CalciMedica announces publication in JCI preclinical study of CM5480

CalciMedica (CALC) announced a publication in JCI, or Journal of Clinical Investigation, Insight of data from a preclinical study investigating one of its proprietary drug candidates, CM5480, as a potential new therapy for pulmonary arterial hypertension, or PAH. CM5480 acts by selectively and potently inhibiting CRAC channels, of which Orai1 is the pore-forming subunit, to control the entry of calcium ions into cells. This mechanism is the same as CalciMedica’s lead drug candidate, Auxora(TM), which is currently in clinical development for acute kidney injury, or AKI, and acute pancreatitis. The study, entitled, ” Combination of Orai1 Inhibitor CM5480 with Specific Therapy Mitigates Pulmonary Hypertension and Its Cardiac Dysfunction” . PAH is a rare pulmonary vascular disease characterized by progressive narrowing and thickening of pulmonary arteries, resulting in chronic elevation in pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular hypertrophy, RV dysfunction, RV failure, and eventually death. Current standard of care therapies for patients with PAH target several key disease-related signaling pathways but do not address the Orai1 pathway. These SOC therapies are not curative and do not directly target RV function, which is the primary determinant of prognosis in PAH. In the study, investigators evaluated CM5480 as both a monotherapy and combination therapy with two SOC PAH therapies in an animal model of PAH. Pulmonary hypertension was induced in rats by monocrotaline, or MCT, exposure and then CM5480 was administered daily at 20 mg/kg. Between day 14 and day 21 in the study, the rats were treated with CM5480, either alone or in combination with ambrisentan, an endothelin-1 receptor antagonist, or with sildenafil, a phosphodiesterase type 5 inhibitor. The study found significant reductions in pulmonary neomuscularization, RV systolic pressure, or RVSP, PVR, and RV hypertrophy in MCT rats treated with CM5480 as a monotherapy. RV remodeling was also reduced in CM5480-treated rats, and several pathways and functions that become dysregulated in animals with PAH were restored or improved. These included heart contraction and cardiac output, gene expression profiles impacted by the disease, DNA repair, and metabolic pathways. Dual therapies combining CM5480 with either ambrisentan or sildenafil yielded significantly greater benefits than the respective therapies administered independently, including more pronounced reductions of RVSP and RV hypertrophy, as well as more prominent improvements in PVR and pulmonary vessel and RV remodeling.