Fusion Protein Holds Promise for Treating Pulmonary Arterial Hypertension

Brigham investigators provide key biological insights that may help solve the mystery of what drives the disease and why a new therapy in clinical trials may work to treat or even reverse it

Pulmonary arterial hypertension (PAH) is an insidious disease. Symptoms may begin slowly, and yet, even before they appear, extensive damage has caused the obstruction of small arteries leading to increased blood pressure in the lungs. By the time symptoms — most notably, shortness of breath — become severe enough for someone with PAH to seek care and obtain a definitive diagnosis, the patient’s chances of survival at five years are slightly better than 50 percent on currently available treatments.

Paul B. Yu, MD, PhD, a cardiovascular medicine specialist at Brigham and Women’s Hospital, has been studying PAH for more than 15 years to better understand the fundamental process in which blood vessels in the lungs are lost to the disease. In a paper published in Science Translational Medicine, members of Yu’s lab and co-authors at Brigham and Women’s Hospital and Acceleron Pharma illuminate the underlying biological pathways that may lead to vessel destruction. Their results provide a biological explanation for why proteins called activins and growth and differentiation factors (GDFs) might contribute to pulmonary vascular disease, and provide an explanation of how the activin/GDF-blocking drug sotatercept, currently in clinical trials, may help treat patients with pulmonary arterial hypertension.

“We were delighted to contribute to the pre-clinical validation of sotatercept, and improve our understanding of the signaling molecules that drive pulmonary arterial hypertension.” said Yu. “We hope these advances will lead to new treatment options for this incredibly vexing disease.”

Currently, PAH is treated with vasodilators to widen lung blood vessels and increase blood flow. Yu and his team have uncovered biological insights that may help to affect the underlying disease process more directly. Previous studies have shown that there are heritable forms of PAH — mutations in certain genes may impact the development, maturation and remodeling of arterial circulation. These genes are involved in two pathways: bone morphogenetic protein (BMP) signaling and transforming growth factor–β (TGFβ) signaling. It was thought that BMP was protective and higher levels TGF-β were destructive, but the specific mechanisms involved remain unclear. There were also indications that two other closely related ligands, known as GDFs and activins, were involved. These play important roles in reproductive biology, but what were they doing in the context of PAH?

In their Science Translational Medicine paper, Yu and colleagues present data from both human and rodent models to cohesively connect these various protein players. The team found increased levels of activin A, GDF8, and to a lesser degree GDF11 in lung lesions from patients with PAH and rodent models of the disease. The team then tested what would happen when they added a “ligand trap” — a fusion protein that captures GDF and activin, blocking their activity. The team found that the fusion protein was more effective than vasodilators at treating PAH and preventing blood vessel remodeling, by restoring a more normal balance between proliferation and cell death of the cells that make up blood vessel walls.  When mouse models were treated in the later stages of severe disease, the treatment increased the number of open lung vessels despite previous damage, in contrast to vasodilators which did not have this effect.

“It was unexpected to find such a prominent role for GDF and activin in PAH, but if they are helping to drive pulmonary vascular disease, it may help explain why a therapy that targets these ligands may be effective against PAH. Our research demonstrates that this central genetic pathway of PAH is tractable and can be exploited as a drug target,” said co-lead author Peiran (Brian) Yang, PhD, a senior member of Yu’s group at Brigham.

The ligand trap is currently under investigation as a treatment for PAH. The human version of this trap, known as sotatercept, was recently granted both Orphan Drug and Breakthrough Therapy designation by the United States Food and Drug Administration (FDA).

Acceleron Pharma, the manufacturers of sotatercept, recently announced the results of PULSAR, a phase 2 trial in patients with PAH. Patients treated with sotatercept experienced a statistically significant reduction in pulmonary vascular resistance (PVR), the trial’s primary endpoint, compared to placebo. A second Phase 2 trial, SPECTRA, sponsored by Acceleron and led in part by Brigham investigators, will continue assessing the efficacy and safety of sotatercept in patients with PAH. The SPECTRA trial is ongoing and currently recruiting patients.

“There are still many unanswered questions, but with the clinically relevant degree of change seen in the clinical trial, coupled with our deeper understanding of the biology of the disease, the story of what drives this disease and how we may be able use that knowledge to treat are coming together in a way that is coherent,” said Yu.

This work was supported by the U.S. National Institutes of Health (HL131910, HL132742, and AR057374), a Gilead Sciences Research Scholars Program award in PAH, an AHA Career Development Award, a Leducq Foundation Transatlantic Network of Excellence Award, and a research gift from Acceleron Pharma Inc., which participated in the conceptualization, design, data collection, and revision of the manuscript in this study. Multiple co-authors are current or former employees of Acceleron Pharma Inc. and hold stock in the company. Two co-authors are inventors on patent application US20180050089A1 covering the use of GDF/BMP antagonists, including ACTRIIA-Fc for the treatment of PH, pulmonary vascular remodeling, and pulmonary fibrosis. Yu serves as a consultant for Acceleron Pharma Inc.

Paper cited: Yung, L.M., and Yang, P. et al. “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension” Science Translational Medicine DOI: 10.1126/scitranslmed.aaz5660

Survey Finds U.S. Adults Largely Supported Measures to Limit Spread of COVID-19 in May

Case Series: Teriflunomide Therapy in COVID-19 Patients with MS

During the COVID-19 pandemic, patients with multiple sclerosis (MS) and their clinicians have had questions and concerns about whether immunotherapies for MS could influence risk for infection or lead to an unfavorable outcome.

In the Journal of Neurology, Rohit Bakshi, MD, a senior neurologist at Brigham and Women’s Hospital, and international co-authors present the cases of five MS patients who developed COVID-19 infection while taking the oral disease-modifying therapy teriflunomide and continued taking the medication. All five patients had favorable outcomes, with their COVID-19 taking a mild course and without experiencing relapse of their MS.

“Managing MS during the COVID-19 pandemic has raised many questions,” said Bakshi, the corresponding author of the paper. “Our observations in these five patients suggest that teriflunomide may not need to be discontinued in patients with MS who develop an active COVID-19 infection. We also discuss potential direct anti-viral effects of teriflunomide.”

In the current international, multicenter study, Bakshi and co-authors, including lead author Amir Hadi Maghzi, MD, a clinical and research fellow in the Brigham’s Neurology Department, report on five patients, ranging in age from 52 to 79, who had been taking teriflunomide for at least six months. The patients continued their teriflunomide therapy after COVID-19 diagnosis and had self-limiting illness without experiencing MS relapse.

Treatment for MS usually requires long-term therapy, often with immunomodulating or immunosuppressing drugs. Teriflunomide modulates the immune response by selectively reducing the level of activated T and B lymphocytes without suppressing the body’s full immune response. One possibility, the authors write, is that teriflunomide could prevent an excessive immune response while maintaining an adequate defense against the virus. The authors also discuss pre-clinical data suggesting that the drug may reduce viral nucleotide synthesis in infected cells.

The case series was small, retrospective, open-label, uncontrolled, and non-randomized, and the authors state that future studies are necessary to understand what role, if any, teriflunomide therapy may play in COVID-19 infection since patient recovery may be unrelated to the treatment.

“A delicate balance may be necessary in the host immune response to successfully confront COVID-19 infection,” said Bakshi. “Additional studies are warranted to further understand the relationship between treatment with teriflunomide and outcomes for MS patients with COVID-19.”

Disclosures: Maghzi is supported by a clinician-scientist development fellowship from the National Multiple Sclerosis Society and American Brain Foundation. Bakshi has received consulting fees from Bayer, Biogen, BMS/Celgene, EMD Serono, Genentech, and Novartis, and research support from BMS/Celgene, EMD Serono, and Sanofi-Genzyme.

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