This morning at the 16th
International Symposium on Amyloidosis (ISA) in Japan, Alnylam Pharmaceuticals, Inc. presented results from the APOLLO Phase 3 study of patisiran, which targets transthyretin (TTR) in hereditary ATTR (hATTR) amyloidosis.
The company originally announced that the Phase 3 clinical trial met its primary endpoint
(improvement in the modified neuropathy impairment score [mNIS+7]) in November. Secondary endpoints, including quality of life (QoL), muscle strength, patient-reported outcome measure of daily living and disability, ambulatory speed, nutritional status, and autonomic symptoms were all also met.
The trial enrolled 225 hATTR amyloidosis patients from 19 countries with 39 genotypes who were randomized 2:1 with either patisiran or placebo. Patisiran was administered at 0.3 mg/kg once every 3 weeks for 18 months.
“The clinical results presented further highlight the robust profile of patisiran and provide evidence supporting patisiran as a potentially transformative treatment approach for patients with hATTR amyloidosis. We believe that, if approved, these results position patisiran as a best-in-class therapeutic option for patients with hATTR amyloidosis,” said Eric Green, Vice President and General Manager, TTR Program at Alnylam in a press release
“Moreover, we believe that the positive correlation between the degree of TTR knockdown and improvement in neurologic impairment validates the hypothesis that reducing hepatic production of TTR confers clinical benefit,” said Green.
Exploratory cardiac assessments included measurement of N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels and echocardiography, and 56% of APOLLO study participants (n
=126) were included in a predefined cardiac subpopulation. The data presented highlighted that significant improvements in measures of cardiomyopathy relative to placebo were associated with the drug treatment. Cardiomyopathy is the leading cause of death in patients with hATTR amyloidosis.
Specifically, there were improvements in cardiac structure and function at 18 months.
“The results presented at ISA highlight the potential of patisiran to alleviate the cardiac manifestations of hATTR amyloidosis through notable improvements in cardiac structure and function relative to placebo-treated patients. These improvements, in conjunction with demonstrated benefits in neurologic impairment, appear to be associated with favorable effects on gait speed, an important indicator of functional status,” said Arnt Kristen M.D., Heidelberg University Hospital, Heidelberg.
Additionally, patisiran treatment led to a significant reduction in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a cardiac stress biomarker, relative to placebo at 9 and 18 months (p = 7.7 x 10-8). It was also associated with a favorable effect on gait speed in the cardiac subpopulation, in comparison to placebo.
“Improvements across a range of echocardiographic parameters, including left ventricular wall thickness and contractile strength, and a positive effect on a cardiac stress biomarker, speak to the potential for significant benefits of patisiran for patients with hATTR amyloidosis with cardiac involvement,” said Dr Kristen.
Increased levels of NT-proBNP are connected to increased mortality in cardiac amyloidosis. The incidence of cardiac adverse events (AEs) and serious AEs were similar in patisiran- and placebo-treated patients in the overall study population. Deaths occurred with similar frequency in the patisiran (4.7%) and placebo (7.8%) arms.
A New Drug Application
(NDA) for patisiran was accepted by the U.S. Food and Drug Administration (FDA) in February, and the regulatory authority also granted Alnylam’s request for Priority Review. A Prescription Drug User Fee Act (PDUFA) action date was set for August 11, 2018. The company continues to work closely with the FDA to enable their review of the patisiran NDA. Assuming patisiran is approved, Alnylam is preparing its commercial and medical affairs organizations to launch in the U.S., and the drug will be available shortly thereafter.
"We have spoken to many physicians, patient advocacy groups, and even some patients, around the US and Europe since the APOLLO data were presented last fall," said Green in an exclusive interview with Rare Disease Report
. "Physicians, particularly in the U.S., are looking forward to potentially having an option to treat their patients with hATTR amyloidosis."
In an interview with Rare Disease Report
last year, Michael Polydefkis, M.D.
, Professor of Neurology at Johns Hopkins University and lead investigator on the Phase 3 APOLLO study emphasized the potential of patisiran: “This opens the door to change people’s lives,” he said. “This drug provides an opportunity to stop, and maybe even reverse, what was once a fatal disease.”
For more from the 16th
ISA, follow Rare Disease Report