Therapy Targeting Neuromuscular Junction Leads to SMA Improvement

New data suggest motor function improves with amifampridine.

New phase 2 data for the spinal muscular atrophy (SMA) therapy amifampridine (Ruzurgi) suggests the drug is safe and effective at improving motor function in patients with type 3 SMA.

The report, published in Journal of Neurology, shows the therapy led to statistically significant improvement in patients’ scores on the Hammersmith Functional Motor Score Expanded (HFMSE) assessment.

SMA is an autosomal recessive disease in which patients have a deficiency of the SMN protein, the authors explained. As a result, patients experience a progressive degeneration of their spinal cord and bulbar motor neurons, leading to weakness and muscle atrophy, and in some cases, respiratory and nutritional impairment. Quality of life in this study was evaluated via the Individualized Neuromuscular Quality of Life (INQoL) questionnaire for adult patients and the Pediatric Quality of Life Inventory.

There are 5 types of SMA, based largely on age of onset and severity of symptoms. Type 3 SMA is the second most common type, and it typically manifests between age 18 and adulthood. People with this type of the disease can typically achieve independent mobility, according to the Muscular Dystrophy Association, although they are subject to falls and often have increasing difficulty with mobility over time.

Therapies are now available that can enhance SMN protein levels in patients, leading to significant improvement. However, the investigators said there is still a need for complementary therapies, since currently available drugs do not fully cure the disease.

One possible avenue of complementary therapy is neuromuscular junction dysfunction (NMJ), which is believed to be a feature of SMA that can lead to muscle dysfunction and fatigue.

Amifampridine is a voltage-dependent K+ channel blocker that promotes neuromuscular transmission and muscle function. It is approved by the FDA to treat the autoimmune disease Lambert-Eaton myasthenic syndrome.

In the new study, the investigators wanted to see whether the therapy would improve neuromuscular transmission in people with SMA, and if so, whether that would improve fatigue and motor function in those patients.

The trial was designed as a randomized, double-blind, placebo-controlled crossover study in which 13 people with type 3 SMA who could walk unaided for at least 30 minutes and who had not been treated with an SMA-enhancing therapy received amifampridine at titrated dosing until an optimized stable dose was achieved. Those who responded with at least a 3-point improvement in their HFMSE scores were randomized to receive either amifampridine or placebo during a 28-day crossover phase. The primary outcome was HFMSE change from randomization, and the secondary outcomes were timed tests and quality-of-life assessment.

The enrollees had a mean age of 34.5 years, and most 61.5% were males. Twelve of the patients were eventually randomized, half in the amifampridine group and half in the placebo group. Those receiving the therapy had a mean improvement of 0.792 in their HFMSE scores vs the placebo group (95% CI, 0.22-1.37; P = .0083). Two patients in the amifampridine group reported transient paresthesia, but there were no serious adverse events reported. There were no statistically significant differences in the 2 secondary outcomes.

“Although not statistically significant, amifampridine showed a tendency toward the improvement in the other disease symptoms and areas of life sections of the INQoL questionnaire, except for emotions,” they wrote.

The authors concluded that increasing evidence suggests NMJ might be an SMN-independent therapeutic target. They said additional research in this vein could lead to important improvements for people with SMA.

“In this landscape, larger, well-powered studies are needed to better define the role of amifampridine in the treatment of SMA patients as adjunctive therapy to SMN-enhancing medications for the cure of SMA,” they wrote.


Bonanno S, Giossi R, Zanin R, et al. Amifampridine safety and efficacy in spinal muscular atrophy ambulatory patients: a randomized, placebo-controlled, crossover phase 2 trial. J Neurol. 2022;1-10. doi:10.1007/s00415-022-11231-7

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