Literature Review
Tafamidis Delays Progression of Rare Polyneuropathy
Tafamidis, an oral non-NSAID and highly specific stabilizer of the TTR protein, delays neurologic progression in early-stage transthyretin...
Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.
The APOLLO Trial
To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.
The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.