• Oral PCSK9 Inhibitor Shows Significant LDL-Lowering Potential: Phase I Data

    A candidate oral PCSK9 inhibitor from Merck is safe and effective at lowering low-density lipoprotein (LDL)-cholesterol by 65% in adults already receiving statin therapy, Phase I trial data reveal.

    The findings from two Phase I studies, which assessed the safety and clinical effectiveness of the novel candidate drug MK-0616 in humans, were reported Monday at the American Heart Association Scientific Sessions 2021 virtual meeting.

    Lead author Douglas Johns, PhD, the clinical director of translational medicine/clinical pharmacology at Merck Research Laboratories, said that despite the existence of numerous therapies, there is an “unacceptably large number” of patients worldwide who continue to struggle with controlling cholesterol.

    Johns said that injectable PCSK9 inhibitors have shown that large reductions in LDL cholesterol are achievable, but he noted that the injectable nature of these treatments means that uptake has been limited and, many times, occurs late in a patient’s treatment journey.

    “Identification of PCSK9 inhibitors that can be delivered orally is proving to be a very difficult challenge for the industry,” he said, noting that Merck “took on this challenge” and sought to identify oral inhibitors of PCSK9 utilizing novel mRNA display technology that allowed for the screening of very large libraries of cyclic peptide molecules for their ability to bind to PCSK9 before optimizing candidate molecules into drug-like entities such as MK-0616, which was evaluated in Phase I trials.

    Data from these two separate Phase I trials conducted with MK-0616 have now demonstrated the candidate’s safety and effectiveness as an oral PCSK9 inhibitor, said Johns.

    “I believe this is the first report of successful oral absorption of a synthesized cyclic peptide-like MK-0616 in people,” he said. “We were pleased that it appeared to be consistently absorbed and concentrated in patients’ blood and that it reduced cholesterol levels so effectively.”     

    Trial details

    Johns noted that the first study of MK-0616 was a first-in-human study that included 60 healthy male volunteers, aged 18-50. Of the 60 participants, 51 received single oral doses of MK-0616 ranging from 10 mg to 300 mg, while 23 received at least one dose of a placebo.

    “These single doses were well-tolerated, and no serious side effects were observed, up to and including the highest dose,” he revealed.

    “We also observed that at all doses – including the lowest dose at 10 mg – we were able to inhibit and lower levels of free PCSK9 in the blood by more than 90%, compared to baseline.”

    The second study of MK-0616 included 40 male and female volunteers, ages 18-65, who had already been taking statin medications to control their cholesterol levels for at least three months.

    “The team assessed the effectiveness of doses of either 10 mg or 20 mg alongside existing statin therapy, finding a reduction in LDL cholesterol of around 65% from baseline with both the 10-mg and 20-mg doses,” Johns noted, adding that administration of MK-0616 before a meal resulted in lower absorption and “a sub-maximal LDL lowering response.”

    Patients treated with the placebo had a less than 5% reduction in cholesterol measures compared to baseline.

    The lead researcher commented that while the initial results from the Phase I trials are encouraging, further clinical studies are needed to confirm the findings.

    “If this agent, as an oral PCSK9, is able to continue clinical development, which we anticipate that it will … we feel like this agent will be able to potentially enable patients who need additional cholesterol-lowering to include this in their treatment,” he said.

    ‘Exciting’ data

    Commenting on the findings of the trials, Erin Michos, MD, from Johns Hopkins Medicine, Baltimore, noted that multiple registry studies showed that high-risk patients with atherosclerotic heart disease remain above LDL goal levels.

    “Patients are under-treated, so I'm very excited to have another potential oral agent that is highly effective for cholesterol-lowering,” she said, noting that the reduction of 65% in LDL cholesterol is “much greater” than other non-statin oral agents currently available, and is on par with injectable PCSK9 inhibitors.

    Michos added that injectable PCSK9 monoclonal antibodies that are administered twice a month have been shown to lower LDL in the range of 50% to 60%, while inclisiran, which is a small interfering RNA that targets PSCK9, is given twice per year and lowers LDL in the range of 40% to 50%.

    "So, this oral agent has robust LDL lowering, at 65%, on top of statin therapy, and that's much greater than other non-statin oral agents that we have available," she said.

    “Of course, we need larger clinical trials to really evaluate this further, but [this is] really exciting early Phase I data.”

    Both Phase I trials were funded by Merck & Co. Inc, the company developing the MK-0616 candidate.

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