Last Two Of Three Big Inclisiran Studies Boosts The Medicines Co.
Executive Summary
Filings for the twice-yearly anti-PCSK9 injection under a partnership with Alnylam are on track, including a fourth quarter submission in the US. Detailed ORION-9 and ORION-10 data will be presented at AHA in November.
The Medicines Co. has completed the Phase III clinical trial program for its PCSK9-targeting small interfering RNA (siRNA) drug inclisiran for the treatment of high LDL cholesterol with positive top-line data from the ORION-9 and ORION-10 studies announced on 25 September. The company said filings for regulatory approvals of inclisiran remain on track for the fourth quarter of 2019 in the US and first quarter of 2020 in the EU.
The ORION-9 results in patients with heterozygous familial hypercholesterolemia (HeFH) and ORION-10 findings in patients with atherosclerotic cardiovascular disease (ASCVD) are "at least as favorable" as the efficacy, safety and tolerability reported recently in ORION-11, The Medicines Co. said. No detailed results from the last two out of three Phase III studies of inclisiran were reported, but the company said they will be presented at the American Heart Association (AHA) Scientific Sessions in November.
A late-breaker presentation of ORION-10 data in ASCVD patients with elevated LDL-cholesterol despite treatment with maximum tolerated doses of other cholesterol-lowering medications – statins or Zetia (ezetimibe) – is scheduled for 16 November at the AHA meeting. The ORION-9 results in HeFH also will be presented in a late-breaker session on 18 November.
For now, TMC noted only that the ORION-9 and ORION-10 studies met all primary and secondary endpoints related to LDL cholesterol reduction as well as changes in lipids and other proteins. No treatment-related renal liver or renal laboratory abnormalities were detected in either study.
The company's stock closed up 5.5% at $49.75 based on the initial ORION-9 and -10 disclosures.
TMC reported top-line results from ORION-11 in late August. Detailed efficacy and safety results presented on 2 September at the European Society of Cardiology congress showed LDL-lowering efficacy on par with the PCSK9-targeting monoclonal antibodies Repatha (evolocumab) from Amgen Inc. and Praluent (alirocumab) from Sanofi and Regeneron Pharmaceuticals Inc., and raised no safety flags. (Also see "What Else Analysts Want To Know About Phase III Data For TMC’s Inclisiran" - Scrip, 26 Aug, 2019.)
While the three-study Phase III program has been completed, TMC is enrolling participants from all three trials in the long-term extension study ORION-8 that's meant to observe safety and efficacy in patients treated with inclisiran for three years.
Preparing To Enter The PCSK9 Battle
The siRNA drug – developed under a collaboration and license agreement with RNA medicines specialist Alnylam Pharmaceuticals Inc. – is designed to be a twice-yearly injection versus Repatha and Praluent, which are administered every two or four weeks.
Inclisiran was given to patients in ORION-9, -10 and -11 at baseline, at three months and every six months thereafter for 18 months. The placebo-controlled studies enrolled a total of 3,660 patients, including 482 people with HeFH in ORION-9, 1,561 people with ASCVD in ORION-10, and 1,617 ASCVD patients in ORION-11.
While inclisiran may have a more convenient, less frequent injection schedule than Repatha and Praluent, the TMC drug has a lot of catching up to do with the Amgen and Sanofi/Regeneron products. Both PCSK9 inhibitors were approved in the US in 2015 and have yet to achieve blockbuster sales despite significant price cuts. (Also see "Sanofi/Regeneron Cut Praluent List Price As PBMs Look To Maintain Rebate Status Quo" - Scrip, 12 Feb, 2019.)
Sanofi and Regeneron won a US label update for Praluent in April that notes the cardiovascular risk reduction observed in the companies' ODYSSEY Outcomes cardiovascular outcomes trial (CVOT). Amgen obtained a similar label claim for Repatha in late 2017. (Also see "Can Sanofi Catch Up With Amgen Now That Praluent Has CV Risk-Reduction Claim?" - Scrip, 29 Apr, 2019.)
An Early CV Benefit Claim For Inclisiran?
TMC initiated its CVOT for inclisiran, ORION-4, in 2018 and the 15,000-patient study has a December 2024 primary completion date, according to clinicaltrials.gov.
However, Evercore ISI analyst Umer Raffat questioned in a 25 September note whether inclisiran could win its initial approvals in HeFH and ASCVD patients with a label claim that the siRNA drug shows cardiovascular benefits beyond its cholesterol-lowering efficacy prior to an ORION-4 readout.
Raffat said the ORION-11 data presented at ESC were "super clean" in regard to safety and efficacy with inclisiran showing a 24% lower rate of cardiovascular events than placebo in the first Phase III study. While the numbers of patients and events were small in ORION-11 relative to the numbers of people and events to be evaluated in the ORION-4 CVOT trial, the analyst said there may be enough events for inclisiran in ORION-10 and -11 to make a cardiovascular benefit assessment relative to the numbers of events reported in the Phase III program for Praluent, which involved shorter studies.
The inclusion of cardiovascular outcomes language on the initial inclisiran label is unlikely, but acknowledgement of cardiovascular event reduction is possible based on recent approvals for some diabetes medicines targeting GLP-1, Raffat noted.
Novo Nordisk AS's first-ever oral GLP-1 agonist Rybelsus (semaglutide) was approved with a label that notes a lower number and rate of major cardiovascular events (MACE) than placebo – 61 MACE (3.8%) for Rybelsus and 76 MACE (4.8%) for placebo, he said. (Also see "Novo Anticipates Q4 Soft Launch For Closely Watched Oral GLP-1 Agent Rybelsus In The US" - Scrip, 20 Sep, 2019.)