Early results show promise of an oral PCSK9 inhibitor
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In two early clinical studies, the first version of an oral PCSK9 inhibitor was well tolerated and effective for reducing LDL, according to phase 1 data reported at the American Heart Association Scientific Sessions.
“Identification of PCSK9 inhibitors which can be delivered orally has proven to be a very difficult challenge for the industry,” Douglas Johns, PhD, FAHA, clinical director of translational medicine/clinical pharmacology at Merck Research Laboratories, said during a press conference.
The PCSK9 inhibitors on the market are injectable. There are currently no oral PCSK9 inhibitors available for commercial use.
Johns presented results of two phase 1 clinical trials with MK-0616 (Merck). Johns said Merck leveraged mRNA display to screen large libraries of cyclic peptide molecules and their ability to bind to PCSK9. He explained, “Merck’s team optimized these molecules into drug-like entities, such as MK-0616, which we are able to take into the clinic.”
A first-in-human, randomized, double-blind, placebo-controlled trial assessed safety and tolerability of MK-0616 in 60 male volunteers aged 18 to 50 years (mean age, 38 years) who received MK-0616 in single oral doses ranging from 10 mg up to 300 mg; 23 men received at least one dose of placebo.
At all doses, including the lowest 10 mg dose, Johns said, MK-0616 inhibited and lowered levels of free PCSK9 in the blood by more than 90% compared with baseline.
A second phase 1, randomized, placebo-controlled, double-blind, multiple-dose trial enrolled 40 men and women aged 18 to 65 years (mean age, 57.7 years) who were on statin therapy for at least 3 months. MK-0616 was administered once daily for 14 days on top of statin therapy (n = 31), while nine patients received placebo.
MK-0616 at 10 mg and 20 mg doses reduced LDL by about 65% after 14 days, Johns said. Patients assigned placebo had a less than 5% reduction in cholesterol measures compared with baseline, according to an AHA press release.
In both trials, doses of MK-0616 were well tolerated, with no deaths, serious adverse events, or treatment-related trends in lab safety, vital signs or ECG, Johns said. Adverse events reported by the investigators as related to the study drug included abdominal discomfort, diarrhea, dyspepsia, headache and maculopapular rash, according to the presentation.
Gastrointestinal absorption of MK-0616 was improved with the use of permeation enhancers. When the researchers looked at different formulations containing a lower dose of a permeation enhancer, they bserved nearly identical LDL lowering, Johns said. When the researchers administered a meal prior to dosing, that caused an attenuation of absorption and a submaximal LDL lowering response, he said.
“If this agent, as an oral PCSK9 [inhibitor], is able to continue clinical development, which we anticipate it will, we acknowledge that additional larger clinical trials are required to confirm safety and efficacy of this agent,” Johns said during a press conference.
Johns said plans are underway for the next phase of clinical development of phase 2 trials for 2022 and the rest of the development program “will be communicated in due course.”
Discussing the results, Anne Carol Goldberg, MD, FACP, FAHA, FNLA, professor of medicine at Washington University School of Medicine, St. Louis, Missouri, echoed the need for efficacy and safety data in larger numbers of patients and in more diverse populations.
“There is a high bar for therapies that are add-ons to statins in terms of cost-effectiveness; however, this is a known target,” Goldberg said.
Goldberg noted several possible advantages of an oral PCSK9 inhibitor, including easier use, especially for patients who are averse to injections; it may require different manufacturing and have less need for special shipping and storing conditions; and it might allow for earlier treatment of at-risk individuals.
“It looks really promising. Will it make it through clinical development? Does it work? Is it safe? Does it decrease cardiovascular risk? What does it cost? Is it cost-effective? These are remaining questions,” Goldberg said.
Perspective
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Perspective
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Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC
The PCSK9 inhibitor monoclonal antibodies currently on the U.S. market are injections administered twice per month. The small-interfering RNA inclisiran (Novartis), which is not yet approved in the U.S., is administered twice per year, but is still an injection. There remain patients who are concerned about injections. There are still some barriers with use. There is a need for effective oral agents. We do have ezetimibe and bempedoic acid (Nexletol, Esperion Therapeutics) as attractive agents for LDL lowering, but as monotherapies, they reduce LDL by about 18%. There is greater efficacy when they are combined with statins. We have a lot of patients who are suboptimally controlled, and I think there is a place for another oral agent.
These were small phase 1 trials not looking at CV outcomes, but rather to understand the pharmacokinetics and safety. There were exciting signals here. We need to take the research up to scale and study the drug more. But I am excited that if we can achieve the same LDL lowering as with the monoclonal antibody injections, an oral PCSK9 inhibitor would have a role, if it is shown to be effective and safe at a large scale and gets approved.
A question will be cost. Even with prices coming down for the PCSK9 inhibitor monoclonal antibody injections, cost is still a barrier for some patients. Adherence is the biggest problem in clinical practice. Having a more affordable option with the same degree of nonstatin LDL lowering would be beneficial. I would be excited to use an oral PCSK9 inhibitor in my clinical practice if it could lower LDL by 65%.
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Johns DG, et al. LBS.06. Fish Oil and Cholesterol: Recipes for CVD Prevention? Presented at: American Heart Association Scientific Sessions; Nov. 13-15, 2021 (virtual meeting).
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