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Inclisiran marches on: ORION-4 cardiovascular outcomes study launches

Highlights from ACC.2018

The pace of development of inclisiran, an investigational GalNAc-conjugated RNA interference therapeutic, which reduces synthesis of PCSK9 protein in liver cells, thereby reducing liver cell LDL-receptor turnover, and lowering plasma LDL cholesterol levels is accelerating. Prior to ACC.2018, it was announced that ORION-10, a Phase III pivotal clinical trial in patients with atherosclerotic cardiovascular disease (ASCVD) has now completed enrolment of more than 1,500 patients in 12 weeks, beating the goal of 22 weeks set by developers.1 In addition, it was announced earlier this year that two other Phase III studies, ORION-9 in heterozygous familial hypercholesterolaemia (FH, inherited high cholesterol)2, and ORION-11 in ASCVD patients,3 have also completed enrolment. In addition, ORION-5 in patients with homozygous FH is due to complete enrolment in quarter 3 of this year.

Extended safety and tolerability data for inclisiran are favourable. In a Data Safety Monitoring Board review in January 2018 including data from 792 patients, here was a very low incidence of reported mild, transient skin reactions and no reports of clinically relevant abnormalities in liver function tests. It is anticipated that during 2018, there will be more 6000 patient-years of safety data, including data for 3 and 4-5 doses.

This rapid development of inclisiran has paved the way for the launch of a cardiovascular outcomes study, ORION-4, which will be conducted jointly by Oxford Clinical Trials Unit in the UK, and the TIMI group in the USA. In this trial, ≥15,000 patients aged at least 55 years with stable ASCVD (with a prior stroke, myocardial infarction [MI] or peripheral artery disease) and LDL cholesterol levels ≥100 mg/dl (2.6 mmol/L) will be randomized to inclisiran 300 mg subcutaneously, administered at randomization (after optimization of concomitant lipid lowering therapy during a 8 week run-in period), 3 months and every 6 months thereafter, or matching placebo.  Patients with an acute coronary syndrome within 4 weeks, planned coronary revascularization procedure within 6 months, known chronic liver disease, or with medical history that might limit participation in this 5-year study will be excluded.

The primary endpoint is a composite of coronary heart disease death, MI, fatal or non-fatal ischaemic stroke or urgent coronary revascularization. The key secondary outcomes will be a composite of CHD death or MI, or cardiovascular death. The median duration of follow-up planned is 5 years.

Professor Marc Sabatine (Brigham and Women’s Hospital and Harvard Medical School, Boston, USA) discusses how the ODYSSEY Outcomes and FOURIER studies have been critical in the development of ORION-4 with inclisiran.

References

  1. The Medicines Company. Press release 8 March 2018.The Medicines Company Reaches Enrollment Target for ORION-10 Ahead of Schedule http://www.themedicinescompany.com/investors/news/medicines-company-reaches-enrollment-target-orion-10-ahead-schedule
  2. The Medicines Company. Press release 20 February 2018. The Medicines Company Reaches Enrollment Target for ORION-9 Ahead of Schedule http://www.themedicinescompany.com/investors/news/medicines-company-reaches-enrollment-target-orion-9-ahead-schedule
  3. The Medicines Company. Press release 25 January 2018. Inclisiran’s First Pivotal Trial Achieves Target Enrollment Ahead of Schedule http://www.themedicinescompany.com/investors/news/inclisiran’s-first-pivotal-trial-achieves-target-enrollment-ahead-schedule

 

Related materials

VIDEO: Prof Kausik Ray: Inclisiran, new kid on the block, looks good in ORION  https://www.pcsk9forum.org/prof-kausik-ray-inclisiran-new-kid-on-the-block-looks-good-in-orion/

ARTICLE: Ray KK, Landmesser U, Leiter LA et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28306389

Inclisiran clinical trial resource https://www.pcsk9forum.org/education-resources/trials/inclisiran/

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