FDA OKs 6MWT as Primary Goal of Potential Reldesemtiv Program for SMA Patients

The U.S. Food and Drug Administration approved the six-minute walk test (6MWT) as an acceptable primary endpoint, or goal, for a potential registration program of the investigational treatment reldesemtiv for spinal muscular atrophy (SMA) patients who are able to walk.

In the feedback provided to therapy developer Cytokinetics, the agency further recommended using a global function scale as a secondary endpoint, such as the Hammersmith Functional Motor Scale – Expanded (HFMSE), a measure of neurological function mainly relevant to infants and toddlers, according to a press release.

The 6MWT is a simple test of exercise capacity that measures the distance a patient can quickly walk on a flat, hard surface over six minutes. It evaluates the global responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, neuromuscular units, and muscle metabolism.

Reldesemtiv is a selective fast skeletal muscle troponin activator designed to slow the rate of calcium release from fast skeletal muscle fibers and improve contraction in muscle groups. The troponin group of proteins are part of the set of regulatory proteins that sensitize the sarcomere — the fundamental unit of striated muscle — to calcium.

Reldesemtiv’s effectiveness on muscle activation was studied in a Phase 2 clinical trial (NCT02644668), in which 70 patients with SMA types 2, 3 or 4 received a high (450 mg) or low dose (150 mg) of the therapy or a placebo twice daily for eight weeks. The trial also was aimed at assessing the therapy’s safety, tolerability, and pharmacokinetics, which refers to a compound’s absorption, distribution, metabolism and excretion in the body.

Results showed that both doses led to an improvement in 6MWD results, which was markedly greater with the higher dose, compared with placebo. Maximal expiratory pressure, a measure of strength of respiratory muscles, also improved with reldesemtiv.

Other measures, including the HFMSE, did not show differences between reldesemtiv and placebo. Treatment with reldesemtiv was well-tolerated and did not lead to serious adverse events or dose-limiting effects.

The FDA granted orphan drug designation to reldesemtiv for the potential treatment of SMA. The investigational therapy is not intended to treat the underlying cause of SMA, which is a lack of the SMN protein in specialized cells called motor neurons, but to be used in a complementary manner with the only approved disease-modifying therapy Spinraza (nusinersen, by Biogen) and with others that may become available, according to Fady Malik, MD, Cytokinetics’ executive vice president of research and development, in a June 2018 interview with SMA News Today.

Reldesemtiv was tested in five Phase 1 studies in healthy volunteers, evaluating parameters such as its safety, tolerability, and pharmacological profile.

Cytokinetics is preparing an additional Phase 1 trial of reldesemtiv in healthy volunteers to explore if higher doses than those used in the Phase 2 study may lead to higher plasma concentrations of the therapy. This study is expected to start in the first quarter.

Besides SMA, reldesemtiv (formerly known as CK-2127107) is being developed in collaboration with Astellas for the treatment of other disorders also associated with skeletal muscle weakness and/or fatigue.

In amyotrophic lateral sclerosis (ALS), a Phase 2 trial (NCT03160898) called FORTITUDE-ALS will evaluate the change in measures of skeletal muscle function at 12 weeks of treatment with reldesemtiv. In November 2018, Cytokinetics announced the completion of patient enrollment. Trial results are expected in the first half of 2019.