BMS Files NDA with FDA
On March 12, 2015 Bristol-Myers Squibb (BMS) announced that the Food and Drug Administration (FDA) had accepted their new drug application (NDA) for the combination of daclatasvir plus sofosbuvir for the treatment of HCV genotype 3. In BMS’s phase 3 studies of genotype 3 patients—101 treatment-naïve, 51 treatment-experienced—the cure rates were 90% and 86% respectively. However, in people who had cirrhosis (F-4) the cure rates were 63% to 73% leaving an unmet need for these patients.
On March 12, 2015 Bristol-Myers Squibb (BMS) announced that the Food and Drug Administration (FDA) had accepted their new drug application (NDA) for the combination of daclatasvir plus sofosbuvir for the treatment of HCV genotype 3. In BMS’s phase 3 studies of genotype 3 patients—101 treatment-naïve, 51 treatment-experienced—the cure rates were 90% and 86% respectively. However, in people who had cirrhosis (F-4) the cure rates were 63% to 73% leaving an unmet need for these patients.
CROI
The Conference on Retroviruses and Opportunistic Infections (CROI) 2015 held in Seattle, WA, had a wealth of information about the treatment of people with HIV and HCV coinfection. Since the introduction of interferon-free therapy the cure rates of HCV in people who are coinfected with HIV and HCV are the same as the cure rates in people who are HCV mono-infected, and importantly the studies presented at CROI reinforce this information.
Daclatasvir/Sofosbuvir
DL Wyles et al., presented “Daclatasvir in Combination with Sofosbuvir for HIV/HCV Coinfection: ALLY-2 Study.” The study included patients with HCV genotype 1 (1a-139 pts; 1b-29 pts), genotype 2 (19 pts), genotype 3 (19 pts) and genotype 4 (3 pts). There were three arms in the study—two arms with 12 weeks treatment duration and one arm with an eight-week treatment period—there were no genotype 4 patients in the eight-week treatment arm. Most of the patients were male (83-91%);
White (56-65%); and there were 29 patients with cirrhosis in the study.
DL Wyles et al., presented “Daclatasvir in Combination with Sofosbuvir for HIV/HCV Coinfection: ALLY-2 Study.” The study included patients with HCV genotype 1 (1a-139 pts; 1b-29 pts), genotype 2 (19 pts), genotype 3 (19 pts) and genotype 4 (3 pts). There were three arms in the study—two arms with 12 weeks treatment duration and one arm with an eight-week treatment period—there were no genotype 4 patients in the eight-week treatment arm. Most of the patients were male (83-91%);
White (56-65%); and there were 29 patients with cirrhosis in the study.
The cure rates were 97% in genotype 1, and 100% in genotypes 2, 3, and 4 in the groups treated for 12 weeks. In the groups treated for eight weeks, the cure rates fell to 76%. There was no impact based on genotype or type of prior treatment response.
Comments: These are remarkable cure rates regardless of genotype, viral load, and other factors at least in the 12-week group. Based on this data 8 weeks of Daclatasvir plus sofosbuvir is not effective.
An unmet medical need is treatment of people with genotype 3 with cirrhosis—this information was not available. Additionally, there were very few genotype 3 patients in the study to draw any conclusions.
Given the results of Harvoni (below) the niche for this combination may be narrow. However, it was noted that, if approved, adjusting the dosing would be easier since these drugs are dosed separately especially for some people on HIV medications.
Harvoni
S Naggie et al., present data from “Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected with HCV and HIV-1: ION-4.” This study was a phase 3 clinical trial of Harvoni (sofosbuvir/ledipasvir) for the treatment of HCV genotype 1 and 4 in people who are coinfected with HIV and hepatitis C. A total of 335 patients were included in the trial—75% were genotype 1a; 23% genotype 1b; 2% genotype 4. The study included 45% treatment-naïve patients, 55% treatment-experienced patients, and 20% of the patients had compensated cirrhosis. The mean age of the patients was 52yo; 82% were male, 34% were Black.
S Naggie et al., present data from “Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected with HCV and HIV-1: ION-4.” This study was a phase 3 clinical trial of Harvoni (sofosbuvir/ledipasvir) for the treatment of HCV genotype 1 and 4 in people who are coinfected with HIV and hepatitis C. A total of 335 patients were included in the trial—75% were genotype 1a; 23% genotype 1b; 2% genotype 4. The study included 45% treatment-naïve patients, 55% treatment-experienced patients, and 20% of the patients had compensated cirrhosis. The mean age of the patients was 52yo; 82% were male, 34% were Black.
The overall cure rate was 96%. There was little difference in cure rates between treatment naïve and treatment experienced (95% vs. 97%) and those with and without cirrhosis (94% vs. 96%). There was a difference in cure rates between Blacks (90%) and non-Blacks (99%). The most common side effects were headache, fatigue and diarrhea.
Gilead is trying to determine the difference in the cure rates between Blacks and non-Blacks. They have ruled out drug concentration levels in the blood and the possible interaction of the HIV medications. During the question and answer period there were a couple of interesting comments about the lower response rates in Blacks:
- Perhaps Black patients coinfected with HIV and HCV may need to be treated longer
- Previous clinical trials have had lower Black patient populations that may not have given us a true picture of treatment cure in Blacks—more Blacks are needed in clinical trials period. In the days of pegylated interferon and ribavirin therapy the cure rates were much lower.
Gilead stated that they are planning to file a New Drug Application (NDA) with the FDA based on the phase 3 data for the treatment of HCV in people with HIV.
Comments: Impressive cure rates and low side effects regardless of prior treatment response or degree of liver damage. Once we learn more about the reason for the lower response rates in Blacks we will keep our readers informed.
Delaying Treatment = More Deaths
Everyone is trying to come to terms with the impact of treating people who are the sickest. Lately, there have been studies showing this approach may not be cost effective. It certainly isn’t patient centered or tied to improving the quality of life for people living with hepatitis C. A study presented at CROI—“Impact of Deferring HCV Treatment on Liver-Related Events in HIV+ Patients, by C Zahnd et al.”—sheds some light on the long-term health risk of delaying treatment.
Everyone is trying to come to terms with the impact of treating people who are the sickest. Lately, there have been studies showing this approach may not be cost effective. It certainly isn’t patient centered or tied to improving the quality of life for people living with hepatitis C. A study presented at CROI—“Impact of Deferring HCV Treatment on Liver-Related Events in HIV+ Patients, by C Zahnd et al.”—sheds some light on the long-term health risk of delaying treatment.
The researchers in the study used a model to predict health outcomes from the Swiss HIV Cohort Study to simulate HIV/HCV patients from the time of acute infection through chronic infection and fibrosis stages using the Metavir system for staging fibrosis/cirrhosis (F0 through F4), decompensated cirrhosis, liver cancer, and death. They assumed that 100% of patients were treated with interferon-free therapies and of these patients 90% were cured.
The highlights of their findings included:
- If patients were treated one month or 1 year after diagnosis—3% would die from liver-related deaths
- If HCV treatment was delayed until later stages, the percentages of patients who were predicted to die dramatically increased: Treated at F-2 a 5% death rate; treated at F-3 a 10% death rate; treated at F-4 a 25% death rate.
http://hcvadvocate.org/news/newsLetter/2015/advocate0415.html#3
