4-aminopyridine Fails to Improve Muscle Function in SMA Type 3 Patients, Small Trial Finds

Treatment with the molecule 4-aminopyridine (4-AP) failed to improve the motor function, endurance, and muscle strength of spinal muscular atrophy (SMA) type 3 patients who are able to walk, according to results from a small Phase 2/3 clinical trial. 

Findings from the trial were published in the study “Lack of effect on ambulation of dalfampridine-ER (4-AP) treatment in adult SMA patients,” in the journal Neuromuscular Disorders. 

The molecule 4-AP (dalfampridine) has been shown to improve motor function in animal models of SMA. As such, it has been considered as a potential add-on treatment to current disease-modifying therapies to further enhance the recovery of motor function.

It works by blocking channels in nerve cells, which increases the release of neurotransmitter signaling molecules, stimulating motor function. 

4-aminopyridine has been approved under the brand name Ampyra (Fampyra outside the U.S.) to help improve walking in people with multiple sclerosis. The approval was based on trials that showed that 4-AP treatment led to improved strength, endurance, and vision, and less fatigue in MS patients. 

To further explore the therapy’s potential effects in SMA, researchers at Columbia University designed a Phase 2/3 trial (NCT01645787) to test the tolerability and efficacy of 4-AP on walking ability and endurance in adults with SMA type 3. 

The study enrolled 11 adults (six men and five women) with a mean age of 37.7 years and a mean disease duration of 9.6 years. All patients were able to walk at least 25 meters without assistance. 

The study was conducted in two parts. A short-term portion comprised a two-week treatment period, followed by a one-week washout period with no treatment, to ensure the medicine was eliminated from the body. That was followed by another two-week treatment period. 

A long-term study followed a two-week washout period after the short-term study and comprised a six-week treatment period, a two-week washout, and then another six weeks of treatment. 

Patients were randomly assigned to receive a 10 mg extended release dosage of 4-AP or a placebo twice daily for the first two weeks. After the first washout period, patients who received 4-AP were switched to the placebo, and those taking the placebo received 4-AP. Clinical assessments were conducted before the study (baseline) and after two and five weeks (following both treatment periods). 

The same treatment regimen was applied in the long-term study. Clinical assessments were carried out at six and 14 weeks. In this crossover study design, the patients acted as their own controls. 

The primary outcomes were distance walked as assessed by the six-minute walk test (6MWT) and fatigue, which was measured by the percent difference walked between six minutes and one minute, in which higher scores equal greater fatigue. 

Secondary measures included motor function determined by Hammersmith functional motor scale expanded (HFMSE) scores; this scale was developed specifically for assessing SMA outcomes.

The researchers also assessed muscle strength, as measured by manual muscle testing on 28 muscle groups. 

In the short-term study, treatment with 4-AP had no significant effect on 6MWT, and greater fatigue (+18.5 points) was experienced by patients who received 4-AP in the first period only. During the second treatment period, there was significantly less fatigue among 4-AP treated patients (-19.2 points). The net effect on fatigue from both treatment periods was close to zero. 

There also were no differences in the HFMSE scores.  In regard to muscle strength, manual muscle testing showed that 4-AP led to a negative effect on the weaker side of the body. No significant effects were shown in additional walking tests. 

Electrophysiology, a test of electrical activity on muscles, found no significant effects of 4-AP treatment except for a positive impact on H-reflex, a reaction of muscles after electrical stimulation, on the body’s more affected side. 

An analysis of the long-term study found no significant effect of 4-AP in 6MWT, either on distance or fatigue, but a small positive impact on the HFMSE score (+0.6). There were no significant carryover effects between the two treatment periods for any functional motor outcomes. In addition, no significant effects were found on muscle strength tests or walking measures. 

4-AP was safe and well-tolerated, with no patients reporting a serious adverse event related to treatment.

“We observed no statistically significant positive effects of [4-AP] treatment on our primary functional motor outcome,” the researchers wrote. “Larger studies with [4-AP] in SMA patients are needed to confirm our findings, especially in light of studies in other populations showing drug effects in only a subset of patients.”