Biotech Tracker News - Suboptimal Study Suggests Rebif Advantage Over Avonex
November 26, 2002 The current issue of Neurology contains a manuscript that demonstrates a treatment effect advantage of Serono’s (NYSE: SRA) Rebif over Biogen’s (NASDAQ: BGEN) Avonex for the endpoints of reducing relapses and active brain lesions in patients with relapsing remitting multiple sclerosis (RRMS) over 24 and 48 weeks. The data extend earlier 24-week data.  However, accompanying editorials point out that the scientific merit of the study is suboptimal. The primary goal of the study was to establish short-term benefit data relative to Avonex to be used in obtaining FDA approval and physician acceptance of Rebif, and not establishment of the long-term benefit of Rebif over Avonex. Therefore, these analyses are not likely to benefit Rebif strongly, although they also will not shift momentum back towards Avonex. The EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study group performed a 677-patient, randomized, single (assessor)-blind, head-to-head trial comparing the efficacy and safety of Rebif (an interferon b-1a formulation delivered 44 µg subcutaneously thrice weekly) and Avonex (an interferon b-1a formulation delivered 30 µg by the intramuscular route once weekly). The primary clinical endpoint was the proportion of relapse-free patients at 24 weeks, and the primary MRI endpoint was the number of active lesions per patient per scan at 24 weeks. 48-week data added a degree of confidence relevant to sustained response. Rebif treatment advantages were seen for: proportion of relapse-free patients  74.9% (254/339) for Rebif recipients  63.3% (214/338) for Avonex recipients  odds ratio favored Rebif for remaining relapse free  1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks  1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks fewer active MRI lesions (p < 0.001 at 24 and 48 weeks).  Rebif’s adverse effect profile, though predictable and manageable, featured significantly greater propensities for injection-site reactions (83% vs. 28%, p < 0.001), asymptomatic abnormalities of liver enzymes (18% vs. 9%, p = 0.002), altered white blood cell counts (11% vs. 5%, p = 0.003), and development of neutralizing antibodies (25% vs. 2%). The development of neutralizing antibodies is unlikely to impact comparative efficacy in RRMS therapy.  An accompanying editorial by Kieburtz and McDermott lays the groundwork for a dampened acceptance of these results. The editorial’s title, “Needed in MS – Evidence, not EVIDENCE,” begins to alert prescribing physicians to the suboptimally constructed clinical trial. The authors noted that the study features major methodological shortcomings : 6 months’ duration – too short  study subjects themselves were not blinded to the treatment regimen is a major bias risk relevant to reporting of relapses  relapse freedom (rather than a disability measure) as the principal outcome variable  higher short-term relapse-free rate, especially of this modest magnitude, by no means provides information on the long-term progression of disability end results provide more questions than clear evidence that can guide therapeutic decisions  unclear whether the relative benefit on relapses and MRI outcomes outweighs the litany of adversity risks  the aspect of the different treatment strategies that led to clinical benefit is unclear (formulation/preparation, frequency of administration, the route of administration, or the higher weekly dosage)  two different commercial products were compared  two different routes of administration were compared  two different dosages were compared  a different frequency of administration was compared. The authors write that EVIDENCE “appears to have been designed to satisfy primarily regulatory and marketing concerns rather than scientific ones,” and cite the significant limitations of such study as it pertains to making decisions regarding standards of clinical practice.  A second editorial, written by Lublin, reiterates much of the concern expressed by the first, reminding physicians more clearly that the goal of the study was to justify overturning specific tenets of the Orphan Drug Act such that Rebif could compete with Avonex. He alerts prescribing physicians that although, “marketing-influenced studies are usually less interesting by their very nature, as the scientific questions tend to be secondary,” the study still, “provides the best available head-to-head comparative data to date of any of the … (MS) studies.… These studies then can help guide physician and patient treatment decisions in a way not previously possible.… We have a true intersection of a marketing interest and a scientific need.… They also highlight the obvious remaining gaps in our knowledge and understanding in treating (MS).”
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