Merck bets big on oral PCSK9 inhibitor, putting 6-year outcome study at heart of phase 3 program

Merck & Co. is betting big on its oral PCSK9 inhibitor. Buoyed by midphase results, the Big Pharma has kicked off a clutch of late-stage studies including a cardiovascular outcomes trial that will follow patients for around six years. 

The New Jersey-based drugmaker has identified the candidate, MK-0616, as a way to bring the powerful cholesterol-lowering effects of PCSK9 inhibition to more patients. Like Amgen’s Repatha and Sanofi and Regeneron’s Praluent, MK-0616 binds to the PCSK9 enzyme to lower LDL-C and thereby reduce the risk of cardiovascular events. But while Repatha and Praluent are injectable antibodies that struggled to live up to sales expectations, Merck’s candidate is an oral peptide that may be more attractive to patients. 

Merck is running three phase 3 clinical trials of MK-0616. First up are two similar studies that will assess the effect of the oral peptide on LDL-C levels after 24 weeks. Merck is targeting a primary completion of September 2025 for both studies.

The third clinical trial is a cardiovascular outcomes study. In that trial, Merck will track 14,500 patients for up to six years to test whether MK-0616 reduces major adverse cardiovascular events in people at high risk. The length of the trial, which has a primary completion date in late 2029, sets it apart from earlier efforts to assess the impact of PCSK9 inhibition on cardiovascular outcomes. 

When Amgen, Regeneron and Sanofi developed their injectable PCSK9 drugs, they assessed the effect of the treatments on cardiovascular outcomes over a median of 2.2 to 2.8 years. Later, long-term follow-up trials found the effect of the drugs on cardiovascular outcomes increases over time, suggesting that the developers could have shown more profound changes if their main studies had kept going for longer.

Dean Li, M.D., Ph.D., president of Merck Research Labs, discussed the lessons of the earlier programs on a conference call with investors earlier this year, describing the need to strike a balance. If the trial is too short, Merck risks missing out on “the full maximum impact that you can have on the label,” Li said, but that “needs to be balanced with whatever the IRA looks like” years from now. 

The threat of the Inflation Reduction Act is so severe that Merck has fielded questions about whether it would choose to delay the launch of the oral PCSK9 drug until it has outcomes data. Merck CEO Robert Davis didn’t dismiss the idea, only saying that “it’s too early to make that kind of decision.” Davis needs to make the most of MK-0616 to help offset the loss of exclusivity on megablockbuster Keytruda.