26 Apr 2014

The experimental muscle-stimulating drug Tirasemtiv was unable to improve amyotrophic lateral sclerosis (ALS) symptoms in a Phase 2 clinical trial, according to top-line data. Announced April 25 by the drug’s developer, South San Francisco-based Cytokinetics, the disappointing results come in the wake of glimmers of improvement observed in earlier studies (see Shefner et al., 2013). 

ALS leads to the degeneration of motor neurons, which deliver signals from the brain to skeletal muscle fibers. Researchers had hoped the drug, which was fast-tracked as an orphan disease drug by both the U.S. Food and Drug Administration and its E.U. counterpart, the European Medicines Agency, would help make the most of what few motor neurons ALS patients had left. Tirasemtiv is thought to work by increasing skeletal muscles’ sensitivity to input from motor neurons (see Russell et al., 2012). The small molecule increases the binding affinity of the skeletal-muscle protein troponin for calcium. In its calcium-bound form, troponin latches onto myosin, which triggers muscle contraction.  

The Phase 2 trial was called BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS). It was large by the standards of ALS trials, having enrolled 711 ALS patients at 73 centers in eight countries. Patients who tolerated a 125mg dose for one week were randomized to receive either placebo or twice-daily oral doses of Tirasemtiv escalating from 125mg to 250mg over 12 weeks. At that point, as well as one month following the final dose, people taking the drug faired no better than those taking the placebo on the ALS functional rating scale. The ALSFR-R assesses how well people perform basic functions and activities such as speaking, swallowing, writing, and using utensils. Secondary measures of respiratory function and skeletal-muscle function produced mixed results, according to the top-line report. Researchers from Cytokinetics plan to present detailed results from the study at the American Academy of Neurology Meeting on April 29 in Philadelphia. 

The company hasn’t closed the door on Tirasemtiv just yet, but plans to reevaluate the drug’s path forward after a closer analysis of the trial data, Cytokinetics CEO Robert Blum said in a press release. News of the drug’s recent failure caused the company’s stock prices to plummet by more than 60 percent.—Jessica Shugart