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

Autor: Juan Buades, Hartmut Schmidt, Akshay Vaishnaw, Josep M. Campistol, David Adams, Jean Pouget, Jared Gollob, Brian Bettencourt, Ole B. Suhr, Isabel Conceição, Teresa Coelho, John L. Berk, Márcia Waddington-Cruz
Přispěvatelé: Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital Sweden, Hospital de Santo António, Centro Hospitalar do Porto, Servicio de Medicina Interna, Hospital Son Llatzer, Hôpital de la Timone [CHU - APHM] (TIMONE), Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Boston University [Boston] (BU), Universitätsklinikum Münster, Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Hospital Clinic, University of Barcelona, Alnylam Pharmaceuticals, National Reference Center for FAP (NNERF)/ APHP/ INSERM U 1191, Hôpital de Bicêtre, HAL AMU, Administrateur
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Male
neuropatías amiloideas
humanos
Transthyretin-mediated familial amyloidotic polyneuropathy
Genetic mutation
Amyloid Neuropathies
Gastroenterology
0302 clinical medicine
RNA interference
Genetics(clinical)
Pharmacology (medical)
RNA
Small Interfering
mediana edad
Genetics (clinical)
Medicine(all)
anciano
0303 health sciences
education.field_of_study
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
Amyloidosis
General Medicine
Middle Aged
RNA interferenc
Phase II
3. Good health
ARN
Clinical trial
Tolerability
Vomiting
Patisiran
Female
medicine.symptom
Polyneuropathy
medicine.medical_specialty
Population
Hereditary disease
03 medical and health sciences
Pharmacokinetics
Internal medicine
medicine
Humans
education
030304 developmental biology
Aged
Amyloid Neuropathies
Familial
Dose-Response Relationship
Drug
business.industry
Research
medicine.disease
Transthyretin
Endocrinology
Pharmacodynamics
biology.protein
RNA
business
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
030217 neurology & neurosurgery
Zdroj: Orphanet Journal of Rare Diseases
Orphanet Journal of Rare Diseases, BioMed Central, 2015, 10 (109 ), ⟨10.1186/s13023-015-0326-6⟩
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação
instacron:RCAAP
ISSN: 1750-1172
DOI: 10.1186/s13023-015-0326-6⟩
Popis: 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.
All authors were responsible for reviewing and interpreting the data. The authors received editorial support from Adelphi Communications Ltd. Biostatistical analyses were conducted by Veristat LLC, Holliston, MA, USA. The authors acknowledge the support of the following co-investigators: Mercedes Uson, Carles Montala, and Cristina Descals (Hospital Son Llatzer, Palma de Mallorca, Spain), and Cecile Cauquil and Marie Theaudin (Univ Paris-Sud, Le Kremlin-Bicetre, Paris, France). The authors also acknowledge contributions from Dorothee Lamann (Universitatsklinikum Munster, Munster, Germany) who provided technical support and Vanessa Benito who was the Study Coordinator at the Hospital Son Llatzer, Palma de Mallorca, Spain. This study was sponsored by Alnylam Pharmaceuticals, Inc.
Databáze: OpenAIRE
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