Opportunity and New Therapies Are Driving Interest in a Rare Cardiovascular Disease

Pictured: Doctor looks at a chest x-ray film/iStock, Chinnapong

The global market for pulmonary arterial hypertension treatments is expected to reach nearly $11 billion by 2030. While not the $24 billion projected for the non-alcoholic steatohepatitis market by 2028 or the $30 billion the obesity market could see by 2030, PAH drugs are hot property.

In 2021, Merck paid $11.5 billion to acquire Acceleron Pharma and its pulmonary arterial hypertension (PAH) drug sotatercept. Bayer and Pfizer are also big players, as is United Therapeutics, which in 2018 paid Arena Pharmaceuticals a potential $1.2 billion for exclusive worldwide rights to develop late-stage PAH candidate ralinepag. So, when it comes to PAH, what’s the big draw for biopharma?

PAH is a rare disease, with between 500 and 1,000 people diagnosed each year in the U.S. A specific type of pulmonary hypertension, PAH occurs when tiny arteries in the lungs thicken and narrow, which makes the heart work harder to pump blood. This extra demand on the heart often leads to fatal heart failure within a few years.

The market may be modest compared with others, but there’s a significant gap waiting to be exploited, said Akash Patel, a healthcare analyst in cardiovascular and metabolic disorders at GlobalData Healthcare.  

“Significant opportunity remains to develop a therapy that addresses the underlying cause of disease and not one that just treats symptoms,” he told BioSpace. “Developing a therapy that addresses the disease pathogenesis and has a good safety profile has the potential to gain $2 billion-plus of market share in the long-term, and this would prove to be significant revenue for any pharma company that can dominate the space.”

Patients with PAH have decreased expression of the enzyme prostacyclin synthase, which leads to reduced prostacyclin in blood vessels in the lungs. In turn, these lower prostacyclin levels decrease levels of cAMP, which constricts blood vessels.

Many existing PAH drugs are PDE5 inhibitors, such as sildenafil, that increase cAMP levels and so promote dilation of blood vessels.

“This doesn’t address the disease mechanism that is causing the decrease in prostacyclin synthase,” Patel said. These therapies are often given in combination with a different class of drugs, prostacylin receptor agonists, that prevent vasoconstriction. These treatments do offer some important relief from PAH symptoms such as shortness of breath, but they do not treat the disease itself, which continues to progress, he added. “The market opportunity for addressing PAH remains significant, especially for a therapy that is disease-modifying.”

A New Wave of Therapies

Sotatercept is a potential game-changer, Patel said, because rather than seeking to promote vasodilation, it can tackle a root cause of PAH—the cell proliferation that drives the problematic arterial thickening. Analysts say the drug could reach sales of $1.4 billion by 2028.

According to Joerg Koglin, vice president for global clinical development at Merck Cardiovascular, this anti-proliferation approach means sotatercept can effectively reverse the disease. In preclinical studies with mice, these vessels essentially looked like normal vessels, Koglin told BioSpace. “I personally have never seen something like that,” he said.

Top-line data from the drug’s Phase III trial, reported in Oct. 2022, have added to the excitement.

PAH trials focus on improvements in how far patients on a treatment can walk in six minutes. But in addition to showing significant benefits there, sotatercept also appeared to slow the progression of clinical symptoms.

“This was the first study where patients didn’t only slow down their progression, but where actually a substantial proportion of patients improved their progression,” Koglin said. The company is now running a trial to see if the drug can reduce deaths and hospitalization. “That’s never been shown with any PAH drug.”

Such anti-proliferation therapies are driving a “new wave” of PAH treatments, said Tim Noyes, CEO of Aerovate Therapeutics, which is developing an inhaled version of the cancer drug imatinib as an anti-proliferation therapy for PAH.

“A lot of the interest now in PAH is studying novel anti-proliferative mechanisms like ours,” Noyes told BioSpace. “We have lots of drugs that dilate blood vessels, [but] you can only dilate them so much. They’re still going to gunk up and narrow from the inside out.”

Anti-proliferation drugs tend to have more-severe side effects than vasodilators, which has stifled progress. But companies are now finding ways to better target the effects. And because they work against different cellular pathways, combinations of anti-proliferation drugs could be used together to maximize the benefits, Noyes said.

“Like cancer, this is a disease that almost certainly, for my lifetime and yours, will be treated with combinations,” he said. “If we can reverse it, certainly arrest it, then we’ve changed the nature of this disease. And hopefully, one day, like HIV, this becomes a chronic disease that people manage with their drugs.”

A Broader Opportunity

There’s a further “elephant in the room” when it comes to work on PAH, Koglin said, and one that can also help to explain the commercial interest in such a rare disease.

While PAH is rare, other forms of pulmonary hypertension are not. Pulmonary hypertension can result from heart failure, which affects more than 64 million people worldwide. And pulmonary hypertension is associated with pulmonary diseases such as chronic obstructive pulmonary disease, which affects more than 10% of people over 40.

In principle, finding ways to use anti-proliferation drugs to control blood vessel vasoconstriction in PAH could open the door to similar benefits in these more common—and so more lucrative—related diseases.

“If you could develop a drug that improves pulmonary hypertension secondary to heart failure, you open up a completely new space,” Koglin said. “We have good preclinical data that shows it should work there.”

David Adam is a freelance science journalist based in the UK. Reach him at [email protected].