By John Gever, Deputy Managing Editor, MedPage Today
Published: April 24, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
AMSTERDAM -- Hitting hepatitis C virus (HCV) from three directions was a winner in a phase II trial involving patients with the particularly hard-to-treat viral genotype 1a, researchers said here.
Sustained 12-week viral response (SVR12) rates, indicating HCV viral loads too low to be measured, were seen in 89% to 94% of patients receiving various regimens that combined the investigational agents daclatasvir, asunaprevir, and BMS-791325, according to data slated for presentation this week at the annual meeting of the European Association for the Study of the Liver.
Two of the 66 patients enrolled in the trial had serious adverse events, but one was judged to be unrelated to study medications and the other occurred after a patient with viral breakthrough went on to receive conventional anti-HCV drugs.
Earlier results were reported last fall by Gregory Everson, MD, of the University of Colorado at Aurora, at which point SVR12 results were available for only one of the ongoing study's four arms. Everson is to present SVR12 outcomes for two of the remaining three arms at the EASL meeting, as well as some SVR24 and SVR36 (24- and 36-week sustained viral responses, respectively) results.
Data were made available at a press conference held prior to Everson's presentation and separately by the study's sponsor, Bristol-Myers Squibb.
Daclatasvir is an NS5A replication complex inhibitor, asunaprevir is an NS3 protease inhibitor, and BMS-791325 is a non-nucleoside NS5B polymerase inhibitor.
The trial assigned previously untreated patients to one of four regimens, all of which involved daclatasvir once daily and the other two agents twice daily. Two doses of BMS-791325 were tested (75 and 150 mg) and treatment duration was either 12 or 24 weeks.
Nearly three-quarters of patients had HCV genotype 1a, with the remainder genotyped as HCV 1b. In an earlier study of daclatasvir and asunaprevir, patients with genotype 1a fared poorly. Leaders of the current trial suspected that adding the polymerase inhibitor could boost responses.
SVR12 results for patients receiving the regimen with 150 mg of BMS-791325 for 24 weeks are still not available. For the other three arms, SVR12 rates were as follows:
- Low-dose BMS-791325, 12 weeks: 94%
- Low-dose BMS-791325, 24 weeks: 94%
- High-dose BMS-791325, 12 weeks: 89%
In addition, SVR24 rates for the low-dose 12- and 24-week treatment groups were 94% and 88%, respectively. In the low-dose group treated for 12 weeks, the SVR36 rate was 88%.
Those data were from an intent-to-treat analysis that classified three patients who failed to complete the planned follow-up as treatment failures. When the analysis was restricted to 28 patients for whom complete post-treatment data were available, all 28 met SVR24 or SVR36 criteria.
Two patients, both receiving the higher dose of BMS-791325, had viral breakthrough. One other patient, also in one of the high-dose groups, experienced a relapse after initially successful treatment.
The most common adverse events, each seen in at least 10% of patients, were headache, asthenia, diarrhea, and nausea. None of these were considered serious except for a case of grade 3 headache, which resolved in one week without interrupting study medications.
Although some elevations in liver enzymes and bilirubin were seen, none reached grade 3 or 4. One case of lymphopenia occurred in a patient with an influenza infection.
No results stratified by patient genotype were available prior to Everson's presentation.
Press conference co-moderator Mark Thursz, MD, of St. Mary's Hospital in London, said the data looked "extremely encouraging, but [based on] small numbers in a phase II study."
He noted that a race is already on to find replacements for the current oral anti-HCV drugs boceprevir (Victrelis) and telaprevir (Incivek), approved less than 2 years ago, because of their substantial side-effect profiles. These agents are now "in sick bay," he said, and before very long are likely to be replaced in clinical practice with newer drugs such as asunaprevir in combination regimens.
The study was funded by Bristol-Myers Squibb.
Everson reported that he had unspecified relationships with commercial entities that could be perceived as having a connection with the presentation.
Thursz reported relationships with Gilead and Abbott.