News on LEMS Treatment and Research

In Lambert-Eaton myasthenic syndrome (LEMS), the immune system attacks the connection between nerve and muscle — the neuromuscular junction — and interferes with the ability of nerve cells to send signals to muscle cells.

Specifically, the attack targets the calcium channels on nerve endings that are required to trigger the release of acetylcholine, a chemical messenger that triggers muscle contraction. With fewer calcium channels, the nerve endings release less acetylcholine. With low levels of acetylcholine, muscles do not contract normally, resulting in muscle weakness.

Stephen Meriney, Ph.D., professor in the department of neuroscience and co-director of the Center for Neuroscience Graduate Program at the University of Pittsburgh, recently completed an MDA-supported research project focused on testing a new calcium channel modifier on LEMS-model mice. Quest asked him about the latest news in LEMS.

What does the treatment landscape for LEMS look like today?

There is no cure for LEMS, as scientists have not yet figured out how to selectively stop the autoimmune attack on motor nerve terminal calcium channels and other nerve terminal proteins targeted by LEMS. Therefore, symptomatic treatments for neuromuscular weakness that results from LEMS are favored.

A potassium channel blocker called 3,4-diaminopyridine (DAP) was discovered in the 1970s and ’80s to be an effective LEMS therapy. By blocking some potassium channels, DAP increases acetylcholine release.

Since its discovery, DAP has been synthesized by compounding pharmacies in many countries and permitted in the U.S. through the “compassionate use” program. A private company in New Jersey called Jacobus Pharmaceutical has been providing DAP at cost, or for free, to many patients for years. As a result, DAP has been the symptomatic treatment standard for more than two decades.

Although less common, some patients may receive treatment with an acetylcholinesterase inhibitor (to prolong the lifetime of acetylcholine after release), by plasmapheresis (to filter out antibodies from the blood), with immunosuppressant drugs or through the administration of intravenous immunoglobulin (which modifies the immune response).

Most recently, a phosphate salt of DAP — Firdapse — was created with a more stable shelf life. Firdapse was approved by the European Medicines Agency (through Biomarin Pharmaceutical). The U.S. Food and Drug Administration (FDA) approved Firdapse in November 2018 (through Catalyst Pharmaceutical), and Catalyst predicts the drug will be available in the United States in 2019.

These regulatory approvals are great news for LEMS patients who were having trouble obtaining DAP previously but have been met with concern from other LEMS patients who were obtaining DAP for little or no cost. It is not yet clear how access to Firdapse for all LEMS patients will be managed. However, Catalyst has indicated that it will work with all patients to ensure access.

What are the most important recent advances in LEMS research?

The most exciting advances are:

• Approval of Firdapse, a stable form of DAP for the symptomatic treatment of LEMS
• Identification of diagnostic criteria that can predict cancer risk for LEMS patients
• Reports that LEMS improves small cell lung cancer prognosis
• Development of new calcium channel gating modifiers

What are researchers exploring now?

Current research includes clinical studies of LEMS patients to advance our understanding of disease progression and association with cancer, studies using a LEMS mouse model to understand in more detail how LEMS antibodies alter the transmitter release site, and the further refinement and preclinical testing of new calcium channel modifiers that hold promise as potential therapeutics.

Are there any promising new treatments in the pipeline?

One new treatment in preclinical development is a small molecule that holds calcium channels open longer. Animal studies have shown that when this calcium channel modifier is combined with DAP, the magnitude of acetylcholine release in LEMS-model mice can be completely restored to normal levels. This combination therapy approach has potential to be a next-generation treatment for LEMS and other conditions with reduced neurotransmitter release.

Why is it important to continue to fund LEMS research?

Current symptomatic treatment, with DAP or Firdapse, usually is not sufficient to allow patients to return to normal activity (due to dose-limiting side effects). Therefore, individuals need more options for treatment (either add-ons or novel treatments). In order to develop such treatments, basic science studies in LEMS that can illuminate potential new targets must continue to be funded.