Patisiran May Reduce Neuropathy in Patients With hATTR Amyloidosis

Assessing Change From Baseline

The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.

At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.

At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.

At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).

“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.

The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.

All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.

In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.

Therapy Is Under FDA Review

There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.

Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).

The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.

Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.

—Jake Remaly

Suggested Reading

Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.

Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.

Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.

Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.