New treatment for pulmonary hypertension: what biotech holds in store?

pulmonary hypertension treatment

Pulmonary hypertension is a complex cardiovascular disorder characterized by high blood pressure in the pulmonary arteries, the vessels that carry blood from the heart to the lungs. This condition can lead to severe health complications, including heart failure, if not managed effectively. Historically, it has been about managing pulmonary hypertension’s symptoms but the industry is working on new treatments for this condition.

Recent advancements in biotechnology have marked a new era for pulmonary hypertension patients, transforming a once grim prognosis into a more manageable condition. Yet, despite these advances, pulmonary hypertension remains a challenging disease to treat. The disease’s heterogeneity means that effective treatment requires precise tailoring. In this article, we delve into the new treatment advances in pulmonary hypertension.

Table of contents

    Understanding pulmonary hypertension

    Pulmonary hypertension is broadly classified into five groups based on its cause and mechanism. Each type has unique pathophysiological features and treatment approaches, highlighting the complexity of diagnosing and managing pulmonary hypertension​.

    Symptoms of pulmonary hypertension can be non-specific and worsen over time. Common symptoms include shortness of breath during routine activities, fatigue, chest pain, and a racing heartbeat. As the condition progresses, symptoms can become more severe, even appearing at rest.

    Pulmonary hypertension is a relatively rare condition but can be devastating to those affected. The prevalence varies depending on the type of pulmonary hypertension, with Pulmonary arterial hypertension (PAH) affecting approximately 500 to 1,000 new individuals each year in the U.S. alone. The disease significantly impacts quality of life, limiting physical activities and leading to severe complications if untreated. Advanced pulmonary hypertension can lead to right heart failure due to the increased workload on the right ventricle, which must pump blood against the high pressure in the pulmonary arteries​​.

    Evolution of pulmonary hypertension treatment: from symptom management to targeted therapies

    Approaches to treating pulmonary hypertension have evolved significantly over the decades. Initially, treatment options were scarce and primarily focused on symptom management rather than addressing the underlying pathology of the disease. Early interventions included the use of conventional therapies such as anticoagulants and diuretics to manage associated conditions like edema and prevent thrombosis, which were often inadequate in altering the disease progression.

    The introduction of epoprostenol in the 1990s marked the first disease-specific treatment for PAH. As a synthetic analog of prostacyclin, epoprostenol helped to reduce pulmonary vascular resistance and improve survival rates, although its use was limited by the need for continuous intravenous administration and its short half-life, requiring complex management strategies​.

    Current standard therapies for pulmonary hypertension

    Modern treatment strategies for pulmonary hypertension have expanded to include a variety of targeted pharmacological interventions that more effectively manage the disease:

    • Vasodilators: These are crucial in the management of pulmonary hypertension, particularly PAH, and include agents such as prostacyclins, which directly dilate the pulmonary arteries and reduce arterial pressure.
    • Endothelin Receptor Antagonists (ERAs): These drugs, such as bosentan, ambrisentan, and macitentan, inhibit endothelin, a potent vasoconstrictor, thereby improving symptoms and exercise capacity.
    • Phosphodiesterase-5 Inhibitors: Sildenafil and tadalafil are examples that help relax the pulmonary arteries and increase blood flow.
    • Soluble Guanylate Cyclase (sGC) Stimulators: For example, riociguat can help relax and widen the blood vessels in the lungs​​.

    These treatments are supplemented by supportive measures such as oxygen therapy, diuretics, and anticoagulants, which help manage symptoms and improve quality of life but do not halt disease progression.

    Recent FDA approvals in the treatment of pulmonary hypertension

    FDA approval of Merck’s activin signalling inhibitor sotatercept

    Merck’s WINREVAIR (sotatercept-csrk) has marked a significant advancement in the treatment of pulmonary arterial hypertension. As the first FDA-approved activin signaling inhibitor therapy for PAH, WINREVAIR works by modulating the balance between pro-proliferative and anti-proliferative signaling pathways, which are crucial in vascular cell proliferation – a fundamental process in the pathophysiology of PAH.

    Clinical benefits highlighted in the STELLAR study include significant improvements in exercise capacity and pulmonary vascular resistance. Specifically, WINREVAIR demonstrated an 84% reduction in the risk of death or clinical worsening of PAH compared to placebo, and significant reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, a marker for heart stress. Moreover, the treatment has shown improvements in patients’ functional abilities and quality of life​​.

    FDA approval of J&J’s Opsynvi

    The FDA has recently approved other treatments that bring new hope to PAH patients. For instance, J&J’s Opsynvi, a once-daily, fixed-dose tablet combining macitentan and tadalafil, has been approved. This combination leverages the benefits of both an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor, simplifying treatment regimens for patients by reducing the number of medications they need to manage their condition daily​​.

    Current research and clinical trials in pulmonary hypertension treatment

    Highlighting research on restoring the TSC2 growth suppressor

    Research at UC Davis Health has uncovered promising results regarding the restoration of the tuberous sclerosis complex 2 (TSC2) growth suppressor, which may lead to reversing pulmonary vascular remodeling in PAH. This novel approach aims to target and potentially reverse the pathological changes in the pulmonary arteries that contribute to the high blood pressure observed in PAH patients. By restoring the function of TSC2, it might be possible to reduce the thickening of the pulmonary artery walls, thereby alleviating the high blood pressure in the lungs and improving overall heart function​​.

    Potential of tyrosine kinase pathway inhibitors

    Tyrosine kinase inhibitors, such as Imatinib, have shown promise in treating PAH by targeting the PDGF (platelet-derived growth factor) pathways, which are involved in the disease’s vascular remodeling processes. The IMPRES trial sponsored by Novartis indicated that Imatinib could improve pulmonary vascular resistance and overall cardiac output in patients with advanced symptoms, highlighting its potential as a supplementary therapy for those not adequately managed by conventional treatments. However, the drug’s side effects such as subdural hematomas, and dropouts due to intolerance, have tempered enthusiasm for its broad use, underscoring the need for careful patient selection and management​​.

    Aerovate Therapeutics is also developing a new form of Imatinib, AV-101, an inhaled dry powder. The company will present phase 2b top line data of its potentially more convenient candidate in June.

    SPHK2/S1P axis and its role in epigenetic mechanisms

    The SPHK2 (sphingosine kinase 2)/S1P (sphingosine-1-phosphate) signaling pathway is another area of intense research focus. This pathway has been identified for its role in the epigenetic regulation of pulmonary vascular remodeling in pulmonary hypertension. By influencing histone acetylation processes, SPHK2 alters gene expression in vascular smooth muscle cells, potentially reversing harmful vascular changes. Initial studies suggest that targeting this axis could provide a new therapeutic approach to treat or even reverse aspects of pulmonary hypertension, although further research is needed to fully understand its efficacy and safety​​.

    Exploring stem cell therapies for pulmonary hypertension

    Stem cell therapies, including induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs), present promising approaches for treating pulmonary hypertension. These cells can differentiate into various cell types needed to repair damaged tissues, potentially reversing the effects of diseases like pulmonary hypertension. In particular, iPSCs, derived from adult cells, can be programmed to act similarly to embryonic stem cells, offering a versatile tool for regenerating diseased lung tissue. MSCs, on the other hand, have shown capabilities in modulating immune responses and ameliorating inflammatory conditions within the pulmonary vasculature, which are crucial aspects of pulmonary hypertension pathology​.

    One notable trial in this is the ALPHA phase 1a/b study,  investigating the safety and efficacy of a novel cell therapy developped by Capricor Therapeutics, CAP-1002. This therapy uses cardiosphere-derived cells (CDCs), which are progenitor heart cells capable of releasing signaling molecules that promote heart health. Unlike fully differentiated heart cells, progenitor cells have the potential to become various types of cells within the heart. This makes them an important focus for regenerative medicine, particularly in treating heart diseases. The trial primarily assesses the safety of CAP-1002 infusions in patients with pulmonary arterial hypertension who are already on PAH-specific medication. 

    Looking to the future of pulmonary hypertension treatment

    The next decade in pulmonary hypertension treatment is poised to witness significant advancements, driven by rapid developments in biotechnology and a deeper understanding of the disease’s molecular underpinnings. We can expect further refinement and expansion of targeted therapies such as those modulating the activin signaling pathways, as well as the introduction of new classes of drugs that could more effectively halt or even reverse disease progression. Additionally, advancements in drug delivery systems, such as nanoparticle technologies, may enhance the efficacy and reduce the side effects of existing treatments.

    Personalized medicine is set to play a pivotal role in transforming the treatment landscape for pulmonary hypertension. As genetic profiling becomes more sophisticated and accessible, it will allow for more precise identification of the forms of pulmonary hypertension at a molecular level, leading to more customized treatment plans. This approach will not only improve the efficacy of treatments but also minimize adverse effects by tailoring therapies based on individual genetic backgrounds and disease phenotypes. The integration of genomic data with clinical practice could lead to the development of predictive models to guide therapy choices and improve outcomes for patients with pulmonary hypertension​.

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