Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease

Summary

This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lipoprotein(a) \[Lp(a)\] levels in participants with hyperlipoproteinemia(a) and established cardiovascular disease (CVD).

Timeline

Start

2017-03-07

Primary completion

2018-07-26

Completion

2018-11-13

Outcome

Met primary endpoint

registry analysis (superiority test); Cohort A: ISIS 681257: 20 mg Q4W vs Placebo; p = 0.0032; Mean Difference in % CFB -31 (95% CI -46 to -12); ANCOVA NCT03070782 ↗

registry analysis (superiority test); Cohort B: ISIS 681257: 40 mg Q4W vs Placebo; p <.0001; Mean Difference in % CFB -54 (95% CI -64 to -41); ANCOVA NCT03070782 ↗

registry analysis (superiority test); Cohort C: ISIS 681257: 60 mg Q4W vs Placebo; p <.0001; Mean Difference in % CFB -70 (95% CI -77 to -62); ANCOVA NCT03070782 ↗

registry analysis (superiority test); Cohort D: ISIS 681257: 20 mg Q2W vs Placebo; p <.0001; Mean Difference in % CFB -56 (95% CI -65 to -43); ANCOVA NCT03070782 ↗

registry analysis (superiority test); Cohort E: ISIS 681257: 20 mg QW vs Placebo; p <.0001; Mean Difference in % CFB -78 (95% CI -83 to -72); ANCOVA NCT03070782 ↗

Publications

• Tekendo-Ngongang C, Gleeson JG, Mignon L. Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases. J Am Soc Nephrol. 2024 Dec 1;35(12):1774-1777. doi: 10.1681/ASN.0000000532. Epub 2024 Sep 27. No abstract available.
• Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, Kroon J, Schnitzler JG, Dzobo KE, Cupido AJ, Tsimikas S, Stroes ESG, de Winther MPJ, Bahjat M. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur Heart J. 2020 Jun 21;41(24):2262-2271. doi: 10.1093/eurheartj/ehaa171.
• Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Pelacarsen	Antisense oligonucleotide	20 mg	Subcutaneous
Subject	Pelacarsen	Antisense oligonucleotide	40 mg	Subcutaneous
Subject	Pelacarsen	Antisense oligonucleotide	60 mg	Subcutaneous

Indications