Date: 2015-09-10
Type of information: Granting of a Market Authorisation in the EU
Product name: Daklinza®
Compound: daclatasvir
Therapeutic area: Infectious diseases
Action mechanism: direct-acting antiviral agent/nonstructural protein 5A (NS5A) inhibitor. Daclatasvir is an investigational NS5A complex inhibitor. The NS5a protein is essential for HCV to replicate.
Company: BMS (USA)
Disease: treatment of adults with chronic hepatitis C (HCV) with compensated liver disease, including genotypes 1, 2, 3, and 4
Latest news: * On September 10, 2015, BMS announced 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. 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. 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%). * On July 24, 2015, the FDA approved Daklinza® (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza® is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin. The safety and efficacy of Daklinza® in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza® 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured. Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza® labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis. Safety information was available for approximately 1,900 patients with HCV treated with the recommended dose of Daklinza® in combination with other anti-HCV drugs in clinical trials. The most common side effects of Daklinza® with sofosbuvir were fatigue and headache. Daklinza® carries a warning for patients and health care providers that serious slowing of the heart rate (symptomatic bradycardia) and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct-acting antiviral, including Daklinza. Co-administration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. Daklinza® was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness. * On March 12, 2015, BMS announced that the resubmitted new drug application (NDA) for daclatasvir has been accepted for review by the 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. 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 (?5%) 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. 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. Daclatasvir was approved in Europe in August 2014 (see below), and more recently in Brazil 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 Japan’s first all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic HCV infection, including those with compensated cirrhosis. * On August 27, 2014, BMS announced that the European Commission has approved Daklinza® (daclatasvir), a 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. 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. 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 completed Daklinza studies have included more than 5,500 patients in a variety of all-oral regimens and with the current interferon-based standard of care. 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. 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 * On June 26, 2014, the Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorisation for Daklinza® (daclatasvir) in combination with other medicines for the treatment of chronic (long-term) hepatitis C virus (HCV) infection in adults. Until very recently, the standard of care for hepatitis C included a combination of the medicines pegylated interferon and ribavirin, with or without an inhibitor of the viral NS3/4A protease enzyme. However, interferon-based therapies are associated with potentially serious side effects, which are sometimes difficult to manage. One of the major benefits of the new antivirals is to provide an interferon-free treatment option for HCV infection. In November 2013, the CHMP gave an opinion on the conditions under which early access to daclatasvir, in combination with sofosbuvir, another direct-acting antiviral medicine, could be given in compassionate-use programmes. The positive opinion granted by the CHMP for the marketing authorisation of Daklinza® is supported by a pivotal trial in which the medicine was evaluated in HCV genotype-1, -2 and -3 infected patients, in combination with sofosbuvir with or without ribavirin. This study included a treatment arm with patients that previously failed on therapy with an NS3/4A inhibitor in combination with pegylated interferon and ribavirin. All such patients in the study reached a sustained virologic response, which is the goal of antiviral therapy for HCV. This trial is supported by a study of Daklinza® in combination with pegylated interferon and ribavirin in patients with genotype 4 infection, and by several phase IIb trials of Daklinza® with other combinations including with pegylated interferon and ribavirin. The opinion adopted by the CHMP at its June 2014 meeting is an intermediary step on Daklinza’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will then take place at the level of each Member State considering the potential role/use of Daklinza in the context of the national health system of that country. * On January 8, 2014, BMS has announced that the European Medicines Agency (EMA) has validated the company’s marketing authorization application (MAA) for the use of daclatasvir for the treatment of adults with chronic hepatitis C (HCV) with compensated liver disease, including genotypes 1, 2, 3, and 4.
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 application seeks the approval of daclatasvir for use in combination with other agents, including sofosbuvir, for the treatment of chronic hepatitis C. The MAA validation marks the start of an accelerated regulatory review process for daclatasvir. The EMA submission is supported by data from multiple studies of daclatasvir with other HCV therapies. To date, daclatasvir has been studied in more than 5,500 patients in a variety of all-oral regimens and with the current interferon-based standard of care. In addition to demonstrating pan-genotypic potency in vitro, daclatasvir has shown a low drug-drug interaction profile, supporting its potential use in multiple treatment regimens and in people with co-morbidities. No clinically relevant safety signals have been observed thus far in daclatasvir clinical trials, and daclatasvir has been generally well-tolerated in all investigational regimens and patient types. The EU submission follows the recent Bristol-Myers Squibb regulatory filing in Japan seeking approval of a DCV-based regimen for the treatment of patients infected with HCV genotype 1b.
Patents:
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2015-07-24
UE authorization: 2014-08-27
Favourable opinion UE: 2014-06-26
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
