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RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.
Watts, Gerald F; Schwabe, Christian; Scott, Russell; Gladding, Patrick A; Sullivan, David; Baker, John; Clifton, Peter; Hamilton, James; Given, Bruce; Melquist, Stacey; Zhou, Rong; Chang, Ting; San Martin, Javier; Gaudet, Daniel; Goldberg, Ira J; Knowles, Joshua W; Hegele, Robert A; Ballantyne, Christie M.
Afiliação
  • Watts GF; School of Medicine, University of Western Australia, Perth, Western Australia, Australia. gerald.watts@uwa.edu.au.
  • Schwabe C; Auckland Clinical Studies, Auckland, New Zealand.
  • Scott R; New Zealand Clinical Research Christchurch, Christchurch, New Zealand.
  • Gladding PA; Te Whatu Ora Waitemata, Auckland, New Zealand.
  • Sullivan D; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
  • Baker J; Middlemore Hospital, Auckland, New Zealand.
  • Clifton P; Royal Adelaide Hospital, Adelaide, South Australia, Australia.
  • Hamilton J; Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
  • Given B; Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
  • Melquist S; Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
  • Zhou R; Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
  • Chang T; Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
  • San Martin J; Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
  • Gaudet D; Department of Medicine, Université de Montréal and ECOGENE 21 Clinical Research Center, Chicoutimi, Quebec, Canada.
  • Goldberg IJ; NYU School of Medicine, NYU Langone Health, New York City, NY, USA.
  • Knowles JW; Stanford Division of Cardiovascular Medicine and Cardiovascular Institute, School of Medicine, Stanford, CA, USA.
  • Hegele RA; University of Western Ontario, London, Ontario, Canada.
  • Ballantyne CM; Baylor College of Medicine, Houston, TX, USA.
Nat Med ; 29(9): 2216-2223, 2023 09.
Article em En | MEDLINE | ID: mdl-37626170
Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aterosclerose / Proteína 3 Semelhante a Angiopoietina Tipo de estudo: Clinical_trials / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aterosclerose / Proteína 3 Semelhante a Angiopoietina Tipo de estudo: Clinical_trials / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália