Monarsen (EN101) is an investigational drug aimed at treating the symptoms of myasthenia gravis (MG). It was originally developed by researchers at Israel’s Hebrew University of Jerusalem; Ireland’s Amarin later acquired rights to further develop Monarsen.

How monarsen works

MG is an autoimmune disease in which the body’s immune system attacks parts of the nervous system that transmit messages between the muscles and the brain. This leads to muscle weakness, resulting in a lack of control over some muscles.

Normally, motor neurons release a chemical called acetylcholine at the neuromuscular junction, where the nerve and muscle cells meet. Acetylcholine binds to acetylcholine receptors (AChRs) found on the muscle cells, triggering muscle contraction. Acetylcholine is then quickly removed by an enzyme called acetylcholinesterase (AChE), stopping the signal to the muscle in what is known as neurotransmission.

MG is commonly caused when the immune system targets AChR, resulting in fewer messages reaching the muscles. Furthermore, increased levels of a different variant of AChE, called AChE-R, are sometimes also produced as part of the stress response in MG patients. This further reduces levels of acetylcholine.

Monarsen is an antisense drug that aims to increase acetylcholine levels by inhibiting the production of AChE-R. The drug works by binding preferentially to the AChE-R messenger RNA — the molecule used by the cell’s protein-producing machinery — stopping it from being read.

With reduced AChE-R, it should take longer to remove acetylcholine, allowing the signal to be carried between the nerves and muscles for a longer time. This should improve muscle activation and contraction in patients with MG.

It is also believed to reduce damaging immune response by reducing levels of cytokines – immune proteins that can trigger inflammation.

Monarsen in clinical trials

In preclinical studies, monarsen was shown to successfully improve survival and muscle strength in a rat model of MG. Monarsen was later studied in two small exploratory clinical trials of patients with MG.

A Phase 1b open-label study tested monarsen treatment in 16 MG patients who were previously receiving Mestinon (pyridostigmine bromide) treatment. They received monarsen for four days, followed by a two-day washout period, and were monitored for adverse effects for four weeks following treatment. The results, published in Annals of the New York Academy of Sciences, suggested that monarsen could markedly improve quality of life in MG patients, but that larger placebo-controlled studies are needed.

Amarin carried out a Phase 2a study testing monarsen at three different doses (10 mg, 20 mg and 40 mg) in 31 participants across six sites in Israel, Serbia and the United Kingdom. Amarin announced that monarsen resulted in a significant improvement in quantitative myasthenia gravis (QMG) score from the start of the trial. The results appeared in the Annals of the New York Academy of Sciences.

In both trials, monarsen was well-tolerated with few mild adverse events; these included dry mouth and headache.

Despite positive results, Amarin has not yet announced plans to further develop monarsen. Other research groups are interested in it, but the drug’s future is currently unknown.

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