Bristol-Myers Squibb Company 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. Daklinza must 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).

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 per cent of the patients were white and 33 per cent were black. Sixty-eight per cent of patients had HCV genotype 1a, 15 per cent had HCV genotype 1b, 8 per cent had genotype 2, 7 per cent had genotype 3, and 2 per cent 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 per cent of patients, including 100 per cent in genotype 3. SVR12 rates were greater than 94 per cent 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 per cent) were fatigue (17 per cent), nausea (13 per cent), and headache (11 per cent).

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 per cent were white, 2 per cent were black, and 2 per cent were defined as other; and, 58 per cent of patients had HCV genotype 1a, 19 per cent had genotype 1b, 21 per cent had genotype 3, and 2 per cent had genotype 6. Among the 60 cirrhotic patients: the median age was 58; 95 per cent were white and 5 per cent were black; 20 per cent were Child-Pugh class A, 53 per cent were Child-Pugh class B, and 27 per cent were Child-Pugh class C; and, 57 per cent of patients had HCV genotype 1a, 18 per cent had genotype 1b, 8 per cent had genotype 2, 10 per cent had genotype 3, and 7 per cent had genotype 4. In the same cohort, median baseline Model for End-Stage Liver Disease (MELD) score was 13. Most (55 per cent) 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 per cent of post liver-transplant patients and 83 per cent of patients in the cirrhosis cohort achieved SVR12, including 92-94 per cent 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 per cent) in either cohort of ALLY-1 were headache (15 per cent, 36 per cent), fatigue (18 per cent, 28 per cent), anemia (20 per cent, 19 per cent), diarrhea (8 per cent, 19 per cent), nausea (17 per cent, 6 per cent) and arthralgia (2 per cent, 13 per cent) in the advanced cirrhotic and post-transplant treatment groups, respectively.

The most common adverse reactions were (= 5 per cent): headache (14 per cent), fatigue (14 per cent), nausea (8 per cent), and diarrhea (5 per cent).