Merck Showcases Tripling of Cardiovascular Pipeline with Key Candidates Including Oral PCSK9 Inhibitor MK-0616 and Sotatercept

Today, MSD held an investor event focusing on the company's R&D strategy and key projects in the cardiovascular disease field. When mentioning MSD, people might first think of the blockbuster PD-1 inhibitor Keytruda. Besides expanding Keytruda’s applications in oncology, MSD is also actively broadening its R&D pipeline in other disease areas. The company highlighted that its current late-stage R&D portfolio and pipeline for cardiovascular diseases are three times larger than last year’s. In this article, the content team at WuXi AppTec will introduce several key cardiovascular disease R&D projects presented during today’s investor event.

Oral PCSK9 Inhibitors

An important risk factor for cardiovascular disease is high levels of low-density lipoprotein cholesterol (LDL-C). Even though many lipid-lowering therapies have been approved, a significant number of patients still cannot reduce their LDL-C levels to within the target range and need differentiated lipid-lowering treatment options.

MK-0616, developed by MSD, is an oral inhibitor targeting PCSK9. PCSK9 is a target that has been validated by genetics and clinical trials. Currently, several injectable PCSK9 inhibitors have been approved, which can reduce LDL-C levels by 50~60%. However, due to issues such as medication adherence, they have not yet been widely used.

MSD's MK-0616 is an oral PCSK9 inhibitor developed based on its macrocyclic peptide technology platform. The macrocyclic peptide technology platform discovers inhibitors capable of inhibiting protein-protein interactions through mRNA display screening technology. The structural characteristics of macrocyclic peptides give them potency and selectivity comparable to monoclonal antibodies, while having a smaller molecular weight, allowing for oral administration.

▲ The macrocyclic polypeptide platform can target proteins that are difficult to drug (Image source: MSD official website)

MK-0616 Reduced Free PCSK9 Levels by Over 90% and Lowered LDL-C Levels by More Than 60% in Statin-Treated Patients in Early Clinical Trials. MSD Hopes It Can Break the Barriers Limiting the Use of Other PCSK9 Inhibitors, Helping More Hypercholesterolemia Patients Reach LDL-C Target Levels and Reduce Cardiovascular Event Risks. Currently, MK-0616 Is Under Evaluation in Phase 2b Clinical Trials.

▲Introduction to MK-0616 (Image Source: MSD Official Website)

Potential "First-in-Class" Therapy for Pulmonary Arterial Hypertension

Sotatercept is a potential “first-in-class” pulmonary arterial hypertension therapy acquired by Merck & Co., Inc. (MSD) through the acquisition of Acceleron Pharma. It is a type IIA activin receptor (ActRIIA) fusion protein that fuses the modified extracellular domain of ActRIIA with the Fc portion of an antibody. It can block the binding of activin to receptors on the cell membrane, thereby reducing activin-mediated signaling. Sotatercept is the first investigational pulmonary arterial hypertension therapy to receive FDA Breakthrough Therapy Designation.

▲Mechanism of Action of Sotatercept (Image Source: MSD Official Website)

In Phase 2 clinical trials, sotatercept met the primary endpoint. Compared with placebo plus standard therapy, sotatercept plus standard therapy significantly improved patients' pulmonary vascular resistance and increased their 6-minute walking distance. In the open-label extension trial, its efficacy was maintained for at least 48 weeks.

▲Results of Phase 2 Clinical Trial for Sotatercept (Image Source: MSD Official Website)

Currently, MSD has launched four Phase 3 clinical trials to explore the efficacy, safety, and tolerability of sotatercept in patients with different types of pulmonary arterial hypertension. The pivotal Phase 3 clinical trial supporting the new drug application is expected to yield results this year. This clinical trial was rated by the industry media Fierce Biotech as one of the top ten clinical trials to watch in 2022.

Oral Guanylate Cyclase Agonist

Verquvo (vericiguat), an oral soluble guanylate cyclase (sGC) stimulator jointly developed by MSD and Bayer, was approved by the U.S. FDA in 2021 for the treatment of symptomatic chronic heart failure patients with an ejection fraction below 45% following a worsening heart failure event. Soluble guanylate cyclase stimulators work by increasing nitric oxide levels in the heart and blood vessels, reducing oxidative stress, and have multiple effects including decreasing stiffness in the myocardium and blood vessels.

▲Mechanism of Action of Oral Guanylate Cyclase Agonists (Image Source: MSD Official Website)

Verquvo has demonstrated its effect in reducing the risk of cardiovascular death in heart failure patients who have experienced worsening heart failure events in clinical trials. Currently, MSD and Bayer are conducting a Phase 3 clinical trial in heart failure patients who have not yet experienced worsening heart failure events, evaluating Verquvo's efficacy in reducing the risk of cardiovascular death and hospitalization in patients with relatively milder heart failure.

▲ Clinical Development Program of Verquvo (Image Source: MSD Official Website)

Inhaled Guanylate Cyclase Agonist

MSD is also developing an inhaled guanylate cyclase agonist for the treatment of pulmonary arterial hypertension. Oral guanylate cyclase agonists have already been approved for treating pulmonary arterial hypertension, but due to their concurrent reduction of systemic blood pressure, they cannot achieve maximum dilation of pulmonary vessels. MSD’s strategy is to combine the already proven mechanism of action of guanylate cyclase agonists with an inhaled delivery system using a dry powder formulation, aiming to develop a lung-selective vasodilatory therapy.

▲Development Strategy of MK-5475 (Image Source: MSD Official Website)

In preclinical studies, an investigational therapy named MK-5475 has demonstrated proof of concept, targeting the reduction of pulmonary vascular resistance and pressure. It is currently being evaluated in a Phase 2/3 clinical trial.

▲MK-5475 has obtained preclinical proof of concept (Image source: MSD official website)

Anticoagulants without increasing the risk of bleeding

Generally, anticoagulant drugs can prevent thrombosis while also increasing the risk of bleeding. However, some patients with certain diseases may experience a simultaneous increase in both thrombotic and bleeding risks, such as those with end-stage renal disease (ESRD). In these patients, the use of anticoagulants may heighten the risk of bleeding, yet they still have significant unmet needs.

Human genetics studies and animal experiments have found that inhibiting coagulation factor XI (FXI) has the potential to effectively reduce blood clotting while lowering the risk of bleeding. Patients with FXI deficiency not only exhibit reduced risks of ischemic stroke and major cardiovascular events, but also show a decreased risk of bleeding. Mice with FXI expression knocked out display the same phenotype. These studies indicate that inhibiting FXI activity may offer a safer anticoagulant drug.

MK-2060 is a dual inhibitor of FXI/FXIa. It can prolong the activated partial thromboplastin time (APTT) but has no effect on prothrombin time (PT). MSD will conduct a Phase 2 clinical trial in specific end-stage renal disease patients to evaluate the efficacy and safety of MK-2060.

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▲Introduction to MK-2060 (Image Source: MSD Official Website)

MSD pointed out that it is expected to launch multiple innovative therapies for cardiovascular diseases between 2024 and 2028. By 2030, eight cardiovascular disease therapies are expected to gain approval. The company will continue to utilize cutting-edge technologies such as artificial intelligence, genomics, and organoids to understand disease-related biology. Additionally, it will develop new therapies and vaccines using innovative treatment modalities like macrocyclic peptides, antibody-drug conjugates, and mRNA.

Image Source: MSD Official Website

References:

[1] Merck Investor Event Today Will Highlight Broad and Growing Cardiovascular Portfolio and Pipeline in Areas of Unmet Patient Need. Retrieved April 5, 2022, from https://www.businesswire.com/news/home/20220405005473/en

[2] Merck Cardiovascular Investor Event. Retrieved April 5, 2022, from https://s21.q4cdn.com/488056881/files/doc_events/2022/04/CV-Investor-Event_Final.pdf

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