With most investor eyes focused on the waited-for FDA approval of Biogen Idec Inc.'s BG-12 for early stage multiple sclerosis (MS), the market hardly flinched at news that dexpramipexole failed in a Phase III trial for amyotrophic lateral sclerosis (ALS).

Weston, Mass.-based Biogen's stock (NASDAQ:BIIB) closed Thursday at $148.86, down $2.14.

Top-line data from EMPOWER did not meet its primary endpoint, a joint rank analysis of function and survival, and no efficacy turned up in function or survival. Key secondary endpoints missed, too, with lack of benefit among subpopulations examined. As a result, Biogen is stopping development.

Not everyone expected much in Phase III from dexpramipexole, a small-molecule modulator of mitochondrial bioenergetics, although the compound, partnered with Knopp Biosciences LLC, of Pittsburgh, seemed worth advancing at its highest dose in Phase II experiments. Function and mortality outcomes, published in Nature Medicine, suggested potential Phase III success. (See BioWorld Today, April 1, 2011.)

Oppenheimer analyst David Ferreiro called the Phase II results "opaque" in a research report published Thursday. The report, "Dex Done; Joins ALS Graveyard," called the dexpramipexole program "fraught with risk" because, although the Phase II study disclosed "positive functional trends," the patient enrollment was small and the results "lacked statistical robustness." The mechanism and pathology of ALS, he noted, are "still not well elucidated."

ALS is simply hard to beat. Paris-based Sanofi SA's Rilutek (riluzole) holds sway over the market, but it hasn't been for lack of attempts at better drugs, including one by Sanofi itself, which gave up on the 5HT1A agonist xaliproden (SR57746) in 2007 because Phase III data did not look satisfactory. Johnson & Johnson's seizure therapy Topamax (topiramate) failed to show benefit in ALS, also known as Lou Gehrig's disease, in a 298-patient study.

Leerink Swann analyst Marko Kozul echoed the general sentiment. "We believe no Street model included any revenue from dexpramipexole," Kozul wrote in a research report.

BG-12 (dimethyl fumarate), the oral drug for MS, brings more hope. With an approval deadline date of March 12 in the U.S. and in the second half of 2013 in the European Union, anticipation is rising, especially given opinions such as Guggenheim analyst Bret Holley. He predicted in a research report that the launch of BG-12 will be "overwhelmingly successful."

That optimism came even without a first-to-market advantage. The spot was taken in September by Aubagio (teriflunomide), from Genzyme, of Cambridge, Mass., a Sanofi company. Genzyme also has in the works Lemtrada (alemtuzumab), an injectable for relapsing MS. The FDA surprised the firm with a refusal-to-file letter for its supplemental biologics license application (sBLA) over the summer. (See BioWorld Today, Aug. 28, 2012.)

Sanofi recently withdrew its leukemia drug Campath (alemtuzumab) in order to rebrand it as Lemtrada, and Genzyme simultaneously submitted sBLAs to the FDA and European regulators in June seeking approval of Lemtrada in its new indication. (See BioWorld Today, Aug. 23, 2012.)

The magic, anyway, seems to lie in the oral MS approach, though Wells Fargo analyst Brian Abrahams was skeptical and "neutral going into the BG-12 approval/launch, given expectations that may be difficult to dramatically exceed," and a share price that already reflects the MS franchise, he wrote in a research report.

Abrahams was doubtful ahead of time about Biogen's ALS drug, as well. "Our recent buy-side survey had shown some caution in the market around these results, with about half of our respondents expecting the study to not reach statistical significance but to at least show trends warranting further study," he wrote. Still, only 14 percent expected a Phase III readout bad enough to quash development altogether.