Tuesday, August 14, 2012

New Studies Investigate Boceprevir in Null Responders, Versus Telaprevir

New Studies Investigate Boceprevir in Null Responders, Versus Telaprevir
by George Ochoa
Two studies presented at the European Association for the Study of the Liver (EASL)/International Liver Congress meeting in Barcelona, Spain, were the first to explore certain aspects of treatment with boceprevir. One study was the first to show the efficacy of boceprevir in the treatment of null responders with hepatitis C virus (HCV) infection. Another study addressed the absence of head-to-head clinical trials between boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals).
Boceprevir in Null Responders
In the first study, investigators found that boceprevir used in combination with peginterferon and ribavirin led to high rates of sustained virologic response (SVR) in patients with HCV who failed prior treatment with peginterferon and ribavirin alone. The study also showed that the combination of boceprevir with peginterferon and ribavirin was effective in prior partial responders and relapsers, which has been previously reported.

“The RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2] trial by Bacon and colleagues [N Engl J Med 2011;364:1207-1217] already established effectiveness of boceprevir in prior relapsers and partial responders, but not in prior null responders,” explained Donald M. Jensen, MD, professor of medicine and director, Center for Liver Disease, University of Chicago Medical Center. “This abstract by Bronowicki demonstrates that 40% of prior nulls [null responders] can respond to this treatment.”

The results were based on an interim analysis of PROVIDE, an ongoing, open-label study of patients who participated in the peginterferon and ribavirin control arms of the Phase II and III studies of boceprevir and who failed to achieve SVR. After treatment with the triple-drug regimen, SVR was achieved in 40% (19 of 47) of prior null responders, defined as a greater than 2-log10 decline in HCV RNA at treatment week 12 in the prior study. Among prior partial responders/relapsers, 68% (62 of 91) of patients achieved an SVR with the triple-drug combination. The total proportion of patients in the study who achieved SVR was 59% (81 of 138), noted lead study author, Jean-Pierre Bronowicki, MD, PhD, of the University Henri Poincaré of Nancy, in Vandoeuvre-les-Nancy, France.
Overall, 7% of patients discontinued treatment because of adverse events: 48% had anemia, 34% dysgeusia and 22% neutropenia.

The degree of interferon responsiveness after lead-in with peginterferon and ribavirin correlated with prior response and could help predict SVR for prior null responders, the researchers concluded.

Indirect ‘Head-to-Head’ Comparison of Boceprevir, Telaprevir
Another study, presented at the EASL meeting by Cooper et al, attempted to compare boceprevir and telaprevir in a head-to-head clinical trial. The researchers used an indirect comparison meta-analysis and meta-regression of the current evidence to evaluate the relative efficacy of the two drugs in combination with peginterferon-α and ribavirin. Phase II and III randomized placebo-controlled trials evaluating the efficacy of boceprevir or telaprevir in adult patients infected with HCV genotype 1 were considered for the analysis; four boceprevir trials and six telaprevir trials met the inclusion criteria.

The researchers found no significant differences between boceprevir and telaprevir in SVR among treatment-naive or -experienced patients (relative risk [RR], 1.14; 95% confidence interval [CI], 0.93-1.37; P=0.20 and RR, 0.80; 95% CI, 0.18-3.45; P=0.30, respectively). Additionally, there were no significant differences between boceprevir and telaprevir in rates of relapse or discontinuation of therapy among naive and experienced patients. Also, boceprevir and telaprevir were shown to be comparable in efficacy for both standard-dose and response-guided therapy. Telaprevir was associated with higher rates of rash (RR, 0.70; 95% CI, 0.54-0.92; P=0.01) and pruritus (RR, 0.67; 95% CI, 0.53-0.85; P=0.001) compared with boceprevir, which was associated with increased rates of neutropenia among treatment-naive response-guided patients (RR, 1.46; 95% CI, 1.09-1.95; P=0.05).

Commenting on the method of data analysis used in this study, Steven D. Pearson, MD, MSc, president of the Institute for Clinical and Economic Review, Boston, pointed out that “indirect comparisons can be ‘valid’ if the technique is well done. Many coverage decisions require indirect comparisons. They are more open to question than direct comparisons, but often direct comparisons are not available or even feasible.”

However, Dr. Jensen said: “I hesitate to put too much reliance on a comparison between two agents that is not head-to-head and would be reluctant to say that these therapies are comparable based on this analysis alone. Nonetheless, it is my personal impression that these therapies are fairly comparable, so in that case, this study confirms my impression.”

The study authors noted that dosing schedule and adverse event (AE) profiles are the key factors that allow for differentiation between the drugs—a point echoed by pharmacist Janet Nguyen, PharmD, BCPS, vice president of network strategy, A-Med Health Care, Huntington Beach, Calif.

“Telaprevir has a much easier dosing schedule compared with boceprevir, with a three-month duration [compared with six to eight months for boceprevir] and one less blood draw,” she said. As for side effects, she noted that the study “called out the most significant [AEs]—rash for telaprevir and neutropenia for boceprevir.”

Helping patients manage AEs can have a positive effect on compliance, Dr. Nguyen stressed, and that in turn can be a cost-saver. “These are expensive drugs,” she noted.

Considering both studies, Dr. Jensen said, “These represent important findings, but may not be that surprising. They demonstrate what many have suspected: that telaprevir and boceprevir therapies provide generally comparable response rates, and that boceprevir is effective in prior interferon/ribavirin null responders.”

Drs. Nguyen and Pearson reported no relevant financial conflicts of interest. Dr. Jensen reported that he is an advisory board member or consultant for Merck & Co. and Vertex Pharmaceuticals.

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