A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis

Abstract

Background: Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II openlabel extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup. Results: Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months. Conclusions: Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/ improvement of polyneuropathy progression in patients with hATTR amyloidosis. Trial registration: The study was registered at ClinicalTrials.gov (identifier: NCT01961921) on October 14, 2013.

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

“…The phase 3 placebo-controlled APOLLO study and the phase 2 open-label extension (OLE) study demonstrated that patisiran achieved robust, rapid, and sustained reduction of serum TTR levels from baseline in patients with ATTRv amyloidosis with polyneuropathy. 6,14 In the 18-month APOLLO study, patients treated with patisiran 0•3 milligrams/kilogram (mg/kg) intravenous (IV) infusion every 3 weeks (q3w) compared with placebo improved in autonomic, sensory, and motor neuropathy as measured by the primary endpoint modified Neuropathy Impairment Score +7 (mNIS+7) as well as across all secondary endpoints including QOL, motor strength, disability, gait speed, nutritional status, 6,15 and exploratory cardiac structure/function endpoints in the pre-specified cardiac sub-population. 16 Patisiran also improved endpoints related to polyneuropathy and QOL, such as mNIS+7 and Norfolk QOL-Diabetic Neuropathy questionnaire (Norfolk QOL-DN), at 18 months compared with baseline in the majority (56% and 51%, respectively) of patients, suggesting reversal of the polyneuropathy of the disease.…”

“…6 The primary objective of the 24-month phase 2 OLE was to evaluate the safety and tolerability of patisiran, and the study demonstrated both safety and secondary efficacy results consistent with those reported in APOLLO. 14 Eligible patients who completed APOLLO (patisiran or placebo arm) or the phase 2 OLE were able to enrol into the Global OLE which aims to assess the long-term efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy.…”

Unusual Pain Disorders – What Can Be Learned from Them?

“…The disease-stabilizing effect of patisiran was shown to be maintained in an open-label extension phase over 24 months with overall acceptable safety profile. 61 …”

“…The disease-stabilizing effect of patisiran was shown to be maintained in an open-label extension phase over 24 months with overall acceptable safety profile. 61 Inotersen is a single-strained antisense oligonucleotide, which is complementary to the TTR mRNA. Inotersen binds to the mRNA, this mRNA/DNA heteroduplex is then cleaved by the nuclear ribonuclease H1 (RNase H1) leading to reduced TTR protein levels.…”

Advances in Treatment of ATTRv Amyloidosis: State of the Art and Future Prospects

“…More recently, a 24-month, phase 2, open-label extension study, conducted on 27 patients, confirmed the good tolerability and showed an improvement in the modified Neuropathy Impairment Score plus 7 (mNIS+7) of nearly 7 points in 24 months. Motor and autonomic function, as well as quality of life, remained stable, whereas an improvement in nerve-fiber density was documented by skin biopsies [ 61 ].…”