HS135 Shows Promise in PH Rat Model, Should Enter Trials Next Year
Data presented in Chicago on the potential treatment for pulmonary hypertension
The experimental therapy HS135 improved heart function and the remodeling of lung blood vessels in a rat model of pulmonary hypertension (PH).
That’s according to data reported by the therapy’s developer, 35Pharma, at the 2022 American Heart Association Scientific Sessions (AHA 2022), held earlier this month in Chicago and online.
The findings “indicate that HS135’s best-in-class target engagement translates into significantly increased and differentiated efficacy,” Maureen O’Connor, PhD and chief scientific officer of 35Pharma, said in a company press release.
PH is characterized by the narrowing of the pulmonary arteries, or the small blood vessels that supply blood to the lungs, which raises blood pressure in those arteries and places a burden on the right ventricle of the heart.
Arterial narrowing is the result of pulmonary vascular remodeling, a process that involves the abnormal growth of smooth muscle cells, which progressively thicken the arterial walls.
HS135 is designed to target the unbalanced TGF-beta superfamily signaling that contributes to PH-associated pulmonary vascular remodeling. Specifically, activin and GDF signaling are increased, while BMP signaling is reduced, causing an imbalance of vascular remodeling-promoting and -suppressing effects.
A ligand trap, the therapy works by specifically “trapping” two TGF-beta ligands, activin A and GDF-8 (also known as myostatin), thereby preventing them from binding to their receptor proteins and activating downstream targets.
It was created by modifying a receptor protein that normally recognizes these ligands, called activin receptor IIB ectodomain (ActRIIB). HS135 has the potential to have the best-in-class potency without affecting blood-related parameters that limit dosing of activin ligand traps, such as ActRIIA-Fc.
Report on the HS135 data
In the AHA 2022 presentation, researchers shared data from experiments done in mice comparing the effects of HS135 with ActRIIA-Fc.
Results showed that HS135 was superior to ActRIIA-Fc at fully blocking activin A and GDF-8 signaling, based on the suppression of follicle-stimulating hormone (FSH) production — which is normally promoted by these signaling molecules.
Treatment with HS135, but not ActRIIA-Fc, also had a positive impact on body composition and muscle metabolism.
Moreover, in a rat model of PH induced with the chemical monocrotaline, HS135 demonstrated superior efficacy to ActRIIA-Fc at reversing pulmonary vascular remodeling and improving the functionality of the heart’s right ventricle. 35Pharma’s therapy also nearly normalized gene activity profiles in the right ventricle.
“I am particularly encouraged by HS135’s pronounced effect on protecting the right ventricle and improving metabolic dysfunction, both of which are established risk factors in cardiopulmonary disease,” O’Connor said.
According to 35Pharma, HS135, administered through under-the-skin injections, is expected to enter clinical trials next year.