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Antisense Drug Reduced LPa; in Phase 3 Study
Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON)
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https://clinicaltrials.gov/ct2/show/NCT04023552
Brief Summary:
This is a pivotal phase 3 study designed to support an indication for the reduction of cardiovascular risk in patients with established CVD and elevated Lp(a).
TQJ230 80 mg injected monthly administered subcutaneously
7680 participants
Recruitment Status : Active, not recruiting
First Posted : July 17, 2019
Last Update Posted : August 25, 2022
Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
Actual Study Start Date : December 12, 2019
Estimated Primary Completion Date : May 29, 2025
Estimated Study Completion Date : May 30, 2025
Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol
J Am Coll Cardiol. 2022 Mar pdf attached
Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%.
The phase 2B trial of pelacarsen was previously reported.12 In brief, it was a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening Lp(a) levels ≥60 mg/dL (≥150 nmol/L). Patients received the hepatocyte-directed antisense oligonucleotide pelacarsen at 20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week (cumulative doses of 20, 40, 60, and 80 mg monthly), or they received saline placebo subcutaneously for 6 to 12 months. The primary endpoint was the percent change in Lp(a) levels from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).
Introduction
Approximately 60 years since its discovery, lipoprotein(a) [Lp(a)] is now accepted as a genetic, independent, and likely causal risk factor for cardiovascular disease.1-3 Lp(a) is a risk factor in primary prevention settings,4,5 as well as in patients on statins and those enrolled in PCSK9 inhibitor trials.6,7 In particular, alirocumab provides significant risk reduction in recurrent events following acute coronary syndromes, with each 5-mg/dL reduction in Lp(a) predicted to reduce the event rate by 2.5%.8 Similarly, the reduction in Lp(a) was associated with reduced risk for recurrent events with evolocumab.6There are now multiple RNA-based therapeutics in clinical development, with the antisense oligonucleotide pelacarsen the most advanced.9 The Lp(a) HORIZON (A Randomized Double-blind, Placebo-controlled, Multicenter Trial Assessing the Impact of Lipoprotein (a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With Established Cardiovascular Disease) trial is currently enrolling subjects with Lp(a) ≥70 mg/dL (∼≥175 nmol/L) and history of prior myocardial infarction, stroke, or significant, symptomatic peripheral arterial disease to pelacarsen 80 mg monthly vs placebo.
In prior studies of pelacarsen, it was been observed that not only does it lower Lp(a) but it also lowers oxidized phospholipids (OxPL) on apolipoprotein(a) [apo(a)] and apolipoprotein B-100 (apoB) by 70%-88% as well modestly lowering laboratory-reported low-density lipoprotein levels (LDL-C) up to 26% and total apoB levels up to 16% at highest doses used.10-12 The reductions noted on OxPL-apo(a) and OxPL-apoB were not unexpected, because it has been shown that Lp(a) is a preferential lipoprotein carrier of OxPL.13,14 However, the effects on LDL-C and apoB were somewhat surprising, because pelacarsen has no known direct effect on hepatic apoB production.15 Whether the changes in LDL-C are a real physiological effect or a byproduct of the fact that laboratory measures of LDL-C include both true LDL-C plus Lp(a) cholesterol [Lp(a)-C],16 which might also be expected to decline, is not known.
Laboratory-reported LDL-C methods, including Friedewald or Martin-Hopkins formulas, ultracentrifugation, or direct LDL-C measurements, all have the limitation that they cannot measure LDL-C independent of Lp(a)-C, and thus, the reported “LDL-C” is a combination of true LDL-C plus Lp(a)-C (and also intermediate density lipoprotein cholesterol if it is present in fasting samples).16 This is likely of little clinical relevance in subjects with normal Lp(a) levels (<30 mg/dL), but in subjects with elevated Lp(a) that may represent 20%-30% of the population, Lp(a)-C may constitute a substantial proportion of the reported LDL-C.17 Currently, a major limitation of interpreting such studies is that Lp(a)-C has to be mathematically estimated, most commonly with the Dahlén formula,18,19 because of the lack of a validated, quantitative method to measure Lp(a)-C.
We recently described a novel, quantitative, sensitive, high-throughput method to directly measure Lp(a)-C on isolated Lp(a) holoparticles.20 We now apply this method to assess the effect of pelacarsen on directly measured Lp(a)-C and on corrected LDL-C without the interference of Lp(a)-C.
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Ionis announces enrollment completion of Phase 3 Lp(a) HORIZON cardiovascular outcomes
study of pelacarsen
Jul 20, 2022, 07:05 ET
• Pelacarsen is a potentially first-in-class treatment specifically targeting elevated lipoprotein(a) (Lp(a)), an independent, inherited and causal risk factor for cardiovascular disease
• There are currently no approved pharmacological therapies to effectively lower Lp(a), which cannot be effectively addressed by diet and other lifestyle changes
• Topline results expected 2025
CARLSBAD, Calif., July 20, 2022 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. ( Nasdaq: IONS) today announced that Novartis has completed patient enrollment of the pivotal Phase 3 Lp(a) HORIZON cardiovascular outcomes study of pelacarsen, with 8,325 study participants. Lp(a) HORIZON is evaluating the safety and efficacy of pelacarsen in reducing cardiovascular events in patients with cardiovascular disease and elevated levels of Lp(a). Topline data from the study are expected in 2025. Novartis licensed pelacarsen from Ionis in 2019.
Pelacarsen, formerly IONIS-APO(a)-LRx, is an investigational antisense medicine designed to inhibit the production of apolipoprotein(a) in the liver to reduce elevated lipoprotein(a) or Lp(a) levels, an independent, inherited and causal risk factor for cardiovascular disease (CVD) and calcific aortic valve stenosis. High Lp(a) levels, which are associated with significant risk of coronary heart disease, cannot be reduced with lifestyle modifications or with existing lipid-lowering therapies. Pelacarsen uses Ionis' Ligand-Conjugated Antisense (LICA) technology platform.
"Completing enrollment of this pivotal outcomes study brings us closer to the day when this potentially transformative treatment is available to patients," said Sotirios "Sam" Tsimikas, M.D., senior vice president, clinical development and cardiovascular franchise leader at Ionis, who specializes in Lp(a). "There are no approved pharmacological therapies to effectively lower Lp(a) for the more than eight million patients living with cardiovascular disease and elevated levels of Lp(a) worldwide. We are grateful to the patients, investigators and site staff who are participating to make the Phase 3 Lp(a) HORIZON study possible."
Data from a Phase 2 study showed pelacarsen reduced Lp(a) levels below the recommended threshold of risk for CVD events (<50 mg/dL, <125 nmol/L) in 98% of participants with the dose being used in the Lp(a) HORIZON study.
Additional information about Lp(a) HORIZON (NCT04023552) may be found at ClinicalTrials.gov.
About Lp(a) HORIZON
Lp(a) HORIZON is a global, multicenter, double-blind, placebo-controlled pivotal Phase 3 study conducted by Novartis. The study is designed to support an indication for the reduction of cardiovascular risk in patients with established CVD and elevated Lp(a) with 80 mg of pelacarsen administered monthly via subcutaneous administration. The study has enrolled 8,325 participants. Topline results are expected in 2025.
The primary objectives of the study are to demonstrate superiority compared to placebo in reducing the risk of expanded MACE (Major Adverse Cardiac Events) such as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and urgent coronary re-vascularization requiring hospitalization in the overall study population with established CVD and Lp(a) ≥ 70 mg/dL, and in the population with Lp(a) ≥ 90 mg/dL.
About Lp(a)
Lp(a) is a lipoprotein particle assembled in the liver that consists of an LDL-C-like particle and apolipoprotein(a). Lp(a) levels in the blood can vary greatly between individuals primarily due to genetic variations and do not correlate with LDL-C levels. Even patients with LDL-C lowered to target levels (<70 mg/dL) remain at high-risk of cardiovascular events if they have high levels of Lp(a). Elevated Lp(a) is a genetically determined condition that is not responsive to lifestyle changes, therefore patients are unable to adequately control their Lp(a) levels through improved diet or increased physical activity. Elevated Lp(a) is recognized as an independent, genetic cause of coronary artery disease, heart attack, stroke, peripheral arterial disease and aortic stenosis. Currently, there is no effective drug therapy to specifically and robustly lower elevated levels of Lp(a).
About Pelacarsen
Pelacarsen, licensed by Novartis for exclusive worldwide development, manufacturing and commercialization, is an investigational antisense medicine designed to reduce apolipoprotein(a) production in the liver to offer a direct approach for reducing circulating lipoprotein(a), or Lp(a), an atherogenic, pro-inflammatory and thrombogenic lipoprotein that induces additional cardiovascular risk independent of LDL-cholesterol, in patients already treated with LDL-C-lowering therapies (such as statins or PCSK9 inhibitors).
https://www.prnewswire.com/news-releases/ionis-announces-enrollment-completion-of-phase-3-lpa-horizon-cardiovascular-outcomes-study-of-pelacarsen-301589746.html
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