Is RNAi Treatment a Game Changer for TTR Amyloidosis in Patients with FAP?

James Radke, PhD

Familial amyloid polyneuropathy (FAP) is a progressive, fatal disease caused by deposition of transthyretin (TTR). Patisiran is an investigational, systemically administered, lipid nanoparticle formulation of a small interfering RNA (siRNA) targeting wild-type and mutant TTR.

At the American Academy of Neurology 67th Annual Meeting in Washington, DC, there is much excitement about the ongoing phase 2 open-label extension (OLE) study with patisiran, developed by Alnylam, for the treatment of TTR amyloidosis in patients with FAP. Data being presented at the meeting showed that patients taking the drug, who had reached the 12-month endpoint (N = 20) at the time of data cutoff, had a mean 2.5-point decrease in modified Neuropathy Impairment Score (mNIS+7).1 This 2.5-point decrease translates to a halting of the neuropathic progression of the disease.

Based on the literature, these patients would normally show a 13- to 18-point increase in mNIS+7 if left untreated. A similar pattern was observed in the Neuropathy Impairment Score (NIS) outcome measure of patients in the 12-month treatment group; they had an NIS of 0.4 compared with the expected 10- to 14-point increase commonly observed in untreated patients.

In a press release,2 investigator David Adams, MD, PhD, head of the Department of Neurology and Coordinator of the French Reference Center for FAP and Other Rare Peripheral Neuropathies, APHP/CHU Bicêtre, Paris, said:

“I view these new clinical activity and safety data from Alnylam’s ongoing patisiran OLE study as very encouraging. In particular, the possibility of halting neuropathic progression over 12 months of treatment is promising in light of the rapid increase in neuropathy impairment scores observed in analysis of other historical data sets. If these results are replicated in a randomized, double-blind, placebo-controlled study, I believe that patisiran could emerge as an important treatment option for patients suffering from this debilitating, progressive and life-threatening disease.”

Added Akshay Vaishnaw, MD, PhD, executive vice president, R&D, and chief medical officer of Alnylam Pharmaceuticals:

 “In this ongoing open-label study with patisiran, we are very encouraged to see what we believe to be continued evidence for possible halting of neuropathy progression after the first 12 months of treatment. Indeed, we believe the 2.5-point mean decrease in the modified neuropathy impairment score is a promising result in light of analysis of multiple historical data sets that would have predicted an increase of 13 to 18 points for untreated FAP patients with similar baseline characteristics. It will be of great interest to see how these data mature going forward, and we now look forward to sharing 18-month clinical results in late 2015.”

In the phase 2 study, patisiran is being administered once every 3 weeks at a dose of 0.3 mg/kg by intravenous infusion. The study is measuring a number of clinical endpoints every 6 months, including mNIS+7, which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time.

A summary of mNIS+7 and NIS results (mean ± standard error of the mean) at 6 and 12 months is provided in the table below.

  6 months (n=27)
12 months (n=20)
Untreated historical data
(12 months)
mNIS 1.4 ± 2.1 2.5 ± 2.9 13-18
NIS 0.7 ± 1.3 0.4 ± 1.2 10-14

A number of additional exploratory clinical measures are also being assessed in the OLE study, including quality of life; timed 10-meter walk test; hand-grip strength test; modified body mass index; level of disability by Rasch-built Overall Disability Scale; autonomic neuropathy symptoms by Composite Autonomic System Score (COMPASS-31); and nerve fiber density in skin biopsies. These clinical measures were largely unchanged over the 12-month evaluation period.

Patisiran administration was also found to be generally well tolerated with minimal adverse events reported for a period of up to 17 months. There were no drug-related serious adverse events. The most common drug-related or possibly drug-related adverse events were flushing (22.2%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations.

A phase 3 clinical trial has begun enrolling patients.


1. Coelho T, Suhr O, Conceiçao I, et al. Phase 2 open-label extension study of patisiran, an investigational RNAi therapeutic for the treatment of familial amyloid polyneuropathy. Presented at American Academy of Neurology 67th Annual Meeting; April 18-25, 2015; Washington, DC. Abstract S9.003.

2. Alnylam Reports 12-Month Clinical Data from Phase 2 Open Label Extension (OLE) Study of Patisiran, an Investigational RNAi Therapeutic for Patients with Familial Amyloidotic Polyneuropathy (FAP) [press release]. Cambridge, MA; Alnylam Pharmaceuticals; April 21, 2015.

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