevir)--and that combo hasn't performed quite as well as the Daklinza-Sovaldi team in trials. Sustained virological response--a common measure in hep C trials--for the latter duo approached 100% in some patients, as Bristol-Myers noted in its E.U. announcement.....

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Medscape

More On: Daclatasvir (Daklinza) for Chronic Hepatitis C Cleared in EU

"HCV is a challenging virus to overcome," Michael P. Manns, MD, professor and chairman, Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Germany, said in the release. Daclatasvir, when combined with other compounds, "often results in cure among even the hardest-to-treat patients," he added.

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MSF urges BMS to make daclatasvir accessible in low-and middle-income countries
Ramesh Shankar, Mumbai
Saturday, August 30, 2014, 08:00 Hrs [IST]

Even as the European Commission (EC) and European Medicines Agency (EMA) approved the new direct-acting antiviral (DAA) daclatasvir to treat hepatitis C, the international medical humanitarian organization Médecins Sans Frontières (MSF) has asked the Bristol-Myers Squibb (inventor of daclatasvir) to ensure that people living with hepatitis C in low- and middle-income countries can actually access this important drug, so that it can have the greatest impact on hepatitis C globally in helping to cure people.

Welcoming the EMA's approval of daclatasvir on August 27, 2014, the MSF said that the BMS must rapidly register daclatasvir in those countries with a high burden of hepatitis C, especially in those countries with a high prevalence of genotype 3. It also urged BMS to ensure daclatasvir is affordable in those countries with a high burden of hepatitis C.

“Intellectual property barriers for daclatasvir, unless they are overcome, could keep affordable versions out of reach of people and may also prevent the development of an optimal fixed-dose combination that can provide simple, highly effective treatment for all people with hepatitis C, regardless of genotype”, said Dr Jennifer Cohn, medical director, MSF Access Campaign.

“Patent barriers that prevent affordable access to daclatasvir and the new DAAs must be addressed by governments to promote robust generic competition, which will enable price reductions, facilitate the development of a pan-genotypic combination, and accelerate availability in all developing countries that are bearing the brunt of the hepatitis C epidemic,” Dr Cohn further said.

On 27 August 2014, the EC and the EMA became the second regulatory authority (after Japan in July) to approve new direct-acting antiviral (DAA) daclatasvir, used to treat hepatitis C. Daclatasvir is the third DAA - a new class of oral drugs used to treat hepatitis C – to be approved.

The approval of daclatasvir is medically significant, as it, in combination with other hepatitis C drugs including other DAAs, results in high cure rates; clinical trials have also shown it to be well tolerated by people. In addition, combining two DAAs is critical to simplifying treatment in developing countries, and combinations which include daclatasvir, such as sofosbuvir+daclatasvir, have pan-genotypic potential; daclatasvir has shown to be effective for genotype 3, which has proven difficult to treat with other DAAs and is highly prevalent among people living with hepatitis C in India and Pakistan.

However, the MSF expressed its concern about the potential lack of affordable access to daclatasvir, and patent barriers that could prevent the development of effective and affordable combinations.

Development and testing of sofosbuvir/daclastavir combination treatment was delayed when Gilead (owner of sofosbuvir) stopped collaboration with Bristol-Myers Squibb (owner of daclatasvir) in favour of Gilead's proprietary sofosbuvir/GS-5816 combination. Only now is BMS able to undertake phase III trials of this combination with commercially available sofosbuvir. Further, BMS has not yet announced any access plans for low- and middle-income countries, where the majority of the hepatitis C burden lies.

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