The Medicines Co. and Alnylam Pharmaceuticals have come to a deal with the FDA on the big Phase 3 test for their RNA-based cholesterol-lowering drug, inclisiran, a potentially longer-lasting alternative to a new group of drugs called PCSK9 inhibitors.
Medicines Co. (NASDAQ: MDCO) and partner Alnylam (NASDAQ: ALNY) will collectively enroll 3,000 patients with atherosclerotic cardiovascular disease or a rare, inherited version of extremely high cholesterol called familial hypercholesterolemia in multiple studies. A total of 1,500 will get a 300 mg dose of inclisiran four times over an 18-month period, and the other 1,500 will get a placebo. The main goal of the studies, as it has been for other Phase 3 trials of similar drugs, will be to lower levels low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol.
Medicines Co. and Alnylam will also run a massive, expensive 14,000 patient study, known as an “outcomes” trial, testing the drug’s ability to lower heart attacks and strokes. Importantly, the study, likely to take several years, won’t be required for FDA approval. But as Amgen (NASDAQ: AMGN) and Regeneron Pharmaceuticals (NASDAQ: REGN), the developers of the two approved PCSK9 blockers evolocumab (Repatha) and alirocumab (Praluent) have seen so far, insurance companies have balked at paying for these drugs without such evidence. Medicines Co. and Alnylam didn’t say how long the study would take, just that it would be lengthy enough to “maximize the clinical effect size” of lowering LDL-C. Amgen’s outcomes study took multiple years and just produced data in March. Data from Regeneron’s study are expected soon.
Should inclisiran succeed in Phase 3, it is unclear just how commercially viable the drug will be. The anti-PCSK9 drugs from Amgen and Regeneron were both approved in 2015 after showing a striking ability to reduce LDL-C in clinical trials, but have nonetheless had difficulty commercially. The big upside for these drugs is to provide an alternative to the cheap, generic cholesterol-lowering drugs like atorvastatin (Lipitor), known as “statins.” Many patients can’t tolerate or don’t respond to statins, and heart disease remains a leading cause of death in the U.S., according to the Centers for Disease Control and Prevention. But the high list price (roughly $14,000 per patient, per year) of evolocumab and alirocumab, combined with other available options and—until recently in the case of evolocumab—their unclear impact on lowering heart attacks and strokes have held them back. That’s why, combined, the two drugs generated only about $80 million worldwide during their last reported quarters. And it’s also why Pfizer (NYSE: PFE) scrapped development of another PCSK9-blocking drug, bococizumab, that was in Phase 3 testing.
When Amgen produced its outcomes study results, cardiologists polled by Xconomy were lukewarm on the data and shares fell. But Amgen was emboldened and began offering a refund to payers that “lower access barriers” if patients on their plans taking evolocumab suffer a heart attack or stroke. Amgen hasn’t yet reported another quarter of financial results, however, so it is unclear as of yet what type of impact the study and its refund promise have had.
Alirocumab and evolocumab are antibodies that bind to PCSK9 in the blood and block its activity. Inclisiran is a drug that uses RNA interference—a method of stopping genes from producing disease-causing proteins—to prevent the liver from making PCSK9 in the first place. The proposed benefit of inclisiran is convenience: Alirocumab and evolocumab have to be administered once or twice a month, while inclisiran could potentially be injected just two or three times a year, which could help with patient compliance. And an investigator in inclisiran’s Phase 2 trials previously told Xconomy that its cholesterol-lowering ability is “in the same ballpark” as the other anti-PCSK9 drugs and no unexpected safety problems have cropped up as of yet. But inclisiran also a new type of drug—there are, so far, no approved RNAi therapies—and its safety profile will be closely watched. And should it get to market a few years from now, Amgen and Regeneron’s drugs will already be well established.
Medicines Co. and Alnylam expect to file for approval by the end of 2019, assuming positive results. They’re betting that inclisiran will ultimately prove superior to alirocumab and evolocumab.
“We believe that positive outcomes data, with primary outcome clinical effects greater than those reported for anti-PCSK9 monoclonal antibodies, will drive a high level of competitiveness in the worldwide market–which we expect to become very large,” said Medicines Co. CEO Clive Meanwell, in a statement.