The Medicines Company touted updated phase II data with its long-lasting PCSK9 inhibitor inclisiran at the European Society of Cardiology meeting this week, but it has more pressing concerns – namely, funding and carrying out its phase III programme alone.
The group is also on the hook for a 14,000-patient cardiovascular outcomes trial and, with a partner still yet to emerge, it looks like it will have to foot the entire bill for that too. With this study alone set to cost $110-150m the question is whether it will be worth it.
The Medicines Company has stressed that the cardiovascular outcomes trial, called Orion-4 and slated to start next year, will not be part of its initial NDA. The filing will instead include data from LDL cholesterol-lowering studies, which have just started and are due to report in the second half of 2019.
In August its chief executive, Clive Meanwell, estimated that the company would have to spend $110-150m to get inclisiran to market, a figure that excludes the cost of the outcome study. The Medicines Company had $334m in cash as of the end of June.
|Inclisiran’s phase III programme|
|Orion-10 & 11||3,000 subjects with ASCVD/risk equivalents|
|Orion-9||400 subjects with heterozygous familial hypercholesterolaemia|
|Orion-5||60 subjects with homozygous familial hypercholesterolaemia|
|Orion-4||CV outcomes trial in 14,000 patients with high-risk ASCVD|
|ASCVD: Atherosclerotic cardiovascular disease. Source: ESC presentation.|
With other PCSK9 inhibitors a commercial disappointment so far, this is a huge outlay for an uncertain reward – which is probably one reason a partner for inclisiran has failed to materialise.
The Medicines Company said at its second-quarter results that it still hoped to recruit a partner, but that if it did not it would push into phase III on its own.
The group does not believe that the two efforts are mutually exclusive, with its chief corporate development officer, Christoper Cox, saying at the time: “We expect that absolutely nothing about commencing phase III development for inclisiran will materially impede the transaction.”
Inclisiran, an RNA interference project, has a different mechanism of action from the anti-PCSK9 MAbs Repatha and Praluent, but the same ultimate effect. Inclisiran is administered twice a year, while the MAbs are given monthly or every two weeks.
The Medicines Company believes that it has identified the optimal dosing regimen, helped by one-year data from the phase II Orion-1 study presented at the ESC meeting on Monday.
That regimen involves two starting doses of 300mg of inclisiran, given at day 1 and day 90, on top of statins. This produced a time-averaged 47% reduction in LDL cholesterol at one year in Orion-1, adding to earlier data reported from the same study. The trial had already met its primary endpoint, significantly lowering LDL cholesterol versus placebo at six months (AHA – Medicines Company’s should-have-been day falls flat, November 16, 2016).
It is this two-dose starting regimen that The Medicines Company plans to take into phase III trials, said the lead investigator of Orion-1, Professor Kausik Ray of Imperial College London, during his presentation at ESC.
He added that the study results suggested that the first maintenance dose of inclisiran should be given nine months after initiation of therapy, with dosing moving to every six months thereafter.
While Professor Ray said there were no safety signals at one year, Professor Philip Barter of the University of Sydney, discussing the Orion-1 results, noted that the trial was fairly small, and recommended a longer study in a larger number of patients to reassure regulators on safety.
Professor Barter added that anti-PCSK9 MAbs acted exclusively in the plasma, while inclisiran exerts its effects within the cell, inhibiting all functions of PCSK9 – the consequences of which are as yet unknown.
Perhaps this is why a partner has yet to emerge – any implications of long-term treatment remain unclear. The Medicines Company has plenty of work to do to answer that question.