- The Medicines Company plans to push its PCSK9 synthesis inhibitor into "aggressive" Phase 3 development, including a cardiovascular outcomes trial, after complete results from a mid-stage study released Friday showed competitive LDL cholesterol-lowering ability.
- A two-injection regimen of 300mg of inclisiran — the dose selected by The Medicines Co. as optimal — lowered LDL-C levels by an average of nearly 53% after six months, meeting the trial's primary endpoint.
- The data helped the company's stock recover from a more than 20% slump earlier in the day in reaction to weaker-than-expected cardiovascular outcomes data from Amgen's own cardiovascular outcomes trial, FOURIER.
Even as uptake remains slow for Amgen's Repatha (evolocumab) and Sanofi's Praluent (alirocumab), The Medicines Co. hopes to carve out a niche for itself in the PCSK9 market.
Evidence to date has supported biannual dosing of inclisiran, which would be a competitive advantage over once- to twice-monthly dosing of the two monoclonal antibodies. That longer duration in between doses means a clean side effect profile is crucial because the effects couldn't be reversed if there was a problem.
And on that front, data from the ORION-1 study boosted confidence in the drug's safety. Treatment with inclisiran did not lead to any liver toxicity imbalance, and no new deaths beyond the two already observed were reported. Both of the deaths were judged to be tied to the underlying disease.
Injection site reactions were more frequent than placebo, but no immunogenicity was observed — important given Pfizer shelved its own PCSK9 inhibitor bococizumab due in part to higher rates of injection site reactions and immunogenicity.
At the 300 mg dose, LDL-C lowering was sustained in between the two initial injections (at day 0 and day 90), as well as in the six months following the second administration of inclisiran.
On an absolute basis, two 300 mg doses of inclisiran lowered LDL-C levels by 64.2 mg/dL, a reduction competitive with that seen from Amgen's Repatha (although baseline levels were higher in The Medicines Company's study).
But discussions of the future prospects for the PCSK9 space are inextricably tied to what was observed in FOURIER. For one, Amgen's study added a significant piece of evidence demonstrating that LDL-C lowering leads to reduced major cardiovascular adverse events. Once in doubt, the so-called "LDL hypothesis" is now likely to be cemented, with important ramifications for regulatory review of hypercholesterolemia medicines.
Medicines Co. CEO Clive Meanwell drew two further conclusions from FOURIER, though, which could hint at how the biopharma might set up its own outcomes trial for inclisiran.
Speaking on an investor call late Friday, Meanwell noted the follow-up for Repatha was relatively short, at just over 2 years. The clinical benefit of Repatha grew over time, suggesting that an outcomes trial with a longer follow-up could pick up stronger efficacy.
Perhaps in light of that, The Medicines Co. plans to start an outcomes study and an LDL-lowering study at the same time, which would allow longer follow-up.
In addition, high-risk populations appear the most relevant for delivering benefit from PCSK9 drugs, Meanwell said. From the little information available so far, The Medicines Co. has indicated an outcomes trial would study inclisiran in high-risk primary and secondary prevention patients with average LDL-C of around 130 mg/dL.