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RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia.
Gaudet, Daniel; Clifton, Peter; Sullivan, David; Baker, John; Schwabe, Christian; Thackwray, Susan; Scott, Russell; Hamilton, James; Given, Bruce; Melquist, Stacey; Zhou, Rong; Chang, Ting; San Martin, Javier; Watts, Gerald F; Goldberg, Ira J; Knowles, Joshua W; Hegele, Robert A; Ballantyne, Christie M.
Afiliação
  • Gaudet D; Department of Medicine, Université de Montréal and ECOGENE 21 Clinical Research Center, Chicoutimi, Quebec, QC, Canada.
  • Clifton P; Royal Adelaide Hospital, Adelaide, SA, Australia.
  • Sullivan D; NSW Health Pathology, Royal Prince Alfred Hospital, Sydney.
  • Baker J; Middlemore Hospital, Auckland, New Zealand.
  • Schwabe C; Auckland Clinical Studies, Auckland, New Zealand.
  • Thackwray S; University of the Sunshine Coast, Sippy Downs, QLD, Australia.
  • Scott R; NZ Clinical Research, Christchurch, New Zealand.
  • Hamilton J; Arrowhead Pharmaceuticals, Inc., Pasadena, CA.
  • Given B; Arrowhead Pharmaceuticals, Inc., Pasadena, CA.
  • Melquist S; Arrowhead Pharmaceuticals, Inc., Pasadena, CA.
  • Zhou R; Arrowhead Pharmaceuticals, Inc., Pasadena, CA.
  • Chang T; Arrowhead Pharmaceuticals, Inc., Pasadena, CA.
  • San Martin J; Arrowhead Pharmaceuticals, Inc., Pasadena, CA.
  • Watts GF; School of Medicine, University of Western Australia, Perth, Australia.
  • Goldberg IJ; Department of Cardiology, Royal Perth Hospital, Perth, Australia.
  • Knowles JW; NYU Grossman School of Medicine, New York.
  • Hegele RA; Stanford Division of Cardiovascular Medicine and Cardiovascular Institute, School of Medicine, Stanford, CA.
  • Ballantyne CM; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
NEJM Evid ; 2(12): EVIDoa2200325, 2023 Dec.
Article em En | MEDLINE | ID: mdl-38320498
ABSTRACT

BACKGROUND:

Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase­mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment.

METHODS:

Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels.

RESULTS:

Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10

participants:

1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo.

CONCLUSIONS:

In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipertrigliceridemia Tipo de estudo: Clinical_trials Limite: Humans Idioma: En Revista: NEJM Evid Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipertrigliceridemia Tipo de estudo: Clinical_trials Limite: Humans Idioma: En Revista: NEJM Evid Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá