Medicines Company goes on the hunt for heartening Orion data

The Medicines Company needs to show decent efficacy and pristine safety with its long-lasting PCSK9 inclisiran to stand a chance of disrupting the market.

The Medicines Company has long maintained that a longer-lasting PCSK9 inhibitor is just what the market needs. Commercial questions aside, the group will soon find out whether its twice-yearly cholesterol-lowering candidate inclisiran has a chance of competing with the current antibodies.

In the third quarter the company will report the first phase III results on inclisiran in cardiovascular disease. The data will come from three studies in the huge Orion programme, and investors will be keeping an eye on safety following concerns with similar RNA interference projects.

Project Inclisiran
Company The Medicines Company/Alnylam
Market cap $2.7bn
Product NPV $2.0bn
NPV as % market cap 74%
Event Phase III data
Timing Q3 2019

There are two US-approved anti-PCSK9 antibodies, Amgen’s Repatha and Sanofi and Regeneron’s Praluent, which are injected subcutaneously every two weeks or monthly. Inclisiran, meanwhile, is an RNA interference project, also given subcutaneously, that is designed to prevent the production of the PCSK9 protein.

Because its effects are longer lasting, it does not need to be administered as often, and The Medicines Company hopes this convenience advantage will help its candidate grab market share, if approved.

Still, the PCSK9 sector is not shaping up to be as big as some had hoped, and price cuts for Repatha and Praluent have already left these rivals fighting for a piece of a smaller pie, even before adding inclisiran to the mix.

Before worrying about inclisiran’s commercial prospects, however, Medicines Company needs to get a positive result in the upcoming Orion trials.

The first to read out should be Orion-11, which completed enrollment in January and could yield data in time for the European Society of Cardiology meeting taking place in Paris in August and September.

Next up will be Orion-9 and 10, with a more likely venue being the American Heart Association conference in Philadelphia in November.

Upcoming phase III Orion trial readouts 
Trial name Setting N ID Primary completion
Orion-9 Heterozygous familial hypercholesterolaemia 482 NCT03397121 Sep 2019
Orion-10 Atherosclerotic CV disease and elevated LDL-C  1,561 NCT03399370 Oct 2019
Orion-11 Atherosclerotic CV disease or risk equivalents and elevated LDL-C  1,617 NCT03400800 Oct 2019
Orion-5 Homozygous familial hypercholesterolaemia 45 NCT03851705 Jun 2021
Orion-8 Phase III long-term extension 3,700 NCT03814187 Aug 2023
Orion-4 CV outcomes in patients with CV disease 15,000 NCT03705234 Dec 2024
Source: EvaluatePharma, clinicaltrials.gov.

The co-primary endpoints of all three trials are percentage change in LDL cholesterol between baseline and day 510, and time-adjusted changes in LDL-C up to 540 days. Patients in the study are either receiving maximally tolerated doses of statins, or have shown intolerance to at least two different statins.

Inclisiran needs to perform at least as well as Repatha and Praluent, which showed placebo-adjusted LDL lowering of around 55% at one year in patients on background statin therapy, in the Descartes and Odyssey long-term trials, respectively.

Liver worries

If inclisiran can do better than this, it would be a bonus, but it is more important that the project shows a clean safety profile. The asset originated at Alnylam and is based on that company’s Galnac delivery platform; Alnylam’s givosiran, which uses the same platform, was recently linked with toxicity worries (Alnylam touts givosiran win despite toxicity fears, March 6, 2019). 

Galnac conjugates target the liver. Since givosiran is being tested in acute hepatic porphyria, a disease that can itself cause liver issues, the delivery platform might have contributed to the problem. Leerink analysts argued that inclisiran should sidestep these worries as it is being evaluated in patients with healthy livers.

Any jittery investors might be reassured by a recent interim analysis from the phase II open-label Orion-3 extension trial, which found a LDL-C reduction of 51% at 210 days, and no major safety worries after three years of follow-up. There was one death due to stroke and one case of elevated liver enzymes, but neither was deemed to be related to inclisiran.

These data were swiftly followed by results from the Orion-7 study in patients with renal impairment, which did not raise any concerns.

The Medicines Company’s stock has risen steadily this year, and anything less than pristine safety in the upcoming phase III trials could see its value plunge. If the group can clear that hurdle, it can then worry about how to make inclisiran a commercial hit.

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