Patisiran Shows Sustained Long-Term Efficacy in Patients With hATTR

David Adams, MD, PhD

An interim, 12-month analysis from the ongoing open-label extension study (NCT02510261) of patisiran (Onpattro; Alnylam) suggest that the therapy maintains its efficacy and an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis (hATTR) with polyneuropathy.

After the 12-month open-label period, those treated with patisiran from the phase 3 APOLLO (NCT01960348) and phase 2 open-label (NCT01961921) parent studies maintained their improvements on the modified Neuropathy Impairment Score +7 (mNIS+7), with mean changes of -4.0 (95% CI, -7.7 to -0.3) and -4.7 (95% CI, - 11.9 to 2.4), respectively. For those who were on placebo in APOLLO that switched in the open-label extension, the mean change from global OLE enrollment was -1.4 (95% CI -6.2 to 3.5).

The study was conducted by David Adams, MD, PhD, Head, French National Reference Centre for Familial Amyloidotic Polyneuropathy, and head, Department of Neurology Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, and a number of colleagues. “Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran,” they wrote.

Data from this extension were also presented at the 2018 AANEM Annual Meeting. The study includes 211 of 212 eligible patients enrolled between July 13, 2015, and August 21, 2017. In total, 137 were enrolled from the APOLLO patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. The data cutoff was September 24, 2018, at which time 126 (92%) from the APOLLO-patisiran group, 38 (78%) from the APOLLO-placebo group, and 25 (100%) from the phase 2 OLE patisiran group had completed 12-month assessments.

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“The global open-label extension is ongoing with no new enrollment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff,” Adams et al. wrote.

As for safety, 204 (97%) of the overall cohort reported adverse events (AEs), and the most common treatment-related AE reported was mild or moderate infusion-related reactions.

There were 82 (39%) patients who reported a serious AE, and 23 (11%) deaths. The APOLLO placebo group experienced a higher frequency of serious AEs (28 of 49; 57%) than the APOLLO patisiran group (48 of 137; 35%) or the phase 2 open-label extension group (6 of 25; 24%). The frequency of deaths in the global cohort was higher in the APOLLO-placebo group (13 of 49; 27%), who had a higher disease burden than the APOLLO-patisiran (10 of 137; 7%) and phase 2 OLE patisiran (0 of 25; 0%) groups.

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 who entered with an mNIS+7 of 101.²

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.

In the APOLLO study, 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.³ 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.

REFERENCE
1. Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Published online November 16, 2020. doi: 10.1016/S1474-4422(20)30368-9
2. 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
3. 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.