SOM3355 is an experimental treatment being developed by SOM Biotech to treat movement disorders in Huntington’s disease. SOM Biotech is currently seeking orphan drug status for SOM3355 from the U.S. Food and Drug Administration (FDA).

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene. Long repeats of CAG nucleotides result in the formation of toxic aggregates in neurons, leading to neurodegeneration. This results in chorea (tremors), as well as other disease symptoms.

How SOM3355 works

Muscle movement is controlled by electrical signals sent from the brain to muscle cells via nerve cells. When the signal reaches a muscle, it is conducted by chemical messengers called neurotransmitters at the neuromuscular junction (where nerve fibers and skeletal muscle cells meet). Cell compartments called vesicles hold neurotransmitter molecules ready. When the nerve signal reaches the neuromuscular junction, these compartments empty their neurotransmitter, which then binds to receptor proteins found on the surface of the muscle cell, and the signal is transmitted to the muscle.

Once the signal has been sent, the neuromuscular junction must be reset for the next signal. Neurotransmitter molecules must either be degraded or be returned to the vesicles, by a transport molecule called VMAT2 (vesicular monoamine transporter-2). VMAT2 is involved in fine-tuning neural signaling. Inhibiting VMAT2 reduces the amount of neurotransmitter stored in the vesicles, and the intensity of nerve signaling.

SOM3355 is a repurposed treatment, meaning that SOM Biotech based its formulation on tetrabenazine (brand name, Xenazine) another VMAT2 inhibitor approved to treat Huntington’s disease, and tested a library of related compounds until company researchers found a molecule that targets the same receptor.

SOM3355 is thought to reduce chorea by inhibiting (blocking) VMAT2 by a mechanism similar to that of tetrabenazine. However, SOM Biotech indicates that the molecule’s chemical structure differs considerably from its reference compound.

SOM3355 in clinical trials

A Phase 2 clinical trial (NCT03575676), taking place at four sites in Spain, is preparing to enroll Huntington’s patients with chorea — hyperkinetic movement — to evaluate the safety and efficacy of SOM3355. The six-month trial aims to enroll 30 patients, who will be divided into two groups by treatment schedule. One group will be given twice daily a placebo for six weeks, then 100 mg of SOM3355 for six weeks, 200 mg of SOM3355 for six weeks, and return 100 mg of SOM3355 for a final six weeks.

The other will be treated twice a day with 100 mg of SOM3355 for six weeks, 200 mg of SOM3355 for six weeks, 100 mg of SOM3355 for six weeks, and then placebo for the final six weeks.

The unified Huntington’s disease rating scale will be used to measure changes in chorea at the end of treatment, compared to scores at the study’s start. Patient and physician global impressions of change will also be recorded.

Other information

Preclinical trials in animal models of Huntington’s showed the therapy — a repurposed treatment — to be well-tolerated and able to cross the brain-blood barrier, SOM Biotech reports.

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