Study of SOM0226 in Familial Amyloid Polyneuropathy

This is an open label interventional Phase IIa proof of concept clinical trial designed in two phases separated by a washout period of 6 weeks (± 2 weeks) , to evaluate the TTR stabilization activity of SOM0226 in healthy volunteers (wild type), TTR-FAP patients and asymptomatic carriers.

* Phase A (24 hours): SOM0226 single dose
* Phase B (32 hours): SOM0226 multiple dose

• SOM0226 (Drug): Oral

Primary outcomes

• TTR stabilization [24 hours and 32 hours]: TTR stabilization will be measured by determining the concentration of tetrameric TTR after denaturation. The ratio of TTR tetramer after denaturation / TTR tetramer before denaturation of plasma samples from treated subjects will be compared to their baseline ratio. TTR stabilization will be determined as percentage of the baseline ratio.

Secondary outcomes

• Pharmacodynamics assessment [24 hours and 32 hours]: Determine the minimal molar ratio SOM0226:TTR that must be reached in plasma to confer maximal TTR stabilization
• Safety [24 hours]: Drug safety will be assessed by blood biochemistry and hematology analysis, patient exploration and adverse event reporting

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Inclusion Criteria:

* Participant is willing and able to give informed consent for participation in the study
* Male or Female, aged 18 years or above at the time of consent
* Two cohorts defined by TTR variant (wild type: healthy volunteers; TTR mutant: asymptomatic carriers with documented mutation in TTR or diagnosed TTR-FAP patients (stage 1 or 2) not undergoing pharmacological treatment with Vyndaqel
* Body Mass Index (BMI) > 17.5 kg/m2
* Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 2 month thereafter
* Able (in the Investigators opinion) and willing to comply with all study requirements

Exclusion Criteria:

* Female participant who is pregnant, lactating or planning pregnancy during the course of the study
* Evidence of history of clinically significant hepatic disease
* An ALT or AST measurement > 2 times the ULN (Upper Limit of Normal)
* Scheduled elective surgery or other procedures requiring general anaesthesia during the study
* Donation of blood during the study or within the past 4 weeks
* Treatment (during the study or within the past 4 weeks) with a prescription or investigational drug for the treatment of TTR amyloidosis
* Treatment with NSAIDs (nonsteroidal antiinflammatory drug) during the study or within the past 4 weeks. The following NSAID are allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, nabumetone, naproxen, nimesulide, piroxicam and sulindac

• Results publication: Gamez J, Salvado M, Reig N, Sune P, Casasnovas C, Rojas-Garcia R, Insa R. Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study. Amyloid. 2019 Jun;26(2):74-84. doi: 10.1080/13506129.2019.1597702. Epub 2019 May 23. PMID 31119947

• Josep Gámez, MD, Principal investigator, Hospital Vall d'Hebron

NIH grants: 2014