Its Back: Daclatasvir Plus Sofosbuvir-Three HCV Clinical Trials Sponsored By Bristol-Myers Squibb

Jan 11 2014
Daclatasvir Plus Sofosbuvir-Three HCV Clinical Trials Sponsored By Bristol-Myers Squibb 

Good day folks,
I hope everyone is getting a chance to enjoy some winter fun this weekend. Our family will be outside observing a number of ice sculptures entered in a special competition this afternoon. The grandkids are visiting over the weekend so Nana didn't have time to elaborate on yesterdays post that included three clinical trials sponsored by Bristol-Myers Squibb using two familiar agents - daclatasvir and sofosbuvir.

2012 Phase II Trial Daclatasvir Plus Sofosbuvir
I assume you all remember the results and controversy over the Phase II trials in 2012 which consisted of Gilead's nucleotide inhibitor sofobuvir (now FDA approved solvadi) and Bristol's daclatasvir - in short the ground breaking interferon-sparing combination achieved SVR12 in 96% of genotype 1 patients.

2012-The Controversy - No Phase III Trial
The controversy whether Bristol and Gilead would enter into Phase III clinical trials using the promising combination ended when Gilead announced they were not interested, instead Gilead  focused on developing an all oral drug regimen using their own pipeline.  Gilead moved forward with sovaldi and ledipasvir - which is a once-daily fixed-dose combination pill. Gilead tested its all oral combination in various treatment durations, with and without ribavirin in genotype 1 hepatitis C patients. In three trials, deemed ION-1, ION 2 and ION-3 initial results demonstrated cure rates in some participants exceeding 90% with only 8 weeks of treatment, view the recent Phase III updates here.

Excerpt (Reuters): Gilead said it would file in the first quarter of 2014 for U.S. approval of the combination treatment that pairs its just-approved Sovaldi (sofosbuvir) and its experimental ledipasvir. The company previously said it would seek marketing approval in the first half of next year. 

Updated Jan 16 2014:
In the January 16 issue of the New England Journal of Medicine researchers reported the all-oral combination of daclatasvir and sofosbuvir achieved cures rates ranging from 89% to 100%, with and without ribavirin. According to reports the combination even worked in people who failed standard therapy with telaprevir or boceprevir, plus peginterferon and ribavirin.
(Full text available @ NATAP)

Paul Pockros, MD, of the Scripps Clinic in La Jolla, Calif., who was not part of the study remarked in an article at MedPage Today that if daclatasvir is approved on its own, it's likely some doctors at least will prescribe it with sofosbuvir off label. Bristol-Myers recently announced daclatasvir will get an accelerated review by European regulators, in addition the EMA allows for compassionate use of daclatasvir-sofosbuvir. 

2014 - New England Journal of Medicine
Excerpt From MedPage Today
In the trial, patients with genotypes 1, 2, or 3 of the virus were given daclatasvir/sofosbuvir, with or without ribavirin, for 12 or 24 weeks.

The primary endpoint -- reached by 201 of 211 patients -- was a sustained virologic response 12 weeks after the end of therapy, or SVR₁₂.

SVR₁₂ rates were:

• 98% in previously untreated genotype 1 patients and the same in genotype 1 patients who had failed previous therapy with interferon, ribavirin, and HCV protease inhibitors
• 92% of patients with genotype 2, and 89% of those with genotype 3 infection
• 98% and 100%, respectively, among patients with HCV subtypes 1a and 1b
• 93% and 98%, respectively, for those with CC and non-CC IL28B genotypes, where the non-CC genotypes are regarded as predicting poor response
• 94% among those who also got ribavirin, and 98% among those who did not

Read more here......... 

Review
2012 - Phase II Trial Results Daclatasvir Plus Sofosbuvir
To refresh your memory, I have provided a slide from NATAP with the SVR rates for daclatasvir plus sofosbuvir with or without ribavirin in genotypes 1-3. As noted SVR did not vary because of IL28b genotype, viral subtype or the administration of ribavirin

View All Slides From AASLD 2012 @ NATAP : High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients 

DCV=daclatasvir SOF=sofobuvir RBV=ribavirin SVR=Sustained virologic response SVR12= sustained virologic response 12 weeks after the end of treatment (SVR₁₂), defined as a viral RNA level too low to quantify. (N=number of subjects)

2014-Daclatasvir Accelerated Review By European Regulators
Submission includes EU’s first all-oral and ribavirin-free investigational regimen for use in treatment naïve genotype 1, 2, 3 patients and protease inhibitor treatment failures.

I'm sure by now you've come across Bristol-Myers recent announcement that daclatasvir will get an accelerated review by European regulators. In addition the company said "The application seeks the approval of daclatasvir for use in combination with other agents, including sofosbuvir, for the treatment of chronic hepatitis C."  Ahhhh Yes.

As noted in the press release: The EU submission follows the recent Bristol-Myers Squibb regulatory filing in Japan seeking approval of a Daclatasvir-based regimen for the treatment of patients infected with HCV genotype 1b. 

2013-Off The Cuff 
**September 2013 at the University of Michigan Hospital, a "Doctor was granted FDA emergency approval to use sofosbuvir/daclatasvir in a hepatitis C transplant patient" 

2014-Daclatasvir Plus Sofosbuvir-Three HCV Clinical Trials Sponsored By Bristol-Myers Squibb
Yesterday on the blog I posted three Phase III clinical trials sponsored by Bristol-Myers using daclatasvir + sofosbuvir, unfortunately recruiting has not started, nor have the trial locations been made available. Click on the links for additional trial information.

Phase III Daclatasvir + Sofosbuvir in Cirrhotic Subjects and Subjects Post-liver Transplant (ALLY 1)

Condition:	Hepatitis C
Interventions:	Drug: Daclatasvir;   Drug: Sofosbuvir;   Drug: Ribavirin
Phase:	Phase 3
NCT Number:	NCT02032875
Study Start:	March 2014

Inclusion Criteria:

• Subjects chronically infected with HCV Genotype 1, 2, 3, 4, 5, or 6 with HCV RNA viral load of ≥ 10,000 IU/mL at screening
• Subjects may be treatment-naïve or treatment-experienced
• Cirrhotic subjects must have cirrhosis confirmed by biopsy, Fibroscan or fibrotest and Aspartate aminotransferase platelet ratio index (APRI) criteria as outlined in the protocol
• Post-transplant subjects must be at least 3 months post-transplant with no evidence of moderate or severe rejection

Purpose
This trial is open to patients with cirrhosis due to chronic HCV, and to patients who have already received a liver transplant for chronic HCV. All subjects will be treated with Daclatasvir and Sofosbuvir for 12 weeks. Under certain conditions, the treatment duration may be extended for cirrhotic subjects. The study will test how well this combination of investigational drugs works to treat chronic HCV.

Phase III Daclatasvir and Sofosbuvir for Genotype 3 Chronic HCV (ALLY 3)

Condition:	Hepatitis C
Interventions:	Drug: Daclatasvir;   Drug: Sofosbuvir
Phase:	Phase 3
NCT Number:	NCT02032901
Study Start:	February 2014

Inclusion Criteria:

• Subjects chronically infected with HCV genotype 3
• Subjects who are HCV-Treatment-naive - Subjects who are HCV-treatment-experienced
• Previous exposure to non-structural 5A (NS5A) inhibitors is prohibited
• HCV RNA ≥ 10,000 IU/mL at Screening

Purpose
To study the combination of Daclatasvir and Sofosbuvir for the treatment of HCV Genotype 3 infection

Phase III HIV/HCV Co-Infection Daclatasvir (DCV)+ Sofosbuvir (SOF) (ALLY 2)

Condition:	Hepatitis C
Interventions:	Drug: Daclatasvir;   Drug: Sofosbuvir
Phase:	Phase 3
NCT Number:	NCT02032888
Study Start:	February 2014

Inclusion Criteria:

• Subjects chronically infected with HCV genotype 1, 2, 3, 4, 5 or 6, as documented by positive HCV RNA at screening
• HCV-Treatment-naive subjects
• HCV treatment-experienced subjects are eligible. 
• All permitted prior anti-HCV therapies must be discontinued or completed at least 12 weeks prior to screening
• Subjects must have an HCV RNA ≥ 10,000 IU/mL at Screening
• Subjects must have HIV-1 infection

Purpose
To study the combination of Daclatasvir and Sofosbuvir for the treatment of HCV/ HIV Coinfection

Enjoy your weekend, see you all soon
Tina

Photo Credit - www.idse.net