BioWorld Insight Contributing Writer

The multiple sclerosis (MS) treatment landscape is on the precipice of a revolution, with Novartis AG's newly approved oral Gilenya (fingolimid) leading the charge. Potential pipeline candidates offer the ease of oral administration and hope to improve upon safety profiles, while the old guard is maturing and carries tolerability and safety baggage.

But even a potential game changer can fall flat, as navigating benefit-risk ratios successfully is a challenge.

The standards in MS therapy likely will give way as new, more convenient entrants join the competition. Currently, the ABCR drugs – Biogen Idec Inc.'s Avonex (interferon beta-1a), Bayer AG's Betaseron (interferon beta-1b), Teva Pharmaceutical Industries Ltd.'s Copaxone (glatiramer acetate) and EMD Serono Inc.'s Rebif (interferon beta-1a) – and Biogen's Tysabri (natalizumab) are injectable, while Basel, Switzerland-based Novartis' oral Gilenya, approved in September, is the first of the "game changers" in the space, according to a December note by Leerink Swann Research. (See Table below.)

An analysis by Leerink suggests the new drugs likely will hit Betaseron and Rebif the hardest in the next several years, followed by Avonex. Copaxone will keep its top spot among the ABCRs, and Tysabri will retain some of its small market share.

Estimates vary on the damage Gilenya and the potential new therapies will do, but the news isn't good – Deutsche Bank Equity Research analyst Robyn Karnauskas predicted that ABCRs would lose about 15 percent of patients to Gilenya next year, and about 40 percent by 2014. (See BioWorld Today, Sept. 23, 2010.)

Both old and new walk a fine line between risk and reward. Copaxone ranks highly in safety and tolerability, for instance, but its efficacy and delivery method aren't as robust, while Tysabri's tolerability and efficacy are excellent but serious safety concerns around its link to progressive multifocal leukoencephalopathy prevent significant market growth. Meanwhile, Darmstadt, Germany-based Merck KGaA's cladribine satisfied the FDA on its efficacy, particularly the relapse rate reduction, but both FDA and European regulators questioned whether cladribine's risk of serious adverse events outweighed the benefit. Cladribine would have been the second oral MS drug to hit the market, but the FDA issued a complete response letter last week. (See BioWorld Today, March 3, 2011.)

So Gilenya appears to be a winner across the board, but as a newcomer, the long-term safety effects are unknown.

The crop of Phase III drugs will have to navigate the same tricky waters. They also will have to determine how to differentiate from the other new kids on the MS block. For oral laquinimod, from Jerusalem-based Teva and partner Active Biotech AB, it may be efficacy – the drug hit its primary endpoint of reduction in annualized relapse rate compared to placebo and significantly reduced disability progression. Full data are expected in April, while results from the trial comparing laquinimod with Avonex are expected in late 2011. (See BioWorld Today, Dec. 10, 2010.)

Another oral immunomodulator, Cambridge, Mass.-based Biogen's BG-12, may be neuroprotective and more selective than Gilenya, and is derived from a known compound already safely in use for psoriasis. But trials in rheumatoid arthritis (RA) were halted early after failing to meet the profile objective. Data from the trials in MS, compared with placebo and with Copaxone, are due later in 2011. (See BioWorld Today, Sept. 23, 2010.)

Data also are expected on Sanofi-Aventis SA's oral immunosuppressant teriflunomide later this year. A potential issue to watch for is teratogenicity, Leerink analysts noted, as teriflunomide is a metabolite of leflunomide, which has been shown to be teratogenic in animal studies. And as many female MS patients are of child-bearing age, that safety signal could impact uptake. On the positive side, possible differentiating factors include its use in clinically isolated syndrome and as an adjunct to interferon. Those trials are expected to complete in three or four years.

The remaining drugs in the late-stage pipeline are injectables. Biogen has two antibodies, the subcutaneous daclizumab partnered with Abbott and the I.V. ocrelizumab in collaboration with Roche. Daclizumab, an anti-IL-2 antibody targeting T-cells, proved more efficacious than Avonex in Phase II trials. Data from a placebo trial are due in the second half of 2011, and the trial testing the drug against Avonex is expected to take another one to two years to complete. Ocrelizumab, an anti-CD20 antibody targeting B-cells, has a safety hurdle to overcome – Roche and Biogen discontinued development of the drug in RA trials after fatalities in Phase III testing. The partners will enroll patients for Phase III trials in MS in mid-2011. (See BioWorld Today, May 20, 2010, and May 25, 2010.)

A "wild card" in the MS pipeline, according to Leerink, is Genzyme Corp.'s Campath (alemtuzumab). The anti-CD52 antibody already is approved for treating B-cell chronic lymphocytic leukemia, and was a sticking point in the negotiations with Paris-based Sanofi, though the companies agreed to a contingent rights value arrangement and settled on an acquisition price last month. (See BioWorld Today, Oct. 15, 2010.)

Campath may be a perfect example of walking the line between benefit and risk. The drug showed impressive results vs. Rebif in two Phase III trials for MS, but was associated with "profound immunosuppression" and unusual autoimmune conditions.

Leerink analysts say projections for the future "are very cloudy" but believe Biogen, Novartis and Teva are best positioned to emerge at the end with a strong MS presence.