| 1. |
- Adams, David, et al.
(författare)
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Phase 2 open-label extension study of patisiran, an investigational RNAi therapeutic for the treatment of familial amyloid polyneuropathy
- 2015
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 86:11
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Familial amyloid polyneuropathy (FAP) is a progressive disease. Patisiran is an investigational small interfering RNA (siRNA) targeting TTR. The primary objective of the Phase 2 study is to evaluate the safety of 0.3 mg/kg patisiran administered intravenously once every 3 weeks. Twenty-seven patients were enrolled; the mean duration of treatment was 7 months (range 3–12), with 282 doses administered (median of 11 doses/patient). Chronic dosing with patisiran has been generally well tolerated. Two patients experienced serious adverse events regarded as being unrelated to study drug. Infusion-related reactions were observed in 14.8% of the patients, were mild in severity, and did not result in any discontinuations. Sustained TTR lowering of at least 80% was achieved based on serial TTR measurements for over 9 months, with further nadir of up to 89.6% between doses. Neurologic impairment scores were stable after 6 months of treatment with patisiran. A mean decrease from baseline in mNIS+7 of 0.95 points (N=19) observed in this study compared favorably to the estimated increase of 7–10 points in mNIS+7 at 6 months from prior FAP studies in a patient population with similar baseline NIS values. Dosing continues in all patients, and 12–month results will be presented.
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| 2. |
- Adams, David, et al.
(författare)
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Phase 2 open-label extention (OLE) study of patisiran, an investigational siRNA agent for familial amyloidotic polyneuropathy (FAP)
- 2015
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Ingår i: Orphanet Journal of Rare Diseases. - : BioMed Central (BMC). - 1750-1172. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Familial amyloidotic polyneuropathy (FAP) is a progressive and fatal, autosomal dominant disease caused by deposition of mutant and wild-type transthyretin (TTR). Patisiran is an investigational, systemically administered lipid nanoparticle (LNP) formulation of a small interfering RNA (siRNA) targeting wild-type and mutant TTR. This formulation delivers the siRNA predominantly to the liver, thereby inhibiting synthesis of TTR at the primary site of production. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in FAP 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 (Suhr O, ISA 2014).Methods: A Phase 2 open-label extension (OLE) study of patisiran in patients with FAP who participated in the aforementioned trial, was initiated in October 2013. The primary objective of the study is to evaluate the safety and tolerability of 0.3 mg/kg patisiran administered intravenously once every 3 weeks for up to 2 years. Secondary objectives include assessment of patisiran's effect on serum TTR levels, as well as evaluation every 6 months of its impact on clinical measures, including the mNIS+7 composite neurologic impairment score and quality of life (QOL).Results: Twenty-seven patients were enrolled; median age 64 years (range: 29-77 years). Chronic dosing with patisiran has been generally well tolerated. Three patients experienced serious adverse events unrelated to study drug. Flushing and infusion-related reactions were observed in 22.2% and 18.5% of the patients, respectively; these were mild in severity, and did not result in any discontinuations. Sustained mean serum TTR lowering of approximately 80% was achieved, with further mean nadir of up to 88% between doses for approximately 16 months. Stabilization of quality of life (QOL) measures was observed. Among the 20 evaluable patients at the time of data cutoff, neuropathy impairment scores were stable through 12 months with a mean change in mNIS+7 and NIS of -2.5 and 0.4 points, respectively; this compares favorably to the 10-18 point increase in neurologic impairment scores estimated at 12 months from prior FAP studies in a patient population with similar baseline NIS.Conclusion: Data from this Phase 2 OLE study demonstrate that 12-months of patisiran administration was well-tolerated, resulted in sustained mean serum TTR lowering, and has the potential to halt neuropathy progression. As of March 2015, dosing continues for all patients; 18-month results will be presented.
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| 3. |
- Schmidt, Hartmut, et al.
(författare)
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Patisiran ph 2 open-label extension study in Familial Amyloidotic Polyneuropathy
- 2016
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 87:12
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Familial Amyloid Polyneuropathy (FAP) is a progressive disease caused by deposition of transthyretin (TTR). Patisiran is an investigational, small interfering RNA (siRNA) inhibiting TTR. This abstract highlights patisiran's long-term safety. Methods: Phase 2 OLE study to evaluate patisiran's safety. Patisiran's effect on serum TTR levels, impact on neuropathy impairment scores and QOL were assessed. Results: 27 patients with FAP enrolled; median age 64 years. Patisiran was generally well tolerated out to 23-months. Five patients experienced SAEs (unrelated) including one discontinuation (gastroesophageal cancer); patient subsequently died. Flushing (25.9%) and infusion-related reactions (18.5%) were mild in severity; no discontinuations resulted. Approximately 80% sustained mean serum TTR lowering resulted with a mean nadir of up to 93% between doses. Among the 20 evaluable patients, neuropathy impairment scores were stable through 18-months; 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 estimated at 18-months from prior FAP studies. Stabilization of QOL measures and improvement of distal thigh sweat gland nerve fiber density observed. Conclusion: Data demonstrates that 18-months of patisiran administration was generally well tolerated, resulted in sustained mean serum TTR lowering, supporting the hypothesis that TTR knockdown potentially halts neuropathy progression.
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| 4. |
- 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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