TY - JOUR
T1 - RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering
T2 - phase 1 basket trial cohorts
AU - Watts, Gerald F.
AU - Schwabe, Christian
AU - Scott, Russell
AU - Gladding, Patrick A.
AU - Sullivan, David
AU - Baker, John
AU - Clifton, Peter
AU - Hamilton, James
AU - Given, Bruce
AU - Melquist, Stacey
AU - Zhou, Rong
AU - Chang, Ting
AU - San Martin, Javier
AU - Gaudet, Daniel
AU - Goldberg, Ira J.
AU - Knowles, Joshua W.
AU - Hegele, Robert A.
AU - Ballantyne, Christie M.
N1 - Funding Information:
This study was supported by Arrowhead Pharmaceuticals, Inc. We thank the patients for their participation in the AROANG1001 study and the staff at each clinical trial site. The study was designed by the lead principal investigator and Arrowhead Pharmaceuticals, Inc. Arrowhead Pharmaceuticals, Inc. contributed to data collection and data interpretation in collaboration with all investigators, funded data analyses and participated in manuscript preparation with all authors. We thank J. Abbott from Arrowhead Pharmaceutical, Inc. for medical writing support, which was funded by Arrowhead Pharmaceuticals, Inc. in accordance with Good Publication Practice guidelines ( http://www.ismpp.org/gpp3 ).
Funding Information:
G.F.W. (corresponding author) reports personal fees for lectures from Amgen, Novartis and Sanofi; research grants from Amgen and Arrowhead Pharmaceuticals; and honoraria for serving on advisory boards from Amgen, AstraZeneca, Esperion, Novartis, Pfizer and Arrowhead Pharmaceuticals. J.H., B.G., S.M., J.S.M., T.C. and R.Z. are, or were recently, Arrowhead Pharmaceuticals employees and shareholders. I.G. reports being on advisory boards for Arrowhead Pharmaceuticals and Ionis. C.B. reports grant/research support (all substantial (>$10,000) and all paid to institution, not individual) from Akcea, Amgen, Arrowhead Pharmaceuticals, Esperion, Ionis, Merck, Novartis, Novo Nordisk, Regeneron and National Institutes of Health and consultant for 89Bio, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Denka Seiken*, Eli Lilly, Esperion, Genentech, Gilead, Illumina, Matinas BioPharma, Merck, New Amsterdam*, Novartis, Novo Nordisk, Pfizer, Regeneron and Sanofi-Synthelabo (*substantial where noted). P.G. reports being principal investigator for Verve101 and receiving consulting fees from Verve Therapeutics. R.H. reports consulting fees from Acasti, Akcea/Ionis, Amgen, Amryt, Arrowhead Pharmaceuticals, Boston Heart, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi and Ultragenyx. D.G. reports grants and/or personal fees from Arrowhead Pharmaceuticals, Acasti, Amgen, Kowa, Regeneron, Uniqure, Akcea, Allergan, Amryt, CRISPR Therapeutics, Eli Lilly, Ionis, Novartis, Biogen, Sanofi, Novo Nordisk, Pfizer, Verve Therapeutics, Aegerion, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Ceapro, Dalcor, Esperion and The Medicine Company. D.S. reports honoraria for serving on advisory boards from Regeneron, Amgen, AstraZeneca, Amarin, Esperion, Novartis and Sanofi, outside the submitted work. No competing interests are reported by C.S., P.C., R.S., J.B. and J.K.
Publisher Copyright:
© 2023, Crown.
PY - 2023/9
Y1 - 2023/9
N2 - 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 T max of 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t ½ 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.
AB - 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 T max of 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t ½ 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.
UR - http://www.scopus.com/inward/record.url?scp=85168959636&partnerID=8YFLogxK
U2 - 10.1038/s41591-023-02494-2
DO - 10.1038/s41591-023-02494-2
M3 - Article
C2 - 37626170
AN - SCOPUS:85168959636
SN - 1078-8956
VL - 29
SP - 2216
EP - 2223
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -
