Phase 2 Trial Evaluating Mestinon, Already Approved for Myasthenia Gravis, for SMA Types 2-4

A Phase 2 clinical trial is testing the effectiveness of Mestinon (pyridostigmine) — an approved medicine for another neuromuscular disease — in treating fatigue in people with spinal muscular atrophy (SMA) types 2, 3 and 4.

The trial’s design was described in the study, “Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial),” in the journal BMJ Open.

The recently completed trial is investigating whether Mestinon tablets can ease symptoms of muscle weakness and fatigue. Researchers are currently analyzing the data and hope to present results later this year, Ludo Van der Pol, MD, PhD, one of the study’s authors and the trial’s principal investigator from UMC Utrecht in the Netherlands, told SMA News Today.

Mestinon is approved in the U.S. and EU as a first-line treatment for myasthenia gravis. It is now marketed  by Bausch Health, previously by Valeant, with generics also available in the U.S.

Similar to SMA, myasthenia gravis is caused by poor communication between nerve cells and muscles at the neuromuscular junction. 

Researchers believe that the medicine’s ability to activate and strengthen muscles might benefit SMA patients.

Its active ingredient, pyridostigmine, prevents the enzyme acetylcholinesterase from breaking down acetylcholine — a chemical messenger (neurotransmitter) released by motor neurons that activates muscles. Mestinon raises acetylcholine levels and prolongs its effects, enhancing the transmission of nerve impulses to muscles.

The randomized, placebo-controlled, double-blind trial, called SPACE (NCT02941328), is investigating the effects of Mestinon on muscle strength and fatigability in 39 SMA patients ages 12 or older.  

In the crossover trial, participants were given both Mestinon and a placebo at different times over the course of the study.

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At the beginning of the trial, they were randomly assigned to one of two groups receiving either oral Mestinon or a placebo for eight weeks, followed by a washout period of one week, when both treatments were stopped.

Then each group switched treatments. Those who had been on Mestinon received placebo and vice versa, for another eight weeks.

The crossover trial design is advantageous for a rare disease like SMA, which has a wide range of disease manifestations, because participants will become their own controls. The crossover is a way of minimizing the variance between groups while requiring fewer participants.

Each treatment was given four times a day, and the dosage was gradually increased during the first week to the maximum dose of 6 mg per kilogram of body weight per day. If side effects were reported on this dose, patients were switched to lower doses.

To determine Mestinon’s effectiveness, a battery of measurements were performed during five visits to the UMC center: at screening, study start, at the end of the first eight-week treatment, at the start of the second eight-week treatment period and at the end of the study.

Two primary objectives were aimed at addressing motor function and fatigue: the Motor Function Measure (MFM), a quantitative scale to measure the motor disabilities, and the repeated nine-hole peg test that evaluates endurance in upper limbs.

Secondary outcome measures included additional tests of muscle strength and resistance, and patient self-reports about their quality of life, their perceived daily functioning, and tendency to get tired. The conduction of nerve impulses to muscles was also recorded.

To assess the treatment’s safety profile, adverse events were reported by the patients or by the clinicians participating in the study.

“We believe that we can properly investigate the effect and efficacy of pyridostigmine in this … cross-over trial and we expect the results to confirm that pyridostigmine could be used as an (add-on) therapy to improve the function of [muscular] defects in patients with SMA resulting in improved strength and/or endurance and/or fatigability,” the researchers wrote.