AASLD: New Drug Boosts HCV Clearance

AASLD: New Drug Boosts HCV Clearance
By John Gever, Senior Editor, MedPage Today
Published: November 03, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco. Earn CME/CE credit
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BOSTON -- Most hepatitis C patients who are initially unresponsive to standard therapy were able to achieve sustained virologic responses when the investigational drug boceprevir was added, a researcher reported here.

Sustained responses were seen in 55% of patients receiving 44 weeks of boceprevir after showing no virologic response to four weeks of pegylated interferon-alfa-2b (PEGIntron) and ribavirin (Rebetol) in a Phase II trial, said Paul Kwo, MD, of Indiana University in Indianapolis.

Kwo, speaking here at the American Association for the Study of Liver Disease meeting, was reporting on two secondary analyses of data from the SPRINT-1 trial of boceprevir, an inhibitor of the hepatitis C virus (HCV) NS3 protease enzyme.

He had presented the main findings of the 520-patient study earlier this year at the European Association for the Study of the Liver meeting in Copenhagen. (See Sustained Response Seen with New Hepatitis C Drug)
Action Points

* Explain to interested patients that boceprevir is not FDA approved for any purpose and is available only in a clinical trial setting.


* Explain that this analysis involved relatively small numbers of patients and needs to be confirmed in larger studies.


* Explain that adverse effects of boceprevir were not addressed in these analyses, but earlier findings had indicated that anemia, fatigue, nausea, and headache may be related to the drug.


* Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

Boceprevir is one of two HCV protease inhibitors in late-stage development, the other being telaprevir. (See DDW: Telaprevir Improves HCV Clearance in Resistant Patients) Phase III trials of both drugs are now under way.

In the SPRINT-1 trial, treatment-naive patients were randomized to five treatment arms, including one in which patients only received pegylated interferon and ribavirin, two involving immediate treatment with all three agents, and two in which boceprevir started after an initial, four-week lead-in with interferon and ribavirin.

All patients had HCV genotype 1a or 1b, mostly the former.

The secondary analyses reported here focused only this last treatment strategy, with patients receiving either 24 or 44 weeks of triple therapy following the four-week, two-drug lead-in.

Boceprevir was dosed at 800 mg three times a day.

In patients with no response to the lead-in -- defined as a reduction in HCV RNA loads of less than ten-fold -- 25% of those receiving boceprevir for 24 weeks still showed viral clearance after an additional 24 weeks of follow-up.

With 55% of initial null responders receiving the drug for 44 weeks showing long-lasting viral clearance, the longer therapy appeared to be more effective, Kwo said.

He also noted that boceprevir for both durations boosted response rates well above what would normally be expected from standard therapy in patients without strong responses in the first four weeks.

He cited results from an earlier large trial in which less than 5% of early nonresponders to standard therapy eventually developed sustained responses.

Among patients showing strong responses in the first four weeks of interferon and ribavirin, sustained responses were seen in most.

More than 80% of those with initial reductions of three to four orders of magnitude in viral RNA levels had sustained responses, as did nearly 100% of those with reductions of at least four orders of magnitude or whose viral RNA became undetectable in the first four weeks.

Duration of boceprevir treatment appeared to make no difference in sustained virologic response rates in these patients.

But Kwo cautioned that the findings in these analyses involved relatively small numbers of patients. Only about 50 patients were considered null responders to the lead-in treatment, and similar numbers had relatively strong initial responses.

Overall, adding boceprevir after the four-week lead-in led to sustained responses in 56% of patients receiving boceprevir for 24 weeks, and in 75% of those taking the drug for 44 weeks, Kwo said. Both response rates were significantly (P<0.01) higher than the 38% rate seen in patients taking only pegylated interferon and ribavirin for 48 weeks.

In a separate analysis, Kwo reported that virologic responses measured later in treatment could identify patients for whom longer or shorter boceprevir treatment would be most appropriate.

For example, only the 18% of patients whose viral RNA became undetectable after four to 12 weeks of boceprevir treatment (after the four-week lead-in with standard therapy) appeared to need the full 44 weeks of boceprevir to hold the response, Kwo said. The remaining 82% all achieved viral clearance within four weeks of starting boceprevir.

He said he hoped the Phase III trial would confirm that most patients could get by with the shorter regimen.

He added that the overall data suggested that HCV protease inhibitors may act primarily to restore sensitivity to interferon, though he emphasized that this theory would have to be confirmed in future studies.

The study was funded by Schering-Plough.

Kwo reported relationships with Schering-Plough, Vertex, Novartis, Gilead, Abbott, Roche, Merck, GlaxoSmithKline, Celgene, Idenex, and Bristol-Myers Squibb. Several co-authors were employees of Schering-Plough.

Primary source: Hepatology
Source reference:
Kwo P, et al "High sustained virologic response (SVR) in genotype 1 (G1) null responders to peg-interferon alfa-2b (P) plus ribavirin (R) when treated with boceprevir (Boc) combination therapy" Hepatology 2009; 50: 331A-332A.

Additional source: Hepatology
Source reference:
Kwo P, et al "Response-guided therapy (RGT) for boceprevir (Boc) combination treatment? – Results from HCV SPRINT-1" Hepatology 2009; 50: 1035A-1036A.