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Data from Phase 2 Study of dexpramipexole in ALS published in Nature Medicine

December 21, 2011

PITTSBURGH, Pa. (November 21, 2011) -- Knopp Biosciences LLC today announced the publication in Nature Medicine of comprehensive results from the Phase 2 study of dexpramipexole, a small-molecule modulator of mitochondrial bioenergetics, in people with amyotrophic lateral sclerosis (ALS). Dexpramipexole is currently in Phase 3 development under an exclusive worldwide license with Biogen Idec.

"Results from this Phase 2 study demonstrate why we're so enthusiastic about the rapid advance of dexpramipexole to a Phase 3 trial," said Merit Cudkowicz, M.D., primary author of the Nature Medicine manuscript and director of the MDA ALS Clinic at Massachusetts General Hospital and the Northeast ALS Consortium. Dr. Cudkowicz was the Principal Investigator for the Phase 2 study of dexpramipexole in ALS. "In this well-controlled Phase 2 study, we detected an apparent clinically significant, dose-dependent effect on both function and mortality - an exciting milestone. This is the first time we've seen data suggesting benefits on both function and mortality from a drug candidate in ALS."

The Phase 2 clinical trial, designed by Knopp and its principal investigators and conducted at 20 U.S. sites, involved a novel design for an ALS trial in which the same subjects were randomized twice, essentially creating two separate, double-blind studies over which treatment effects could be observed on safety, functional decline, and mortality. In Part 1 of the study, 102 subjects received daily divided doses of 50 mg, 150 mg, or 300 mg of dexpramipexole or placebo for 12 weeks. In Part 2, 92 continuing subjects received placebo during a 30-day, single-blind washout period, followed by re-randomization to divided daily doses of either 50 mg or 300 mg for 24 weeks.

The Nature Medicine article details treatment effects across both parts of the study, including mortality effects. During the 12 weeks of Part 1, there were no deaths. During the 30-day placebo washout period, there were three deaths, limited to patients who had received placebo or low-dose treatment (50 mg) during Part 1. During the 24-week double-blind active treatment period in Part 2, there were 12 deaths, with nine deaths involving patients receiving the low dose (50 mg) and three deaths involving patients receiving the high dose (300 mg). This represented a 68% reduction in the hazard of mortality for the 300 mg group over the 24 weeks of Part 2 (p=0.07).

The article also describes treatment effects on measures of disease progression in both parts of the study, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), a widely used and validated measure of function. In Part 1, while the overall effect on function across all dose groups was not significant (p=0.11), the mean slope of decline for patients receiving 300 mg was reduced by 39% compared to the placebo group (0.88 units per month versus 1.28 units per month, respectively). A dose-dependent trend was seen in the attenuation of median decline in ALSFRS-R scores from baseline to 12 weeks (4.0 points for the placebo group, 3.0 points for the 50 mg group, 2.5 points for the 150 mg group, and 2.0 points for the 300 mg group, representing a 50% attenuation of median decline in the 300 mg group compared to the placebo group).

The trend in function favoring the 300 mg group was sustained in Part 2 of the study, with a 20.5 percent attenuation in the rate of decline compared to the active control group receiving 50 mg (p=0.177).

A significant effect was seen in a Combined Assessment of Function and Survival (CAFS), a joint-rank test that analyzes functional outcomes while accounting for in-study mortality. In this pre-specified test in Part 2 of the Phase 2 study, the mean CAFS score for the 300 mg group was 27 percent higher (more favorable outcomes) than for the 50 mg group (p=0.046).

Dexpramipexole demonstrated favorable safety and tolerability profiles in this Phase 2 trial, supporting further investigation in a Phase 3 trial. Adverse events noted in the trial included falls, muscle weakness, post-lumbar puncture syndrome, and headache, with no trend in differences in frequency among dose groups. Infrequent, reversible neutropenia was observed in both parts of the study among subjects in the 300 mg group.

About dexpramipexole

Dexpramipexole (also known as KNS-760704) is a low molecular weight benzothiazole which in pre-clinical models has been shown to improve mitochondrial function and to confer significant protection to neurons under stress. Dexpramipexole is highly orally bioavailable, water soluble, renally excreted, and only moderately protein bound. The compound was originally identified as a candidate therapy for ALS by James Bennett, M.D., Ph.D., then of the University of Virginia. Dexpramipexole has received orphan drug designation from the U.S. Food and Drug Administration and the European Commission for the treatment of patients with ALS, as well as Fast Track designation from the FDA.

About ALS

Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease and motor neuron disease, is a universally and rapidly fatal neurodegenerative disorder characterized by progressive muscle weakness and wasting. ALS affects adults in the prime of life and creates a substantial burden for caregivers and the health care system. U.S. prevalence is approximately 20,000 and the global incidence is approximately two per 100,000. Beyond symptomatic care, only one drug has been approved for the treatment of ALS. Life expectancy after symptom onset is usually three to five years.

About Knopp Biosciences LLC

Knopp Biosciences LLC, based in Pittsburgh, PA, USA, is a drug discovery and development company focused on delivering breakthrough treatments for unmet needs in neurology through innovation, experience, and partnership. The company's lead product candidate is dexpramipexole, an orally bioavailable small molecule in Phase 3 development for the treatment of ALS. Biogen Idec holds an exclusive worldwide license from Knopp to develop and commercialize dexpramipexole, with Knopp providing development support and conducting certain U.S. commercialization activities. Knopp's discovery platform is directed to identifying next generation mitochondrial bioenergetic modulators for the treatment of Parkinson's disease and other neurodegenerative disorders.

This press release contains "forward-looking statements," including statements relating to planned regulatory filings and clinical development programs for dexpramipexole. All forward-looking statements are based on management's current assumptions and expectations and involve risks, uncertainties and other important factors, specifically including the uncertainties inherent in clinical trials and product development programs, the availability of funding to support continued research and studies, the availability or potential availability of alternative therapies or treatments, the availability of patent protection for the discoveries and strategic alliances, as well as additional factors that may cause Knopp's actual results to differ from our expectations. There can be no assurance that dexpramipexole will be successfully developed or manufactured or that final results of clinical studies will be supportive of regulatory approvals required to market the product. Knopp undertakes no obligation to update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise.

Media Contact:
Thomas Petzinger Jr.