Z Gastroenterol 2015; 53 - KC091
DOI: 10.1055/s-0035-1559481

siRNA Phase 2 Open-Label Extension Study for Treating Familial Amyloid Polyneuropathy

H Schmidt 1, T Coelho 2, O Suhr 3, I Conceicao 4, M Waddington-Cruz 5, J Buades 6, J Campistol 7, J Pouget 8, J Berk 9, J Gollob 10, D Adams 11
  • 1Universitätsklinikum Münster, Klinik für Transplantationsmedizin, Münster, Deutschland
  • 2Institution, Klinik, Hospital de Santo Antonio, Porto, Portugal
  • 3Institution, Umea University, Abteilung, Umea, Schweden
  • 4Hospital de Santa Maria, Klinik, Abteilung, Lisbon, Portugal
  • 5Institution, Hospital Universitario Clementino Fraga Filho, Abteilung, Rio de Janeiro, Brasilien
  • 6Institution, Hospital Son Llatzer, Abteilung, Palma de Mallorca, Spanien
  • 7Institution, Hospital Clinic, Abteilung, Barcelona, Spanien
  • 8Institution, Hopital de la Timone, Abteilung, Marseille, Frankreich
  • 9Institution, Boston University, Abteilung, Boston, Vereinigte Staaten
  • 10Institution, Alnylam Pharmaceuticals, Abteilung, Cambridge, Vereinigte Staaten
  • 11Institution, Hopital de Bicetre, Abteilung, Paris, Frankreich

Einleitung: Familial amyloid polyneuropathy (FAP) is a progressive and fatal, autosomal dominant disease caused by deposition of mutant and wild-type transthyretin (TTR). Liver transplantation serves currently as therapeutic standard. Patisiran is an investigational systemically administered lipid nanoparticle formulation of a small interfering RNA (siRNA) targeting wild-type and mutant TTR.

Material und Methoden: A Phase 2 open-label extension (OLE) study of patisiran in patients with FAP who participated in the Phase 2 patisiran trial, was initiated in October 2013. The primary objective of the study is to evaluate the safety and tolerability of patisiran 0.3 mg/kg every 3 weeks.

Ergebnisse: Twenty-seven patients were enrolled onto the trial; as of September 8, 2014, 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 in FAP patients, including those on concurrent TTR tetramer stabilizers (tafamidis or diflunisal). 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. No clinically significant changes in liver function tests, renal function or hematological parameters have been observed. 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 in patients with or without concurrent TTR tetramer stabilizers. 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. Stabilization of QOL measures as well as of additional neurologic and cardiac assessments were also observed in this Phase 2 OLE study.

Schlussfolgerung: As of March 31st, 2015, dosing continues in all patients, and results for these various measures from the next follow-up at 12 months will be presented.