Pfizer and Medivation’s Alzheimer Drug Fails in First Phase III Trial

Pfizer and Medivation reported that their Alzheimer disease (AD) therapy dimebon did not meet its co-primary or secondary efficacy endpoints compared to placebo in a Phase III trial called Connection. Medivation has lost almost 68% of its value, opening trading at $12.87.

Dimebon was well tolerated in the Connection study, which involved patients with mild-to-moderate disease. A separate late-study trial in the same indication determined that the drug was tolerable when dosed alone or in combination with approved AD medicines.

Pfizer ponied up $225 million up front for global rights to dimebon in September 2008. Furthermore, it agreed to pay 60% of development expenses, up to $500 million in milestones related to clinical and regulatory success, and additional success-based fees tied to sales achievements.

The drug is being tested in four other randomized, double-blind, placebo-controlled Phase III studies, which currently are enrolling. The Concert trial is a 12-month study testing dimebon in patients with mild-to-moderate AD who are taking Pfizer’s Aricept. The Contact and Constellation trials are six-month trials testing dimebon in patients with moderate-to-severe disease taking currently approved AD medications. In Contact, subjects must also be taking Aricept, while in Constellation they must also be taking memantine. Finally, the Horizon trial, is a six-month study evaluating dimebon in patients with Huntington disease.

The Connection trial was a multinational, double-blind, placebo-controlled safety and efficacy trial involving 598 patients with mild-to-moderate AD at 63 sites in North America, Europe, and South America. Co-primary endpoints were measures of cognition and global function. Patients had a mean age of 74.4 years. Patients were randomized to one of three treatment groups receiving dimebon 20 mg three times a day (TID), dimebon 5 mg TID, or placebo TID for six months. The 5 mg arm was included in the study to help define the effective dose range for dimebon treatment.

No statistically significant improvements for the 20 mg TID group relative to placebo were achieved on the co-primary endpoints. One primary endpoint evaluated the effect of dimebon on cognition. It showed that dimebon-treated patients achieved a 0.1 point difference from patients receiving placebo. Neither group was significantly changed from baseline.

Another primary endpoint evaluated the effect of dimebon on independently rated global function. Of the patients treated with dimebon 20 mg TID, 64.9% showed improvement or no change at week 26 compared to 65.4% of placebo-treated patients.

The 20 mg TID dimebon-treated patients also showed no statistically significant differences compared to placebo on the secondary efficacy endpoints such as improvements in activities of daily living. The most frequently reported adverse events in patients in the 20 mg dimebon group that also occurred more commonly than in the placebo group included somnolence, dry mouth, headache, dizziness, constipation, cough, and depression.