Healio Interview

Disclosures: Yu reports receiving research support and/or serving on the scientific advisory board for Acceleron Pharma, Gossamer Bio, Inozyme Pharma, Keros Therapeutics, Pfizer, Regeneron Pharmaceuticals and Vascular BioSystems.
October 29, 2021
8 min read

Peering into future of PAH treatment


Healio Interview

Disclosures: Yu reports receiving research support and/or serving on the scientific advisory board for Acceleron Pharma, Gossamer Bio, Inozyme Pharma, Keros Therapeutics, Pfizer, Regeneron Pharmaceuticals and Vascular BioSystems.
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As understanding of pulmonary arterial hypertension grows and novel therapies emerge, the treatment of PAH appears to be entering a new era.

“There have been a lot of new developments in therapy that have grown out of the extensive research that has been applied to this condition over the past several decades, and everything that we’ve learned up until now is coming to bear,” Paul B. Yu, MD, PhD, FAHA, associate professor of medicine at Harvard Medical School and section head of cardiovascular life sciences in the division of cardiovascular medicine at Brigham and Women’s Hospital, told Healio in an interview.

Paul B. Yu, MD, PhD, FAHA
Paul B. Yu

Yu reviewed some of these advances and how they are translating to novel approaches to treatment for patients with PAH.

A paradigm shift

There are three major categories of therapies for PAH: prostacyclin analogs, nitric oxide and cyclic guanosine-3'-5'-monophosphate (GMP) modulators, and endothelin receptor antagonists. One of the major developments in therapy for PAH, according to Yu, pertains to how physicians select the most appropriate treatment for each patient.

Endothelin receptor antagonists, such as macitentan, ambrisentan and bosentan, nitric oxide modulators — which include the long-acting phosphodiesterase type 5 inhibitors sildenafil and tadalafil — and the soluble guanylate cyclase activator riociguat (Adempas, Bayer) are all oral compounds.

Physicians typically use these more convenient oral medications first to treat patients who are NYHA functional class I or II and prioritize prostacyclin analogs administered parenterally (intravenously or subcutaneously) for those who are NYHA functional class III or IV. More recently oral prostacyclin analogs have been added to the mix with a role that probably lies somewhere between the traditional oral and parenteral agents.

However, over the past decade, randomized controlled studies on the impact of using drugs from two or three classes upfront, as opposed to waiting for the patient to deteriorate, have led to a paradigm shift in treatment, according to Yu.

“Using two or three drugs seems to be far more effective than using one and treating in an expectant fashion gradually, according to the way the disease does or does not progress,” Yu said, citing data from the landmark AMBITION trial, which studied use of ambrisentan and tadalafil. “Giving these two drugs upfront yielded nice improvements in outcomes compared with just giving either drug alone.”

Consequently, AMBITION established the template for those seeking to investigate other multidrug combinations, according to Yu.

“The jury is still out on whether the clinical benefit can justify the potential increase in side effects or costs of triple therapy,” Yu said. The TRITON trial showed similarly robust clinical improvements with up-front dual vs. triple therapy after 26 weeks, and similar tolerability, but suggested potential improvements in progression of disease with triple therapy. “Intuitively, people might feel that three drugs are better than two, particularly if the three-drug regimen includes a prostacyclin, but we’re just starting to get signals to indicate whether or not that’s true.”

Yu noted that the decision to forge ahead with combination therapy as opposed to using a single drug is broadly based on NYHA functional class, but more quantitative approaches do exist. Specifically, the REVEAL Registry Risk Score can help estimate prognosis and, theoretically, be used to prioritize treatment.

“People used to do this sort of heuristically and based on their own clinical experience, but increasingly, and maybe even as a requirement from payers, we will have to justify it in quantitative terms,” Yu said.

Interestingly, a retrospective analysis of the AMBITION trial data by Frost and colleagues suggested that upfront dual-drug therapy yielded improved outcomes regardless of REVEAL score stratification, according to Yu.

Importance of genetics

One of the most significant developments in diagnosis of PAH arose from several large gene sequencing efforts that were designed to improve understanding of the genetics of PAH, according to Yu.

“We now know that loss-of-function mutations occurring in potentially  18 different genetic loci that can increase the risk of PAH and that number of genes continues to rise as we sequence more individuals and have better algorithms for identifying potential disease-causing mutations,” Yu told Healio.

At least seven of these, Yu noted, lie in the bone morphogenetic protein (BMP) signaling pathway, including BMPR2, ALK1, endoglin, SMAD4, SMAD9, BMP9 and BMP10, suggesting a particularly important role of the BMP signaling family in regulating pulmonary vascular disease.

“The discovery of these and other mutations in patients in broader populations with PAH attributed to other non-genetic etiologies may change the way we think about PAH clinically,” Yu said. “While in the past we typically associated these mutations with patients having either a known family history, or with an obvious syndrome, we are now finding these mutations in those who might have another equally compelling explanation, such as severe liver disease, congenital heart disease or use of anorexigens or stimulant drugs.”

Based on recent genome and exome sequencing work from large U.S. and U.K. cohorts, approximately 14% of all WHO group 1 PAH is associated with a loss-of-function mutation in one of the currently known genes, according to Yu.

“Genetics might be a tool for understanding the kind of PAH you have and what your risk factors are, but it’s also transformed our way of thinking about how to treat this because if seven out of 18 lesions are located in the BMP signaling pathway, it might seem reasonable that correcting the signaling defect in that particular pathway could help cure disease. This is the basis for several of the treatment strategies that are currently being developed,” Yu said.

Promise of sotatercept

Many new therapies for PAH have emerged in recent years, some of which have stemmed from the latest data on genetics. Sotatercept (Acceleron Pharma), for example, is a biologic therapy based on the extracellular domain of ACTRIIA, a receptor from the BMP and transforming growth factor-beta signaling pathway. Sotatercept, a recombinant ACTRIIA extracellular domain fused with IgG-Fc domain to prolong its half-life in circulation, and collects and neutralizes activin proteins and growth differentiation factor (GDF)-8 and GDF-11.

“The idea was that by using sotatercept to block the activin and GDF ligands, which generally have actions that oppose those of BMP ligands, you might restore a balance to a system that does not have enough BMP signaling,” said Yu, who is the senior author on a preclinical study of sotatercept that was published in Science Translational Medicine in 2020. “We tested that molecule in a number of preclinical models of PAH and found that it was potent in not only preventing the progression of PAH in animal models, but could even reverse the disease once it was established.”

Researchers subsequently evaluated the treatment in humans in the randomized controlled PULSAR trial, which was published in The New England Journal of Medicine in April. In the study, they found significant improvements in pulmonary vascular resistance (PVR) at 24 weeks in patients treated with sotatercept vs. standard of care. Notably, the patients in the study had fairly severe disease, with an average baseline PVR of nearly 10 Wood units and more than half of patients already on triple therapy at enrollment, according to Yu.

Yu said these results spawned several follow-up studies, including the open-label phase 2 SPECTRA study and double-blind, placebo-controlled phase 3 STELLAR study. In SPECTRA, researchers are looking in detail at right ventricular function changes in patients on sotatercept treatment over several months using cardiac MRI and invasive cardiopulmonary exercise test. In STELLAR, 284 patients with PAH will be randomly assigned sotatercept or placebo, with 6-minute walk distance at 24 weeks serving as the primary endpoint.

Investigation into novel therapies

The evolving landscape of PAH treatment also includes the emergence of new drugs, novel formulations of existing drugs and innovative devices.

In 2005, researchers in Germany published a case report in NEJM that demonstrated the benefit of using imatinib, which is FDA-approved for a variety of tumors, in a patient with severe PAH. This report led to the IMPRES clinical trial that linked imatinib to improvement in 6-minute walk distance and PVR at 24 weeks, but development ceased when the treatment was associated with subdural hemorrhage in a percentage of patients in the trial, according to Yu.

“That bleeding had not really been seen before in the trials evaluating imatinib for its approved cancer indications, but due to the fact that in the late 2000s, many patients were on blood thinners for PAH, the common thinking is that the combination of systemic therapy with imatinib and blood thinning may have precipitated intracranial bleeds,” Yu said.

However, researchers are revisiting the treatment’s potential in two ongoing trials that are evaluating the use of a dry powder formulation of imatinib. Aerovate Therapeutics, the company that opted to study imatinib in this new formulation, has conducted a phase 1 study in healthy volunteers and is planning a phase 2b/3 study — dubbed the IMPAHCT trial — that will investigate the treatment’s efficacy in 400 patients with PAH, according to Yu.

“These patients won’t be on blood thinners to the degree that those in the previous trial were and the treatment is being delivered to the lungs in an aerosolized form, with less systemic exposure, so people are cautiously optimistic about this,” Yu said.

In the same vein, researchers are also studying seralutinib (Gossamer Bio), which is designed to be a selective inhibitor of platelet-derived growth factor receptor-alpha and beta kinases and is also given in an aerosolized powder formulation.

“That set of growth factors are important in causing the expansion of smooth muscle that leads to the increased vascular tone and eventually contributes to the obliterative remodeling in pulmonary vessels. If you can inhibit the growth factors, either with imatinib or a next-generation kinase inhibitor, not have intracranial bleeds and maybe get it into the lungs selectively, you might be better off,” Yu said.

Interestingly, both IMPAHCT and the phase 2 study of seralutinib are using PVR as their primary endpoints.

“This represents a shift in thinking and PVR is going to be used increasingly in their proof-of-concept phase 2 clinical trials,” Yu said.

In addition to potential disease-modifying anti-remodeling therapies, researchers are also evaluating the Aria CV Pulmonary Hypertension System — a device that involves permanent implantation of a compressible balloon into the pulmonary artery, that is connected to a reservoir.

“The whole principle is that this balloon that’s compressible stores energy from the right ventricle when it’s contracting in systole, and is designed so it is much more compressible and distensible than the obstructed and remodeled lung vessels of the person with PAH,” Yu said. “Rather than trying to push the blood forward, the right ventricle will have a much easier time of storing that energy into this compressible balloon. The balloon, during diastole, then releases its energy against a closed pulmonary valve to propel the blood forward.”

This might improve right ventricular function, Yu said, which is a critical factor in determining outcomes in PAH.

Short-term safety testing of the device has been previously done, an open label clinical trial in 15 subjects called ASPIRE PH to explore its longer term feasibility and potential efficacy has been initiated, according to Yu.

Looking ahead

Other therapies, which are not as far along in the development process, are also under investigation, according to Yu. Several appear promising preclinically, including bromodomain and extraterminal domain (BET) inhibitors

“I don’t know how far BET inhibitors will move forward clinically in PAH, but their success in experimental models is certainly giving a lot of weight to the idea that treatments that modify our epigenetic regulation could be useful for PAH,” Yu told Healio.

Although several of these compounds were initially explored for oncology indications, a lot of what will determine their eventual success in PAH may be the long-term tolerability of the specific molecule, or the mode of delivery, Yu noted.

In addition to treatments, researchers and physicians are seeking to make strides in diagnosis as well, according to Yu. Research into biomarkers that would help confirm diagnosis or predict disease course is ongoing. Yu noted that having a noninvasive way of monitoring changes in the lung circulation in patients with PAH as an adjunct or even a substitute for performing the right heart catheterization, the current gold standard for diagnosis and monitoring, would be beneficial.

“One promising strategy is using different positron emission tomography/CT imaging modalities, which by virtue of using radionuclide probes, are incredibly sensitive for detecting cellular or molecular changes in the lung circulation, possibly even before the development of clinical symptoms or changes in function,” Yu said. “We’ve looked at a variety of different probes that might detect the abnormal expression of growth factors, including vascular endothelial growth factor, or other changes in the composition of inflammatory cells that reflect changes in the lung circulation in people with PAH.”

The ideal noninvasive testing modality, according to Yu, would allow physicians to predict disease progression or risk, monitor therapies for evidence of anti-remodeling effects, tailor or adjust regimens for specific patients or even help evaluate a patient with undiagnosed PAH who presents with vague symptoms.

In light of these developments, the future of PAH treatment looks bright, Yu said.

“It’s been a long road. We had thought the timeframe from an advance like discovering mutations in the BMPR2 gene for heritable PAH in 2000 to having something concrete to help our patients would be short, but it has been a long process. However, all the diligent work that it took from many groups trying to understand the meaning of the human genetics in terms of vascular cell biology, and having useful pharmacologic tools to target this biology has brought us to the point where you can start to make inroads, like with sotatercept, where all that work starts to pay off,” Yu told Healio. “We’re making great progress now, and it was the product of many people doing great work to try and get to the genetic, molecular and cellular underpinnings of this disease.”


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