AJMC: Can you explain the etiology and progression of PAH and the importance of early diagnosis?

HASSOUN: Pulmonary arterial hypertension (PAH) refers to World Health Organization (WHO) group 1 pulmonary hypertension.¹ It includes many different diseases, such as idiopathic PAH or heritable PAH, wherein the patient has genetic mutations that lead to the disease; this type of PAH can affect families or individuals. PAH is a severe disease characterized by significant remodeling of the small vessels in the lungs. This remodeling can increase resistance in pulmonary circulation and lead to remodeling of the right ventricle and eventually failure. Right ventricular failure is the main cause of morbidity and death in pulmonary hypertension.

Patients who receive a diagnosis with PAH are assessed through the WHO functional classification (WHO-FC) to determine the severity of PAH symptoms.² Class I would be considered “normal,” wherein patients are not experiencing any symptoms of breathlessness during rest or activity. Patients in class IV experience severe and debilitating symptoms, even at rest, and usually have very limited survival unless they receive treatment.

Oftentimes, when patients present to specialists in pulmonary hypertension, they are already in functional class II or class III and are already late in their disease course. Clinicians need to do a better job at diagnosing patients with PAH earlier so that they can start on treatment earlier. There are actions that can help to address this. For example, although there is nothing that can help with earlier identification of idiopathic PAH, for those patients who are known to be predisposed to the disease—such as those withconnective tissue disease (eg, scleroderma, lupus, dermatomyositis, or mixed connective tissue disease)—screening through echocardiography and other laboratory tests can help ensure that the disease is identified earlier.

AJMC: How should clinicians confirm or rule out a PAH diagnosis in patients who show signs and symptoms of the disease?

HASSOUN: The first rule, if a clinician suspects their patient has pulmonary hypertension, is to refer him or her directly to a center with expertise in the field. This is imperative. Clinicians can find US-based Centers of Excellence that have received accreditation through the Pulmonary Hypertension Association’s website.³ These centers “have demonstrated an ability to properly diagnose [pulmonary hypertension] and have the capability to manage these complex patients” based on a site review conducted by physicians and coordinators with expertise in the disease.

Because survival can be very limited if patients are not started on appropriate therapy early, it is important to refer patients with pulmonary hypertension and/or PAH to these centers so they can receive the multidisciplinary care they need. In our group at Johns Hopkins, for example, we pulmonologists work very closely with cardiologists, rheumatologists, radiologists, echocardiographers, and others—all with expertise in pulmonary hypertension in order to coordinate care of these patients.

AJMC: What are the current unmet clinical needs in PAH?

HASSOUN: There are many unmet needs in PAH, the greatest of which is that there is no cure and that survival is dependent upon the health of the patient’s right ventricle. However, treatment of PAH has greatly improved in the last 40 years. Currently, there are about 15 different treatments available, and these essentially target 3 mechanistic pathways in PAH: the endothelin, nitric oxide, and prostacyclin pathways.⁴ Before there were PAH-targeting therapies, the median survival for patients with PAH was less than 3 years. The use of these PAH-targeting therapies has increased the median survival to about 10 years for patients with idiopathic PAH. That is a considerable improvement in patient health and survival; however, there is still no cure, and there are no treatments that target the right ventricle when it fails. There are no treatments that can deremodel the abnormal pulmonary vasculature.

AJMC: What would be the value of a therapy that could address the root cause of the disease?

PAUL M HASSOUN, MD: Some patients with PAH have genetic mutations that mainly affect the bone morpho­genetic protein receptor 2 (BMPR2) signaling pathway. These mutations can occur in families, as well as in patients without any family history. This type of PAH is called heritable PAH, but regardless of the presence of this mutation, patients with pulmonary hypertension have decreased signaling of the BMPR2 pathway. Recently, research has been completed on the use of sotatercept, a treatment that seems to target this pathway. Sotatercept is a fusion protein that is a trap for activin. Activins typically bind to a TGF-β receptor, which is part of the TGF-β superfamily. There is a ying-yang between TGF-β and BMPR2 to keep the pulmonary vasculature in check. Sotatercept seems to target the disequilibrium that exists between BMPR2 signaling and TGF-β. As a result, there is a lot of hope for this new therapy. This is the first drug that really gets us closer to treating the underlying mechanism in the pathogenesis of PAH. Based on what I’ve seen, the results of phase 2 and phase 3 trials have been extremely positive.^5-8 Currently, there are no treatments that can improve BMPR2 signaling when it is deficient in patients with or without mutations.

Furthermore, over the last 10 to 15 years, the use of dual therapy for PAH has been shown to have better outcomes than monotherapy. It is possible that triple therapy targeting different pathways would be better than mono- or dual therapy. From what I’ve seen, treatment with sotatercept [in trials] was associated with positive outcomes, regardless of whether patients were also on mono-, dual, or triple therapy. Whether sotatercept alone can improve the remodeling and improve PAH is unclear but adding it to existing therapies seems to be beneficial. There is no evidence to support improved survival yet; it is still too early.

AJMC: What other interventions are in the pipeline for PAH?

HASSOUN: This is a very active field, and there are several ongoing trials for different therapies. One therapy being studied is imatinib, a tyrosine kinase inhibitor (TKI) used for the treatment of some forms of blood cancers. Preclinical (animal model) data showed that imatinib seemed to improve pulmonary hypertension and counteract remodeling of the pulmonary vascu­lature.⁹ Clinical data from both phase 2 and phase 3 trials seemed to show improvement in functional status and hemodynamics in patients who received imatinib.^10,11 However, some patients experienced severe adverse events (eg, subdural hemorrhage in some patients who were on background anticoagulants) during the trial. An inhaled form of imatinib is being studied in early clinical trials.¹² The hope is that by delivering the drug to the lung, where the remodeling occurs, the systemic effects can be avoided. Until we have the results, however, it remains to be seen whether imatinib will be a good addition to our armamentarium of treatments for PAH. There are alternative pathways that are being targeted through other research, but, in my mind, the most promising treatments are sotatercept, which targets the TGF-β signaling pathway, and imatinib or other TKIs that might be helpful in preventing or inhibiting further remodeling of the vessels.

AJMC: How are patients with PAH involved in shared decision-making for treatment?

HASSOUN: Generally, patients with PAH are started on dual therapy—a combination of an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor—administered within 2 to 3 weeks of each other. This combination has been associated with improved survival and improved hemodynamics (eg, in the AMBITION trial).¹³ Patients with severe PAH are more likely to be offered enrollment in ongoing phase 2 or phase 3 trials. Johns Hopkins has a large center specialized in pulmonary hypertension and, as in other academic centers, the team is involved in multicenter trials, such as those involving sotatercept or inhaled imatinib, for example. Patients with PAH are usually very motivated to participate in clinical trials—they want to get better, and so they are open to participating in new trials that may help them.

Furthermore, although treatments are covered by insurance, they can be costly. The least costly drug we have is still about $8000 to $9000 a year, whereas others can be upwards of $90,000 to $100,000 a year per patient. Once the diagnosis of PAH is firmly established, we work with the patient’s insurer to secure treatment approval. The process can be burdensome and challenging. Despite letters of support, occasionally insurers do not accept providers’ recommendations for treatment with dual therapy or for a specific drug. In these instances, oftentimes pharmaceutical companies offer assistance programs that help patients to afford treatment. The hope is that with time, these treatments may become more affordable.

AJMC: How may the management of PAH change in the years ahead?

HASSOUN: This is a very exciting time in the field of PAH. Treatments that have been approved in the last 30 years have been associated with improved survival and improved quality of life in patients with PAH. Although we are still far from finding a cure for the disease, there are many research opportunities available. These include the ability to work closely with the National Institute of Health—which has a specific interest in pulmonary vascular disease—and pharmaceutical companies to design better treatments and targeted therapies. PAH is a disease that necessitates collaboration between not only cardiologists and pulmonologists but also immunologists and geneticists, because many patients with PAH have an autoimmune disease or genetic mutations. There may be an opportunity to target inflammation as a potential protagonist in the remodeling of the vessels in the lung, or explore the use of gene therapies. By targeting several aspects of the remodeling process, the hope is that pulmonary circulation can be restored to a quiescent, clear lumen that will return pulmonary vascular resistance to its normal low state.

References

1. A study of AV-101 (dry powder inhaled imatinib) in patients with pulmonary arterial hypertension (PAH) (IMPAHCT). Clinicaltrials.gov. Updated February 17, 2023. Accessed March 13, 2023. https://clinicaltrials.gov/ct2/show/NCT05036135?term=imatinib&cond=Pulmonary+Hypertension&phase=12&draw=2&rank=8
2. Find a PH care center. Pulmonary Hypertension Association. Accessed March 13, 2023. https://phassociation.org/phcarecenters/accredited-centers/
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