Updated Label for Daklinza (daclatasvir) for the 12-week Treatment of Non-cirrhotic Patients with Chronic Hepatitis C Genotype 3 Approved by the European Commission
Bristol-Myers Squibb Company (NYSE: BMY) announced today that the European Commission has approved an updated label for Daklinza for the treatment of genotype 3 chronic hepatitis C (HCV). The update allows the use of Daklinza in combination with sofosbuvir for 12 weeks in patients without cirrhosis in all 28 Member States of the European Union, and marks the first time these patients with genotype 3 HCV have a once-daily, all-oral treatment regimen of this shorter duration.
"The burden of hepatitis C – and genotype 3, specifically – remains significant in many parts of Europe," said Graham R. Foster, FRCP, Ph.D., Professor of Hepatology, Blizard Institute, Queen Mary University of London, London, United Kingdom. "Despite advances in therapy, genotype 3 HCV patients are still some of the most challenging to treat with direct-acting antivirals. The cure rates achieved by Daklinza in combination with sofosbuvir for 12 weeks represent a positive step forward for genotype 3 patients without cirrhosis."
Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A and P-glycoprotein transporter, as this may lead to lower exposure and loss of efficacy of Daklinza. Daklinza must not be administered as a monotherapy.
In August 2014, Daklinza was approved by the European Commission for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic HCV infection in adults. The original label included treatment of patients with genotype 3 (with or without compensated cirrhosis and/or treatment-experienced) with Daklinza and sofosbuvir and ribavirin, for 24 weeks. The updated label, which removes the requirement for ribavirin and reduces treatment duration to 12 weeks for patients without cirrhosis, is based on data submitted to the European Medicines Agency and the Committee for Medicinal Products for Human Use from the ALLY-3 clinical trial. The updated treatment regimen for patients with cirrhosis is for Daklinza plus sofosbuvir with the optional use of ribavirin, which may be added based on clinical assessment of the patient. The treatment duration for these patients has not changed.
Affecting an estimated 54.3 million people (30% of all HCV patients) worldwide, genotype 3 is the second most common HCV genotype globally and is considered one of the most difficult to treat. The more aggressive nature of genotype 3 lies in the damage it causes to the liver, as it is associated with accelerated fibrosis progression. Recent research has also shown the risk of cirrhosis for patients infected with HCV genotype 3 is 31% greater than for those with HCV genotype 1.
ALLY-3 Study Design
The European Commission's approval is based on data from the Phase 3 open-label ALLY-3 clinical trial, which was published in Hepatology in April 2015. In the trial, 152 patients with chronic HCV genotype 3 infection and compensated liver disease (101 treatment-naïve patients and 51 treatment-experienced patients) received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post-treatment. The co-primary endpoints were defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12 (SVR12) in each treatment group. Most treatment-experienced patients had failed prior treatment with peginterferon/ribavirin, but seven patients were treated previously with a sofosbuvir regimen and two patients with a regimen containing an investigational cyclophilin inhibitor. Previous exposure to NS5A inhibitors was prohibited. In the trial, the Daklinza plus sofosbuvir regimen demonstrated overall SVR12 in 90% of treatment-naïve and 86% of treatment-experienced chronic HCV genotype 3 patients. SVR12 rates were higher (96%) in genotype 3 patients without cirrhosis, regardless of treatment history. In the more difficult-to-treat patients with cirrhosis, SVR12 rates were reduced (63%) following the 12 weeks of treatment with the Daklinza plus sofosbuvir regimen.
In the trial, there were no treatment-related serious adverse events (SAEs), no discontinuations due to adverse events (AEs), and no new safety signals. The most common treatment-related AEs were headache (20%), fatigue (19%), nausea (12%) and diarrhea (9%). The updated Summary of Product Characteristics will be available at www.ema.europa.eu.
About Bristol-Myers Squibb in HCV
Bristol-Myers Squibb's research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio is daclatasvir, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden, such as pre- and post-transplant patients and HIV/HCV coinfected patients, as part of the ongoing Phase 3 ALLY Program.
In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic HCV. Since then, daclatasvir-based regimens have been approved in more than 50 countries, including the United States, across Europe, and in numerous other countries in North, Central and South America, the Middle East and the Asia-Pacific region.
U.S. Indication and Important Safety Information (ISI) - Daklinza™ (daclatasvir)
The following ISI is based on information from U.S. Prescribing Information for Daklinza. Please consult the full Prescribing Information for all labeled safety information.
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.
Limitations of Use:
- Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.
IMPORTANT SAFETY INFORMATION
Drugs Contraindicated with Daklinza: strong inducers of CYP3A
that may lead to loss of efficacy of Daklinza include, but are not
- Phenytoin, carbamazepine, rifampin, St. John's wort (Hypericum perforatum).
WARNINGS and PRECAUTIONS
- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir
and Amiodarone: Post-marketing cases of symptomatic bradycardia
and cases requiring pacemaker intervention have been reported when
amiodarone is coadministered with sofosbuvir in combination with
another direct-acting antiviral, including Daklinza. A fatal cardiac
arrest was reported with ledipasvir/sofosbuvir.
- Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
- Bradycardia generally resolved after discontinuation of HCV treatment.
- Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
- The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).
- CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
- P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.
Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.
Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.
Please click here for the Daklinza full prescribing information.
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 Daklinza's approval for the updated label mentioned above will lead to increased commercial success. 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.