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Daklinza(Daclatasvir Tablets)
FDA Approves Daklinza (daclatasvir) for the Treatment of Patients with Chronic Hepatitis C Genotype 3
Daklinza in combination with sofosbuvir is the first 12-week, all-oral therapy that offers SVR12 for the vast majority of genotype 3 patients
Hepatitis C genotype 3 is one of the most difficult-to-treat genotypes
Announcement marks the first approval of Daklinza in the United States
U.S. Food and Drug Administration (FDA). This approval marks the first time patients with chronic hepatitis C virus (HCV) genotype 3 have a 12-week, once-daily, all-oral treatment option. Daklinza is indicated for use with sofosbuvir for the treatment of patients with chronic HCV genotype 3 infection. Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving this regimen. The recommended dosage of Daklinza is 60 mg in combination with sofosbuvir for 12 weeks.
“The U.S. approval of Daklinza means that chronic HCV genotype 3 patients may now complete treatment in just 12 weeks with an all-oral, once-daily regimen,” said Chris Boerner, Head of U.S. Commercial, Bristol-Myers Squibb. “We believe this Daklinza-based regimen may be a solution to improving the standard of care for these patients. This approval is the result of many years of partnership with the HCV community to address the complexities of genotype 3, and an important achievement in our ongoing Daklinza development program, which focuses on patients that are most challenging to treat.”
The pivotal Phase III open-label ALLY-3 clinical trial enrolled 152 patients with chronic HCV genotype 3 infection and compensated liver disease (101 treatment-naïve patients and 51 treatment-experienced patients). The co-primary endpoints were sustained virologic response rates 12 weeks after completing therapy (SVR12) in each treatment group. The full study design is outlined below. In the trial the Daklinza plus sofosbuvir regimen demonstrated 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%). These SVR12 rates were achieved with 12 weeks of therapy without the use of ribavirin.
Daklinza is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daklinza. Daklinza also may be associated with the risk of adverse reactions or loss of virologic response due to drug interactions. In addition, there is a risk of serious symptomatic bradycardia when coadministered with sofosbuvir and amiodarone. Please see full Important Safety Information below for more details.
In the pivotal Phase III trial, there were no treatment-related serious adverse events (SAEs) and no discontinuations due to adverse events (AEs). The most common treatment-related AEs at a frequency of ≥5% were headache (14%), fatigue (14%), nausea (8%) and diarrhea (5%).
“The treatment landscape for HCV has radically evolved in recent years, and while we have achieved impressive SVR12 rates in genotype 1, genotype 3 still represents a clinical challenge,” 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. “Not only are genotype 3 patients more complicated to manage, but the aggressive nature of their disease means there is a greater urgency to treat them. Daklinza in combination with sofosbuvir gives healthcare providers a new option to achieve a high overall SVR12 rate in this difficult-to-treat patient population.”
Daklinza is an inhibitor of NS5A with dual modes of anti-viral activity that inhibits both RNA replication and virion assembly. In in vitro studies, Daklinza has shown anti-viral activity across genotypes 1-6, with EC50 values from picomolar (pM) to low nanomolar (nM) against wild type replicons.
About the ALLY-3 Clinical Trial
The efficacy and safety of Daklinza in combination with sofosbuvir were eva luated in the Phase III ALLY-3 clinical trial. ALLY-3 was an open-label trial that included 152 patients with chronic HCV genotype 3 infection and compensated liver disease who were treatment-naïve (n=101) or treatment-experienced (n=51). 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 had been treated previously with a sofosbuvir regimen and two patients with a regimen containing an investigational cyclophilin inhibitor. Previous exposure to NS5A inhibitors was prohibited. The 152 treated patients in ALLY-3 had a median age of 55 years (range, 24-73); 59% of the patients were male; 90% were white, 5% were Asian, and 4% were black. Most patients (76%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 21% of the patients had compensated cirrhosis, and 40% had the IL28B rs12979860 CC genotype.
About Hepatitis C Genotype 3
Genotype 3 is estimated to affect 12 percent of chronic HCV patients in the U.S. and is the second most common hepatitis C genotype globally after genotype 1. Hepatitis C genotype 3 is considered one of the most difficult-to-treat genotypes.
DAKLINZA Rx
Pharmacological Class:
HCV NS5A inhibitor.
Active Ingredient(s):
Daclatasvir 30mg, 60mg; tablets.
Company
Bristol-Myers Squibb
Indication(s):
In combination with sofosbuvir, for the treatment of 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 daclatasvir with sofosbuvir for 12 weeks.
Pharmacology:
Daclatasvir inhibits NS5A, a nonstructural protein encoded by HCV, by binding to the N-terminus within Domain 1 and thereby inhibiting both viral RNA replication and virion assembly.
Clinical Trials:
The safety and efficacy of Daklinza in combination with sofosbuvir were supported by data from ALLY-3, a Phase 3, open-label trial that included 152 treatment-naive (n =101) or treatment-experienced (n = 51) subjects with chronic HCV genotype 3 infection and compensated liver disease. Most treatment-experienced subjects had failed prior treatment with peginterferon/ribavirin, but 7 subjects had been treated previously with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational cyclophilin inhibitor. Previous exposure to NS5A inhibitors was prohibited. Subjects received Daklinza 60mg plus sofosbuvir 400mg once daily for 12 weeks and were monitored for 24 weeks post treatment.
The primary endpoint was sustained virologic response (SVR), defined as HCV RNA <25 IU/mL at post-treatment week 12.
Overall, post-treatment results demonstrated that the majority of the subjects, 89%, achieved SVR (90% in treatment-naive group vs. 86% in treatment-experienced group). In 120 subjects without cirrhosis, 96% achieved SVR (98% in treatment-naive group vs. 92% in treatment-experienced group). The presence of cirrhosis reduced SVR rates in both treatment-naive and treatment-experienced groups, 58% and 69%, respectively. For subjects not achieving SVR, 0.7% had on-treatment virologic failure and 11% relapsed.
For more clinical trial data, see full labeling.
Legal Classification:
Rx
Adults:
≥18 years: 60mg once daily for 12 weeks (with sofosbuvir). Concomitant strong CYP3A inhibitors (eg, clarithromycin, itraconazole, ketoconazole, ritonavir): reduce to 30mg once daily. Concomitant moderate CYP3A inducers (eg, bosentan, dexamethasone, efavirenz, etravirine, modafinil, nafcillin, rifapentine): increase to 90mg once daily. If sofosbuvir is permanently discontinued, daclatasvir should also be discontinued.
Children:
<18 years: not established.
Contraindication(s):
Concomitant strong CYP3A inducers (eg, phenytoin, carbamazepine, rifampin, St. John’s wort).
Warnings/Precautions:
Increased risk of symptomatic bradycardia when concomitant amiodarone and with sofosbuvir, esp. in patients taking beta-blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Decompensated cirrhosis. Liver transplant patients. Pregnancy. Nursing mothers.
Interaction(s)
See Adults & Contraindications. Concomitant amiodarone with daclatasvir in combination with sofosbuvir: not recommended; if no alternatives, monitor cardiac function. May potentiate P-gp, OATP 1B1, OATP 1B3, or BCRP substrates, statins (monitor). May be potentiated by strong CYP3A inhibitors. Concomitant moderate CYP3A inhibitors (eg, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil); monitor. Potentiates dabigatran etexilate mesylate: not recommended in specific renal impairment groups (see full labeling). Concomitant digoxin: if already on daclatasvir, initiate digoxin at lowest appropriate dose and monitor; if already receiving digoxin prior to daclatasvir initiation, reduce digoxin dose by 30–50% or modify dosing frequency and monitor.
Adverse Reaction(s)
Headache, fatigue, nausea, diarrhea; symptomatic bradycardia.
How Supplied:
Tabs—28
LAST UPDATED:
8/21/2015 |
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