Serono Rebif Efficacy Gain Over Avonex Likely To Persist Past 48 Weeks–FDA

The efficacy advantage of Serono's multiple sclerosis agent Rebif (interferon beta-1a) over Biogen's Avonex (interferon beta-1a) will likely be maintained beyond 48 weeks, FDA reviewers concluded in review documents for the BLA.

The advantage of Rebif vs. Avonex "was demonstrated on a 24-week endpoint, observed to be maintained on the 48-week outcomes and can be reasonably expected to persist beyond that time frame given the prior experience with interferon betas in many large studies," FDA reviewers Cynthia Rask, MD, Ellis Unger, MD, and Marc Walton, MD, stated in a memo issued on the day of Rebif approval, March 7.

Serono submitted preliminary 48-week data from a head-to-head study of Rebif and Avonex with its BLA. Twenty-four week data from the study (EVIDENCE) was used to support an efficacy advantage for Rebif, thus allowing the product to break Avonex's orphan marketing exclusivity, which expires in May 2003. The NDA also was based on results from a two-year placebo-controlled trial evaluating two doses of Rebif.

Rebif, which is administered subcutaneously three times a week, is indicated for treatment of "relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability." Avonex, administered once weekly through an intramuscular injection, carries essentially the same indication.

Rebif's efficacy advantage over Avonex is reflected in the premium pricing for the product: a wholesale acquisition cost of $1,156 and an average wholesale price of $1,334.13 for a month's treatment. The AWP figure represents a 35% increase over Avonex's AWP of $985.22 and a 24% increase over Berlex's Betaseron (interferon beta-1b)AWP of $1,080.

The EVIDENCE study evaluated MS exacerbation-free status for patients receiving either 44 mcg Rebif three times weekly or 30 mcg Avonex once weekly. At the end of 24 weeks, 75% of Rebif patients were exacerbation-free vs. 63% of Avonex patients (p<0.001).

"This is a meaningful difference," FDA's Rask, et al. stated, "because it means, among other things, that a patient on Rebif is 32% less likely to experience an MS exacerbation, which can substantially lower his or her quality of life for weeks or months." The FDA reviewers added that the 48-week results "confirm the data and effects observed" at 24 weeks.

Rebif patients were also shown to have fewer active MRI brain lesions than Avonex patients, which included "the mean number of combined unique (CU) T1 + T2 active MRI lesions per subject per scan...and the mean number of T2 active lesions per MRI scan."

Speaking at a March 13 SG Cowen conference, Biogen CEO Jim Mullen emphasized that the company has been preparing for the early approval of Rebif. The company increased sales reps from 65 to 80, and "increased our marketing spending to maintain our voice in the marketplace," he said. Biogen is not specifying what its marketing budget is for Avonex. Serono has budgeted $60 mil. to launch Rebif.

Serono expects "to capture more than 25% market share...within the next three to four years," CEO Ernesto Bertarelli said during a March 11 analysts' call. By 2005, the firm expects Rebif worldwide sales to more than triple, exceeding $1 bil.; sales were $379.6 mil. in 2001. Biogen has predicted $1.1 bil. in Avonex sales for 2002.

FDA's review documents for Rebif may be useful to Serono for promotions. Bertorelli said the firm is reviewing the FDA documents "to extract the most relevant findings."

"It is clear that our marketing strategy will be based" on FDA's findings of "greater efficacy of Rebif," he said. "We are permitted to promote consistent with the package insert. We don't see any problem in using our superiority in our marketing strategy."

Though FDA reviewers concluded "Rebif is clinically superior to Avonex" on the measured endpoint, they are careful to state that orphan regulations "indicate that only a selected aspect may constitute a sufficient basis to reach a conclusion of clinical superiority."

Biogen is disputing Rebif's superiority claim, pointing out that "there isn't a difference in the second six months on the efficacy."

Biogen was referring to data showing that among patients who were exacerbation-free during the initial six months, 82% of Rebif patients and 83% of Avonex patients remained exacerbation-free between weeks 24 and 48. However, FDA's interpretation of that data is that the benefit shown for Rebif "during the initial 24 weeks on study was maintained during the succeeding six months."

At the end of the 48-week period, 62% of the Rebif patients were exacerbation-free vs. 52% of the Avonex patients, and "this difference was statistically significant (p=0.006)," FDA said.

Serono will present more detailed findings from the 48-week study on April 16 at the American Academy of Neurology meeting in Denver.

Biogen feels "there's no evidence of superiority" in the Rebif label "with respect to the most important outcome of treatment, which is impact on progression of disability over an extended period of time," Executive VP-R&D Bert Adelman, MD, said during the March 11 analysts' call. The Rebif data "are actually somewhat inferior to the Phase III Biogen data on impact on progression of disability."

Adelman also pointed to the statement in Rebif labeling that the design of the Avonex comparative trial "does not support any conclusion regarding effects on the accumulation of physical disability."

Rebif labeling reports disability data from the placebo-controlled trial. In the two-year Rebif study, patients receiving either 22 mcg or 44 mcg Rebif or placebo three times weekly were assessed for time to onset of progression of disability, defined as a 1 point or greater increase in the Kurtzke Expanded Disability Status Scale (EDSS) score sustained for at least three months. The two-year Avonex trial defined progression of disability as a 1-point or more increase in EDSS sustained for at least six months.

In the Rebif trial, the rate of sustained disability progression was 26% for 44 mcg Rebif and 29% for 22 mcg vs. 37% for placebo, for relative reductions of 29.7% and 21.6%, respectively. In the Avonex trial, 21.9% of patients had disability progression vs. 34.9% of placebo patients, for a 37.2% relative reduction over placebo.

Biogen also argues that Avonex has a superior safety profile compared to Rebif, emphasizing lower rates of injection site reactions and occurrence of neutralizing antibodies.

The Rebif approval "turns the clock back on MS therapeutics. It takes us back to interferons with multiple injections and higher incidences of adverse events, higher risk of skin necrosis," Biogen's Mullen said at the SG Cowen conference. Avonex was approved in 1996 over Betaseron exclusivity by demonstrating superiority in the incidence of injection site necrosis.

Because Rebif "is administered subcutaneously, whereas Avonex is administered intramuscularly...skin reactions are much more readily observable than reactions within muscle," FDA stated. The rate of injection site reactions in the two-year Rebif clinical trial ranged from 92% (44 mcg) to 89% (22 mcg); the injection site reaction rate for Avonex in clinical trials was 4%.

FDA reviewers noted that while "injection site necrosis associated with use of Rebif was not observed with Avonex...Rebif-induced skin necrosis is less frequent than observed with Betaseron, and does not seem to pose a serious limitation to the use of the product." In clinical trials, 5% of Betaseron-treated patients had injection site necrosis; for Rebif, the adverse event was reported for 1% (22 mcg) and 3% (44 mcg) of patients in the placebo-controlled study.

Mullen also emphasized that "Avonex has a fraction of the neutralizing antibodies" that Rebif has: 35% for Rebif patients vs. 5% for Avonex in the EVIDENCE study.

However, Rebif labeling notes that "the observed incidence of neutralizing antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Rebif with the incidence of antibodies to other products may be misleading."

Rask et al. explained in their memo that "the rates of antibody formation" with Rebif and Avonex "are not directly comparable, because the assays performed by Serono measure antibodies by their ability to bind to Rebif. It is possible that some patients who received Avonex developed antibodies to Avonex but not Rebif. Thus there was the potential to differentially underestimate the rate of antibody formation in the Avonex group."

The reviewers also pointed out that antibody formation does not appear to affect efficacy. "In the Rebif group, there was no association between antibody status and the probability of remaining exacerbation-free, for either the week 0-24 or the week 24-28 period. Comparisons between the two treatment groups with respect to antibody status and clinical outcome demonstrated that all subsets of Rebif-treated patients, categorized by antibody titer, experienced lower exacerbation rates than Avonex-treated patients."

FDA has directed Serono, as part of its Phase IV commitments, to assess the "immunosuppressive effects of chronic Rebif treatment" in 100 patients and to submit validation studies on sensitivity of the ELISA assay and the neutralizing antibody assay used in the clinical trials.

Biogen also called attention to hepatic abnormalities observed with Rebif in the EVIDENCE trial. FDA reviewers noted that "unanticipated differences were observed in the incidences of hepatic enzyme elevations and hematologic abnormalities; however, none of these AEs were of sufficient magnitude to alter FDA's previous determination that Rebif is licensable under the PHS Act."

Rebif labeling includes a section on hepatic injury, which states that the agent "should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum SGPT (>2.5 times ULN), or a history of significant liver disease."

Labeling also states that "symptomatic hepatic dysfunction" has been reported as a rare complication of Rebif use and treatment should be discontinued "if jaundice or other clinical symptoms of liver dysfunction appear." Neither Avonex nor Betaseron labeling includes similar information.

In addition to the Phase IV immunosuppressive study, Serono's post-approval commitments include a dose comparison study of 22 mcg and 44 mcg Rebif in 750 patients with relapsing-remitting MS, to be completed in 2006, and a pregnancy registry study to prospectively collect data on 266 pregnant women exposed to Rebif, slated for completion in 2008.