Short-term Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR)
Status:
Completed
Trial end date:
2019-04-26
Target enrollment:
Participant gender:
Summary
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.