Sanofi's oral multiple sclerosis drug Aubagio (teriflunomide) has passed one hurdle with FDA' acceptance of an NDA filing, but the larger commercial challenge of competing against other new contenders and trusted old-time treatments still looms.

Sanofi announced that the agency had accepted the filing in relapsing MS on Oct. 20. The application is supported by the pivotal, two-year TEMSO trial, which compared two doses of the drug (7 mg and 14 mg) to placebo in 1,088 patients. Sanofi plans to file in Europe in the first quarter of 2012.

In the TEMSO study, both doses of the drug met the primary endpoint, reducing annual relapse rate by 31% compared to placebo - about on par with traditional beta interferon products in MS. The drug also met endpoints related to disability progression and burden of disease, as measured on MRI studies.

Building on the previously released results, Sanofi had 15 presentations on teriflunomide, including a number of TEMSO post hoc analyses, at the joint meeting of the European and Americas Committee For Treatment And Research In Multiple Sclerosis (ECTRIMS/ACTRIMS), held from Oct. 19-22 in Amsterdam.

The new presentations highlighted reductions in rates of hospitalizations per relapse (6% for the low dose and 43% for the high dose) and ER visits (31% and 42%), which has potential to save money for health systems. Sanofi also reported long-term results from a Phase II extension study showing that the drug was safe and efficacious over nine years of exposure.

But writing in an Oct. 21 note, Credit Suisse's Ravi Mehrohtra noted that data is lacking about how Aubagio stacks up to the standard and trusted injectable "ABCR" treatments: Avonex (Biogen Idec); Betaseron (Bayer); Copaxone (Teva); and Rebif (Merck).

"We remain a little concerned that teriflunomide has been filed in the U.S. with no active comparator data. However, FDA has accepted the filing," Mehrohtra wrote.

Furthermore, he noted, it's possible that the company could use results from the Phase III TENERE study, which compares Aubagio to Rebif, to support the application. That study of 324 patients is due to report by the end of this year.

"We want to understand the relative efficacy and safety of the product," said Anita Burrell, multiple sclerosis unit head at Sanofi.

Beyond regulatory hurdles, differentiating the drug in a highly active development space presents a challenge for the candidate.

Meeting A High Safety Bar

Traditionally, the MS market has been dominated by injectables. There is said to be demand for an oral alternative, but not at the expense of severe side effects (Also see "Side Effects Dampen Neurologists' Enthusiasm For Novel MS Drugs" - Pink Sheet, 25 February, 2009.).

Novartis' Gilenya (fingolimod), became the first FDA approved oral MS treatment and managed a successful launch ([A#0110808014]).

Teva's laquinimod - another oral MS contender - missed an ARR primary endpoint in a second Phase III study, raising doubts about approval prospects (Also see "Disappointing BRAVO Data Raise Doubts About Laquinimod's Chances With FDA" - Pink Sheet, 1 August, 2011.).

Merck KGaA ditched its oral cladribine after the drug got bogged down with regulators over safety concerns (Also see "Germany's Merck Scraps MS Drug Cladribine After Regulators' Rebuff" - Pink Sheet, 22 June, 2011.) but has recently restocked the pipeline by obtaining rights to Ono Pharmaceutical Co. Ltd.'s Phase II MS candidate ONO-4641 (Also see "Merck KGaA Signs Cancer-MS Barter Deal With Japan's Ono" - Pink Sheet, 5 October, 2011.).

All eyes are on another candidate - Biogen Idec's BG-12 (dimethyl fumarate), which demonstrated good efficacy in the Phase III DEFINE trial, with a 49%-50% reduction in annualized relapse rates. Results were detailed at the ECTRIMS/ACTRIMS meeting.

Commenting on sentiment at the meeting, Mehrohtra reported: "Overall enthusiasm for BG-12 is high."

Similarly, Bernstein Research's Geoffrey Porges reported that BG-12 became the most anticipated drug at the meeting, "captivating neurologists." However, the drug's position depends on the outcome of a second Phase III trial called CONFIRM, which tests against Copaxone.

Pregnancy A Key Issue In MS

Aubagio's competitive position is somewhat unclear based on the drug's profile and efficacy results.

Women of child-bearing age account for a big part of the MS patient population. As Mehrohtra pointed out, the drug is not easy to eliminate from the body, which could be a problem for patients who want to become pregnant.

Teriflunomide is an active metabolite of Arava (leflunomide), which is approved for rheumatoid arthritis. The parent compound is contraindicated for pregnant women and women with child-bearing potential who are not using contraception.

Mehrohtra noted: "Any drug with teratogenic baggage will likely have limited utility by the average neurologist."

And while Sanofi reported that the drug's profile overall is similar to placebo, its side effects include mild hair thinning, another downside for a young patient population.

As for efficacy, Bernstein Research's Porges questioned whether a 31% reduction in ARR will be enough to persuade doctors to switch from injectables.

"Physicians are still unwilling to switch patients from their current treatments unless there is a treatment failure or an overwhelming benefit for the new treatment," Porges wrote. "We thus caution investors that cheaper injectables may stay with us a lot longer than one may think, preventing patients from switching to presumably more expensive new drugs and oral agents."

-Emily Hayes (e.hayes@elsevier.com)

Sanofi's Oral Aubagio Jostles For Position In Multiple Sclerosis Market

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