Bristol-Myers Announces Receipt of EC Approval for Daklinza in HCV Genotypes 1, 3 and 4

European Commission Approves Daklinza (daclatasvir) for the Treatment of Genotype 1, 3 and 4 Chronic Hepatitis C Patients with HIV Coinfection, Advanced Cirrhosis and Post-liver Transplant Recurrence of HCV

Updated label provides additional treatment options for multiple HCV patient populations, including difficult-to-treat patients with decompensated cirrhosis

HIV/HCV coinfected patients experience more rapid fibrosis progression than mono-infected HCV patients

Thursday, January 28, 2016 12:41 pm EST

Bristol-Myers Squibb Company (NYSE: BMY) announced that the European Commission has approved Daklinza for the treatment of chronic hepatitis C (HCV) in three new patient populations. The expanded label allows for the use of Daklinza in combination with sofosbuvir (with or without ribavirin, depending on the indication and HCV genotype) in HCV patients with decompensated cirrhosis, HIV-1 (human immunodeficiency virus) coinfection, and post-liver transplant recurrence of HCV in all 28 Member States of the European Union.

“The European Commission’s approval of these new indications for Daklinza is an important step forward for a significant group of patients with chronic hepatitis C who are still in need of treatment options that can deliver high cure rates,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “The complex clinical considerations for physicians treating HCV/HIV coinfected patients and patients with cirrhosis, decompensated cirrhosis or post-transplant recurrence of HCV reinforces the vast diversity of this disease, and we have worked hard to continue to identify and address those patients who require additional solutions for cure.”

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. Daklinzamust not be administered as a monotherapy.

Daklinza is already 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, and the Daklinza + sofosbuvir regimen is the only approved 12-week, all-oral treatment for genotype 3 HCV patients without cirrhosis. The new indications are based on data from the ALLY-1 clinical trial (in post-transplant patients and patients with advanced cirrhosis) and ALLY-2 clinical trial (in HIV-coinfected patients). The recommended treatment regimens and durations are as follows:

Patient population*								Regimen and duration
HCV GT 1 or 4
Patients without cirrhosis								Daklinza + sofosbuvir for 12 weeks
Patients with cirrhosis
Child-Pugh Class (CP) A or B								Daklinza + sofosbuvir + ribavirin for 12 weeks
								or
								Daklinza + sofosbuvir (without ribavirin) for 24 weeks
CP C								Daklinza + sofosbuvir +/- ribavirin for 24 weeks
HCV GT 3
Patients without cirrhosis								Daklinza + sofosbuvir for 12 weeks
Patients with cirrhosis								Daklinza + sofosbuvir +/- ribavirin for 24 weeks (see section 5.1 of the Summary of Product Characteristics)
Recurrent HCV infection post-liver transplant (GT 1, 3 or 4)
Patients without cirrhosis								Daklinza + sofosbuvir + ribavirin for 12 weeks
Patients with CP A or B cirrhosis
GT 1 or 4								Daklinza + sofosbuvir + ribavirin for 12 weeks
GT 3								Daklinza + sofosbuvir +/- ribavirin for 24 weeks
Patients with CP C cirrhosis								Daklinza + sofosbuvir +/- ribavirin for 24 weeks

*		Includes patients coinfected with human immunodeficiency virus (HIV). For dosing recommendations with HIV antiviral agents, refer to full Summary of Product Characteristics.

ALLY-2 Study Design

In the ALLY-2 Phase 3 open-label clinical trial, 153 patients with chronic HCV coinfected with HIV (101 treatment-naïve patients and 52 treatment-experienced patients) received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks, and 50 treatment-naïve patients received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 8 weeks. Patients with genotypes 1-6 were eligible to enroll, including those with compensated cirrhosis (Child-Pugh A), and the dose of Daklinza was adjusted for concomitant antiretroviral use. 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. The 153 patients who received 12 weeks of treatment had a median age of 53 years (range, 24-71); 63% of the patients were white and 33% were black. Sixty-eight percent of patients had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Sixteen percent of all patients had compensated cirrhosis.

In the 12-week arms, the Daklinza plus sofosbuvir regimen demonstrated overall SVR12 in 97% of patients, including 100% in genotype 3. SVR12 rates were greater than 94% across all combination antiretroviral therapy (cART) regimens, including boosted-protease inhibitor-, NNRTI-, and integrase inhibitor-based therapies.

In the trial, there were no treatment-related serious adverse events (SAEs) and no discontinuations due to adverse events (AEs). The most common treatment-related AEs (≥10%) were fatigue (17%), nausea (13%), and headache (11%).

ALLY-1 Study Design

In the ALLY-1 Phase 3 open-label clinical trial, 113 patients with chronic HCV and Child-Pugh A, B or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53) received Daklinza 60 mg plus sofosbuvir 400 mg once daily with ribavirin (600 mg starting dose) for 12 weeks. Patients with genotypes 1-6 were eligible to enroll. 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. Among the 53 post-liver transplant patients: the median age was 59; 96% were white, 2% were black, and 2% were defined as other; and, 58% of patients had HCV genotype 1a, 19% had genotype 1b, 21% had genotype 3, and 2% had genotype 6. Among the 60 cirrhotic patients: the median age was 58; 95% were white and 5% were black; 20% were Child-Pugh class A, 53% were Child-Pugh class B, and 27% were Child-Pugh class C; and, 57% of patients had HCV genotype 1a, 18% had genotype 1b, 8% had genotype 2, 10% had genotype 3, and 7% had genotype 4. In the same cohort, median baseline Model for End-Stage Liver Disease (MELD) score was 13. Most (55%) of the 53 patients in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE® results). The trial permitted a wide variety of immunosuppressants in the post-transplant cohort, including cyclosporine, tacrolimus, sirolimus, everolimus, corticosteroids, or mycophenolate mofetil.

In the trial, 94% of post liver-transplant patients and 83% of patients in the cirrhosis cohort achieved SVR12, including 92-94% of patients with Child-Pugh A or B. In the cirrhosis cohort, 4 subjects with hepatocellular carcinoma underwent liver transplantation after 1 to 71 days of treatment; 3 of the 4 subjects received 12 weeks of post-liver transplant treatment extension and 1 subject, treated for 23 days before transplantation, did not receive treatment extension. All 4 subjects achieved SVR12.

In the trial, there were no treatment-related SAEs, and 16 patients discontinued study drugs due to AEs; 14 discontinued ribavirin only, and 2 discontinued the entire regimen. The most common treatment-related AEs (≥10%) in either cohort of ALLY-1 were headache (15%, 36%), fatigue (18%, 28%), anemia (20%, 19%), diarrhea (8%, 19%), nausea (17%, 6%) and arthralgia (2%, 13%) in the advanced cirrhotic and post-transplant treatment groups, respectively. The updated Summary of Product Characteristics will be available at www.ema.europa.eu.

European Commission Approves Daklinza (daclatasvir) for the Treatment of Genotype 1, 3 and 4 Chronic Hepatitis C Patients with HIV Coinfection, Advanced Cirrhosis and Post-liver Transplant Recurrence of HCV