Current therapy for Lambert–Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment

Abstract

Background:

Lambert–Eaton myasthenic syndrome (LEMS) is a rare pre-synaptic auto-immune disorder of neuromuscular transmission that is characterised by proximal muscle weakness, depressed tendon reflexes and autonomic dysfunction. This review summarises the clinical symptoms, aetiology, diagnosis and treatment options for LEMS. Focus is placed on symptomatic treatment with the potassium channel blocker 3,4-diaminopyridine (3,4-DAP).

Research methods:

English-language publications were searched in MEDLINE and EMBASE to retrieve relevant literature on LEMS. The data submitted to obtain regulatory approval of 3,4-DAP phosphate by the European Medicines Agency (EMA) were also used.

Findings:

LEMS is a rare disease with few treatment options which are generally categorised as anti-tumour, immunomodulating or immunosuppressing, and symptomatic treatments. Anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS. While several immunomodulating or immunosuppressing treatments have been identified, these treatments should be initiated when symptomatic treatments are inadequate. As expected, due to the rarity of the disease, few reports of randomised controlled trials (RCTs) exist. Seven RCTs have been conducted to evaluate treatment of patients with LEMS. One RCT evaluated immunomodulating treatment with intravenous immunoglobulin (ivIg), while six evaluated symptomatic treatment with the potassium channel blocker 3,4-DAP. Improvements in LEMS symptoms after ivIg treatment were observed, leading to the recommendation for treatment in patients when symptomatic treatment does not provide satisfactory improvement. Potassium channel blockers evaluated for the treatment of LEMS include guanidine, 4-aminopyridine (4-AP) and 3,4-DAP. However, only 3,4-DAP has been evaluated in RCTs. Results of these RCTs demonstrated that treatment with 3,4-DAP is efficacious in treatment of LEMS and has an acceptable tolerability profile. Hence, 3,4-DAP has been recommended as first-line symptomatic treatment for LEMS by the European Federation of Neurological Societies. While 3,4-DAP base has only been available via named-patient programmes, requiring ad hoc preparations in compounding pharmacies, tablets containing 3,4-DAP phosphate salt, equivalent to 10 mg base, have become available. This formulation has obtained the orphan medicinal product status both in the European Union and in the United States of America, and has received marketing authorisation in Europe as Firdapse. These tablets have been shown to be essentially bioequivalent with the base preparation.

Conclusions:

The results of this review show that anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS and that one RCT has shown that immunomodulating treatments should be initiated when symptomatic treatments do not provide satisfactory results. A number of RCTs have shown that 3,4-DAP is effective in symptomatic treatment of patients with LEMS and has been recommended as first-line symptomatic treatment of patients with LEMS. The 3,4-DAP phosphate salt formulation was shown to be safe and effective in the treatment of LEMS with a positive benefit:risk ratio.

Key words:

• 3,4-diaminopyridine
• Drug compounding
• Drug therapy
• Lambert
• Eaton myasthenic syndrome
• Neuromuscular junction diseases
• Orphan drug production

Transparency

Declaration of funding

The preparation of this review was funded by BioMarin Pharmaceutical Inc.

Declaration of financial/other relationships

A.Q. has declared that he is an employee of BioMarin Europe Ltd. S.T. and D.L. have declared that they are employees of BioMarin Pharmaceutical Inc.

Some peer reviewers receive honoraria from CMRO for their review work. The peer reviewers of this paper have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors acknowledge medical writing assistance from Ismar Healthcare NV (Lier, Belgium). The authors also thank Curtis Gravance and Jackie Walling for their editorial support.

Notes

*Firdapse is a registered trade name of BioMarin Pharmaceutical Inc., Novato, CA, USA.