- Category: Experimental HCV Drugs
- Published on Monday, 12 May 2014 00:00
- Written by Liz Highleyman
AbbVie's all-oral "3D" regimen containing ABT-450, ombitasvir, and dasabuvir, used with or without ribavirin, led to sustained virological response in 90% to 100% of genotype 1a and 1b hepatitis C patients in the Phase 3 PEARL trials, according to data reported at the Digestive Disease Week (DDW 2014) meeting last week in Chicago and in the May 4 online edition of the New England Journal of Medicine.
PEARL-III and PEARL-IV
Findings from PEARL-III and PEARL-IV were described in the New England Journal of Medicine report, and PEARL-IV data were also reported in a poster at DDW.
Both randomized clinical trials tested an interferon-free regimen consisting of the HCV protease inhibitor ABT-450 boosted with ritonavir and the NS5A inhibitor ombitasvir (formerly ABT-267) in a coformulation, plus the HCV NS5B polymerase inhibitor dasabuvir (formerly ABT-333). Participants were randomly assigned to receive the "3D" combo either with or without ribavirin for 12 weeks.
PEARL-III evaluated previously untreated non-cirrhotic hepatitis C patients with easier-to-treat HCV subtype 1b, while PEARL-IV looked at treatment-naive participants with harder-to-treat subtype 1a. People with hepatitis B or HIV coinfection were excluded in both studies.
PEARL-III enrolled 419 genotype 1b participants at 50 sites in the U.S., Europe, and Russia. Just over half were women, most were white, and the mean age was approximately 48 years. 21% had the favorable IL28B CC gene variant. More than two-thirds had absent or mild liver fibrosis (stage F0-F1), about 20% had moderate fibrosis (F2), and about 10% had advanced fibrosis (F3); those with cirrhosis (F4) were excluded.
PEARL-IV enrolled 305 genotype 1a patients at 53 sites in the U.S., Canada, and the U.K. About 65% were men, most were white, and the mean age was 51 years. Just under one-third had the IL28B CC variant. About 63% had absent or mild fibrosis, about 20% had moderate fibrosis, and 17% had advanced fibrosis; again, people with cirrhosis were excluded.
At 12 weeks after completing treatment, sustained virological response (SVR12) rates were high across the board. Among genotype 1b patients, 99.0% in the ribavirin-free arm and 99.5% in the ribavirin-containing arm achieved SVR12. 1 participant experienced virological rebound during treatment and 2 did not have SVR12 data available.
Among genotype 1a patients, cure rates were 90.2% and 97.0% in the ribavirin-free and ribavirin-containing arms, respectively. The difference was mainly due to more frequent virological failure among patients not taking ribavirin (7.8% vs 2.0%); 7 people experienced viral rebound during treatment and 11 relapsed after finishing treatment. All but 1 of the participants with virological failure showed evidence of good adherence. All had at least 1 resistance-associated viral variant -- most commonly D168V (NS3), M28T and Q30R (NS5A), and S556G (NS5B) -- at the time of virological failure.
Treatment was generally safe and well-tolerated in both studies. Only 2 patients (0.3%), both with genotype 1a, stopped therapy early due to adverse events. The most frequently reported side effects were fatigue, headache, nausea, pruritis (itching), and insomnia. Adverse events overall, and anemia in particular, were more common in the ribavirin-containing arms.
"Twelve weeks of treatment with ABT-450/ritonavir [+] ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection," the researchers concluded. "Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection."
Response rates in all treatment groups were superior to historical response rates using pegylated interferon, they noted.
"As compared with the groups that did not receive ribavirin, the groups that did receive it had more adverse events, particularly pruritus, nausea, and insomnia -- events that are known to be associated with ribavirin," they elaborated in their discussion. "In addition, laboratory abnormalities that have historically been associated with ribavirin -- decreases in the hemoglobin level and increases in the total bilirubin level -- were more common in the groups that received ribavirin."
At a late-breaker session at DDW, Pietro Andreone from the University of Bologna presented findings from PEARL-II, a randomized trial testing the "3D" regimen, again with or without ribavirin for 12 weeks, in genotype 1b chronic hepatitis C patients without cirrhosis who had previously received unsuccessful interferon-based treatment. Prior non-responders traditionally do not respond as well to re-treatment as treatment-naive people do to first-time therapy.
This analysis included 179 participants. Just over half were men, the mean age was 54 years, and less than 10% had the IL28B CC variant; prior relapsers, partial responders, and null responders were roughly equally represented.
SVR12 rates in this study were 100% among patients who received the "3D" combo alone and 97% among those who included ribavirin. Similar high cure rates were seen regardless of type of prior non-response. There were no virological failures, but 2 people in the ribavirin-containing arm discontinued early due to adverse events.
Here too, treatment was generally safe and well-tolerated. The most frequently reported adverse events were fatigue, headache, and nausea, and side effects were more common overall in the ribavirin group; 2 people in the ribavirin arm developed anemia (hemoglobin <10 g/dL).
These findings indicate that previously treated genotype 1b patients are just as likely to be cured with the "3D" regimen -- even without ribavirin -- as those being treated for the first time. Further studies are needed to determine whether this is also the case for harder-to-treat genotype 1a patients.
Results from the PEARL-I study of people with HCV genotype 4, reported at the EASL International Liver Congress in April, showed that ABT-450/ritonavir plus ombitasvir, used alone or with ribavirin, cured 91% and 100% of previously untreated patients, respectively (dasabuvir is not effective against this genotype).
Based on these results and data from the Phase 3 SAPPHIRE I, SAPPIRE-II and TURQUOISE-II trials, AbbVie recently requested approval of the "3D" regimen from theU.S. Food and Drug Administration and the European Medicines Agency. The combo has been designated as an FDA "breakthrough therapy" and a decision is expected by the end of the year.
P Andreone, M Colombo, JV Enejosa, et al. PEARL-II: Randomized Phase 3 Trial of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333 With or Without Ribavirin in Hepatitis C Virus Genotype 1b-Infected, Treatment-Experienced Patients. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 929e.
D Bernstein, J Lalezari, Y Luo, et al. PEARL-IV: a 12-Week Regimen of ABT-450/r/ABT-267 and ABT-333, with or without Ribavirin Achieves SVR12 Rates >90% in Treatment-Naive Adults Infected with Hepatitis C Virus Genotype 1a. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Su1061.
P Ferenci, D Bernstein, J Lalezari, et al. ABT-450/Ritonavir/Ombitasvir and Dasabuvir with or without Ribavirin for HCV Genotype 1. New England Journal of Medicine. May 4, 2014 (Epub).
Medical University of Vienna. New Combination Therapy for Hepatitis C. Press release. May 5, 2014.