| 21. |
- Conceicao, I., et al.
(författare)
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Phase 2 open-label extension study of patisiran, an investigational siRNA agent for hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN)
- 2016
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Ingår i: Neuromuscular Disorders. - : Elsevier. - 0960-8966 .- 1873-2364. ; 26, s. S142-S142
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease that can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death. Patisiran is an investigational, systemically administered small interfering RNA (siRNA) targeting wild-type and mutant TTR. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in hATTR-PN patients (N = 29) showed >80% sustained mean knockdown of serum TTR when administered at a dose of 0.3 mg/kg every 3 weeks with a generally favorable safety profile. Phase 2 open label (OLE) study to evaluate patisiran's safety effect on serum TTR levels, impact on neuropathy impairment scores and QOL. Twenty-seven patients with hATTR-PN were enrolled; median age 64 years (range: 29–77 years). Patisiran was well tolerated throughout the23-months of follow-up. Five patients experienced SAEs (unrelated) including one discontinuation and subsequent death (gastroesophageal cancer). Flushing (25.9%) and infusion-related reactions (18.5%) were mild AEs; and did not result in any discontinuations. Approximately 80% sustained mean serum TTR lowering was obtained with a mean nadir of up to 93% between doses. Among the 20 evaluable patients, neuropathy impairment scores were stable with a mean change in mNIS+7 and NIS of 1.7 and 4.2 points, respectively. This compares favorably to 17–26 point mNIS+7/NIS increase at 18-months from prior hATTR-PN studies. Stabilization of quality of life (QOL) measures and significant improvement of distal thigh sweat gland nerve fiber density was observed. Long-term (>18 months) patisiran administration was generally well tolerated, resulted in sustained mean serum TTR lowering; supporting the hypothesis that TTR knockdown potentially halts neuropathy progression. As of March 2016, dosing continues; updated results will be presented.
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| 22. |
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| 23. |
- Solomon, Scott D., et al.
(författare)
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Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis : Analysis of the APOLLO Study
- 2019
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 139:4, s. 431-443
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed.Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness 13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis.Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference SEM: -0.90.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3 +/- 3.9 mL, P=0.036), decreased global longitudinal strain (-1.4 +/- 0.6%, P=0.015), and increased cardiac output (0.38 +/- 0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01).Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis.
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| 24. |
- Suhr, Ole B., et al.
(författare)
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Efficacy and safety of patisiran for familial amyloidotic polyneuropathy : a phase II multi-dose study
- 2015
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development.
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