5 Things We Now Know About Pulmonary Arterial Hypertension

European Commission Approves Winrevair To Treat PAH In Adults

Winrevair (sotatercept-csrk), Merck's injection therapy for adults with pulmonary arterial hypertension (PAH), has been approved in the European Union, as well as in Iceland, Liechtenstein, and Norway.

The approval from the European Commission specifically covers Winrevair when used in combination with other PAH therapies to improve exercise capacity in PAH patients with World Health Organization (WHO) functional class 2 or 3.

The decision follows a positive opinion recently issued by the Committee for Medicinal Products for Human Use, an arm of the European Medicines Agency, which recommended the use of Winrevair for this indication. Winrevair was also recently approved by the U.S. Food and Drug Administration for PAH.

"We are proud to bring this innovative treatment to more patients and remain committed to further investigating the potential of Winrevair in areas where there are unmet needs in the management of PAH," Joerg Koglin, MD, PhD, senior vice president and head of general medicine, global clinical development at Merck Research Laboratories, said in a company press release. Merck is known as MSD outside of the United States and Canada.

PAH is a type of pulmonary hypertension characterized by high blood pressure in the pulmonary arteries, which are the blood vessels that transport blood from the heart to the lungs. This is caused by a narrowing of the pulmonary arteries that is driven by the abnormal growth of the endothelial cells that line their walls. This, in turn, is driven by the action of signaling molecules called growth factors.

'Devastating disease for patients'

"Pulmonary arterial hypertension is a devastating disease for patients, who suffer from debilitating symptoms that can severely limit their daily activities," said Marc Humbert, MD, PhD, director of the Pulmonary Hypertension Reference Center at Université Paris-Saclay. "New treatment opinions continue to be needed for patients."

Winrevair's active ingredient is a fragment of a growth factor receptor that acts as a trap for excess growth factors, thereby reducing cell growth. The treatment is given once every three weeks by subcutaneous (under-the-skin) injection, and may be administered by patients or caregivers who have received proper training.

The therapy's approval in Europe was supported by data from the Phase 3 STELLAR trial (NCT04576988) which enrolled 323 PAH patients who were randomly assigned to receive Winrevair, starting at a dose of 0.3 mg/kg and up to 0.7 mg/kg, or a placebo, in addition to standard treatments, for about six months.

After six months, Winrevair led to a significant increase in the distance walked in six minutes, a common measure of exercise capacity, relative to the placebo (mean of 40.8 meters or about 134 feet).

Also, a higher proportion of patients on Winrevair experienced an improvement in WHO functional class than those receiving the placebo (29% vs. 14%).

Treatment can reduce risk of clinical worsening or death by 82%

The treatment also reduced the risk of clinical worsening or death by 82% compared with standard therapy alone.

In addition, Winrevair was shown to improve measures of heart health and blood flow, and was predicted to extend patient survival by more than a decade.

The most commonly reported adverse events included headache, nose bleeds, skin redness and rash, dilated veins under the skin, diarrhea, and dizziness.

"These findings are significant and reinforce that WINREVAIR, in combination with other PAH therapies, should be considered as a new standard of care for the treatment of functional class II and III adult patients," Humbert said.

Winrevair was previously granted orphan drug and priority medicines designations by the European Medicines Agency for PAH.

New Insights And Potential Treatments For Pulmonary Hypertension

A new study from researchers with UCLA Health and collaborating organizations has found that asporin, a protein encoded by the ASPN gene, plays a protective role in pulmonary arterial hypertension (PAH).

Their findings, published on August 21 in the peer-reviewed journal Circulation, offer new insights into this incurable, often-fatal disease and suggest potential new ways to treat it.

"We were surprised to find that asporin, which previously had not been linked to PAH, gets upregulated to increased levels as a response to counteract this disease process," said Dr. Jason Hong, a pulmonary and critical care physician at UCLA Health and the study's corresponding author. "This novel finding opens up new avenues for understanding PAH pathobiology and developing potential therapies."

Pulmonary hypertension is a serious medical condition characterized by high blood pressure in the arteries that supply the lungs. It causes these arteries to narrow or become blocked, which, in turn, slows blood flow to the heart, requiring it to work harder to pump blood through the lungs. Eventually, the heart muscle becomes weak and begins to fail.

Need for New Therapies

According to recent estimates, PAH affects about 1% of the global population, but that number climbs to 10% in people who are 65 or older.

There's no cure for the disease, but medications and lifestyle changes can help slow progression, manage symptoms and prolong life.

The urgent need for new therapies, combined with the potential of multiomics -- an integrated approach to drive discovery across multiple levels of biology -- inspired Hong and research colleagues, including co-first author Lejla Medzikovic and senior author Mansoureh Eghbali to take a deep dive into the disease. Both work at UCLA's Eghbali Laboratory.

Methodology

For the study, the researchers applied novel computational methods, including transcriptomic profiling and deep phenotyping, to lung samples of 96 PAH patients and 52 control subjects without the condition from the largest multicenter PAH lung biobank available to-date. They integrated this data with clinical information, genome-wide association studies, graphic models of probabilities and multiomics analysis.

"Our detailed analysis found higher levels of asporin in the lungs and plasma of PAH patients, which were linked to less severe disease," Hong said.

Additionally, Medzikovic noted that their cell and living-organism experiments found that asporin inhibited pulmonary artery smooth muscle cell proliferation and a key signaling pathway that occurs with PAH.

"We also demonstrated that recombinant asporin treatment reduced PAH severity in preclinical models," said Medzikovic.

Next Steps

Hong and colleagues plan to further investigate the mechanisms by which asporin exerts its protective effects in PAH and explore potential therapeutic applications, focusing on how to translate their findings into clinical trials.

"Asporin represents a promising new target for therapeutic intervention in pulmonary arterial hypertension," he explained. "Enhancing asporin levels in PAH patients could potentially lead to improved clinical outcomes and reduced disease progression."

Authors: Jason Hong, MD, PhD,* Lejla Medzikovic, PhD*, Wasila Sun, BS‡, Brenda Wong, BA‡, Gregoire Ruffenach, PhD, Christopher J. Rhodes, PhD, Adam Brownstein, MD, Lloyd L. Liang, MS, Laila Aryan, PhD, Min Li, PhD, Arjun Vadgama, Zeyneb Kurt, PhD, Tae-Hwi Schwantes- An, PhD, Elizabeth A. Mickler, MS, Stefan Graf, PhD, Melanie Eyries, PhD, Katie A. Lutz, BS, Michael W. Pauciulo, MBA, Richard C. Trembath, MD, Frederic Perros, PhD, David Montani, MD, PhD, Nicholas W. Morrell, MD, Florent Soubrier, MD, PhD, Martin R. Wilkins, MD, William C. Nichols, PhD, Micheala A. Aldred, PhD, Ankit A. Desai, MD, David-Alexandre Tregouet, PhD, Soban Umar, MD, PhD, Rajan Saggar, MD, Richard Channick, MD, Rubin M. Tuder, MD, Mark W. Geraci, MD, Robert S. Stearman, PhD†, Xia Yang, PhD†, and senior author, Mansoureh Eghbali, PhD†. Legend: *Joint first authors; ‡ Joint second authors; †Joint last authors

Funding: This work was supported by American Heart Association grant 23POST1022457 (L.M.), American Thoracic Society Early Career Investigator Award in Pulmonary Vascular Disease (J.H.), and U.S. NIH grants K08HL169982 (J.H.), R01HL147586 (M.E.), R01HL162124 (M.E.), R01HL159865 (M.E.), R01HL147883 (X.Y.), R24HL105333 (W.N. And M.P.), R01HL160941 (W.N., A.D., and M.P.), British Heart Foundation Senior Basic Science Fellowship FS/SBSRF/21/31025 (C.R.), and funding for the PHBI is provided by NHLBI R24HL123767 and by the Cardiovascular Medical Research and Education Fund (MAA).

Asporin Identified As Potential Therapeutic Target For Pulmonary Arterial Hypertension

A new study from researchers with UCLA Health and collaborating organizations has found that asporin, a protein encoded by the ASPN gene, plays a protective role in pulmonary arterial hypertension (PAH).

Their findings, published on August 21 in the journal Circulation, offer new insights into this incurable, often-fatal disease and suggest potential new ways to treat it.

"We were surprised to find that asporin, which previously had not been linked to PAH, gets upregulated to increased levels as a response to counteract this disease process," said Dr. Jason Hong, a pulmonary and critical care physician at UCLA Health and the study's corresponding author. "This novel finding opens up new avenues for understanding PAH pathobiology and developing potential therapies."

Pulmonary hypertension is a serious medical condition characterized by high blood pressure in the arteries that supply the lungs. It causes these arteries to narrow or become blocked, which, in turn, slows blood flow to the heart, requiring it to work harder to pump blood through the lungs. Eventually, the heart muscle becomes weak and begins to fail.

Need for new therapies

According to recent estimates, PAH affects about 1% of the global population, but that number climbs to 10% in people who are 65 or older.

There's no cure for the disease, but medications and lifestyle changes can help slow progression, manage symptoms and prolong life.

The urgent need for new therapies, combined with the potential of multiomics—an integrated approach to drive discovery across multiple levels of biology—inspired Hong and research colleagues, including co-first author Lejla Medzikovic and senior author Mansoureh Eghbali to take a deep dive into the disease. Both work at UCLA's Eghbali Laboratory.

Methodology

For the study, the researchers applied novel computational methods, including transcriptomic profiling and deep phenotyping, to lung samples of 96 PAH patients and 52 control subjects without the condition from the largest multicenter PAH lung biobank available to-date. They integrated this data with clinical information, genome-wide association studies, graphic models of probabilities and multiomics analysis.

"Our detailed analysis found higher levels of asporin in the lungs and plasma of PAH patients, which were linked to less severe disease," Hong said.

Additionally, Medzikovic noted that their cell and living-organism experiments found that asporin inhibited pulmonary artery smooth muscle cell proliferation and a key signaling pathway that occurs with PAH.

"We also demonstrated that recombinant asporin treatment reduced PAH severity in preclinical models," said Medzikovic.

Next steps

Hong and colleagues plan to further investigate the mechanisms by which asporin exerts its protective effects in PAH and explore potential therapeutic applications, focusing on how to translate their findings into clinical trials.

"Asporin represents a promising new target for therapeutic intervention in pulmonary arterial hypertension," he explained. "Enhancing asporin levels in PAH patients could potentially lead to improved clinical outcomes and reduced disease progression."

More information: Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension., Circulation (2024). DOI: 10.1161/CIRCULATIONAHA.124.069864

Citation: Asporin identified as potential therapeutic target for pulmonary arterial hypertension (2024, August 21) retrieved 29 August 2024 from https://medicalxpress.Com/news/2024-08-asporin-potential-therapeutic-pulmonary-arterial.Html

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