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FDA Approves Sotatercept, First-in-Class Treatment For Adults With PAH

Adults with pulmonary arterial hypertension (PAH) have a new treatment available with the FDA approval of sotatercept (Winrevair; Merck), an activin signaling inhibitor biologic.

Sotatercept (Winrevair; Merck) has been approved by the FDA for the treatment of patients with pulmonary arterial hypertension (PAH), according to a press release from Merck.1 The approval comes after sotatercept was granted priority review in September 2023.2 The treatment was also granted FDA breakthrough therapy and orphan drug designations for the 45 mg and 60 mg doses.

PAH is a life-threatening disease that causes blood vessels in the lungs to narrow and increase strain on the heart, and can result in heart failure, reduced physical activity, and reduced life expectancy among other adverse effects. The 5-year mortality rate for patients with PAH is about 43%, with approximately 40,000 people in the US living with the condition.

SotaterceptImage credit: Merck

Sotatercept is an activin signaling inhibitor that has been found to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events in patients with PAH when added to background standard-of care therapy.1 The approval of sotatercept marks the first for an activin signaling inhibitor for PAH.

The approval is based on data from the multicenter, double-blind, phase 3 STELLAR trial, with results published in The New England Journal of Medicine in April of 2023.3 The trial assigned all participants 1:1 to receive either a sotatercept (n = 163) or placebo (n = 160) every 3 weeks in addition to background standard-of-care therapy for PAH. Change in 6-minute walking distance (6MWD) from baseline to week 24 was the primary end point of the study.

The researchers found a 34.4 m (95% CI, 33.0-35.5) median change in baseline for 6MWD by week 24 in the group that received sotatercept vs a 1.0 m (95% CI, –0.3 to 3.5) median change in 6MWD for the placebo group. The estimated difference in 6MWD after 24 weeks between the sotatercept and placebo groups was 40.8 m (95% CI, 27.5-54.1).

"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. Sotatercept added to background therapy has the potential to become a new standard of care option for patients with pulmonary arterial hypertension" Aaron Waxman, MD, executive director of the Center for Pulmonary Heart Diseases at the Brigham and Women's Hospital and investigator on the Phase 3 STELLAR study, said in a statement.1

The secondary end points, tested hierarchically, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in World Health Organization functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores. Except for the PAH-SYMPACT Cognitive/Emotional Impacts domain score, all secondary end points were significantly improved with sotatercept compared with placebo; they were assessed at week 24 except for time to death or clinical worsening.

Adverse effects of sotatercept include epistaxis, telangiectasia, dizziness, headache, rash, thrombocytopenia, increased hemoglobin, and increased blood pressure. These occurred more often in the sotatercept group compared with placebo. Hemoglobin and platelets should also be monitored by health care providers before a dose of sotatercept for the first 5 doses given these potential adverse effects.

"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," Matt Granato, president and chief executive officer of Pulmonary Hypertension Association, said.1

The medication will be available for all patients starting in April, the company stated in the press release.

References

FDA approves Merck's WINREVAIR (sotatercept-csrk), a first-in-class treatment for adults with pulmonary arterial hypertension (PAH, WHO group 1). News release. Merck; March 26, 2024. Accessed March 26, 2024.

Merck receives priority revew from FDA for new biologics license application for sotatercept, an activin signaling inhibitor to treat adults with pulmonary arterial hypertension. News release. Merck. September 28, 2023. Accessed March 22, 2024. Https://www.Merck.Com/news/merck-receives-priority-review-from-fda-for-new-biologics-license-application-for-sotatercept-an-activin-signaling-inhibitor-to-treat-adults-with-pulmonary-arterial-hypertension-pah/

Hoeper MM, Badesch DB, Ghofrani A, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. Doi:10.1056/NEJMoa2213558

FDA Approves First-in-class Drug For Rare Lung Disorder

Credit: Merck & Co.

A 45 mg vial of Merck & Co.'s drug sotatercept, marketed as Winrevair

The US Food and Drug Administration has approved a fusion protein made by Merck & Co. For a rare, life-threatening lung disorder.

The drug, called sotatercept and set to be marketed under the name Winrevair, is designed to treat pulmonary arterial hypertension (PAH) by trapping ligands of the transforming growth factor-β superfamily of proteins. It's a new approach to treating PAH, wherein small arteries in the lung thicken and narrow, blocking blood flow. Over time, it becomes more difficult for blood to get through the lungs, forcing the heart to work harder and eventually wear out.

People with PAH have so far relied on classic vasodilators, but 21% of these people with the disorder die within 3 years of initiating treatment—a number that goes up to 55% for those considered high risk (J. Am. Heart Assoc. 2022, DOI: 10.1161/JAHA.121.024969).

"The progression slows down a little bit, but [the vasodilators] don't treat the underlying root cause," says Joerg Koglin, senior vice president of clinical development at Merck, where he oversees cardiovascular and other therapeutic divisions. "Despite us now having many of those patients on two or three of those vasodilators, the mortality hasn't really changed."

In a 323-person Phase 3 clinical trial, sotatercept bested a placebo when it came to exercise capacity, pulmonary vascular resistance, and overall function and survival. At 33 weeks, nearly five times as many study participants in the placebo group died or had their symptoms worsen than in the sotatercept group (N. Engl. J. Med. 2023, DOI: 10.1056/NEJMoa2213558).

Credit: A box containing a 45 mg vial of Merck & Co.

A box containing a 45 mg vial of Merck & Co.'s drug sotatercept, marketed as Winrevair

Somewhere between 15 and 50 people per million in the US and Europe have PAH, making it a rare disorder (Respir. Med. 2020, DOI: 10.1016/j.Rmed.2020.106099), but analysts expect high demand given the unmet clinical need. Leerink Partners' Daina M. Graybosch wrote in a research note Monday that the drug's approval would "unleash strong demand, with the US sales ramp gated by the practical logistics of rolling out the therapy."

The drug comes in a refrigerated vial that holds either 45 mg or 60 mg. It needs to be drawn down into a needle and injected just underneath the skin under the guidance of a physician. Some of the most common adverse events in trials were hemoglobin increases, which occurred in about 15% of recipients, and bleeding, which occurred in about 4%.

Sotatercept was at the heart of Merck's $11.5 billion acquisition of Cambridge-based Acceleron Pharma, which initially developed the drug, in 2021. Early preclinical data, Koglin remembers, were "nothing short of stunning." And he knows what it's like to treat PAH patients. Koglin practiced as a cardiologist in the 1990s, before PAH had any approved medications.

"When you see those individual patients, you have maybe a 40- or 50-year-old woman sitting in front of you, saying, 'Hey, a couple months ago, I started getting short of breath when exercising. I think maybe it's nothing, but can we look at it?' And you have to give them a diagnosis that will ultimately limit their life expectancy," Koglin says. "That makes you, by definition, a patient advocate."

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FDA Approves Potential 'Game Changer' For Pulmonary Arterial Hypertension

Pictured: Merck Research Laboratories in California/iStock, Michael Vi

Merck's $11.5 billion acquisition of Acceleron Pharma paid dividends Tuesday as the FDA approved sotatercept, the cornerstone of the deal, to treat pulmonary arterial hypertension.

The drug, which will carry the brand name Winrevair, is the first FDA-approved activin signaling inhibitor therapy for PAH, according to Merck's announcement. This new therapeutic class improves the balance between pro- and anti-proliferative signaling to regulate vascular cell proliferation, an underlying cause of PAH. 

Winrevair is intended to be used alongside existing PAH therapies to increase exercise capacity, lessen the severity of PAH and reduce the risk of disease worsening.

Merck has priced Winrevair at $14,000 per vial before insurance, according to multiple sources.

The drug came into Merck's possession with the 2021 acquisition of Acceleron. "[Winrevair] was the main opportunity that we saw with the Acceleron acquisition," Mahesh Patel, VP of global clinical development at Merck Research Laboratories, told BioSpace. "We have been so fortunate in how well things have gone in the acquisition, executing on the clinical development program and seeing paradigm-changing clinical trial results through it."

In October 2022, Winrevair hit the primary Phase III endpoint, eliciting a statistically significant and clinically meaningful improvement in the 6-minute walk distance test after 24 weeks. The drug also reached statistical significance in secondary endpoints, including time to patient death or the first occurrence of a clinical worsening event. 

Patel said that before Winrevair, treatments for PAH had only dilated the arteries, opening blocked or narrowed blood vessels and allowing more oxygen to flow. However, earlier medicines have not addressed the root causes of the disease. Winrevair has the chance to "dramatically change" patients' physical function and quality of life, Patel said.

Tuesday's approval follows that of Johnson & Johnson's Opsynvi, a single-tablet combination of macitentan and tadalafil, which received the FDA's green light on March 22 for adults with PAH.

But Jeremy Feldman, director of the pulmonary hypertension program and medical director for high-risk care at Summit Heath, who was also involved in Winrevair's Phase II and III trials, expressed more excitement about this medicine.

"Without a doubt, sotatercept is a game changer," he told BioSpace. "I think the way that that will impact patients is very different than the availability of a combo tablet that doesn't advance the care of patients. It may advance the convenience of patients a little bit." He added that Winrevair is a particularly effective agent on top of the approved therapies and is particularly well-tolerated in terms of day-to-day side effects. "I think there's a question mark that still has not been fully answered about the long-term safety of the medication, but that's not an unfamiliar space for us to be in with a disease process that has still a very high mortality."

Winrevair's label lists warnings for erythrocytosis, which may increase the risk of thromboembolic events and hyperviscosity syndrome, and severe thrombocytopenia, which may increase the risk of bleeding. 

Winrevair and Opsynvi enter a growing PAH market, which Prophecy Market Insights projects will be worth $12.2 billion by 2032. An increasing geriatric population married with global increases in chronic diseases has led to a rise in the need for PAH medicines, according to the report. As of December 2023, approximately 129 drugs were in development for PAH by 110 companies, institutes and universities, Pharmaceutical Technology reported.

Patel said Merck plans to investigate Winrevair for other unmet needs in PAH, including on trial its potential use within one year of diagnosis and a second trial in patients who potentially are at very high risk for progressive morbidity and mortality.

Tim Noyes, CEO of Aerovate Therapeutics, which is also developing a PAH candidate, said this is an "exciting" time to be in the space. For the past 20 years, the "bedrock" of care has been using dilators, or vasodilators, Noyes told BioSpace. While this has made a difference for patients, the underlying problem with PAH is cell proliferation with arteries narrowing from the inside out, he said.

"To get to that next level, to allow patients to really start to have an agent that addresses the underlying cause of their disease, it's anti-proliferative agents and [that's] why there's so much enthusiasm for sotatercept," Noyes said.

Aerovate's candidate, a tyrosine kinase inhibitor, is a dry-powder aerosol version of Novartis' cancer drug Gleevec. Noyes sees the drug as complementary to Winrevair as opposed to being necessarily a competitor. "Each has its . . . Specific benefits to patients, entirely different mechanisms," he explained.

Winrevair will be available to patients at select pharmacies at the end of April, according to Merck's announcement.

"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," Matt Granato, president and CEO of the Pulmonary Hypertension Association, said in a statement. "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."

Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.Patchen@biospace.Com. Follow him on LinkedIn.

Correction (March 27): This story has been updated from its original version to reflect that Aerovate does believe that its candidate, if approved, could be used in combination with Winrevair. BioSpace regrets the error. 

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