In what is poised to be one of the biggest marketing battles of the year, as Merck's Victrelis (boceprevir) and Vertex's Incivek (telaprevir) close in upon approval, how FDA handles different subgroups of hepatitis C patients in labeling for each of the protease inhibitors could be a determining factor.

Acknowledged as significant advances in therapy, each drug received 18-0 votes in favor of approval from FDA's Antiviral Drugs Advisory Committee in back-to-back sessions April 27 and 28 (Also see "Post Panels, Telaprevir And Boceprevir Now Face FDA's Risk Management Review" - Pink Sheet, 2 May, 2011.).

The issue before FDA and the companies as they negotiate labeling is identifying which subgroups could achieve sustained viral response (the mark of a cure) sooner than the 48 weeks that is the typical length of therapy with pegylated interferon plus ribavirin, the current standard-of-care.

Both Merck and Vertex propose to use response-guided therapy that will allow certain patients to use a shorter course of SOC, a significant advantage given the side effects of peginterferon and ribavirin.

Merck offers several options for combining boceprevir with SOC, with duration of treatment ranging between 28 weeks and the full 48 weeks; Vertex proposes 12 weeks of telaprevir therapy in combination with either 24 or 48 weeks of SOC (see chart, Also see "A Guide To Response-Guided Therapy" - Pink Sheet, 9 May, 2011.).

The easy sell to advisory panel members was shorter treatment regimens for early responders. Merck defines these as patients whose HCV RNA is undetectable by week 8, following an initial four week lead-in with SOC. Vertex would cut off therapy at 24 weeks for patients with extended rapid virologic response (eRVR) – those who have undetectable HCV RNA at both weeks 4 and 12.

Merck proposes shorter therapy for early responders among treatment-naïve patients and those who relapsed or partially responded to prior SOC. Vertex would make response-guided therapy available to the first two groups of patients but have partial responders complete 48 weeks of treatment.

In its review of boceprevir, the advisory panel was less certain about treatment length for treatment-naïve late responders.

Advisory Committee members wanted less prescriptive labeling for boceprevir, to leave some decisions about response-guided therapy to physicians.

Merck's dosage and administration guide for boceprevir calls for a full 48 weeks of therapy for these patients. But several panel members supported labeling that is less prescriptive, to leave the choice of whether or not to shorten treatment up to doctors and patients.

The difference in treatment effect in the clinical trials between those receiving response-guided therapy and those on the full 48 weeks of treatment in these patients is so slight "it's not even close to a statistically significant difference," Susan Ellenberg, University of Pennsylvania, pointed out.

"I don't see how we can make any kind of strong statement that shorter therapy is clearly to be avoided in these late responders," she said. "People can look at the data."

Given that efficacy for late responders was higher with longer treatment, Michelle Roland, California Department of Health, expressed discomfort with recommending response-guided therapy for this group.

But she conceded that a choice on length of treatment may be an "individualized decision where for some patients, it's going to be more important to have an absolute best chance of an SVR, and for others, they're more than willing to take a little bit of risk that maybe this isn't quite as effective and they're going to have a shorter duration of therapy."

Panel members supported 48-week therapy for cirrhotics, but found that data on use of response-guided therapy in African-Americans were limited and provided less clarity on its effectiveness. "They probably do better with the full 48 weeks of treatment as opposed to the response-guided therapy," Doris Strader, University of Vermont, concluded.

FDA has some leeway in addressing issues presented by the absence of definitive data, Division of Antiviral Drug Products Director Debra Birnkrant indicated during a press briefing following the meeting. The agency can "look at the whole data set and … try to extrapolate a little bit to be able to have a more informative label," she said.

For the subgroups other than early responders, she added, "we have a lot of scientists working on this and we'll sit down and decide what can we come up with that would work for the majority," she noted.

FDA will be mindful of panelists' desire to give physicians leeway in their prescribing through "some creative labeling that sets some parameters without actually being too dogmatic," DAVP Deputy Director Jeffrey Murray said.

The validity of response-guided therapy in early responders who previously relapsed on SOC did not arise during the advisory committee's review of boceprevir, but was a topic of discussion during its assessment of telaprevir.

Correlation Between eRVR And SVR

During the sponsor presentation April 28, Shelly George, Vertex VP and HCV therapeutic area lead, said that a strong correlation between SVR rates for prior relapsers who achieved eRVR suggested that there would be little difference in outcome if such patients were treated for 24 weeks or 48 weeks.

Vertex did not perform a Phase III study investigating response-guided therapy in prior relapsers, but while response-guided therapy wasn't tested in its Phase III C216 trial, it found that 66% of prior relapsers achieved eRVR. Of these, 96% achieved SVR during the standard 48-week course of therapy.

A similar population in a pair of Phase II trials showed high cure rates for prior relapsers who achieved eRVR and then were treated on the 24-week response-guided therapy regimen. In study 106, 67% of such patients achieved eRVR and 89% of those went on to achieve SVR. In the 107 study, 96% of prior relapsers achieved eRVR and 100% of those achieved SVR during the shorter course of therapy.

“In summary, both prior relapsers and treatment-naïve patients represent populations of high interferon response and, in both of these patient populations, patients with eRVR achieved high SVR rates,” George said. “Of note, SVR rates were high in prior relapsers regardless of the duration of pegylated interferon and ribavirin [therapy]. This suggests that achievement of eRVR was the critical factor in determining outcomes.”

The advisory committee clearly supported response-guided therapy for treatment-naïve patients (Also see "Vertex's Telaprevir Slides By Advisory Committee, But Panelists Want Limits On Some Patients" - Pink Sheet, 28 April, 2011.). But there was some disagreement over whether FDA should ask Vertex to conduct additional studies on the suitability of the shortened regimen for prior relapsers, where the evidence was extrapolated from the Phase II trials.

“For the prior relapsers, my intuition … is that [response-guided therapy] is probably going to be okay,” said Ellenberg. “However, I think the data are really pretty sparse. I think we’re drawing from several different sort of datasets that are all kind of suggestive. I feel like it may be a greater than 50% chance prior relapsers can do fine with [response-guided therapy], but I’m not sure it gets to the level that I would say the FDA should make [response-guided therapy] the preferred regimen in this group."

"I don’t see data that suggest it’s not going to work," she added, "but I think more data would be necessary before it can be documented that this is the optimal regimen.”

Marc Ghany of the Liver Diseases Branch of the National Institute of Diabetes, Digestive and Kidney Diseases said he thought response-guided therapy might work fine for prior relapsers with good baseline characteristics, but wondered about patients with less clean bills of health.

“My concern is really the prior relapsers who are difficult to treat, who have poor baseline characteristics, those who are overweight, high viral load, cirrhotic,” he said. “I’d like to see some more studies on response-guided therapy in that particular group of individuals.”

Panelists also discussed a desire to see more data on telaprevir’s efficacy in African-American patients, patients with cirrhosis of the liver and patients over 65 years of age.

“For both blacks and people with cirrhosis, I think that the data are definitely adequate to suggest efficacy,” said Roland. “But … I think that with the previous question [on response-guided therapy], lumping all treatment-naïve subgroups together and saying that [for] response-guided therapy, the evidence supports that, it just doesn’t for people with cirrhosis.”

Simplicity Matters

While response-guided therapy offers some patients early relief from side effects, which include flu-like symptoms and anemia, the variations in treatment regimens add complexity to patient treatment.

"What clinicians are looking for is something simple and easy to remember and not complicated, and that's good for adherence for patients too," Lawrence Friedman, Harvard Medical School, said during the boceprevir review.

"When you get in all these subgroups, it gets too complicated," one panelist told FDA.

Response-guided therapy is going to have a role for the early responders in treatment-naïve patients, he conceded. "But when you get in all these subgroups, it gets too complicated. … People are not going to be following it, following the protocols precisely, and patients are not going to be adhering precisely, so I'd consider that in the decision making," he advised FDA.

The American Association for the Study of Liver Diseases has planned to address the complexity of the treatment regimens with boceprevir and telaprevir during its annual meeting this fall (Also see "Vertex, Merck Face Education Challenge With Complex Hep C Regimens" - Pink Sheet, 3 January, 2011.).

Introduction of the direct-acting antivirals and the advance in hepatitis C treatment they represent will add a new dimension to physician education in the field, Patrick Clay, Kansas City University of Medicine, maintained. The number of people seeking therapy may increase to a point that family physicians and primary care doctors will become part of the health care provider network, he said.

"Education across the board – the Katie Couric effect for prostate cancer, if you will – really is going to have to be replicated in order for people to understand not only the importance of the therapy, but the importance of getting proper therapy and adhering to that proper therapy."

By Cathy Dombrowski, Joseph Haas

FDA Must Decide How To Handle Subgroups In Labeling For Boceprevir, Telaprevir

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