In late March, the Food and Drug Administration approved a new drug to treat pulmonary arterial hypertension (PAH), a cardiopulmonary disease that limits activity and often shortens the lives of its sufferers. The FDA’s green light for sotatercept (brand name Winrevair) was welcome news for Dr. David Badesch, a clinician and clinical investigator at UCHealth University of Colorado Hospital on the University of Colorado Anschutz Medical Campus, who has spent a good portion of his medical career leading a team that helps patients live with PAH.

Badesch began working with PAH patients nearly 35 years ago, helping to develop and co-direct the Pulmonary Hypertension Program at the University of Colorado. At that time, there was no specific drug treatment for the disease, which causes high blood pressure in the pulmonary arteries, the vessels that carry blood from the right side of the heart to the lungs. The condition can lead to right-side heart failure. A PAH diagnosis in those early days was close to a death sentence, Badesch recalled.

“The median or average survival from the date of diagnosis was about 2.8 years,” he said.

That grim statistic improved significantly in the ensuing years with the development of more than a dozen FDA-approved therapies for PAH, Badesch said. The Pulmonary Hypertension Program team – which includes physicians, research nurse coordinators, nurse practitioners, registered nurses, schedulers, and other contributors – played a role in the development of nearly all the therapies, he added.

The teamwork produced crucial improvements in the length and quality of life for patients suffering from PAH, Badesch said.

“It’s become largely a treatable and manageable condition, as opposed to a uniformly fatal disease,” he noted.

A need for additional treatment options for pulmonary arterial hypertension

However, for some patients, PAH continues to make activity difficult and life shorter, even with combinations of drugs from three different classes, Badesch said. That “therapeutic gap” leaves lung transplant as their sole remaining option.

The development that led to the sotatercept approval aimed to help close that gap. Badesch and the Pulmonary Hypertension Program team played an important role in the clinical trials that led to the FDA approval of the new agent.

University of Colorado Hospital was the lead site for the Phase 2 PULSAR trial of sotatercept; Badesch was the global principal investigator. The study showed that compared to placebo, sotatercept reduced the resistance to blood flow through the pulmonary arteries in PAH patients who were already receiving other therapies for their disease. Badesch co-authored a New England Journal of Medicine (NEJM) article that detailed the results of the PULSAR study.

In addition, Badesch was on the steering committee for the Phase 3 STELLAR trial of sotatercept, which showed the drug improved the capacity of patients who were already receiving other therapies to complete a six-minute walk test versus a placebo. He also co-authored last year’s NEJM article describing the STELLAR study results and their significance for patients with PAH.

“The six-minute walk test is a key endpoint in our studies that attempt to improve patients’ functional capabilities,” and their quality of life, Badesch said. He explained that the test helps clinicians measure patients’ ability to conduct daily activities like walking, biking, climbing stairs, and wheeling a cart around a supermarket.

Badesch added that the STELLAR trial showed that patients in the sotatercept group took longer to have a “clinical worsening” event – a downturn in their health, including death – than those in the placebo group.

“The FDA likes to see a drug has a favorable impact on these sorts of things, and with good reason,” he said.

A unique approach to treating PAH

How does sotatercept work and what makes it different from other treatments for PAH? Badesch explained that sotatercept is thought to address an imbalance in the signals that control the growth of cells in the walls of blood vessels. One set of signals inhibits the growth of these cells, while another promotes their growth.

In healthy vessels, these signaling pathways find an equilibrium, like a perfectly poised teeter-totter, Badesch said. But in PAH, the pro-growth pathway takes control, causing the blood vessels in the pulmonary arteries to thicken and impede blood flow.

Sotatercept, Badesch said, uses a molecule that helps to “rebalance these two signaling pathways,” decrease the thickening and improve blood flow to the lungs. Thus, sotatercept does more than widen the arteries, as other PAH therapies do.

“It is thought to more directly target the mechanisms underlying the structural changes in the blood vessels in patients with PAH,” he said.

Limitations of sotatercept

Badesch cautioned that sotatercept will not be widely available for patients treated at the UCHealth Pulmonary Vascular Disease Clinic – Anschutz Medical Campus for a few months while protocols for administering and monitoring its safety are ironed out. Nor will it be available for all PAH patients, he added.

For example, it is not intended for individuals with other respiratory complications, like chronic obstructive pulmonary disease, Badesch said.

The Phase 2 and 3 trials of sotatercept enrolled only adults with pulmonary arterial hypertension. However, Dr. Dunbar Ivy, director of the Pediatric Pulmonary Hypertension Program at Children’s Hospital Colorado, said a pediatric trial of the drug, dubbed Moonbeam, has begun and is still in the process of enrolling patients. Children’s Colorado is a site for that trial, Ivy said.

Badesch emphasized that sotatercept is not perfect – it has risks, such as increased red blood cell counts, development of blood vessel malformations known as telangectasias, and an increased chance of bleeding – and providers will have to monitor its long-term effects carefully. But he expressed hope that the drug’s mechanism – “remodeling” the structure of blood vessels – could be a “paradigm shift” in finding new ways to treat PAH and possibly other diseases.

“Even if this drug doesn’t end up doing everything we hope for, it leads us into another approach to the disease,” Badesch said. “That’s what I think has people in the field excited.”

A benefactor of the new pulmonary arterial hypertension treatment

Toni Propson of Longmont shares that excitement. Propson, now 34, was just 21 years old and still in college when she began experiencing shortness of breath, fatigue, and heart palpitations. The changes were puzzling. Propson said she’d previously played soccer, run cross country, and swam and surfed in the ocean near her childhood home in Amelia Beach, Florida.

“I had never had anything like those symptoms,” she said.

The debilitating changes finally forced Propson to visit an emergency room in 2011, which led to a right-heart catheterization and a diagnosis of PAH – the result of a genetic predisposition to it on her father’s side, she later learned. Shortly thereafter, she began seeing Badesch, who prescribed epoprostenol (brand name Flolan), an intravenous medication that helps to open the pulmonary arteries.

“I was relieved to have the therapy,” Propson said. She always had to carry the Flolan with her in a fanny pack, but she breathed more easily and was able to walk longer distances. She got a job as a systems engineer at Boulder Community Hospital (now Boulder Community Health), married, and “found different ways to enjoy life” with short hikes around lakes and reservoirs and on the Longmont-to-Boulder (LoBo) Trail near her home.

Improving the life-limiting effects of PAH

Despite the improvement, Propson periodically needed to have her Flolan dosages increased, which produced painful side effects, including jaw and foot pain and migraines. She also received other oral medication for her PAH. She left her full-time job in 2017 after deciding it “didn’t have a positive impact” on her overall health.

The PAH also continued to limit Propson’s activity and options. If she traveled to a town at a higher elevation, like Estes Park or Breckenridge, she noticed that she got badly out of breath, became confused and had trouble remembering where she parked the car or other simple things. Even in Boulder – only about 500 feet higher than Longmont – Propson said she got dizzy and saw speckles floating before her eyes.

She was a candidate for the Phase 2 PULSAR trial, and became Badesch’s first enrolled patient, in 2019. She initially received the placebo, but after a second right-heart catheterization, she entered an extension phase of the study and received sotatercept through regular infusions at UCH.

After a period of adjustment, Propson said she felt her stamina increase. She could walk farther and Badesch was able to decrease her Flolan dosage. Then the COVID-19 pandemic hit in March 2020. Understandably fearful of getting infected if she visited the hospital, she missed two doses of the sotatercept. She soon felt a change.

“I breathed heavier, had trouble catching my breath and tossed and turned at night,” Propson said. “I thought, ‘This hasn’t happened in a long time.’ Once I started receiving the doses [of sotatercept] again, I felt much better.”

A clinical trial that offers promise for patients and science 

Today, Propson said she continues to improve slowly. She can now travel to mountain towns without battling breathing, memory, and vision symptoms.

“I know what I’m doing and can stop and have coffee,” she said. “I would never have felt comfortable doing that before.”

At home in Loveland, Propson experiences another benefit of her improved health every day: enjoying active time with her son Austin, who will turn two in September.

“I may never get off Flolan altogether, but if I can keep my body improving at a steady pace, I’m eternally grateful,” she said.

Badesch said that he, in turn, greatly values patients like Propson who volunteer to join clinical trials despite not knowing whether they will get the drug that is being tested, whether it will work if they do, or what side effects it might produce.

“These people want to do it, understanding the drug may not benefit them personally,” Badesch said. “You can’t really go forward without that.”