Abstract
Objective: Describe the interim 12-month safety and efficacy data (as of 09/24/2018) for patients in the ongoing Global Open-Label Extension (OLE) study.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life-threatening disease; majority of patients develop a mixed phenotype including polyneuropathy and cardiomyopathy. Patisiran’s efficacy and safety over 18–24 months have been demonstrated in Phase 2 and Phase 3 (APOLLO) studies in hATTR amyloidosis with polyneuropathy.
Design/Methods: Multicenter, international, OLE, safety and efficacy study (NCT02510261) in eligible patients who completed parent studies, including APOLLO patients randomized to placebo (APOLLO/placebo, n=49) or patisiran (APOLLO/patisiran, n=137) and Phase 2 OLE patients (n=25).
Results: 211 patients enrolled into Global OLE; 189 had 12-month assessments by September 24, 2018. Safety profile remained consistent with previous studies. After 12 months of additional patisiran treatment in Global OLE, durable improvement was seen for mNIS+7 (mean change [SEM]) in APOLLO/patisiran (−4.0 [1.9]) and Phase 2 OLE (−4.7 [3.5]) groups compared to parent study baselines. Norfolk QOL-DN (only measured at parent study baseline in APOLLO) showed durable improvement in APOLLO/patisiran patients (−3.9 [2.1]) following additional 12-months treatment. In the Global OLE, APOLLO/placebo patients experienced improvement on average after 12 months of patisiran (mNIS+7: −1.4 [2.4], Norfolk QOL-DN: −4.5 [2.5]), although they had progressed relative to APOLLO baseline (mNIS+7: +24.0 [4.2], Norfolk QOL-DN: +15.0 [3.4]) given the progression while on placebo in APOLLO.
Conclusions: Long-term patisiran treatment continues to show a positive benefit:risk profile, including patients dosed for 4 years or more. Overall, patients with longer-term exposure to patisiran demonstrated durability of effect. Despite marked progression on placebo during the 18-month APOLLO study, previously untreated patients exhibited halting of disease progression and QOL improvement following 12 months of patisiran. However, delay in treatment resulted in these patients accumulating greater disease burden compared to patients treated earlier with patisiran.
Disclosure: Dr. Polydefkis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam Pharmaceuticals, Akcea, Biogen, Vertex. Dr. Gonzalez-Duarte has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Coelho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam, Ionis, Prothena. Dr. Coelho has received research support from Pfizer, Ionis, Alnylam, Prothena. Dr. Wixner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam. Dr. Wixner has received research support from Pfizer, Alnylam. Dr. Kristen has received research support from Pfizer, Alnylam, Ionis. Dr. Schmidt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam, Akcea, Pfizer. Dr. Berk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intellia Therapeutics (SAB), Corino Therapeutics (SAB), Alnylam Pharmaceuticals (Seminar lecture), Akcea (presentation, AAN). Dr. Berk has received research support from Study site investigator for Alnylam, Akcea, Corino. Dr. Berber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Berber holds stock and/or stock options in Alnylam, Exelixis, Fibrogen, Arbutus, Glaxo-SmithKline, Ionis, and Akcea. Dr. Sweetser has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Sweetser holds stock and/or stock options in Alnylam which sponsored research in which Dr. Sweetser was involved as an investigator. Dr. Sweetser holds stock and/or stock options in Alnylam. Dr. White has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam, Pfizer.
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