Peripheral Venous Pressure-Assisted Exercise Stress Echocardiography in the Evaluation of Pulmonary Hypertension During Exercise in Patients With Suspected Heart Failure With Preserved Ejection Fraction

MSD Leaps On FDA Approval Of PAH Drug Sotatercept

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MSD

MSD's sotatercept has become the first FDA-approved therapy for pulmonary arterial hypertension (PAH) that addresses the underlying mechanism behind the disease, rather than its symptoms.

The first-in-class activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, given the trade name Winrevair, has been cleared to improve exercise capacity, improve lung function, and reduce the risk of worsening clinical events in adults with PAH after a priority review.

PAH is a life-threatening disease, caused by the narrowing of blood vessels in the lungs, which is currently treated mainly with drugs that dilate the blood vessels, like endothelin antagonists and prostacyclin analogues, as well as phosphodiesterase inhibitors to increase blood flow through the lungs.

Winrevair is thought to work by blocking abnormal signalling between cells in the pulmonary blood vessels, which scientists think could lead to a partial reversal of the disease process in PAH. MSD – known as Merck & Co in the US and Canada – has predicted sales of the drug could reach upwards of $3 billion a year, while some analysts think that it could make $5 billion or more.

Shares in the company rose nearly 5% in after-hours trading following the approval announcement. Winrevair is a key component of the pharma group's strategy to generate $10 billion in cardiovascular disease therapy sales in the 2030s, and also one of the drugs that could help it prepare for the loss of patent protection on $25 billion cancer blockbuster Keytruda (pembrolizumab) in 2028.

The approval had been widely anticipated after the results of the STELLAR trial, which showed patients treated with sotatercept given on top of standard PAH therapy had an 84% lower risk of death or worsening of their condition compared with those on standard therapy alone.

That increase in survival is seen as a major advance in PAH treatment, which has a five-year survival rate of a little over 40%, and is backed up by functional improvements, including a significant 40.8-metre increase in exercise capacity, measured using the six-minute walking test (6MWT).

Winrevair has been approved with a recommendation that patients are monitored for haemoglobin and platelet levels before and during treatment, as it has been linked to increased haemoglobin levels that may lead to high levels of red blood cells (erythrocytosis) that could raise the risk of clotting and other side effects.

In addition to STELLAR, MSD is running the phase 3 HYPERION trial of sotatercept in newly diagnosed intermediate- and high-risk PAH patients, seeking to move it up the treatment pathway, as well as the phase 2 CADENCE study in pulmonary hypertension due to left heart disease. There are estimated to be around 40,000 to 60,000 people in the US living with PAH.

MSD acquired sotatercept as part of its $11.5 billion takeover of Acceleron Pharma in 2021, a deal which also gave it Reblozyl (luspatercept) for anaemia associated with rare blood disorders.

The company said it plans to launch Winrevair by the end of next month and has set a list price of $14,000 per vial. The drug is administered as a subcutaneous injection every three weeks, and MSD says it expects that most patients will need a single vial, for an annual cost of about $243,000 before any discounts or rebates.

That is well above the $17,900 to $35,400 per year cost-effectiveness range that the Institute for Clinical and Economic Review (ICER) modelled in a report published in January, which nevertheless assumed a "placeholder" price of $400,000 for the drug and estimated that 7% of the eligible patients in the US could be treated within five years without crossing the ICER potential budget impact threshold of $777 million per year.

"A diagnosis of PAH is a life-changing experience for patients and families due to its chronic, progressive nature," said Matt Granato, president and chief executive of Pulmonary Hypertension Association (PHA).

"We are excited to see industry research leading to a better understanding of PAH and the development of a medicine in a novel treatment pathway that expands options for the patient community," he added.

Winrevair's approval comes a few days after the FDA approved Johnson & Johnson's Opsynvi, a fixed-dose combination of endothelin antagonist macitentan and PDE-5 inhibitor tadalafil. J&J sells macitentan on its own as Opsumit, currently a top-selling drug for PAH with sales of $2 billion a year, and also makes $1.6 billion from prostacyclin analogue Uptravi (selexipag).

Analysis Supports Initial Combination Therapy For Patients With PAH, Comorbidities

Patients with pulmonary arterial hypertension and cardiopulmonary comorbidities are typically started on monotherapy, but new data suggest some patients would do well with initial combination therapy.

Patients with pulmonary arterial hypertension (PAH) and one or two cardiac comorbidities experience a similar benefit from initial combination therapy with macitentan (Opsumit) and tadalafil (Cialis) as patients without comorbidities, according to a new analysis.

The findings are important because they call into question existing guidelines for patients with cardiopulmonary comorbidities, which suggest beginning with initial monotherapy with either an endothelin receptor antagonist (ERA; e.G. Macitentan) or phosphodiesterase 5 inhibitor (PDE5i; e.G. Tadalafil) and then escalating as appropriate based on individual patient responses.

The new analysis comes as the demographics and characteristics of people diagnosed with PAH appear to have shifted in recent decades. For instance, a 2016 study from Sweden found the majority of patients diagnosed with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) were over the age of 65, and tended to have "several" comorbidities, including systemic hypertension, diabetes, ischemic heart disease, and atrial fibrillation.

Similarly, a 2012 report based on a registry of patients with pulmonary hypertension in the United Kingdom and Ireland suggested that patients were being diagnosed at older ages, and that those patients were more likely to have more comorbidities but also better survival. At the time, the investigators said the change might be due to changes in referral patterns, rather than changes in the actual disease.

For instance, they noted an increase in referrals to pulmonary hypertension specialty centers over the years of the study. An alternative cause, they said, could be that there were emerging subtypes of the disease: older patients with more comorbidities and younger patients with fewer comorbidities, higher functional capacity, and more severe hemodynamic impairment.

Vallerie V. McLaughlin, MD, of the University of Michigan, and colleagues, noted that to date there is limited data on the use of initial combination therapy in patients with few comorbidities. In a new study published in the European Journal of Heart Failure, they explain that more data are needed to better understand how to tailor treatment to individual patients and risk profiles.

"While this stepwise approach may particularly resonate for older patients with a high cardiopulmonary comorbidity burden, the question remains whether a more aggressive treatment strategy with initial combination therapy would be beneficial for younger patients with a lower comorbidity burden," they wrote.

Fortunately, they said data already exist regarding how patients with PAH and 1-2 cardiac comorbidities respond to initial combination macitentan and tadalafil—it just needed to be analyzed. The authors turned to the TRITON and REPAIR studies, both of which included patients who received initial combination therapy. The investigators noted that most trials now exclude patients with pulmonary comorbidities or with 3 or more cardiac comorbidities, but patients with 1-2 cardiac comorbidities are generally included.

McLaughlin and colleagues identified a set of 148 patients between the two studies who weretreated with initial macitentan and tadalafil combination therapy. From that pool, they constructed two subgroups of patients: those with no cardiac comorbidities (62 participants), and those with one or two cardiac comorbidities (78 participants). Overall, patients in the two trials had a median duration of exposure to the combination of 513.0 days, which the authors said was similar between the two subgroups.

From baseline to week 26, both groups benefited from the combination. The no-comorbidity subgroup had an average reduction of pulmonary vascular resistance (PVR) of 55%, an improvement of six-minute walking distance (6MWD) of 67 meters, and a reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) of 77%.

In the group with one or two comorbidities, participants had a 50% reduction of PVR, 54-meter increase in 6MWD, and 76% decrease in NT-proBNP. Patients in both groups also had improvement inWorld Health Organization functional class, McLaughlin and colleagues found. Both cohorts had similar safety profiles, and their experiences were consistent with previously reported safety data, the authors said.

The investigators said this information should be helpful to clinicians treating newly diagnosed patients, though they cautioned that comorbidity burden should be assessed on an individualized basis.

"It is important to acknowledge that comorbidity burden cannot be measured by simply counting the number of comorbidities; information on severity, duration and controlled/not controlled status must also be considered," they wrote.

However, they concluded that these data suggest some patients with comorbidities might be good candidates for initial combination therapy.

FDA Approves Merck's Winrevair

Winrevair is used for the treatment of adults with pulmonary arterial hypertension to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events.

The Food and Drug Administration has approved Merck's Winrevair (sotatercept-csrk) injection, 45 mg, 60 mg, for the treatment of adults with pulmonary arterial hypertension to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. 

Winrevair is the first FDA-approved activin signaling inhibitor therapy for PAH, representing a new class of therapy that works by improving the balance between pro- and anti-proliferative signaling to regulate vascular cell proliferation underlying PAH.

"Pulmonary arterial hypertension is a rare, progressive and ultimately life-threatening disease in which blood vessels in the lungs thicken and narrow, causing significant strain on the heart," said Marc Humbert, professor of medicine and director of the Pulmonary Hypertension Reference Center at the Université Paris-Saclay and investigator on the Phase 3 STELLAR study. "Based on the Phase 3 STELLAR trial, adding Winrevair to background PAH therapy demonstrated significant clinical benefits compared to background PAH therapy alone. This approval is an important milestone, as it offers healthcare providers a novel therapeutic option that targets a new PAH treatment pathway."

[Read more: FDA gives Merck green light for new indication for Keytruda]

"The Pulmonary Hypertension Association welcomes the development of new therapies for those with PAH," said Matt Granato, president and CEO of the Pulmonary Hypertension Association. "A diagnosis of PAH is a life-changing experience for patients and families due to its chronic, progressive nature. Patients with PAH experience limiting symptoms such as shortness of breath and fatigue. We are excited to see industry research leading to a better understanding of PAH and the development of a medicine in a novel treatment pathway that expands options for the patient community."

"New treatment options continue to be needed for patients with pulmonary arterial hypertension that support important clinical goals, including increasing exercise capacity and improving functional class," said Aaron Waxman, executive director of the Center for Pulmonary Heart Diseases at Brigham and Women's Hospital and investigator on the Phase 3 STELLAR study. "Sotatercept added to background therapy has the potential to become a new standard of care option for patients with pulmonary arterial hypertension."

"PAH remains a debilitating disease with high morbidity and mortality," said Eliav Barr, senior vice president and head of global clinical development, chief medical officer of Merck Research Laboratories. "This approval of WINREVAIR is an important milestone and a testament to our science-led strategy and focus on the development of innovations that can help people affected by rare diseases like PAH. We are proud to bring this novel medicine to patients."

[Read more: Merck acquires Themis]

Merck estimates that Winrevair will be available for dispensing by select specialty pharmacies in the U.S. By the end of April.

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