Promising Antegren data ruffles Serono
(Published 19 November 2004)

Newly-released phase III trial data for Biogen-Idec/Elan's multiple sclerosis pipeline drug Antegren was a key issue at Serono's recent investor's meeting, giving the company an opportunity to raise concerns over the paucity of the presented data. Indeed, without supplying further details over the safety and efficacy of the drug, Biogen may struggle to gain approval in the near future.

Biogen-Idec/Elan's Antegren (natalizumab) is a novel, first-in-class drug for the treatment of multiple sclerosis (MS). Biogen's biologics license application (BLA) in May 2004 was designated for priority review, and Biogen currently anticipates a positive response from the FDA by the end of November 2004. The BLA was based on one-year data from two ongoing two-year phase III trials, examining the safety and efficacy of Antegren as a monotherapy and as a combination with Biogen-Idec's Avonex.

Details of this phase III data released on the same day as Serono's investor meeting this week indicates that one-year Antegren monotherapy reduced the clinical relapse rate by 66% versus placebo. This compares favorably to the 54% relapse rate recently reported for Rebif; however, this was over a two-year treatment period.

Serono highlights data weakness

At its investors meeting, Serono raised a number of issues associated with the phase III Antegren data. Primarily, the company expressed disappointment at the paucity of information released. The two-year Antegren monotherapy trial was designed to evaluate the effect of Antegren on progression of disability and rate of relapse in MS, but there was no information released on the progression of disability.

Serono also highlighted that there was no information on placebo patients, none on what happens following the discontinuation of the product, and no combination data with Avonex. Biogen justified this by reiterating that the FDA application was based on the relapse rate observed in the placebo-controlled trial, and therefore this was the focus of their phase III trial data release.

Additionally, Serono raised concerns over the interpretation of the relapse rate data. As the average relapse rate is between 0.7-1.2 relapses per year, Antegren's one year evaluation period may not have been long enough. Antegren's side-effect profile also came in for criticism, following reports that hypersensitivity reactions were observed during one-year treatment with the drug. Such reactions may require monitoring, and may therefore reduce uptake, although Biogen did not comment on this.

Serono indicated that Rebif has long-term safety data stretching back eight years, which is important, given that long-term use of immunosuppressants is linked with increasingly severe side effects. There is therefore a case for Biogen to produce further data evaluating the safety profile and tolerance of Antegren, though equally we should not be surprised at Serono's attempt to highlight these issues, given the threat Antegren potentially poses to Rebif's revenues.

There is a high unmet need in the MS market for non-interferon beta products: a sizeable number of patients cannot tolerate interferon beta therapy, switch therapies due to symptom breakthrough following the generation of neutralizing antibodies, or receive no medication at all. Antegren is the first novel MS drug in over ten years and, following approval and launch, it is forecast rapid uptake in the interferon beta-intolerant and naive patient population.

Antegren to take on Rebif

MS drugs compete on efficacy, side-effect profile and safety, cost and delivery. As a result of the phase III trial data, Biogen is set to position Antegren on improved efficacy and a less frequent treatment regime, since no data was released on safety and side-effect profile, and Antegren is expected to be approximately twice as expensive as Rebif.

If Biogen is successful in this positioning, the erosion of interferon beta market sales is likely to affect Avonex most significantly, following data indicating that high-dose Rebif demonstrated superior relapse efficacy over Avonex in the "Evidence" study. Whether Antegren, once approved, is able to take market share from Rebif will to a large extent depend on physician perception, which may in turn depend on full two-year data, but it must nevertheless be a worry for Serono.

Rebif generated $819 million in 2003 for its manufacturer, which equated to 41% of Serono's total ethical sales. Serono has stated that it is not concerned by Antegren and is not planning to run a head-to-head trial with the Biogen product. The company believes that Rebif will hold a leading position in the MS market by 2006 and that its principal competition will come from oral MS drugs, which are set to significantly increase patient compliance.

The extent of Antegren's penetration of the interferon beta market will depend on strong efficacy data. Although Antegren's phase III trial data shows promise, there are still several gaps and it is possible that Antegren's approval will be delayed over the short term until a greater data pool on efficacy and safety is generated.

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