Hopkins Professor of Neurology: "Patisiran Is Life-Changing"

Jim Radke, PhD

At the ATTR Amyloidosis Meeting in Paris on November 2nd and 3rd, data presented from the phase 3 APOLLO study exhibited the profound improvement patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy when treated with Alnylam’s patisiran, an investigational RNA interference (RNAi) drug.

ATTR amyloidosis is a rare genetic disease due to a misfolding of transthyretin (TTR) proteins that results in the deposition of amyloid fibrils in different organs.

In ATTR amyloidosis with polyneuropathy, the amyloid deposits mostly affect the peripheral or autonomic nerves. Common symptoms may include numbness, tingling, pain, weakness, loss of sensations, postural hypotension, urinary retention, impotence, body temperature irregularities, and gastrointestinal problems.

Patisiran is a RNAi drug that is designed to target and silence specific messenger RNA that prevents the production of TTR protein.

The APOLLO trial randomized hATTR amyloidosis patients with polyneuropathy (n=225) to receive patisiran (0.3 mg/kg every 3 weeks) or placebo for 18 months. The primary outcome measure was modified Neuropathy Impairment Score +7 (mNIS+7) and the study observed that after 18 months, the patisiran-treatment group (n=148) had a mean decrease in their mNIS+7 score of 6.0 points vs an increase of 28.0 points observed in the placebo group. The mean difference in mNIS+7 scores between the 2 groups was 34.0 which was highly statistically difference (P = 9.26 x 10-24).

mNIS+7 scores also favored patisiran treatment across all defined patient subgroups, including age, sex, race, geographic region, baseline neuropathy scores, genotype, prior use of TTR stabilizers, and baseline familial amyloid polyneuropathy stage.

Secondary outcomes measures were also found to statistically favor patisiran over placebo, including improved quality of life, activities of daily living, nutritional status, motor strength, and ambulatory ability, with reduced disease symptoms and disability.

The most common adverse events (AEs) reported in patisiran-treated patients were generally mild to moderate.

Based on the results of the study, Alnylam plans to start filing their results with regulatory authorities in late 2017 with the goal of getting approval in mid-2018.

In an exclusive interview with Rare Disease Report, one of the lead investigators of the APOLLO trial, Michael Polydefkis, MD, Professor of Neurology at John Hopkins University said: “This opens the door to change people’s lives. This drug provides an opportunity to stop, and maybe even reverse, what was once a fatal disease.”

“Patisiren is an RNA drug that is encapsulated in a lipid nanoparticle. The lipid nanoparticle delivers the drug, the drug binds to the messenger RNA, and via a catalytic mechanism, the RNA will no longer make the disease causing protein. So, patisiran interrupts the disease cascade.” 

In regard to the clinical trial results showing an mNIS+7 score that is not increasing, Polydefkis noted, “What that means is that the patient is not graduating to a cane. Is not graduating to a wheelchair. They are living a better life. For patients, this offers tremendous hope. This disease comes with an incredible burden on the family. It comes with an emotional toll. So this drug is life changing.”

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