Schering-Plough Shows Off Once-Daily Hep C Drug Narlaprevir At AASLD

Next-generation ritonavir-boosted protease inhibitor is headed into Phase IIb, and if all goes well, could be a significant player in the hepatitis C market.

BOSTON - Schering-Plough's next-generation hepatitis C therapy narlaprevir may shape up as a better competitor for the Vertex hepatitis C drug telaprevir than Schering's first generation protease inhibitor boceprevir, if the ritonavir-boosted Phase IIa trial for narlaprevir stays true to the initial results.

Lead investigator John Vierling, Baylor College of Medicine, Houston, presented interim data from the Phase IIa NEXT-1 trial study Nov. 2 at the American Association for the Study of Liver Diseases meeting in Boston.

A dose-finding study, NEXT-1 assigned 111 treatment-naive patients with genotype-1 HCV to 200 mg or 400 mg narlaprevir once-daily or 100 mg twice daily with low-dose ritonavir (100 mg); patients were also randomized with or without a four-week lead-in with standard-of-care interferon and ribavirin (in this case Schering-Plough's Peg-Intron and Rebetol ). That regimen was followed by the standard of care alone for another 12 or 36 weeks (24 or 48 weeks total), based on the patient's response at four weeks on study drug. A control arm was given Peg-Intron and Rebetol for 48 weeks.

More than 85 percent of patients that received the narlaprevir/ritonavir combination after lead-in met the primary endpoint of rapid virologic response - compared to 58-75 percent in the group that went straight into the experimental drug combo and no patients in the standard of care interferon/ribavirin arm.

Looking at individual patients, "many individuals would plummet to undetectability in one to two weeks of narlaprevir," Vierling said in an interview. "Those particular kinetics, the rapidity, are striking. That speaks to potency. It also speaks to certainty that this is probably going to be durable," he said. "You're not sneaking up on it as you have more drug exposure - it's an immediate effect."

The importance of having a rapid virologic response is that it translates into high positive predictive value for sustained virologic response later. Looking retrospectively at all the databases across the industry for standard of care, the minority of patients that achieved RVR at four weeks have a greater than 90 percent chance of attaining a sustained virologic response, which qualifies as a cure, if they stay on treatment, Vierling said.

Of 12 patients who failed on the standard of care therapy in the four-week lead-in phase of NEXT-1, eight went on to achieve undetectable viral RNA.

Narlaprevir produced no unique adverse events. Rates were similar in the investigational drug arms to the standard of care, with the exception of an increase in anemia that did not result in any discontinuations.

Schering is finalizing a Phase IIb study, which will have arms with differences in treatment duration, with the narlaprevir combination exceeding 12 weeks in some of the arms, Vierling said.

Defining Detectable: Trials Should Set Low Levels

It is also important to note that the limit of detectability in NEXT-1 is extremely sensitive, Vierling said. The viral load defined for RVR in this study was set at <10 IU/mL.

That should be a standard for hepatitis C trials, the investigator suggested.

"I think going forward all the companies realize we can't have wiggle room for low abundance of virus. We really need to know complete undetectability."

In its C208 study of telaprevir with response-guided therapy, which is also slated for presentation at AASLD, Vertex also used <10 IU/mL as a determination of RVR (Also see "Vertex's Telaprevir Works In Twice Daily Dose; Response-Guided Therapy Cuts Down Drop-Outs" - Pink Sheet, 31 Oct, 2009.).

"Boost" Really Means "Inhibit"

When Schering-Plough and Vertex began developing their competing Phase III protease inhibitors boceprevir and telaprevir, it seemed logical to borrow a design feature from HIV studies: the practice of adding a second protease inhibitor to improve the performance of the first. Ritonavir, which was not particularly potent on its own, has become a standard "booster" in antiretroviral combinations. It did not, however, work with telaprevir or boceprevir.

With narlaprevir, Schering has identified a PI that will work with ritonavir. Narlaprevir is a mechanism-based drug developed to be metabolized in the liver by a specific isoform of the metabolizing enzymes, CYP3A4, the pathway that is inhibited by ritonavir. So, the ritonavir combination provides not so much a boost as it an inhibition or delay of the metabolism.

"Any drug being metabolized through that pathway will have a slower metabolism in the presence of ritonavir, allowing enhanced concentration in the blood to be delivered over time into the tissues," and enabling narlaprevir's once-daily dosing, Vierling explained. "So that's where the ritonavir comes in. It enhances drug availability of the narlaprevir by design, not by chance."

Roche and InterMune are investigating a Phase II ritonavir-boosted protease inhibitor, ITMN-191, as part of their experimental all STAT-C combination therapy. A combination regimen using only the novel STAT-C mechanisms would eliminate ribavirin and pegylated interferons, and their significant side effects, from hep C treatment.

The investigational therapy combines ITMN-191 with a Phase II nucleoside polymerase inhibitor partnered with Pharmasset. Roche presented Phase I data from the INFORM-1 trial in April at the European Association for the Study of the Liver conference to much excitement (Also see "INFORM-1 Data Show Potential Efficacy And Safety Of Roche HCV Combo" - Pink Sheet, 4 May, 2009.).

- Shirley Haley ([email protected])