SOM0226 (tolcapone) is a repositioned compound being evaluated for the treatment of familial amyloid polyneuropathy (FAP). A repositioned compound is one that already is approved to treat a different disease and thought to be of use in others.
Repositioning existing medicines can speed a treatment’s development and lower its cost, because the compound’s safety already is established. This could facilitate the use of SOM0226 in countries like Brazil and Portugal, where FAP is highly prevalent.
How SOM0226 works
FAP is a form of ATTR amyloidosis characterized by abnormal deposits of a protein called transthyretin (TTR), especially around peripheral nerve cells. TTR serves to transport the thyroid hormone thyroxine and vitamin A.
SOM0226 works by imitating the process by which thyroxine binds to TTR in the bloodstream.The amyloid fibrils in FAP are formed by the dissociation of native TTR tetramers into unstable monomers that unfold and aggregate. SOM0226 binds closely to the TTR protein in a similar way as the hormone, keeping the four protein subunits together without any change in the protein’s structure.
Tolcapone, under the brand name Tasmar, was approved in the late 1990s to treat Parkinson’s disease due to its activity as a catechol-O-methyltransferase (COMT) inhibitor. But it was found to also work as a potent stabilizer of TTR, serving as a TTR aggregation inhibitor. SOM Biotech then sought to reposition it as a potential FAP treatment.
Researchers have conducted in vitro studies in cell cultures as well as ex vivo trials in human plasma and in mouse models of the disease to show that SOM0226 is a powerful inhibitor of the aggregation of TTR amyloid fibers. This stabilizes the protein’s structure to slow the advance of the disease. SOM0226 turns out to be four times more effective than the only medicine currently available for treating FAP. In addition, the treatment was shown to cross the blood-brain barrier, making it the first to tackle the disease variants that affect the central nervous system.
A proof-of-concept Phase 2a clinical trial (NCT02191826) was conducted in about 17 asymptomatic carriers, diagnosed FAP patients, and healthy volunteers to determine whether treatment with SOM0226 stabilizes TTR protein in the blood. This interventional open-label study was organized in two phases, separated by a washout period of six weeks. During the first phase, patients were administered a single dose of 200 mg of SOM0226 and a blood sample was collected at different times to determine drug levels and TTR stabilization activity, which was the study’s primary efficacy endpoint. The second phase was similar but involved multiple doses of 100 mg of SOM0226, one every four hours up to a total of three doses.
Both treatments, a single, 200 mg oral dose and three 100 mg doses of SOM0226 induced clear and robust TTR stabilization in the study’s participants, allowing 100% protection of TTR present in the blood plasma samples. This activity was most comprehensive after two hours of dosing and clearly correlated with drug levels in the plasma. The treatment was also seen to be safe, with no adverse events related to its use.
The U.S. Food and Drug Administration (FDA) designated SOM0226 as an orphan drug for the treatment of ATTR amyloidosis, which includes FAP, in 2014.
SOM Biotech entered into its licensing agreement with Corino in May 2017 for further development of SOM0226, now also known as CRX-1008.
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