The US Food & Drug Administration (FDA) has granted Orphan Drug Designation to Selten Pharma's lead compound tacrolimus (SPI-026) an Orphan Drug Designation for the treatment of pulmonary arterial hypertension (PAH).
SPI-026 is an investigational BMPR2 pathway activator being evaluated for the treatment of patients with pulmonary arterial hypertension. It prevented the development of PAH in mice with a deletion of BMPR2 endothelial cells in a chronic hypoxia model, and reversed PAH and neointimal/occlusion in the lungs in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. It has been shown to be safe and tolerable in patients with PAH.
An inactivating mutation in the BMPR2 gene has been linked to primary pulmonary hypertension.
What is BMPR2?
Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase. It binds Bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signalling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which it phosphorylates.
What is the clinical significance of BMPR2?
BMPR2 functions to inhibit the proliferation of vascular smooth muscle tissue. It functions by promoting the survival of pulmonary arterial endothelial cells, therefore preventing arterial damage and adverse inflammatory responses. It also inhibits pulmonary arterial proliferation in response to growth factors, which prevents the closing of arteries by proliferating endothelial cells. When this gene is inhibited, vascular smooth muscle proliferates and can cause pulmonary hypertension, which, among other things, can lead to cor pulmonale, a condition that causes the right side of the heart to fail. The dysfunction of BMPR2 can also lead to an elevation in pulmonary arterial pressure due to an adverse response of the pulmonary circuit to injury.
1. Gilboa, L.; et. al. Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 2000,
2. Rabinovitch, M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012, 122(12), 4306-4313.
3. Selten Pharma is a privatively held biopharmaceutical company formed in 2013 that is focused on the development and commercialization of therapies for the treatment of rare diseases.