Amifampridine in LEMS and Beyond: Unraveling Its Therapeutic Potential

Kevin Chang, PharmD

Amifampridine (Firdapse), or 3,4-diaminopyridine, increases acetylcholine (ACh) concentrations at the neuromuscular junction (NMJ) by blocking presynaptic potassium channels and prolonging the opening of calcium channels to improve neuromuscular transmission and ameliorate muscle weakness.¹ The presynaptic mechanism of action of amifampridine makes it a promising candidate for addressing NMJ dysfunction not only in Lambert-Eaton myasthenic syndrome (LEMS) but also in other disorders.

LEMS Pathophysiology and Diagnosis

LEMS is a rare neuromuscular disorder characterized by autoimmune-mediated dysfunction at the NMJ. Approximately 85% to 90% of patients with LEMS have antibodies directed against P/Q-type voltage-gated calcium channels (VGCC).^1,2 In LEMS, autoantibodies target presynaptic VGCCs, impairing calcium influx into nerve terminals and diminishing the release of ACh.^1,2 Consequently, the reduced availability of ACh hampers neuromuscular transmission and leads to muscle weakness.¹ A classic triad of symptoms—proximal muscle weakness, autonomic disturbances, and areflexia—characterizes the clinical presentation of LEMS.3 Approximately 10% to 15% of patients, however, are seronegative (ie, have no detectable P/Q-type VGCC antibodies)yet exhibit the same clinical features of the disease,^1,4 which may be due to antibody concentrations below the level of detection or different antibodies that generate a similar phenotype.4

LEMS is also a common paraneoplastic syndrome of small cell lung cancer (SCLC) and is usually diagnosed 2 to 3 years before a cancer diagnosis.3 Recent studies have found that approximately 50% of patients with LEMS had associated SCLC but only 3% of patients with SCLC develop LEMS.³ It’s crucial that medical professionals conduct thorough evaluations to rule out any underlying malignancy, especially in older patients presenting with LEMS symptoms.

Diagnosis of LEMS involves a combination of clinical assessment, electromyography to evaluate nerve and muscle function, and blood tests to detect antibodies against VGCCs. Neurophysiological assessments and immunological assays should be performed, and needle electromyography examinations are helpful for patients suspected of having disorders of synaptic transmission. Repetitive nerve stimulation is also an essential test for the diagnosis of LEMS; in patients with LEMS, their compound muscle action potential (CMAP) amplitude is already low, and it goes even lower at stimulating frequencies of 2 to 5 Hz.¹ A reduction in CMAP amplitude of 10% is considered abnormal but is not specific to LEMS because it is also seen in myasthenia gravis (MG).^1,5

A key method for differentiating between LEMS and MG is high-frequency stimulation (50 Hz) or postexercise stimulation, which can increase CMAP amplitude by more than 100%.⁵ Oh et al, however, found that lowering the cutoff value for abnormal increases in CMAP amplitude from 100% to 60% demonstrated an increased sensitivity (85% to 97%, respectively) for the diagnosis of LEMS and a specificity of 99% for excluding MG.⁵

Amifampridine as First-Line Treatment for LEMS

Aminopyridines, which are potassium channel blockers, have garnered attention for their ability to modulate neuronal excitability and enhance neurotransmission.⁶ Specifically, these agents prolong the duration of the action potential in nerve terminals by blocking potassium channels, particularly Kv1.5 channels.⁶ This blockage leads to prolonged depolarization of the cell membrane, enabling the opening of calcium channels and enhanced release of ACh, which improves neuromuscular transmission and ameliorates muscle weakness.¹

Because LEMS is a presynaptic neuromuscular disease, active sites where ACh can be released at the presynaptic terminals are still intact.⁷ By prolonging depolarization, the increase in ACh is nonlinearly dependent on calcium influx, so small increases in calcium can generate much larger neurotransmitter release at the presynaptic terminal.⁸ As a result, aminopyridines exert their therapeutic effects by augmenting calcium influx through VGCCs and amplifying ACh release at the NMJ.¹

Amifampridine, also known as 3,4-diaminopyridine, has established itself as a mainstay in LEMS management and has been approved as first-line symptomatic LEMS treatment in the European Union since 2009^9,10 and in the US since 2018.¹¹ The approvals were based on 2 clinical trials studying the efficacy and safety of amifampridine vs placebo.

The first phase 3 trial, LMS-002 (NCT01377922), was a double-blind, placebo-controlled, randomized discontinuation study with an open-label run-in phase for 7 to 91 days, with patients subsequently randomly assigned to continue amifampridine or taper to placebo for 14 days.¹⁰ The Quantitative Myasthenia Gravis (QMG) score was used to evaluate muscle weakness, with higher scores indicating more impairment, and the Subject Global Impression (SGI) scale measured patients’ overall impression of the effects of the study treatment on their physical well-being, with higher scores indicating more perceived benefit.^10,11 The trial met its coprimary end points for change from baseline to day 14 in QMG score (6.4 to 6.7, respectively, for amifampridine vs 5.6 to 7.9 for placebo; P = .0452) and SGI score (5.6 to 4.9 for amifampridine vs 5.9 to 3.2 for placebo; P = .0028).¹⁰ Both scores tended to worsen in both treatment groups, but significantly greater worsening occurred in the placebo group.¹⁰

The confirmatory phase 3 trial, LMS-003 (NCT02970162), evaluated the efficacy of amifampridine vs placebo over a 4-day period. All participants had been receiving amifampridine at the optimal dose and frequency for at least 1 week before being randomly assigned to amifampridine or placebo for 4 days. The coprimary end points were met in favor of amifampridine compared with placebo for change from baseline to day 4 for QMG score (7.8 to 7.9, respectively, for amifampridine vs 8.5 to 15.0 for placebo; P = .0004) and SGI score (6.1 to 5.8 for amifampridine vs 5.3 to 2.4 for placebo; P = .0003). These findings confirmed the efficacy of amifampridine as symptomatic treatment for patients with LEMS.¹²

Amifampridine Beyond LEMS

Amifampridine shows promise in addressing NMJ dysfunction beyond its indication in LEMS. Clinical investigations are currently exploring its potential efficacy in other NMJ disorders, such as muscle-specific kinase (MuSK) MG and spinal muscular atrophy (SMA).

Amifampridine in MuSK

The randomized, placebo-controlled, crossover phase 2b MuSK-001 trial (EudraCT2015-003127-62) of amifampridine in patients with MuSK MG evaluated patient-reported outcomes using the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale, with higher scores indicating more severe symptoms, and physician-reported outcomes using QMG scores. Study recruitment was halted early due to a clear clinical benefit of amifampridine compared with placebo (QMG score: 0.1 vs 6.9, respectively; P = .0003; and MG-ADL score: –0.1 vs 5.6, P = .0006). The investigators noted that a larger multicenter trial is warranted to confirm these results.¹³

Amifampridine in SMA

In the randomized, placebo-controlled, crossover phase 2 SMA-001 trial (NCT03781479), patients with SMA who met eligibility criteria entered a run-in phase, during which amifampridine was titrated up to an optimal, stable dose. Only patients who increased at least 3 points on the expanded Hammersmith Functional Motor Scale (HFMSE) were randomly assigned to amifampridine or placebo in the 28-day double-blind crossover phase.

The trial’s primary efficacy end point of HFMSE change from randomization was met because patients receiving amifampridine had a statistically significant increase in HFMSE score vs those receiving placebo (least squares mean difference, 0.792; 95% CI, 0.22-1.37; P = .0083), although the investigators noted that the difference was not considered a “clinically significant change as defined in the literature.” However, a clinically relevant change in HFMSE was demonstrated during the run-in period by patients who experienced a 3-point or greater improvement. Study investigators concluded that “larger, well-powered studies are needed to better define the role of amifampridine in the treatment of [patients with SMA] as adjunctive therapy to [SMN protein–enhancing] medications....”¹⁴

Amifampridine in botulism

Preclinical investigations into amifampridine’s utility extend to botulism, a severe paralytic illness caused by botulinum neurotoxins (BoNTs) inhibiting ACh release at the NMJ. Animal studies have explored amifampridine’s ability to mitigate BoNT-induced paralysis, potentially by counteracting toxin-mediated neurotransmission blockade specifically before and after peak paralysis.¹⁵ By enhancing ACh release despite BoNT interference, amifampridine could alleviate respiratory depression and support neuromuscular recovery in botulism.^15,16

Together these findings underscore the broader therapeutic potential of amifampridine in NMJ disorders, warranting further translational research and clinical investigations.

Conclusion

The presynaptic mechanism of action of amifampridine makes it a promising candidate for addressing NMJ dysfunction in various disorders beyond LEMS. Clinical exploration in SMA and MuSK MG holds potential for expanding therapeutic options, and preclinical studies in botulism highlight amifampridine’s broader applicability in neuromuscular pathology. Continued research efforts are imperative to elucidate the efficacy, safety, and mechanistic underpinnings of amifampridine across diverse NMJ conditions to advance treatment strategies and ultimately improve patient outcomes.

For correspondence:
Kevin Chang, PharmD
kevinchang1@gmail.com

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