Oral PCSK9 inhibitor lowers LDL similar to injection in short-term phase 2 trial
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NEW ORLEANS — In a phase 2 trial, an oral PCSK9 inhibitor lowered LDL about the same amount observed with injectable PCSK9 inhibitors for 8 weeks, researchers reported at the American College of Cardiology Scientific Session.
For the phase 2b, randomized, double-blind, placebo-controlled trial, researchers evaluated safety and efficacy of the oral PCSK9 inhibitor (MK-0616, Merck) in patients with hypercholesterolemia.
“The PCSK9 inhibitors have all been given by injection, every 2 to 4 weeks for the fully human monoclonal antibodies and 3 months after initial dose and then every 6 months for inclisiran (Leqvio, Novartis), a small-interfering RNA molecule,” Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine, told Healio. “This would be a pill, which people have used traditionally, and has some advantages, one being that some people don’t like injections and another being ease of taking medications while traveling. The PCSK9 inhibitors are very effective, but there hasn’t been as much uptake compared to other options in the prevention field. The hope would be to improve access, which has been frustrating for clinicians, and uptake so that people can get this highly effective therapy.”
The 381 patients (median age, 62 years; 49% women; 65% white; about 40% with clinical atherosclerotic CVD and most of the rest at intermediate to high ASCVD risk; 55% with diabetes) were assigned to placebo or one of four doses of the oral PCSK9 inhibitor: 6 mg, 12 mg, 18 mg or 30 mg, all once daily. The results were simultaneously published in the Journal of the American College of Cardiology.
“A key mission was to figure out the dose in terms of tolerability, side effects and efficacy,” Ballantyne told Healio. “Phase 2b studies are not that big, but you’d like to have as diverse a population as possible, and I was pleased with the design. The primary objective was to see the effects on LDL cholesterol, but we also wanted to see the effects on non-HDL, as well as in apolipoprotein B, which is in all the bad particles.”
At 8 weeks, the differences in least squares mean percentage change in LDL compared with placebo were as follows:
- –41.2% for the 6 mg group;
- –55.7% for the 12 mg group;
- –59.1% for the 18 mg group; and
- –60.9% for the 30 mg group (P for all < .001).
“This was a very robust response,” Ballantyne told Healio. “We know that the monoclonal antibodies give us around 60% reduction, so this is comparable; inclisiran is a little less, around 50%, because it is given less frequently. The hoped-for outcome was to have a pill that would give the same efficacy as an injection. It is not that easy to achieve, and it was nice to achieve it.”
The 8-week differences in least-squares mean percentage change in ApoB compared with placebo ranged from –32.8% for the 6 mg dose to –51.8% for the 30 mg dose of MK-0616, and for non-HDL, the range was from –35.9% for the 6 mg dose to –55.8% for the 30 mg dose, Ballantyne and colleagues found.
“This is also in line with what you’d expect from the PCSK9 monoclonal antibodies,” he told Healio.
Protocol-defined LDL goals were achieved in 80.5% of those in the 6 mg dose group, 85.5% of those in the 12 mg dose group, 90.8% of those in the 18 mg dose group and 90.8% of those in the 30 mg dose group, compared with 9.3% of those in the placebo group, according to the researchers.
The adverse event rates at 16 weeks ranged from 39.5% to 43.4% in the PCSK9 inhibitor groups, similar to the 44% rate in the placebo group, Ballantyne and colleagues found.
No more than two participants from any group discontinued their medication during the study.
“This is a short-term study that is not very large, but the safety and tolerability data are very encouraging,” Ballantyne told Healio.
A phase 3 program is planned to begin in the second half of 2023, he said.
“I had been told about a decade ago that it was impossible to make an oral inhibitor to PCSK9,” Ballantyne told Healio. “This is a macrocyclic peptide that went through a tremendous amount of medicinal chemistry. It’s fascinating to see how the technology keeps advancing.”
Reference:
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Michelle A. Albert, MD, MPH, FACC, FAHA
A number of patients from diverse clinical backgrounds still do not get to optimal LDL levels on statins alone. Adding a PCSK9 inhibitor on top of statins allows them to get closer to optimal levels. It is an important alternative for people who cannot get to optimal levels on statins and for people who are intolerant to higher doses of statins. Adding something on top of statins can be very effective.
The study population was at intermediate to high risk for coronary disease and about 55% had diabetes. Despite so many of these patients having diabetes, only 20% were taking a high-intensity statin in accordance with guidelines. A lot more of these patients should have been on high-intensity statins; it should parallel close to the percentage of those with diabetes.
What was very intriguing is that lipoprotein(a) levels in those who took the oral PCSK9 inhibitor were lowered by about 20%, even though that was not what the researchers were looking to study. That is important for the Black population, who have higher Lp(a) levels than other groups.
There were very few Black people in this study, but it was gratifying to see that each assignment group was 17% to 23% Asian, and there were a few American Indian/Alaska Native participants, who are traditionally not well represented in studies.
University of California, San Francisco
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This oral therapy is clearly a novel approach to the administration of a PCSK9 inhibitor. However, the patients that I have been treating using PCSK9 inhibitors have not complained about the need for injection or the injector. Just the opposite; many have asked me if I could put some of their other medications into the self-injector. They also note that they like the idea of being able to self-administer the drug every month in the privacy of their own homes.
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Ballantyne CM, et al. Late-Breaking Clinical Trials V. Presented at: American College of Cardiology Scientific Session; March 4-6, 2023; New Orleans (hybrid meeting).
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