By: NEIL OSTERWEIL, Internal Medicine News Digital Network
ORLANDO – The investigational protease inhibitor simeprevir was associated with high levels of sustained virologic response in patients with both treatment-naive and relapsed hepatitis C viral infections, reported investigators at the annual Digestive Disease Week.
In the QUEST-2 phase III trial, 81.3% of previously untreated patients with hepatitis C (HCV) genotype 1 infections randomized to simeprevir (TMC435) and pegylated interferon-alfa (pegIFN/RBV) had a sustained virologic response following 12 weeks of therapy (SVR12, the primary endpoint), compared with 50% of those assigned to pegIFN/RBV and placebo (P less than .001), reported Dr. Fred Poordad from the University of Texas Health Science Center in San Antonio.
In the phase III PROMISE trial, 79.2% of patients with HCV genotype 1 infections who had a relapse following prior therapy with an interferon-based regimen had an SVR12 when treated with simeprevir, compared with 36.8% of patients treated with pegIFN/RBV and placebo (P less than .001), said Dr. Eric Lawitz, also from the University of Texas in San Antonio.
"Safety and tolerability appear to be comparable to placebo, and patient-reported outcomes support both the efficacy and the safety profiles of simeprevir," Dr. Poordad said.
Simeprevir is a once-daily oral inhibitor of the HCV NS3/4A protease with demonstrated antiviral activity against HCV genotypes 1, 2, 4, 5, and 6.
In QUEST-2, 391 patients were randomized on a 2:1 basis to receive either simeprevir 150 mg daily plus pegIFN/RBV or placebo plus pegIFN/RBV for 12 weeks, followed by an additional 12 or 36 weeks of pegIFN/RBV depending on response-guided therapy criteria. If patients had HCV RNA less than 25 IU/mL at week 4 and undetectable at week 12, they received an additional 12 weeks of pegIFN/RBV. Patients outside of the response-guided criteria received a total of 36 additional weeks of pegIFN/RBV. In both treatment arms, patients were followed for an additional 24 months, for a total of 72 months.
A total of 235 of the 257 patients assigned to simeprevir (91.4%) met the response-guided criteria by week 24, completed therapy, and were then followed until study end. Of this group, 86% (202 patients) achieved SVR12.
Simeprevir was statistically significantly superior to placebo regardless of IL28B polymorphism genotype or METAVIR (fibrosis and inflammation) scores.
On-treatment failures, defined as a confirmed detectable HCV RNA level at the actual end of treatment, occurred in 7% of patients on simeprevir and 32.1% of controls. Relapses, defined as detectable HCV RNA on one or more follow-up visits following undetectable end-of-treatment levels, occurred in 12.7% and 23.9%, respectively (P values not shown).
Of the simeprevir-treated patients who did not achieve an SVR, 97.6% had emerging mutations in the NS3 protease domain at the time of treatment failure, Dr. Poordad said.
In the PROMISE trial, 393 patients who had experienced a relapse following interferon-based therapy were randomized to response guided therapy as described in the QUEST-2 study.
As noted before, 79.2% of patients assigned to simeprevir/pegIFN/RBV met the primary endpoint of SVR12, compared with 36.8% of patients assigned to placebo/pegIFN/RBV (P less than .001).
In this trial, simeprevir was significantly better than placebo in patients with both HCV genotypes 1a and 1b, and as in QUEST-2 was superior to placebo regardless of IL28B genotype or METAVIR score.
On-treatment failures occurred in 3.1% of simeprevir-treated patients and 27.1% of those on placebo and pegIFN/RBV. The respective relapse rates were 18.5% and 48.4%. As in QUEST-2, the large majority (92.3%) of simeprevir-treated patients who did not have an SVR had emerging mutations in the NS3 protease domain.
In QUEST-2, patients on simeprevir had more cases of rash, 27% vs. 20%, and photosensitivity, 4% vs. 1%. Anemia occurred in 13.6% and 15.7%, respectively. The incidences of other adverse events were similar between the groups.
In PROMISE, the most common adverse events were fatigue, influenzalike illness, pruritus, and headache. Anemia occurred in 17% of patients on the active drug plus pegIFN/RBV, compared with 20% for those on placebo/pegIFN/RBV. Neutropenia occurred in 18% and 22%, respectively. Rates of pruritus and rash were comparable between simeprevir and placebo.
The Food and Drug Administration has granted priority review status to simeprevir for the treatment of chronic HCV genotype 1.
The studies were funded by Janssen. Dr. Poordad and Dr. Lawitz have received grants and/or research support from the company, and several of their coauthors are employees of Janssen or its parent company Johnson & Johnson.