San Francisco—A second Phase IIb study of a new oral therapy for hepatitis C, PSI-7977, taken once daily, increased sustained virologic response (SVR) rates up to 91% in patients with difficult-to-treat hepatitis C virus (HCV) genotype 1 infection—a substantial improvement from the 50% reported in patients who received standard peginterferon and ribavirin (Peg-IFN/RBV) therapy. The study also showed significant advantages of PSI-7977 in patients who typically have poor responses to interferon.

Investigators say the new drug has the potential to dramatically alter the treatment paradigm for patients with hepatitis C virus (HCV) infection. “That’s true for all genotypes and all patients,” said lead author Eric J. Lawitz, MD, medical director of Alamo Medical Research, in San Antonio.
Patients who have the interleukin-28B (IL28B) TT genotype generally have a much lower chance of responding to IFN than people with the CC or CT genotypes. Yet in this study, these patients achieved high SVR rates to PSI-7977. Of the 13 patients who carried the TT allele, all tested negative for HCV by the third week of treatment and achieved SVR at week 12.
“The high SVR of greater than 90% in HCV genotype 1 patients was independent of predictors of poor IFN response,” Dr. Lawitz said.

The trial—known as PROTON—was the second Phase IIb study of PSI-7977 presented at The Liver Meeting 2011. In the first study, the ELECTRON study, investigators reported that 100% of patients who received PSI-7977 without IFN achieved an SVR (see “New Polymerase Inhibitor Could Become Cornerstone of Interferon-free HCV Treatment Regimen”).

Results from the two studies sparked considerable excitement among attendees of The Liver Meeting about this investigational therapy.

“I think it’s proof of principle that the proper combination of direct-acting antivirals can, in fact, produce enough suppression of viral replication to result in extinction of infection without the benefit of a broadly acting antiviral like IFN,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, in Boston.
The PROTON study was designed to examine dose-dependent response rates for PSI-7977 in HCV genotype 1–infected patients. Investigators enrolled 121 treatment-naive patients with this genotype in a randomized, double-blind, placebo-controlled, dose-ranging fashion. All patients were at least 18 years old with an HCV RNA level of 50,000 IU/mL or greater, platelets greater than 90,000/mm3, neutrophils greater than 1,500/mm3, and a hemoglobin level of at least 11 g/dL, with no evidence of cirrhosis.

Trial participants were randomized in a 2:2:1 ratio to one of three treatment arms: PSI-7977 200 or 400 mg daily in combination with IFN and RBV (n=48 and n=47, respectively) or Peg-IFN/RBV alone (n=26). Patients in the PSI-7977 arms received triple therapy for 12 weeks, followed by an additional 12 weeks of Peg-IFN/RBV. All patients who achieved early rapid virologic response (RVR) discontinued therapy at 24 weeks, while all others continued therapy for a total of 48 weeks. Patients in the IFN and RBV arm received treatment for 48 weeks.

Analysis showed robust response rates among all PSI-7977 patients regardless of dose. Patients who received 200 mg daily showed an RVR rate of 98%, an early RVR rate of 98% and an end-of-treatment response rate of 91%. Patients receiving 400 mg showed a 98% RVR, 91% early RVR and 91% end-of treatment response through 24 weeks. In contrast, response rates among patients who received Peg-IFN/RBV alone were 19%, 50% and 50%, respectively.

In an as-treated analysis of patients who received at least eight weeks of PSI-7977, 88% of those in the 200-mg arm and 98% of those in the 400-mg arm achieved an SVR at 12 weeks.

Several failures occurred in the trial.
Three patients in the 200-mg arm who had viral suppression during the first 12 weeks of treatment with PSI-7977 experienced a virologic breakthrough during the follow-up treatment period with Peg-IFN/RBV. No breakthroughs were observed among patients in the 400-mg arm, although one patient had a viral relapse before SVR at 4 weeks. “This suggests that [the] 400-mg dose achieved a deeper viral suppression,” said Dr. Lawitz.

The extent of viral suppression may be the key difference between the 200- and 400-mg doses of PSI-7977, he said. PSI-7977 at a 400-mg dose may provide a more thorough viral suppression with lower risk for virologic breakthrough. Patients in both groups quickly became negative for HCV RNA after PSI-7977 was started, but patients who received the 200-mg dose had more virologic breakthroughs after the PSI-7977 therapy was completed. No patient in either treatment arm developed an S282T mutation.

Investigators said they were pleased to see that the adverse events reported in the PROTON trial were typical of those seen with Peg-IFN/RBV treatment, except for a small increase in insomnia. Overall, 15% of patients in the 400-mg arm and 8% of those in the Peg-IFN/RBV–only arm reported insomnia.

More cases of neutropenia occurred with PSI-7977 than with Peg-IFN/RBV, but it was unlikely that the difference was significant, said the investigators. Three patients who received PSI-7977 had grade IV neutropenia compared with none in the Peg-IFN/RBV arm. However, the numbers of patients were too low to result in meaningful conclusions.

Still, experts say more patients must be studied to confirm that the new drug is safe.

“The numbers for neutropenia and anemia are confusing to me. They are small numbers but I’m still not certain about the safety of this compound,” said Paul Pockros, MD, head of gastroenterology and hepatology, and director of the Center for Liver Diseases, Scripps Clinic, in La Jolla, Calif.
The study was not powered to detect differences in neutropenia and anemia between the three groups, but differences would be statistically significant if 1,000 patients had participated in the trial, Dr. Pockros explained. “Is this drug going to be safe in 1,000 patients?” he asked.

Dr. Lawitz said investigators would expect to see a difference in adverse events between the 200- and 400-mg arms in this trial if PSI-7977 increased the risk for neutropenia, but that was not the case, with more neutropenia and anemia occurring in the patients receiving the lower dose.
“To me, that suggests that this is a trial with small numbers, and when we get larger numbers the difference is probably not going to be significant,” he said.

PSI 7977, in combination with RBV as dual therapy, is set to enter Phase III trials