Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy

David Adams,Peter J Dyck,Jihong Chen,William J Litchy,Teresa Coelho,Raina G Leahy,Jared Gollob,Ole B Suhr

doi:10.1186/s12883-017-0948-5

Abstract

BackgroundPatisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality.MethodsHere we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18–85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5–130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study.DiscussionAPOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease.Trial registrationThis trial is registered at clinicaltrials.gov (NCT01960348); October 9, 2013.

Highlights

Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality
Hereditary ATTR amyloidosis, formerly known as familial amyloid polyneuropathy (FAP), is a progressive, life-threatening disease caused by misfolded transthyretin (TTR) protein that accumulates as amyloid fibrils in multiple organs, including the nerves, heart, and gastrointestinal tract [1, 2]. hereditary ATTR (hATTR) amyloidosis is a multisystemic disease with a heterogeneous clinical
quality of life (QoL), motor function, health status, autonomic symptoms, cardiac assessments, and everyday functioning are included as secondary or exploratory endpoints to assess the impact of patisiran on a range of disease involvement

Summary

Methods

Study oversight This study is conducted according to the guidelines of the International Conference on Harmonisation, the. Patients have the option of discontinuing study drug if they experience a protocol-defined rapid disease progression at 9 months, defined as ≥24-point increase in mNIS+7 from baseline (estimated 24-point increase in mNIS+7 score in the placebo group expected by 18 months based on natural history study [47]), and FAP stage [7] progression relative to baseline, confirmed by an external adjudication committee. Such patients may receive alternative therapy (local standard of care) and will be monitored based on a modified visit schedule if they decide to stay on study. Cardiac function is assessed through echocardiograms and cardiac biomarkers (troponin I and N-terminal pro-brain-type natriuretic peptide)

Discussion

Background

Objective

Findings

68. Amyloidosis Foundation