How recent developments in pulmonary arterial hypertension impact managed healthcare
A Q&A with Aaron B. Waxman, MD, PhD
MHE: What are the latest insights into the underlying pathophysiology of pulmonary arterial hypertension (PAH)?
Waxman: Lately, we’ve learned a great deal about the roles of vascular remodeling and endothelial dysfunction in PAH. Historically, the focus was on vasoconstriction, which appears to have a minor role compared to the current understanding of a pro-proliferative, anti-apoptotic state. Key findings highlight the role of the TGF-β signaling pathway in promoting this state and the involvement of various growth factors in vascular remodeling. These insights are crucial for developing targeted therapies for PAH.
MHE: How do genetic mutations influence the development of PAH?
Waxman: Genetic mutations play a significant role. Historically, BMPR2 mutations — especially in heritable PAH — have been the most studied. However, this pathophysiology accounts for a small minority of cases. Increasingly, acquired mutations in BMPR2 signaling are being recognized across various PAH types; acquired defects in this pathway eventually present in all forms of PAH. Other genes have also been identified as crucial for vascular remodeling in various PAH subsets.
MHE: Has PAH diagnosis advanced in recent years?
Waxman: Enhanced imaging technology in echocardiography has come to provide clearer images for better screening. However, this technique alone is insufficient for a definitive diagnosis.
Right heart catheterization remains the gold standard for PAH diagnosis, with technological advancements leading to more digital approaches. Despite some noise associated with fluid-filled catheters, we rely on them for diagnosis. Additionally, vasodilator testing can inform disease duration, severity and likelihood of treatment response, further refining the diagnostic process. While these diagnostic tools have seen some advancements, the fundamental approaches have not changed drastically.
MHE: What constitutes the standard of care for PAH?
Waxman: PAH care involves both diagnostic and treatment approaches. Diagnostically, right heart catheterization is essential to confirm whether the condition is precapillary, postcapillary or combined. Without it, a definitive PAH diagnosis cannot be made.
From a treatment standpoint, several pathways have been targeted with a key focus on risk stratification to inform treatment decision-making. The standard of care emphasizes the importance of assessing a patient’s risk profile to guide treatment decisions and the role of combination therapies.
MHE: How, if at all, has the March 2024 FDA approval of sotatercept impacted the treatment of PAH?
Waxman: The approval has had a significant impact. The results of clinical trials demonstrated impressive improvements in hemodynamics and exercise tolerance, making sotatercept a crucial addition to the treatment arsenal. Most studies have focused on patients already receiving background therapy, with sotatercept enhancing overall treatment outcomes.
Sotatercept’s efficacy has prompted consideration of de-escalating other PAH therapies, particularly those with significant side effect profiles. This approach has the potential to reduce patients’ medication burden and enhance their overall disease management and long-term prognosis.
MHE: How might the more recent results from the ZENITH trial impact the future of PAH care?
Waxman: The ZENITH trial, which evaluated sotatercept in patients with advanced PAH, demonstrated excellent efficacy including significantly improved hemodynamics and exercise tolerance. These results clarify the role of sotatercept, which is a ligand trap that inhibits activin and growth differentiating factors targeting the TGF-β signaling pathway, as a crucial tool in PAH treatment. These results may shape future PAH care by reinforcing the importance of specific pathway-targeted therapies in improving patient outcomes.
MHE: What investigational therapies are in the pipeline?
Waxman: Activin inhibitors, growth factor inhibitors and refined soluble guanylyl cyclase activators all demonstrate promise as PAH therapies. They all target the underlying pro-proliferative and pro-fibrotic states rather than act as vasodilators, and they are expected to impact vascular remodeling. Additionally, the intersection of multiple pathways may lead to combination effects that may simplify long-term treatment. Among these, inhibitors of activin and growth factor pathways such as PDGF are particularly promising.
MHE:What barriers do patients face in accessing PAH treatment?
Waxman: Cost is the biggest barrier. All available treatments including older vasodilator therapies are very expensive. Securing insurance approval is important, and obtaining coverage without prohibitive copayments remains a significant challenge.
MHE: What strategies can healthcare organizations implement to improve access to PAH therapies?
Waxman: Healthcare organizations should focus on streamlining coverage processes to ensure that patients can receive necessary treatments without facing insurmountable copayments. Many patients cannot afford these drugs or their associated costs; development of strategies to reduce financial barriers is crucial. Organizations could also explore partnerships with pharmaceutical companies, involving patients in clinical trials or negotiating larger contracts, to lower drug costs and expand access.
MHE: How can managed-care organizations help to optimize treatment pathways and cost-effectiveness in PAH management?
Waxman: Managed-care organizations can do a lot. Currently, we risk-stratify patients to tailor treatment strategies. For those with advanced disease or a high risk of progression, a multimodal treatment approach that is similar to cancer treatment is employed. High-risk patients with PAH are often treated with three or four drugs. Targeting multiple pathways has proven more effective, especially as new treatments like activin and growth factor inhibitors emerge.
Starting with treatments that target multiple pathways in a way similar to that of chemotherapy can yield significant responses. With the availability of these new therapies, this approach may allow the de-escalation of therapy over time. Although it has a high initial cost, this strategy can lead to cost savings if there is a good initial response, and it may ultimately reduce the long-term medication burden.
MHE: What policy changes or healthcare reforms would help improve access to PAH treatments?
Waxman: Improving access requires addressing two key issues. First, early disease recognition is paramount. Identifying PAH early allows for less aggressive treatment, as patients diagnosed at an earlier stage have better treatment responses with less aggressive therapy. Encouraging clinicians to consider PAH when patients present with symptoms like exercise-induced shortness of breath can lead to simpler treatments.
Second, for patients with advanced disease, aggressive treatment approaches can drive up costs. To manage this, healthcare policy should explore strategies like pooled funding models to help reduce the burden of expensive therapies. Additionally, revising orphan disease designation policies could help reduce medication costs, as current patent protections often drive up prices. Balancing the need to fund research and development with the high costs of approved therapies is a complex challenge, but these policy changes could improve both access and affordability.
MHE:What role might digital health tools play in the coming years?
Waxman: The future of PAH care will certainly involve the integration of digital health tools, with remote monitoring being an important aspect. Small, implantable monitors can track pulmonary artery pressures daily to allow more targeted treatment adjustments. While these tools are approved for group 2 pulmonary hypertension secondary to left heart disease, they are not yet approved for PAH. However, they hold great potential for more precise management.
Telemedicine, while useful, presents challenges in PAH care. During the COVID-19 pandemic, telemedicine was essential, but it became clear that patients with PAH may not fare well without in-person visits. The inability to conduct physical examinations or observe body language limits the ability to assess their condition and adjust treatments effectively. Digital health tools show promise, but further research and refinement are needed to fully integrate them into PAH care.
MHE: What unmet needs exist in PAH research and patient care?
Waxman: The most critical unmet needs are threefold: treatment options, early identification and affordability. Currently, only one nonvasodilator drug is available, although more are on the horizon. There is significant potential for additional therapeutic targets in terms of pathogenesis, particularly in areas like the interstitium, growth factors, cell death regulators and cell cycle regulators. Gene therapies also remain a promising but untapped area.
In patient care, insufficient recognition of PAH remains a major issue. Many patients with unexplained shortness of breath are not properly evaluated for PAH, which delays diagnosis and treatment. Early detection should be a priority.
Additionally, the affordability of treatments is a significant barrier — without access to necessary medications, even an accurate and early diagnosis is not enough to improve patient outcomes.
MHE: What closing thoughts do you have about the future of PAH care?
Waxman: The future of PAH care looks promising but faces significant challenges. Advancements in understanding the disease’s pathophysiology have led to new targeted therapies like sotatercept, which have shown impressive results in clinical trials. The shift toward multimodal treatment approaches, similar to cancer care, offers hope for better patient outcomes. However, key issues remain, including the need for earlier diagnosis, improved access to expensive treatments and the development of more nonvasodilator drugs. Digital health tools, particularly implantable monitors for daily tracking of pulmonary artery pressures, show potential for enhancing patient management. As research continues, addressing affordability and expanding treatment options will be crucial to improving PAH care. The field is poised for significant progress, but overcoming these challenges will require collaborative efforts from healthcare providers, researchers, policymakers and managed care organizations.
