Short-term Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether Tolcapone crosses from the blood stream into the fluid around the brain and stabilizes the protein that makes leptomeningeal amyloid. Tolcapone is a commercially available generic drug that treats Parkinson's disease. The Investigator plans to evaluate Tolcapone as a treatment for ATTR (Transthyretin Amyloidosis), a rare genetic disease often causing death within 5-15 years after diagnosis. ATTR is characterized by deposition of misfolded protein known as amyloid, in one or more organ systems (including the peripheral and autonomic nervous systems, the heart, the brain and the eyes). The age at which symptoms begin to develop varies widely ranging between 20 to 70 years old. ATTR is progressive, and some variants can have a fatal outcome within a few years of presentation. Treatment options include supportive and symptomatic care that may slow or stop progressive decline in functional state but do not alter the pathological process. Liver transplant can be performed in selected patients but is limited by organ supply, requires lifelong immunosuppression, and may be complicated by progressive heart and nerve amyloid deposition. Importantly, liver transplant does not alter the natural course of central nervous system amyloid disease. To date, no treatment for ATTR penetrates the CNS. At present there is no FDA approved treatment for ATTR amyloidosis in the US. In Europe, Tafamidis has been approved for treatment of stage 1 ATTR-polyneuropathy since 2012. Tafamidis and Tolcapone bind to the thyroxine binding site of TTR (with different drug-transthyretin interactions) and in so doing stabilizes the tetrameric form of TTR, preventing dissociation and amyloid fibril formation The preclinical and clinical data from a variety of experimental systems support the therapeutic activity of TOLCAPONE in TTR mediated disease.

Detailed Description
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This study is designed as a clinical proof-of-concept evaluating whether TOLCAPONE is capable of stabilizing tetrameric TTR (Transthyretin) in the plasma and CSF of symptomatic or asymptomatic patients with leptomeningeal ATTR. Additionally the study will determine the plasma and CSF concentrations of TOLCAPONE needed to induce maximal stabilization of TTR across different TTR variants (TTR mutations). The study will be carried out in two different populations of subjects, defined by the TTR variant expressed: Mutant TTR (up to 10 subjects): symptomatic leptomeningeal TTR patient with any documented leptomeningeal mutations in the TTR gene. Mutant TTR (remaining subjects up to 10): asymptomatic leptomeningeal TTR patient with any documented leptomeningeal mutation in the TTR gene. TTR tetramers stability in plasma and CSF samples will be determined by urea-induced denaturation methodology.

Official Title
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An Open-Label, Investigator Study to Evaluate the Short-term (4 Weeks) Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR) With and Without CNS Manifestations

Conditions
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Transthyretin Amyloidosis, Amyloidosis, Leptomeningeal, Transthyretin-Related

Intervention / Treatment
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* Drug: Tolcapone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genotyping of variant TTR Documented CNS manifestation or expression of variant TTR with leptomeningeal potential Exclusion Criteria: Patients who are unable to provide informed consent Contraindication for Tolcapone An ALT or AST measurement > 2 times the ULN (Upper Limit of Normal) Estimated glomerular filtration rate (eGFR) ≤ 25 ml/min/1.72M2 Treatment with a known TTR tetramer protein stabilizer within the last 2 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients with hATTR mutations conferring leptomeningeal amyloidosis.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolcapone<br>Tolcapone will be administered to assess the short-term (4 weeks) effects on plasma and CSF TTR tetramer stability in subjects with TTR CNS Amyloidosis. Tolcapone is currently licensed for the treatment of Parkinson's disease in combination with levodopa/carbidopa. It is an immediate release product and is currently used at either 100 mg or 200 mg three times a day during waking hours. During this trial, participants will be taking 100mg for 14 days, and then 200mg for 14 days. | Drug: Tolcapone<br>* Tolcapone will be administered at 300 mg/day (100mg TID) orally to participants for 14 days and then 600 mg/day (200 mg TID) orally to participants for 14 days (approximately 5 hours apart). Participants will initiate 200mg TID after blood collection on Day 14.<br>* Other names: Tasmar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma TTR stabilization | TTR stabilization will be measured in plasma samples from each participant before the first dose of study drug and 2 hours after the last 100 mg study drug dose. | pre-treatment (Day 0) and Day 28 | 
| Change in CSF TTR stabilization | TTR stabilization will be measured in CSF samples obtained from each participant before the first dose of study drug and 2 hours after the last 200 mg dose. | pre-treatment (Day 0) and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in plasma TTR stabilization | TTR stabilization will be measured in plasma samples from each participant before the first dose of study drug and 2 hours after the day 14 study drug dose. | pre-treatment (Day 0) and Day 14 | 
| Changes in plasma TTR stabilization | TTR stabilization will be measured in plasma samples from each participant 2 hours after the day 14 study drug dose.and 2 hours after the 28 day study dose | Day 14 and Day 28 | 
| Tolcapone Concentration in CSF | Tolcapone concentration will be measured in CSF at Day 14 prior to starting 200mg TID dosing. | Day 14 | 
| Tolcapone Concentration in CSF | Tolcapone concentration will be measured in CSF at Day 28 2 hours after dose | Day 28 | 
| Tolcapone Concentration in Serum | Tolcapone concentration will be measured in serum at Day 14 prior to initiating 200 mg TID dosing | Day 14 | 
| Tolcapone Concentration in Serum | Tolcapone concentration will be measured in serum at Day 28 2 hours after last dose | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolcapone, Transthyretin (TTR), Mutant TTR, Plasma TTR, CSF TTR, Tetramer stability, Leptomeningeal, Amyloidosis