WHAT HAPPENED

Winrevair (sotatercept) is a new drug indicated for the treatment of pulmonary arterial hypertension (PAH) in adults.

Winrevair, marketed by Merck & Co., is intended to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events.

Winrevair is approved by the U.S. Food and Drug Administration (FDA) at the end of March 2024 [1].

The European Medicines Agency (EMA) is reviewing the Marketing Authorization Application (MAA) for sotatercept.

The list price of one vial of Winrevair for American patients with PAH is $14,000. Since the drug is administered by subcutaneous injections every three weeks, an annual course of treatment will cost $242,000.

According to the Institute for Clinical and Economic Review (ICER), the economically acceptable cost of an annual course of treatment with sotatercept for American patients with PAH should be in the range of $17,900 to $35,400 [2].

Alternative trade names for sotatercept include Sotreveve, Welvasq, Ayrovasq, Alynorst, Kybalus, and Eltruic.

 

WHY IT MATTERS

Pulmonary arterial hypertension (PAH) is a rare type of pulmonary hypertension (PH, PHTN) characterized by the hemodynamic and pathophysiologic condition of elevated mean pulmonary arterial pressure (> 20 mm mmHg at rest) in the absence of concomitant lung or left-sided cardiac abnormalities as a cause for the increased pressure [1].

PAH is characterized by proliferative and obstructive remodeling (change of wall structure) of the small pulmonary arteries, resulting in progressive narrowing of their lumen. Associated vasoconstriction, inflammation, and thrombosis further increase pulmonary vascular resistance (PVR), which in turn elevates the pressure in the pulmonary artery, putting a strain on the heart. Ultimately, this can lead to right ventricular failure and death [2].

Despite the many drugs approved for the treatment of PAH, median survival ranges from 5 to 7 years after diagnosis, and there has been no significant improvement in survival over the past decade [3].

 

BACKGROUND

There are the following pharmacologic treatments for pulmonary arterial hypertension (PAH) [1] [2]:

  • Phosphodiesterase type 5 inhibitors (PDE5i): sildenafil, tadalafil;
  • Endothelin receptor antagonists (ERAs): ambrisentan, macitentan, bosentan.
  • Soluble guanylate cyclase (sGC) stimulators: riociguat.
  • Prostacyclin signaling pathway agonists: epoprostenol, treprostinil, iloprost, selexipag.
  • L-type (long-lasting) calcium channel blockers (CCBs; prescribed rarely): nifedipine, diltiazem, amlodipine.

When used alone or in combination, these drugs improve pulmonary hemodynamics, increase physical performance, and slow the progression of PAH. However, these therapies act mainly as vasodilators without any significant beneficial effect on the biological cause of the disease.

 

WHAT’S INNOVATIVE

Winrevair (sotatercept) targets the direct pathophysiologic mechanisms of pulmonary arterial hypertension (PAH) instead of treating symptoms like other drugs on the market. Essentially, they act as vasodilators, relieving hypertension and reducing pressure on the heart.

Sotatercept can reduce cell proliferation in the pulmonary artery wall and eliminate arterial stiffness, which are underlying factors in the pathophysiology of PAH. Therefore, sotatercept has the potential to alter the course of pulmonary arterial hypertension, rather than just temporarily alleviating its symptoms.

 

HOW IT WORKS

Pulmonary vascular remodeling, which affects all layers of the vessel wall, is predominantly due to uncontrolled increased proliferation and decreased apoptosis of endothelial and smooth muscle cells [1].

According to several studies, unbalanced signaling by members of the transforming growth factor beta (TGF-β) superfamily contributes significantly to these pathophysiological processes [2] [3] [4].

Sotatercept (MK-7962, ACE-011) is a first-in-class fusion protein consisting of the Fc domain of human immunoglobulin G1 (IgG1) linked to a modified extracellular domain of activin receptor type IIA (ACVR2A, ActRIIA).

Sotatercept acts as a ligand trap for selected TGF-β superfamily members, rebalancing pulmonary vascular homeostasis towards growth-inhibiting and proapoptotic signaling. In animal models of pulmonary hypertension (PH), sotatercept inhibited cell proliferation, promoted apoptosis, and ameliorated inflammation in vessel walls, leading to revers remodeling and restoration of vessel patency [5] [6] [7].

 

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WHAT IT FOUND OUT

The STELLAR (NCT04576988) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) pivotal clinical trial enrolled adult patients (n=323) with pulmonary arterial hypertension (PAH).

After 24-week therapy with subcutaneously administered sotatercept at a target dose of 0.7 mg/kg every 3 weeks on the background of standard therapy for PAH, a greater improvement in exercise capacity (as assessed by the 6-minute walk test, 6MWT) than placebo was demonstrated [1].

Sotatercept resulted in statistically significant improvements in multiple other clinical outcomes important in PAH, such as World Health Organization (WHO) Functional Class of PAH, pulmonary vascular resistance (PVR), N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, risk of worsening of disease course or death, and symptoms and impacts.

The beneficial effects of sotatercept modifying the course of LAH were maintained and improved after one year of treatment [2].

Sotatercept was characterized by acceptable tolerability, no serious adverse events (AEs), frequent or potentially harmful, were reported.

 

WHAT’S NEXT

Merck & Co. is currently conducting clinical validation of Winrevair (sotatercept) in order to expand the population of patients for whom it can be prescribed.

The phase 3 clinical trial ZENITH (NCT04896008) is investigating the use of sotatercept to treat patients with severe pulmonary arterial hypertension (PAH). In contrast to the pivotal STELLAR trial (NCT04576988), which enrolled patients with PAH of functional class II or III as classified by the World Health Organization (WHO), this trial includes participants with functional class III and IV and a high risk of death. The study aims to determine the extent to which sotatercept delays critical events such as death, the need for lung transplantation, or hospitalization.

The HYPERION (NCT04811092) phase 3 clinical trial aims to determine whether sotatercept prolongs the time to clinical deterioration among patients with functional class II or III and intermediate or high risk of PAH progression.

The MOONBEAM (NCT05587712) phase 2 clinical trial is evaluating the use of sotatercept in a pediatric population (ages 1–17) with PAH.

The ongoing SOTERIA (NCT04796337) phase 3 clinical trial aims to determine the long-term safety and efficacy of sotatercept administered over a period of 6 years.

Merck & Co. believes that sotatercept may be used to treat combined pre- and postcapillary pulmonary hypertension (Cpc-PH) due to heart failure with preserved ejection fraction (HFpEF). A phase 2 clinical trial, CADENCE (NCT0494545460), is currently underway to investigate this potential application.

 

BETWEEN THE LINES

Merck & Co. obtained sotatercept as part of its $11.5 billion acquisition of Acceleron Pharma, which closed at the end of November 2021 [1] [2].

Merck & Co. will have to share 22% of Winrevair (sotatercept) revenues with Bristol-Myers Squibb, which bought Celgene, which previously had a co-development agreement with Acceleron and had an 11.5% stake in it [3] [4] [5] [6].

 

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SERIOUS MONEY

There is no doubt that Winrevair (sotatercept) has a bright business outlook ahead of it. The global pulmonary arterial hypertension (PAH) treatment market was valued at $7.3 billion in 2023 and is expected to grow to $12.2 billion by 2032, according to industry forecasts [1].

Johnson & Johnson currently controls half of the PAH market with its drugs Uptravi (selexipag) and Opsumit (macitentan), which earned $1.58 billion and $1.97 billion in 2023, respectively, representing an increase of 11% and 20% from 2022.

Given the range of large-scale beneficial therapeutic effects that sotatercept has on the course of PAH that all other drugs have little or no effect on, the focus of physicians and patients will increasingly shift in its direction.

Optimistic industry forecasts put the peak annual sales that Winrevair could reach at $7.5 billion. More restrained predictions point to amounts between $3 billion and $4 billion. Merck & Co. itself speaks in a streamlined manner, assuring that sotatercept will become a “multibillion-dollar drug.”

 

HOPEFUL FUTURE

Merck & Co. has recently entered the cardiometabolic business, with the goal of developing new drugs. The company is optimistic that this new area of activity could generate up to $15 billion in sales by the mid-2030s.

Currently, Merck & Co. has only one commercialized cardiometabolic drug, Verquvo (vericiguat). This oral soluble guanylate cyclase (sGC) stimulator, co-developed with Bayer and launched in January 2021, is indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure in a specific category of patients [1] [2].

All of Merck & Co.’s other cardiometabolic medicines, with the exception of Verquvo and Winrevair (sotatercept), are under investigation. The oral PCSK9 inhibitor enlicitide (MK-0616) has the potential to be a blockbuster drug due to its ability to potently lower low-density lipoprotein (LDL) cholesterol.

The monoclonal antibody MK-2060, which targets factor XI (FXI), is being evaluated for its effectiveness in preventing thrombosis in end-stage renal disease (ESRD). MK-5475, a small-molecule sGC stimulator, is being studied for the treatment of pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). Efinopegdutide (MK-6024, HM12525A, JNJ-64565111), an injectable dual agonist of GLP1R and GCGR licensed from Korea’s Hanmi Pharmaceutical, targets the treatment of nonalcoholic steatohepatitis (NASH).

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