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AASLD 2012: Interferon Lambda Shows Good HCV Suppression, Better Tolerated than Interferon Alfa

Pegylated interferon lambda works as well as pegylated interferon alfa for treating chronic hepatitis C, but with fewer side effects, according to studies presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) last month in Boston. Researchers also reported the first data on interferon lambda in combination with direct-acting antivirals.

Pegylated interferon alfa-2a (Pegasys) or alfa-2b (PegIntron) in combination with ribavirin has been the mainstay of hepatitis C treatment for several years. But interferon alfa can cause difficult side effects including flu-like symptoms and depression, which leads many people to refuse treatment, stop therapy early, or reduce their doses. Direct-acting antiviral agents (DAAs) -- the first of which were approved last year -- increase response rates and allow for a shorter duration of treatment. These drugs can add their own side effects, however, and many patients and providers are awaiting all-oral, interferon-free regimens.

Another approach is to substitute different types of interferon that may be better tolerated. Bristol-Myers Squibb's pegylated interferon lambda-1a uses a different receptor that is mainly present in the liver, with limited distribution elsewhere in the body; this is expected to improve tolerability compared with interferon alfa.

Andrew Muir from Duke University Medical Center and fellow investigators with the EMERGE Study Group compared the safety and efficacy of pegylated interferon lambda versus pegylated interferon alfa for previously untreatedpatients with HCV genotypes 1 or 4 (abstract 214).

This analysis included approximately 400 treatment-naivechronic hepatitis C patients without liver cirrhosis; about 95% had hard-to-treat HCV genotype 1, the rest genotype 4. They were randomly assigned to receive 120, 180, or 240 mcg interferon lambda-1a or 180 mcg interferon alfa-2a once-weekly for 48 weeks, both in combination with ribavirin.

Results

• Sustained virological response rates at 24 weeks after completing treatment (SVR24) were similar for the 2 regimens.
• Viral breakthrough and post-treatment relapse rates were also similar.
• However, interferon lambda produced a more rapid decline in HCV RNA levels.
• Patients treated with interferon lambda experienced less hematologic toxicity (blood cell deficiencies), fewer musculoskeletal and flu-like symptoms, and fewer ALT elevations (1% vs 4%), although they had more bilirubin elevations (5% vs 2%).

"This improved safety profile supports further evaluation of [interferon] lambda in combination with direct-acting antiviral agents," the researchers concluded. The 180 mcg dose was selected for further study.

In 2 related poster presentations researchers reported that pegylated interferon lambda was also associated with fewer clinically significant neuropsychiatric symptoms, in particular depression (abstract 793), and less autoimmune thyroid disease and serious autoimmune disease (abstract 781) relative to pegylated interferon alfa.

Interferon Lambda and DAAs

John Vierling from Baylor College of Medicine and the D-LITE Study Team (abstract LB-9) evaluated pegylated interferon lambda in combination with 2 investigational Bristol-Myers Squibb direct-acting antivirals: the HCV protease inhibitor asunaprevir (formerly BMS-650032) and the NS5A replication complex inhibitor daclatasvir  (formerly BMS-790052).

This international Phase 2b trial enrolled more than 100 treatment-naive patients with HCV genotype 1. They were randomly assigned to receive one of 3 regimens:

• 180 mcg/week interferon lambda-1a + weight-based ribavirin + 200 mg twice-daily asunaprevir;
• 180 mcg/week interferon lambda-1a + weight-based ribavirin + 60 mg once-daily daclatasvir;
• 180 mcg/week interferon alfa-2a + weight-based ribavirin + placebo.

People in both DAA arms who achieved protocol-defined response -- HCV RNA <25 IU/mL at week 4 and undetectable at week 12 -- were treated for 24 weeks, while the rest received an additional 24 weeks of interferon lambda plus ribavirin alone. People in the interferon alfa/ribavirin/placebo arm took this regimen for 48 weeks.

Results

• About 90% of participants taking the DAA regimens completed 24 weeks of treatment, and 87% were eligible for the shorter regimen.
• All patients in both DAA arms had complete early virological response (EVR), or undetectable HCV RNA at week 12 of treatment.
• Overall, 75% of patients taking the asunaprevir combo and 76% taking the daclatasvir regimen had continued undetectable viral load at 12 weeks post-treatment (SVR12).
• Among people with protocol-defined response, response rates in the 2 arms were 91% and 93%, respectively, for people with HCV subtype 1b, and 67% and 65%, respectively, for those with subtype 1a.
• The daclatasvir regimen worked equally well for people with the favorable IL28B CC gene pattern and the unfavorable CT or TT variants (75% and 76%, respectively).
• The asunaprevir combo, however, worked better for CC patients (90% vs 68%, respectively).
• Both DAA regimens were generally safe and well-tolerated.
• 3 people in the asunaprevir arm and 1 person in the daclatasvir arm experienced serious adverse events.

"Despite the desire for all-oral regimens without alfa interferons for the treatment of chronic hepatitis C, it is likely that certain patient populations will require interferon-based therapies to eradicate hepatitis C," Vierling said in a press release issued by Bristol-Myers Squibb. "Treatment with lambda interferon combined with daclatasvir and ribavirin achieved high rates of sustained virologic response, and the data support further study of regimens using lambda interferon to address the medical needs of hepatitis C patients who cannot use alfa interferons."

Namiki Izumi from Musashino Red Cross Hospital in Tokyo presented data from the D-LITE Japanese sub-study (abstract 234). This analysis included 21 treated patients, all with HCV subtype 1b. About two-thirds were women and the average age was approximately 55 years; nearly three-quarters had the favorable IL28B CC gene variant.

100% of patients with protocol-defined response in both the asunaprevir and the daclatasvir arms achieved complete EVR, end-of-treatment response at week 24, and continued undetectable HCV RNA at 4 weeks post-treatment (SVR4). Again, the DAA combos were generally well-tolerated. There was 1 serious adverse event and 2 people who stopped treatment due to adverse events in the asunaprevir arm, but none of either in the daclatasvir arm.

Pegylated interferon lambda and ribavirin in combination with a DAA "yields excellent rates of SVR among Japanese patients with genotype 1b infection," the researchers concluded. Since the daclatasvir regimen was better tolerated, they added that data support further investigation of this combination in a larger genotype 1b population. Shorter regimens of pegylated interferon lambda/ribavirin/daclatasvir are also being explored.

12/21/12

References

AJ Muir, JL Hillson, TE Gray, et al. Peginterferon lambda-1a (lambda) compared to peginterferon alfa-2a (alfa) in treatment-naive patients with HCV genotypes (GT) 1 or 4: SVR24 results from EMERGE Phase 2b.Abstract 214.

AJ Muir, S Srinivasan, S Sapra, et al. Peginterferon lambda-1a (lambda) is less likely to induce clinically significant neuropsychiatric symptoms during the treatment of chronic hepatitis C virus (HCV) infection, compared to peginterferon alfa-2a (Alfa). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 793.

P Fredlund, JL Hillson, TE Gray, et al. Peginterferon lambda-1a (lambda) is associated with less autoimmune thyroid disease and serious autoimmune disease than peginterferon alfa-2a (alfa) when used in combination with ribavirin (RBV) for the treatment of chronic hepatitis C virus infection. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 781.

JM Vierling, M Lataillade, EJ Gane, et al. Sustained virologic response (SVR12) in HCV genotype 1 patients receiving peginterferon lambda in combination with ribavirin and either daclatasvir or asunaprevir: interim results from the D-LITE study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract LB-9.

N Izumi, M LaTaillade, K Chayama, et al. First report of peginterferon lambda/ribavirin in combination with either daclatasvir or asunaprevir in HCV genotype 1 Japanese subjects: early sustained virologic response (SVR4) results from the D-LITE Japanese sub-study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 234.

Other Source

Bristol-Myers Squibb. Bristol-Myers Squibb’s Investigational Hepatitis C Compounds Lambda and Daclatasvir Plus Ribavirin Achieved SVR12 in 93% of Genotype 1b Treatment-Naive Patients In Phase IIb Study. Press release. November 12, 2012.