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


BACKGROUND
NCT01617967 .
Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, Sweden. Ole.suhr@medicin.umu.se.
Ole B
OB
Suhr
Hospital de Santo António, Centro Hospitalar do Porto, 4099-001, Porto, Portugal. tcoelho@netcabo.pt.
Teresa
T
Coelho
Servicio de Medicina Interna, Hospital Son Llatzer, Carretera Manacor KM, 7198, Palma de Mallorca, Spain. doctorjuanbuades@gmail.com.
Juan
J
Buades
Hôpital de La Timone, 264 rue Saint Pierre, 13005, Marseille, France. jeanyves.pouget@ap-hm.fr.
Jean
J
Pouget
Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Piso 7, Av, Prof Eqas Moniz, Lisboa, 1649-028, Portugal. imsconceicao@gmail.com.
Isabel
I
Conceicao
Boston University, 72 East Concord Street, K-503, Boston, MA, 02118, USA. jberk@bu.edu.
John
J
Berk
Universitätsklinikum Münster, Transplant Hepatology, Domagkstr. 3A, Munster, 48149, Germany. hepar@ukmuenster.de.
Hartmut
H
Schmidt
Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Ilha do Fundao, Rio de Janeiro, CEP21941-913, Brazil. mwaddingtoncruz@gmail.com.
Márcia
M
Waddington-Cruz
Hospital Clinic, University of Barcelona, IDIBAPS, Escalera 12 (5 Planta), C/ Villarroel, 170, Barcelona, 8036, Spain. jmcampis@clinic.ub.es.
Josep M
JM
Campistol
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA. bbettencourt@alnylam.com.
Brian R
BR
Bettencourt
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA. avaishnaw@alnylam.com.
Akshay
A
Vaishnaw
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA. jgollob@alnylam.com.
Jared
J
Gollob
National Reference Center for FAP (NNERF)/ APHP/ INSERM U 1191/ Hôpital de Bicêtre, 78, rue du General Leclerc, 94275, Le Kremlin-Bicêtre, France. david.adams@bct.aphp.fr.
David
D
Adams
D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*
D034741:RNA, Small Interfering; C000606954:patisiran