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AASLD 2012: Sofosbuvir + Daclatasvir Dual Regimen Cures Most Patients with HCV Genotypes 1, 2, or 3

A 12-week once-daily regimen of 2 direct-acting hepatitis C drugs -- sofosbuvir (formerly GS-7977) and daclatasvir (formerly BMS-790052) -- produced sustained virological response rates for treatment-naive patients in the 90% to 100% range, and appeared effective regardless of HCV subtype, IL28B pattern, or use of ribavirin, according to a late-breaker presentation at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this week in Boston. The developers are not planning further studies of this combination, however, leaving its fate uncertain.

Last year's approval of the first direct-acting hepatitis C drugs ushered in a new era of treatment, but many patients and providers are holding out for all-oral therapy without pegylated interferon and its difficult side effects -- and if possible without ribavirin, which causes anemia.

It has become difficult to keep track of the numerous investigational anti-HCV drugs in the pipeline and the many different combination regimens at various stages of the development process.

But one combination that stands out on the basis of early studies is Gilead Sciences' once-daily nucleotide analog polymerase inhibitor sofosbuvir plus Bristol-Myers Squibb's HCV NS5A replication complex inhibitor daclatasvir.

Sofosbuvir is among the most potent HCV polymerase inhibitors tested to date; in fact, many market observers have suggested that acquiring the drug (then known as PSI-7977) was the impetus behind Gilead's purchase of Pharmasset last year.

Daclatasvir was the first-in-class NS5A inhibitor. Although its mechanism of action is not fully understood, NS5A appears to play an important role in HCV replication in conjunction with the NS5B polymerase. Based on studies to date, it looks like NS5A inhibitors plus polymerase inhibitors may be particularly powerful combos.

Mark Sulkowski from Johns Hopkins Medical School and colleagues tested various oral combinations of sofosbuvir plus daclatasvir, with or without ribavirin, in an open-label Phase 2a trial (AI-444040).

Because this was one of the earlier ribavirin-free regimens to be evaluated, researchers started with easier-to-treat patients and moved on to more challenging groups as they saw promising results. All study participants were treatment-naive, a group with better prospects for a cure than non-responders to prior interferon-based therapy.

The first stage of the study looked at people with easier-to-treat HCV genotypes 2 or 3, randomizing them to receive 400 mg once-daily sofosbuvir plus 60 mg once-daily daclatasvir -- some with a 7-day sofosbuvir lead-in and some with the addition of 800 mg ribavirin -- for 24 weeks.

The second stage enrolled people with harder-to-treat HCV genotype 1, about 75% of whom had the most difficult subtype 1a. The first 3 of these arms received the same doses of sofosbuvir plus daclatasvir, with or without ribavirin, again for 24 weeks. Then 2 additional arms received the sofosbuvir/daclatasvir combo, 1 group with and 1 without ribavirin, for 12 weeks, to test if shorter duration therapy is adequate.

The study enrolled about 170 total participants in 8 study arms. The median age was approximately 54 years. Gender distribution varied across arms, with men making up 36% to 69%. At least 70% were white in all arms.

The proportion with the favorable IL28B CC gene variant associated with good interferon response ranged from about 20% to nearly 60%; the figure is typically much lower when studying prior null responders. At baseline, approximately 40% had absent to mild fibrosis (Metavir F0-F1), about half had moderate to advanced liver disease (F2-F3), and roughly 15% had cirrhosis (F4).

Results

• Looking first at the genotype 2/3 participants in a modified intent-to-treat (mITT) missing=failure analysis, 100% achieved rapid virological response (RVR) at week 4 of treatment.
• Thereafter, 1 patient experienced viral breakthough, 1 relapsed after treatment, 1 was temporarily lost to follow-up, and 1 was lost permanently.
• Sustained virological response rates at weeks 4, 12, and 24 post- treatment ranged from 88% to 100%.
• Addition of ribavirin -- which plays a role in preventing relapse after treatment -- did not improve response rates.
• Turning to the genotype 1 participants, again in a mITT analysis, all but 1 patient receiving sofosbuvir/daclatasvir for 12 or 24 weeks, with or without ribavirin, achieved RVR.
• That single patient went on to suppress HCV with further therapy, so end-of-treatment response rates at week 12 or week 24 were 100% across the board.
• In all 3 of the 12-week arms, SVR4 and SVR12 rates were 100%.
• All genotype 1 participants treated for 12 weeks went on to achieve SVR24, except for 1 individual who had measurable HCV RNA at post-treatment week 24; however, sequencing showed that the new virus was different from the original one, indicating reinfection rather than relapse.
• The 2 remaining 24-week treatment arms were still undergoing follow-up; of the 68 patients who reached post-treatment week 12, all achieved SVR12.
• Sofosbuvir and daclatasvir were generally safe and well-tolerated.
• The most common side effects overall were fatigue, headache, and nausea, with no clear patterns across arms.
• Moderate-to-severe adverse events occurred somewhat more often in the 24-week lead-in arm and the arm receiving ribavirin for 24 weeks, but numbers per arm were too small to draw definitive conclusions.
• There was a clear association between ribavirin use and anemia, however, with 6 and 5 participants in the 2 triple-therapy arms developing anemia (hemoglobin < 9 g/dL) compared with none in the ribavirin-sparing arms.

In summary, the researchers concluded that sofosbuvir plus daclatasvir, with or without ribavirin, achieved SVR in more than 93% of patients with HCV genotype 1, 2, or 3. They added that virological response "did not differ according to IL28B genotype, viral subtype, or the administration of ribavirin."

During the discussion after his presentation, Sulkowski noted that until recently ribavirin "played a critical role" in hepatitis C treatment, and we are "still very early in understanding its role" in interferon-free therapy. One member of the audience suggested that including ribavirin or perhaps other direct-acting antivirals might allow treatment duration to be shortened to 8 weeks.

As promising as the sofosbuvir/daclatasvir combination is, its future is uncertain. Earlier this year Gilead indicated that it would no longer pursue development of this particular regimen, though Bristol-Myers Squibb was interested in doing so.

Some advocates have suggested that Gilead would rather focus on combinations of its own drugs that allow for proprietary single-tablet regimens -- the company's specialty in the HIV arena. Gilead also has a promising NS5A inhibitor, GS-5885. In another study presented at AASLD, sofosbuvir/GS-5885/ribavirin produced high SVR4 rates for genotype 1 treatment-naive patients and prior null responders analyzed to date.

It remains to be seen how well sofosbuvir/GS-5885 without ribavirin works, or whether sofosbuvir/daclatasvir (with or without ribavirin) works for prior non-responders. Notwithstanding company decisions about which investigational agents to test together, once individual drugs are approved, clinicians and patients will be able to mix and match them as they like.

11/16/12

Reference

MS Sulkowski, DF Gardiner, M Rodriguez-Torres, et al. 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 Chronically Infected with HCV Genotype 1, 2, or 3. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract LB-2.