MedicalResearch.com: What is the background for this study?
Response: Hereditary transthyretin amyloidosis is an autosomal dominant, multisystemic, progressive, life-threatening disease caused by mutations in the gene encoding transthyretin (TTR ).
The liver is the primary source of circulating tetrameric TTR protein. In hereditary transthyretin amyloidosis, both mutant and wild-type transthyretin deposit as amyloid in peripheral nerves and the heart, kidney, resulting in polyneuropathy and cardiomyopathy. Neuropathic changes result in profound sensorimotor disturbances, with deterioration in activities of daily living and ambulation, hypotension, diarrhea, impotence, and bladder disturbances.
Until now, only few patients have access to anti-amyloid therapy : Liver Transplantation or TTR stabilizers which are able only to slow progression of the disease at very early stage of the disease.
Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin and is specifically addressed to the liver by lipid nanoparticle (LNP) formulation.
This study carried out a multicenter, international, randomized, double-blind, placebo-controlled, phase 3 trial of patisiran in patients with hereditary transthyretin amyloidosis with polyneuropathy.
MedicalResearch.com: What are the main findings?
· This is the largest study of hTTR amyloidosis with polyneuropathy, at different stages of the disease.
· The study is positive: Primary endpoint is reached ; variation of composite neuropathic score mNIS+7 at 18 months compared to placebo is highly statistically significant. All secondary endpoints including NORFOLK quality of life score(QOL) and many neuropathic markers are positive compared to placebo.
· For the first time: 1) anti-amyloid therapy is able to improve polyneuropathy and QOL at 18 months compared to baseline showing reversal of the disease. 2) Efficacy is observed regardless of the stages of the disease.
· As an example, “one patient with stage IIIb (walking with 2 crutches) and a disabling explosive diarrhea that prevented him from having a social life. He was in patisiran arm and improved significantly after 18 months: he is able now to walk with only one cane, his balance disorders decreased. He had no more diarrhea and gained 4 kilos. he has a normal social life again. He began again to hunt, and to have projects”.
· Safety is excellent, no death due to patisiran, only minor or moderate adverse events (mainly infusion related reaction). No particular biological monitoring is required.
MedicalResearch.com: What should readers take away from your report?
· A revolution for a degenerative disease : hereditary TTR amyloidosis with polyneuropathy. Ability to reverse the disease. “By comparison, if such progress was transposed to the neurodegenerative disease of the brain due to amyloidosis: Alzheimer’s disease, this would result in the ability of patients to recover their memory.”
· This study gives hope for all hTTR amyloidosis patients to have access to an effective anti-amyloid therapy regardless of the stage of the disease to recover functions such as walking, digestive disorders due to autonomic dysfunction.
· This study gives hope for rare hepatic genetic disease that could be targeted by specific RNAi : porphyria, severe hypercholesterolemia,
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
· Future research should confirm long term benefit efficacy and safety of RNAi in open label extension (OLE) study of APOLLO study.
· Research is required to control ocular production of TTR which induces severe ocular manifestations.
· Future research should assess efficacy of RNAi administration by subcutaneous injection with a long lasting effect.
MedicalResearch.com: Is there anything else you would like to add?
· Early Access Program for PATISIRAN is ongoing in USA and Europe
· This study will be the last placebo controlled study for hereditary TTR amyloidosis with polyneuropathy because of the positivity of APOLLO trial.
Disclosures: I participated in advisory boards for ALNYLAM to elaborate the design of the study APOLLO.
· I participated in advisory boards of Pfizer, GSK, Prothena therapeutics.
· Consultant for Alnylam Pharmaceutical.
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