Patisiran Shows Sustained Improvements in Disease Progression for hATTR Amyloidosis


Patisiran maintained improvements in mNIS+7 and rapidly halted neurologic disease progression in hATTR amyloidosis.

Dr Alejandra Gonzalez-Duarte

Alejandra Gonzalez-Duarte, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Alejandra Gonzalez-Duarte, MD

Treatment with patisiran (Onpattro) maintained improvements in modified neuropathy impairment score (mNIS+7) with rapid halting of neurologic disease progression for patients with hereditary transthyretin-mediated (hATTR) amyloidosis, according to findings from a global open-label extension study at the 2018 AANEM Annual Meeting.1

In the APOLLO study,2 which led to the FDA approval of patisiran for hATTR amyloidosis in August 2018, the least mean square change in mNIS+7 from baseline for those treated with patisiran was -6.0 ±1.7 versus 28.0 ±2.6 with placebo. Following 52 weeks of treatment with patisiran in the extension study, patients originally treated with the RNA inhibitor had sustained improvements in neuropathy, and those initially receiving placebo experienced a rapid halting disease progression.

The open-label global extension study included 211 total patients enrolled from the pivotal phase 3 APOLLO study and from a separate phase 2 open-label extension study. Findings from the open-label extension trial represent the longest available follow-up for an RNA inhibitor therapy, with some patients receiving the therapy for longer than 4 years.

"Patients treated with patisiran early in their disease demonstrated continued improvement in neuropathy up through one additional year on the global open-label extension," lead author Alejandra Gonzalez-Duarte, MD, and colleagues wrote in their poster. "Placebo-treated patients from APOLLO exhibited rapid halting of neurologic disease progression after initiation of patisiran treatment and subsequent improvement in neurologic function, despite more advanced disease at global open-label extension baseline."

The median age of patients in the extension trial was 64 years, and 74% were male. The mean time since hATTR amyloidosis diagnosis to first patisiran dose was 2.9 years. Overall, 54% of patients had a non-V30M transthyretin (TTR) genotype and 52% were enrolled in Western Europe. The most common polyneuropathy disability scores were II (27%) and IIIA/B (41%). The mean baseline mNIS+7 was 77, which was driven primary by those enrolling from the placebo arm of the APOLLO study (n = 49) who entered with an mNIS+7 of 101.

Patients switching from placebo to patisiran experienced robust reductions in serum TTR levels. By week 6 of the extension studies, mean serum TTR levels had decline by 79% for patients receiving patisiran for the first time. TTR levels were maintained in the extension study for those treated with the RNA inhibitor in the phase II trial and APOLLO, even out to 4 years, showing the durability of benefit.

At the August 2018 data cutoff for the extension study, the mean duration of treatment was 18 months. The mean for those receiving placebo in the APOLLO trial was 16 months, whereas the overall mean for those in the investigational arm of APOLLO was 34 months. Patients from the open-label phase 2 trial had received an overall mean of 51 months of treatment with patisiran.

The most commonly reported adverse events (AEs) with patisiran were infusion-related reactions (IRR), which occurred in 12% of patients in the global extension trial. These events were most common in patients who previously received placebo and decreased over time. There were no serious IRRs or discontinuations due to IRR.

AEs were experienced by 96% of patients, and were mostly mild or moderate. Severe AEs were experienced by 27% of patients in the global extension trial, with AEs leading to discontinuation for 10% of patients. There were 18 deaths in the extension trial, all of which were deemed unrelated to treatment.

The overall mortality rate for patients exposed to patisiran was 4.3 per 100 patient years. Across other studies for the disease, the mortality rate for patients with hATTR amyloidosis is 7 to 18 deaths per 100 patient-years, the authors wrote. "Based on a review of the literature using studies that had sufficient information to estimate a mortality rate, the mortality rate in patients who received patisiran appears lower than the expected range for patients with hATTR amyloidosis.”

With FDA approval in August, patisiran became the first treatment approved to treat polyneuropathy in adult patients with hATTR amyloidosis. Moreover, patisiran is the first FDA-approved RNA inhibitor. The global open-label extension study continues to evaluate outcomes with patisiran, and is designed to provide treatment with the RNA inhibitor for up to 5 years.


  1. Gonzalez-Duarte A, Coelho T, Adams D, et al. Long-term use of patisiran, an investigational RNAi therapeutic, in patients with hereditary transthyretin-mediated amyloidosis: 12 month efficacy and safety from global open-label extension study. Presented at: 2018 AANEM Annual Meeting, National Harbor, MD, October 10-13, 2018. Abstract 10
  2. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018; 379:11-21.
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