SOM0226, a repositioned compound for the treatment of TTR amyloidosis

Background: SOM0226 (Tolcapone) is a repositioned compound with a newly identified activity as a potent TTR stabilizer and TTR fibril disruptor.Objective: To determine whether SOM0226 stabilizes plasmatic TTR in healthy subjects, TTR Familial Amyloid Polyneuropathy patients and asymptomatic carriers.Methods: A proof of concept Phase IIa clinical trial (EUDRA CT number: 2014-001586-27) has been conducted in diagnosed Familial Amyloid Polyneuropathy (FAP) patients, asymptomatic carriers and healthy volunteers to determine whether treatment with SOM0226 stabilizes plasmatic TTR. The trial involved 6 healthy individuals and 15 asymptomatic carriers with mutations in the TTR gene and FAP patients at varying stages of disease progression. TTR stabilization was measured in plasma samples, using an immunoturbidity assay after urea denaturation and cross-linking with glutaraldehyde. Safety endpoints were also determined.Results: Treatment with a single oral dose of 200mg or three doses of 100mg SOM0226 induce a clear and robust stabilization of plasmatic TTR in all patients studied, protecting 100[percnt] of the TTR present in the plasma samples. This activity peaks 2 hours after the dose is administered, and gradually decreases thereafter, with 50[percnt] of the maximum effect after 8 hours, and clearly correlates with drug levels in plasma. The administration regime studied has been proven to be safe, with no observed adverse events related to the investigational product. Moreover, no significant clinical or analytical hepatotoxicity has appeared in any patient.Conclusion: SOM0226 is capable of stabilizing all TTR present in plasma samples in all the patients studied, supporting further development of SOM0226 for the treatment of TTR amyloidosis. As a repositioned drug, SOM0226 can bypass much of the early cost and time required to bring a drug to market, and has the potential to become the most potent TTR stabilizer in the market for preventing the progression of the various forms of TTR amyloidosis. Disclosure: Dr. Gamez has received royalty, license fee or contractual rights payments. Dr. Reig has nothing to disclose. Dr. Ventura has nothing to disclose. Dr. Maria Salvado has nothing to disclose. Dr. Insa has nothing to disclose.