Wednesday 29 June, 2016 13.00 EDT
Triple therapy with asunaprevir + daclatasvir + BMS-791325
Bristol-Myers Squibb (BMS) is developing at least the following three anti-HCV agents:
- impairs the activity of an HCV protein called NS5A
- active against several strains of HCV in lab experiments
- taken at a dose of 60 mg once daily
- has a low potential for drug interactions
- tested in nearly 6,000 participants and appears to be well tolerated
- impairs the activity of an HCV protein called NS3
- active against several strains of HCV such as genotypes 1, 4, 5 and 6 in lab experiments
- taken at a dose of 100 mg twice daily
- studied in more than 2,000 participants
- impairs the activity of NS5B
- is a polymerase inhibitor
- active against several strains of HCV including genotypes 1, 3, 4, 5 and 6 in lab experiments
- taken twice daily at a dose of 75 mg or 150 mg
- studied in more than 500 participants
For the study reported here, researchers gave participants 12 consecutive weeks of therapy.
- daclatasvir was given at a dose of 30 mg twice daily
- asunaprevir was given at a dose of 200 mg twice daily
BMS plans to put these drugs into a single pill in the future.
The average profile of participants at the start of the study was as follows:
- 67% men, 33% women
- age – 54 years
- 82% of participants had HCV genotype 1a and 18% had genotype 1b
- HCV viral load – 2.5 million IU/ml
- 9% of participants had severe liver injury (cirrhosis) confirmed by biopsy
- 46% of participants had no or minimal livery injury
Researchers gave all participants daclatasvir and asunaprevir in the dose and schedule previously mentioned, and then randomly assigned them to receive one of the following two doses of BMS ’325:
- 75 mg twice daily – 80 participants
- 150 mg twice daily – 86 participants
Results – SVR12
According to the interim analysis, the rates of SVR12 (highly suggestive of cure) were distributed as follows:
- 3 DAAs (including ’325 given at a dose of 75 mg twice daily) – 88.8%
- 3 DAAs (including ’325 given at a dose of 150 mg twice daily) – 89.5%
Data are incomplete for five missing participants and researchers are attempting to locate these people.
Among those without an SVR12 (11 participants) there were five breakthroughs by HCV and six others relapsed.
Five participants had mutations that conferred resistance to asunaprevir and daclatasvir and six participants had HCV that had become resistant to all three drugs.
Eight participants prematurely left the study for the following reasons:
- throat tumour – one person
- throat tightness – one person
- lack of effectiveness – three people
- abdominal infection – one person
- imprisonment – two people
According to researchers, ’325 was well tolerated.
Common side effects reported in this study were as follows:
- headache – 25%
- diarrhea – 15%
- fatigue – 11%
- nausea – 10%
Abnormal blood test results
- one case of the elevated liver enzyme AST on day 24 of the study; this returned to normal 50 days after the study began
- two cases of elevated blood sugar; both occurred in participants with a history of type 2 diabetes
Bear in mind
The present study and its results should be considered preliminary in nature. Still, they showcase a trio of drugs that are relatively powerful, with cure rates approaching 90%. This happened in a regimen free of interferon and ribavirin among participants with the difficult-to-treat strain of HCV—genotype 1a.
Further studies with this combination of BMS drugs are underway. These studies have the code name Unity One (which will enroll participants without cirrhosis who have not been previously treated) and Unity Two (which will have participants with cirrhosis).
In case of resistance
When one of the study physicians was asked about possible salvage regimens for participants who developed resistance to the study medicines, he suggested that the following strategies be considered:
- sofosbuvir + ribavirin
- sofosbuvir + interferon + ribavirin
- wait until the drug-resistant HCV has disappeared from their blood
—Sean R. Hosein
Everson GT, Thuluvath PJ, Lawitz E, et al. All oral combination of daclatasvir, asunaprevir, and BSM-791325 for HCV genotype 1 infection. In: Programs and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014, Boston, U.S. Abstract 25.