Merck announces its latest pipeline progress, a focus area that has tripled in one year

▎ WuXi AppTec content team editor

Today, Merck (MSD) highlighted its R&D layout and key projects in the field of cardiovascular disease at its investor event. When it comes to Merck, the first thing that may come to mind is the blockbuster PD-1 inhibitor Keytruda, which is also actively expanding its R&D pipeline in other disease areas in addition to expanding Keytruda's oncology scope. The company noted that its existing pipeline of late-stage R&D and products for cardiovascular disease is three times higher than last year. In today's article, WuXi AppTec's content team will introduce several key research and development projects for cardiovascular diseases introduced at 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 for marketing, there are still many patients who are unable to reduce LDL-C levels to the target range and need differentiated lipid-lowering treatment options.

Merck developed MK-0616 is an oral inhibitor that targets PCSK9. PCSK9 is a target that has been validated by genetics and clinical trials. A number of injectable PCSK9 inhibitors have been approved to reduce LDL-C levels by 50 to 60 percent, but they have not been widely used due to problems such as medication adherence.

Merck's MK-0616 is an oral PCSK9 inhibitor developed based on its macrocyclic peptide technology platform. The macrocyclic peptide technology platform uses mRNA display screen technology to discover inhibitors that inhibit interactions between proteins. The structural characteristics of macrocyclic peptides give them similar potency and selectivity to monoclonal antibodies, while having a small molecular weight and can be administered orally.

▲The macrocyclic peptide platform can target proteins that are difficult to make medicines (Image source: Merck official website)

MK-0616 was able to reduce free PCSK9 levels by more than 90% in early clinical trials and by more than 60% in patients treated with statins. Merck expects it to break down barriers that limit the use of other PCSK9 inhibitors, allow more patients with hypercholesterolemia to reach LDL-C target levels, and reduce the risk of cardiovascular events. Currently, MK-0616 is being evaluated in Phase 2b clinical trials.

▲Introduction to MK-0616 (Image source: MERCK official website)

Potential "first-in-class" therapy for pulmonary hypertension

Sotatercept is a potential "first-in-class" pulmonary hypertension therapy obtained by Merck's acquisition of Acceleron Pharma. It is an IIA-type activator receptor (ActRIIA) fusion protein that fuses ActRIIA's engineered extracellular domain with the Fc end of the antibody. It blocks the binding of activatin to receptors on the cell membrane, thereby reducing activatin-mediated signaling. Sotatercept is the first pulmonary hypertension treatment to be recognized by the FDA as a breakthrough therapy.

▲The mechanism of action of Sotatercept (Source: MERCK official website)

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

▲ Sotatercept Phase 2 clinical trial results (Source: MERCK official website)

At present, Merck has initiated four Phase 3 clinical trials to explore the efficacy, safety and tolerability of sotatercept in patients with different types of pulmonary hypertension. One of the key Phase 3 clinical trials that support new drug applications is expected to yield results this year, and this clinical trial was named one of the top ten clinical trials to watch in 2022 by industry media Fier Biotech.

Oral guanylate cyclase agonist

Vericiguat, an oral guanylate cyclase (sGC) agonist developed jointly by Merck and Bayer, has been approved by the U.S. FDA in 2021 to treat patients with symptomatic chronic heart failure who experience an ejection fraction below 45 percent after an event experiencing worsening heart failure. Guanylate cyclase agonists have multiple effects such as reducing stiffness of myocardium and blood vessels by increasing the level of nitrogen oxide in the heart and blood vessels, reducing oxidative stress.

▲Mechanism of action of oral guanylate cyclase agonists (Image source: Merck official website)

Verquvo has shown in clinical trials the effect of reducing the risk of cardiovascular death in patients with heart failure after experiencing a worsening event of heart failure. Currently, Merck and Bayer are conducting Phase 3 clinical trials in patients with heart failure who have not yet experienced a heart failure exacerbation event to evaluate verquvo's effect on reducing the risk of cardiovascular death and hospitalization in patients with relatively mild heart failure.

Verquvo's clinical development plan (Image source: MERCK official website)

Inhaled guanylate cyclase agonist

Merck is also developing an inhaled guanylate cyclase agonist to treat pulmonary hypertension. Oral guanylate cyclase agonists have been approved for the treatment of pulmonary hypertension, but because they also lower systemic blood pressure, they do not maximize the relaxation of blood vessels in the lungs. Merck's strategy is to develop a selective vasodilating therapy for the lungs using a proven mechanism of action of guanylate cyclase agonists and an inhalation delivery system using dry powder preparations.

▲MK-5475's R&D strategy (Image source: MERCK official website)

In preclinical studies, an investigative therapy called MK-5475 has received a proof of concept that targets reduced pulmonary vascular resistance and stress. Currently, it is being evaluated in Phase 2/3 clinical trials.

▲MK-5475 has received a preclinical proof of concept (Image source: MERCK official website)

Anticoagulants that do not increase the risk of bleeding

Often, anticoagulants increase the risk of bleeding while preventing thrombosis. However, patients with some diseases experience an increased risk of both thrombosis and bleeding, such as those with end-stage renal disease (ESRD). The use of anticoagulants may increase the risk of bleeding in these patients, who still have significant unmet needs.

Human genetic studies and animal experiments have found that inhibitory coagulation factor XI (FXI) has the potential to reduce the risk of bleeding while effectively anticoaguling. Patients with FXI deficiency not only have a reduced risk of ischemic stroke and major cardiovascular events, but also have a reduced risk of bleeding. Mice that knock out FXI expression exhibit the same phenotype. These studies have shown that inhibiting FXI activity may provide safer anticoagulant drugs.

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

▲Introduction to MK-2060 (Image source: MERCK official website)

Merck pointed out that it is expected to launch a number of innovative therapies for cardiovascular diseases between 2024 and 2028, and by 2030, 8 cardiovascular disease therapies are expected to be approved. The company will continue to use cutting-edge technologies such as artificial intelligence, genomics, and organoids to understand disease-related biology, and develop new therapies and vaccines using innovative treatment models such as macrocyclic peptides, antibody-coupled drugs, and mRNA.

Image source: MERCK official website

Resources:

[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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