Oral PCSK9 Inhibitor Shows Encouraging LDL Lowering

March 14, 2023

A new oral formulation of a PCSK9-inhibitor, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.

The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, Texas at the recent American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023.

It was also simultaneously published online in the Journal of the American College of Cardiology on March 6. 

"In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups," Ballantyne reported.

"Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL," he noted.  

He added that the drug was well tolerated with no difference in adverse events across the treatment groups compared with placebo.

"These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk," Ballantyne concluded. "The results are encouraging for a phase 3 program that is now being designed."

He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.

Ballantyne described the new drug, MK-0616, as a "macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight."

The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.

They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.

Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg).

The mean percentage changes in ApoB from baseline vs placebo were -32.8%, -45.8%, -48.7%, and -51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were -35.9%, -50.5%, -53.2%, and -55.8% respectively.

The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.

Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy. 

"This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg," he added.   

Adverse events occurred in a similar proportion of participants in the MK-0616 groups (39.5% to 43.4%) as placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.

"Super Exciting"

Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the Department of Pharmacotherapy and Translational Research at the University of Florida in Gainesville, commented.

"For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins," she said. "This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive."

She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available "which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues."

Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was "super exciting."

She added: "We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor."

She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).

She said the two oral drugs promised a "very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients," adding that "we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes."

This study was funded by Merck. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma Inc, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.

American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023: Late Breaking Clinical Trials. Presented March 6, 2023.

J Am Coll Cardiol. Published online March 6, 2023. Full text

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