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Clinical Trial
. 2023 Sep;29(9):2216-2223.
doi: 10.1038/s41591-023-02494-2. Epub 2023 Aug 25.

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts

Gerald F Watts  1 , Christian Schwabe  2 , Russell Scott  3 , Patrick A Gladding  4 , David Sullivan  5 , John Baker  6 , Peter Clifton  7 , James Hamilton  8 , Bruce Given  8 , Stacey Melquist  8 , Rong Zhou  8 , Ting Chang  8 , Javier San Martin  8 , Daniel Gaudet  9 , Ira J Goldberg  10 , Joshua W Knowles  11 , Robert A Hegele  12 , Christie M Ballantyne  13
Affiliations
Clinical Trial

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts

Gerald F Watts et al. Nat Med. 2023 Sep.

Abstract

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.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. CONSORT diagrams.
a,b, Participant allocation for the SAD and MAD HP cohorts (a) and dyslipidemic cohorts (b) in the phase 1 AROANG1001 study. Note: The key results from this study are first reported for HPs and individuals with hepatic steatosis.
Extended Data Fig. 1
Extended Data Fig. 1. Study Schema.
This schema reflects the basket trial approach taken in this Phase 1 study AROANG1001 to evaluate early proof of-concept, in which healthy participants (HPs) and patients with various dyslipidemias were enrolled. In this report, we present the key results from this study showing the safety, tolerability, and pharmacodynamic effects of single ascending doses of ARO-ANG3 in HPs and multiple doses of ARO-ANG3 in both HPs and a cohort of patients with baseline hepatic steatosis. These cohorts are shown in red boxes.
Extended Data Fig. 2
Extended Data Fig. 2. Individual absolute changes in liver fat content measured using magnetic resonance imaging-proton density fat fraction at Day 71 (A) and Day 168 (B) post dose for participants with hepatic steatosis receiving repeat doses of 200 mg ARO-ANG3 or placebo.
Waterfall plots showing individual absolute changes in liver fat content, measured using magnetic resonance imaging-proton density fat fraction (MRI-PDFF), at post-dose Day 71 (A) and Day 168 (B) for participants with hepatic steatosis receiving repeat doses of 200 mg ARO-ANG3 or receiving placebo.
Extended Data Fig. 3
Extended Data Fig. 3. Reductions in serum ANGPTL3, TG, LDL-C, VLDL-C, HDL-C, and non-HDL-C concentrations in healthy participants with single ascending doses of ARO-ANG3 or placebo.
Median percent change (+/-Q1,Q3) from baseline in triglycerides (B). Mean percent change (±SD) from baseline in ANGPTL3 (A), VLDL-C (C), non-HDL-C (D), LDL-C (E), HDL-C (F), and ApoB (G) in healthy participants receiving a subcutaneous dose of ARO-ANG3 (n = 4 per cohort of 35 mg [blue] 100 mg [red], 200 mg [green], 300 mg [purple]) or placebo [orange] on Day 1). Abbreviations: ApoB = Apolipoprotein B; HDL-C = high density lipoprotein cholesterol; Q1, Q3 = quartile 1, quartile 3; LDL-C = low density lipoprotein cholesterol; SD = standard deviation; VLDL = very low density cholesterol.
Extended Data Fig. 4
Extended Data Fig. 4. Reductions in serum ANGPTL3, TG, LDL-C, VLDL-C, HDL-C, non-HDL-C, and ApoB concentrations in healthy participants with multiple ascending doses of ARO-ANG3.
Median percent change (Q1, Q3) from baseline in triglycerides (B). Mean percent change (±SD) from baseline in ANGPTL3 (A), VLDL-C (C), non-HDL-C (D), LDL-C (E), HDL-C (F), and ApoB (G) in healthy participants receiving a subcutaneous dose of ARO-ANG3 (n = 4 per cohort of 100 mg [red], 200 mg [green] or 300 mg [purple]) on Days 1 and 29). Abbreviations: ApoB = Apolipoprotein B; HDL-C = high density lipoprotein cholesterol; Q1 = quartile 1; Q3 = quartile 3; LDL-C = low density lipoprotein cholesterol; SD = standard deviation; VLDL = very low density cholesterol.
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