Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study

Orphanet Journal of Rare Diseases

David Adams⁸  Jared Gollob⁷  Akshay Vaishnaw⁷  Brian R. Bettencourt⁷  Josep M. Campistol⁵  Márcia Waddington-Cruz⁶  Hartmut Schmidt¹  John Berk⁹  Isabel Conceicao^1,10  Jean Pouget³  Juan Buades⁴  Teresa Coelho²  Ole B Suhr^1,11 

[1] Universitätsklinikum Münster, Transplant Hepatology, Domagkstr. 3A, Munster 48149, Germany;Hospital de Santo António, Centro Hospitalar do Porto, Porto, 4099-001, Portugal;Hôpital de La Timone, 264 rue Saint Pierre, Marseille, 13005, France;Servicio de Medicina Interna, Hospital Son Llatzer, Carretera Manacor KM, Palma de Mallorca, 7198, Spain;Hospital Clinic, University of Barcelona, IDIBAPS, Escalera 12 (5 Planta), C/ Villarroel, 170, Barcelona 8036, Spain;Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Ilha do Fundao, Rio de Janeiro CEP21941-913, Brazil;Alnylam Pharmaceuticals, 300 Third Street, Cambridge 02142, MA, USA;National Reference Center for FAP (NNERF)/ APHP/ INSERM U 1191/ Hôpital de Bicêtre, 78, rue du General Leclerc, Le Kremlin-Bicêtre, 94275, France;Boston University, 72 East Concord Street, K-503, Boston 02118, MA, USA;Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Piso 7, Av, Prof Eqas Moniz, Lisboa 1649-028, Portugal;Department of Public Health and Clinical Medicine, Umeå University, Umeå, 901 87, Sweden

关键词: Clinical trial;    Phase II;    Genetic mutation;    Hereditary disease;    Polyneuropathy;    Transthyretin-mediated familial amyloidotic polyneuropathy;    RNA interference;    Patisiran;   

Others  :  1224095
DOI  :  10.1186/s13023-015-0326-6

 received in 2015-04-16, accepted in 2015-08-25,  发布年份 2015

【 摘 要 】

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.

Trial registration number

NCT01617967.

【 授权许可】

   
2015 Suhr et al.

【 图 表 】

Fig. 1.

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