- Category: HCV Treatment
- Published on Tuesday, 24 January 2012 00:00
- Written by Liz Highleyman
A dual oral regimen of Bristol-Myers Squibb's hepatitis C virus (HCV) protease inhibitor asunaprevir (formerly BMS-650032) and HCV NS4A inhibitor daclatasvir (BMS-790052) cleared the virus in one-third of genotype 1 prior null responders to prior interferon-based therapy, and both of those with genotype 1b, according to data published in the January 19, 2012, New England Journal of Medicine.
The first 2 direct-acting antiviral agents (DAAs) -- boceprevir (Victrelis) and telaprevir (Incivek) -- were approved in 2011, ushering in a new era of hepatitis C treatment, especially for people with HCV genotype 1, people of Africa descent, those with the unfavorable "CC" IL28B gene pattern, and other difficult-to-treat groups. But the first DAAs must still be combined with interferon and ribavirin, leaving all-oral regimens as a major goal of drug development research.
Anna Lok from the University of Michigan at Ann Arbor and colleagues conducted a randomized, open-label Phase 2a proof-of-concept study that included 21 genotype 1 chronic hepatitis C patients who did not achieve substantial HCV RNA reduction (at least a 2-log decline) during previous interferon-based therapy -- so-called "null responders."
Participants were randomly assigned to receive 60 mg daclatasvir once-daily plus 600 mg asunaprevir twice-daily, either alone or in combination with pegylated interferon alfa-2a (Pegasys) and ribavirin, for 24 weeks. The researchers determined rates of sustained virological response (SVR), or continued undetectable HCV RNA, at 12 and 24 weeks after the end of treatment.
- 36% of participants (4 out of 11) taking the dual oral regimen achieved 12-week SVR, compared with 100% (10 out of 10) of those taking the 4-drug regimen.
- The same number of patients on the dual regimen maintained undetectable HCV RNA at 24 weeks post-treatment, while 1 person in the 4-drug group relapsed.
- Both of the 2 people with HCV genotype 1b in the dual regimen group achieved SVR, compared with 2 of 9 (22%) with genotype 1a.
- 6 patients in the dual regimen group -- all with genotype 1a -- experienced viral breakthrough while on therapy, and all developed mutations conferring resistance to both antiviral drugs.
- Diarrhea, mostly mild to moderate, was the most common adverse event in both treatment groups.
- 6 patients experienced transient alanine aminotransferase (ALT) elevations to more than 3 times the upper limit of normal (a separate study showed this effect was due to asunaprevir, and a lower dose was selected for further trials).
Based on these findings, the researchers summarized, "This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with 2 direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin."
This was the first study to demonstrate the possibility that hepatitis C could be cured without the use of interferon, Bristol-Myers Squibb stated in a press release. These findings were previously presented in part at the 2010 AASLD Liver Meeting and the 2011 EASL Liver Congress.
While the sustained response rate was significantly higher in the 4-drug combination group, these findings show that a subset of patients should be able to avoid interferon and its side effects. In particular, response was excellent among people with HCV genotype 1b.
At the recent AASLD meeting in November 2011, researchers presented findings from another study testing the dual daclatasvir plus asunaprevir regimen in Japan, where most hepatitis C patients have genotype 1b. Here too, 90% of patients achieved SVR at 12 and 24 weeks post-treatment.
In an accompanying editorial, Raymond Chung from Massachusetts General Hospital and Harvard Medical School wrote, "This is a watershed moment in the annals of HCV therapy because it shows that a sustained virologic response can be achieved without interferon."
"Implicit in this finding is the concept that 2 potent agents with complementary resistance profiles, given for a sufficient duration, can impose a stranglehold on viral replication and result in clearance of the virus," he continued. "Can we do even better? Certainly. With inclusion of nucleotide polymerase inhibitors, which are unique among direct-acting antiviral classes because they offer a high barrier to the selection of viral resistance...we can anticipate regimens with substantially lower breakthrough rates."
"With improvements in potency, resistance profiles, and pharmacokinetic characteristics and reductions in toxic effects expected for each of the direct-acting antiviral classes, we can envision approval of oral antiviral combination regimens within the next 3 years," he concluded. "We are on the threshold of a treatment revolution that will greatly improve the effectiveness of HCV therapy by dramatically increasing the number of persons treated. There has never been a more exciting time for patients and providers who grapple with this silent killer."
Investigator affiliations: University of Michigan, Ann Arbor, MI; Bristol-Myers Squibb Research and Development, Hopewell, NJ, Wallingford, CT, and Princeton, NJ; Alamo Medical Research, San Antonio, TX; Research Institute, Springfield, MA; University of Colorado at Denver, Aurora, CO; Texas Clinical Research Institute, Arlington, TX; Carolinas Center for Liver Disease, Statesville, NC; Metropolitan Research, Fairfax, VA.
AS Lok, DF Gardinar, E Lawitz, et al. Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. New England Journal of Medicine 366(3):216-224. January 19, 2012.
RT Chung. A Watershed Moment in the Treatment of Hepatitis C. New England Journal of Medicine 366(3):273-275. January 19, 2012.
Bristol-Myers Squibb. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published. Press release. January 18, 2012.