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

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

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.

Study Overview

• Status: Completed
• Conditions: Transthyretin Amyloidosis; Amyloidosis, Leptomeningeal, Transthyretin-Related
• Intervention / Treatment: Drug: Tolcapone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Amyloidosis Center, Boston Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tolcapone; 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; 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.; Other Names: Tasmar

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: Corino Therapeutics, Inc.
• Investigators: Principal Investigator: John L Berk, MD, The Amyloidosis Center, BUSM

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2018
• Primary Completion (Actual): April 26, 2019
• Study Completion (Actual): April 26, 2019

Study Registration Dates

• First Submitted: July 9, 2018
• First Submitted That Met QC Criteria: July 9, 2018
• First Posted (Actual): July 19, 2018

Study Record Updates

• Last Update Posted (Actual): June 14, 2019
• Last Update Submitted That Met QC Criteria: June 12, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Amyloidosis; Tolcapone; Transthyretin (TTR); Mutant TTR; Plasma TTR; CSF TTR; Tetramer stability; Leptomeningeal
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; Tolcapone
• Other Study ID Numbers: H-37757

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes