Study Reveals How Sotatercept Works in PAH Rat Model, Supporting Its Potential for Patients

Newly published research has detailed the underlying biochemical process behind Acceleron Pharma’s investigational therapy sotatercept (ACE-011) for the potential treatment of people with pulmonary arterial hypertension (PAH).

The findings, in two rat models of PAH, provide a rationale for the positive top-line results recently reported from the PULSAR Phase 2 clinical trial (NCT03496207) showing the therapy eased heart strain and improved the exercise capacity of PAH patients.

The animal study was published in the journal Science Translational Medicine in an article, titled “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension.”

Sotatercept — which has been given orphan drug and breakthrough therapy designations by the U.S. Food and Drug Administration — is designed to bind and entrap proteins from the transforming growth factor-beta (TGF-beta) family. 

These proteins play a role in the regulation of the bone morphogenic protein (BMP) pathway, an important player in the maintenance of blood vessel structure in the lungs. Trapping TGF-beta proteins is thought to restore the balance of BMP signaling and potentially reverse blood vessel remodeling associated with PAH.

While the role of BMP and TGF-beta in PAH has been well-described, scientists are unclear about the importance of other proteins that share common receptors with BMP and TGF-beta, including proteins known as activins, and growth and differentiation factors (GDF), which have been detected in the lungs of people with PAH. 

To further investigate the role of these proteins, a team led by researchers at Harvard Medical School in Boston created a rodent version of sotatercept — called ACTRIIA-Fc — designed to bind and trap activin A, activin B, GDF8, and GDF11. ACTRIIA-Fc was then tested in cells and rat models of PAH. 

In contrast to proteins associated with the BMP pathway, activin and GDF proteins are involved in the related ACTRIIA pathway, which is thought to promote blood vessel remodeling.

The team first established that ACTRIIA-Fc suppressed the growth of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells — types of cells that line the inside of blood vessels. 

In rat models of PAH (rats exposed to the chemical monocrotaline that triggers pulmonary hypertension), animals regularly treated with ACTRIIA-Fc (prophylactic treatment) showed improved blood flow (hemodynamics), reduced pulmonary pressure, less excessive growth of right ventricular muscles (hypertrophy) of the heart, improved right ventricular function, and attenuated vascular remodeling.

As a comparison, PAH rats treated with Revatio (sildenafil, marketed by Pfizer), a standard PAH therapy that expands blood vessels (vasodilator), had more modest effects on blood flow and did not reduce vessel remodeling. 

Delayed treatment with ACTRIIA-Fc, given four weeks after monocrotaline exposure, potently reduced pulmonary hypertension at all doses tested.

In a second rat model (SU-Hx) known to develop progressive PAH mimicking severe human disease, prophylactic ACTRIIA-Fc treatment normalized pulmonary pressure and reduced blood vessel muscle growth compared to untreated rats. 

In rats treated after a five-week delay, which allowed severe disease to become established, ACTRIIA-Fc reversed existing pulmonary hypertension and right ventricular hypertrophy. It also reduced the number of blocked blood vessels and the thickness of vessel walls. These effects were not seen in rats treated with Revatio. 

Overall, “ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease,” the researchers wrote.

“We demonstrate that the murine [rodent] version of sotatercept rebalances [BMP and TGF-beta] signaling to improve hemodynamics and attenuate vascular remodeling, at the same time revealing how large a role activin A, activin B, GDF8, and GDF11 play as drivers of pulmonary vascular disease,” Paul B. Yu, MD, PhD, study lead author and associate professor at Harvard Medical School, said in a press release.

Jay T. Backstrom, MD, executive vice president and head of research and development at Acceleron, added: “the publication of Paul Yu’s elegant research highlights the importance of TGF-beta superfamily biology to the underlying pathology of pulmonary vascular disease and provides biological support for sotatercept’s activity in PAH.” 

Acceleron is also exploring sotatercept’s impact in the Phase 2 clinical trial SPECTRA (NCT03738150), an open-label, one-arm study investigating the effects of sotatercept plus standard of care in adult PAH patients. According to its page, the trial is currently recruiting participants at several locations in the U.S.

“Based on our recent clinical trial results establishing proof-of-concept, we have great enthusiasm for sotatercept’s potential as a novel therapy for patients with PAH,” Backstrom said.“This research brings added confidence in and clarity to the underlying biology behind sotatercept’s hypothesized mechanism of action as we shape our clinical development plans in the pulmonary space.”