CalciMedica Reveals Promising Data on CRAC Channel Inhibitor for Pulmonary Arterial Hypertension
CalciMedica Inc., a clinical-stage biopharmaceutical entity, has recently published significant preclinical data in the Journal of Clinical Investigation Insight, shedding light on the potential of their CRAC channel inhibitor, CM5480, in treating pulmonary arterial hypertension (PAH). This groundbreaking research marks CM5480 as a possible first-in-class therapy, distinguishing itself from existing treatments and highlighting its dual role as both a standalone and combinational therapy.
The pharmacological action of CM5480 involves the precise inhibition of CRAC (Calcium Release-Activated Calcium) channels, specifically targeting the Orai1 subunit, which regulates calcium ion influx into cells. This mechanism mirrors that of CalciMedica's leading drug candidate, Auxora™, which is currently under development for acute kidney injury (AKI) and acute pancreatitis. Such a focus on CRAC channels stems from comprehensive research indicating their crucial involvement in various inflammatory and immunologic diseases.
The paper titled "Combination of Orai1 Inhibitor CM5480 with Specific Therapy Mitigates Pulmonary Hypertension and Its Cardiac Dysfunction" was co-authored by Sudarshan Hebbar, M.D., Chief Medical Officer at CalciMedica, and Kenneth A. Stauderman, Ph.D., the company's Chief Scientific Officer. Significant contributions came from the research team at Inserm, France's National Institute of Health and Medical Research, under the guidance of Professor Marc Humbert, a prominent authority in the field of PAH.
PAH remains a rare and debilitating condition characterized by the progressive constriction and thickening of pulmonary arteries, which leads to heightened pulmonary artery pressure and resistance. Such pathological changes can result in adverse outcomes such as right ventricular hypertrophy and dysfunction, culminating in right ventricular failure and potentially, death. Current treatments primarily target various signaling pathways associated with the disease, leaving room for innovative strategies that directly address the underlying mechanisms.
Previous studies corroborate that the dysregulation of calcium entry via CRAC channels significantly contributes to the pathogenesis of PAH and associated right ventricular dysfunction (RVD). Moreover, research indicates an elevated expression of Orai1 among patients suffering from pulmonary veno-occlusive disease, supporting the importance of this pathway in disease management.
Dr. Humbert noted the pressing challenge in PAH therapy: "Despite recent advancements, the quest for effective PAH treatment continues as we seek novel therapeutic options. Our findings suggest CRAC channel inhibition may unveil new strategies to enhance patient outcomes."
In the experimental design, CM5480 was administered in an animal model exhibiting pulmonary hypertension induced by monocrotaline (MCT). The study's findings revealed that CM5480, utilized in both monotherapy and in conjunction with existing treatments such as ambrisentan and sildenafil, led to a remarkable reduction in key clinical parameters, including right ventricular systolic pressure (RVSP), pulmonary vascular resistance (PVR), and right ventricular hypertrophy. Notably, combination therapies yielded significantly enhanced therapeutic benefits compared to individual treatment regimens.
Dr. Antigny emphasized, "Given the complexity of PAH, optimal treatment strategies will likely involve a multi-faceted approach to effectively manage combinatorial signaling pathway dysregulation."
Beyond its implications for PAH, the study hints at broader applications of CRAC channel inhibition for conditions like sepsis-associated RVD, which is prevalent in a substantial cohort of AKI patients. With a remarkable threefold increase in mortality associated with RVD, Dr. Hebbar highlighted the potential clinical implications for the ongoing KOURAGE trial, further exploring the benefits of CRAC channel inhibition in severe AKI with acute respiratory failure.
CalciMedica is committed to advancing innovative CRAC channel therapies targeting a range of inflammatory and immunologic conditions, aspiring to provide essential therapeutic options where few exist. The promising outcomes of CM5480 reaffirm the company's dedication to pioneering much-needed advances in the realm of pulmonary arterial hypertension and beyond.
For more information about CalciMedica and their ongoing research efforts, visit CalciMedica's website.
The pharmacological action of CM5480 involves the precise inhibition of CRAC (Calcium Release-Activated Calcium) channels, specifically targeting the Orai1 subunit, which regulates calcium ion influx into cells. This mechanism mirrors that of CalciMedica's leading drug candidate, Auxora™, which is currently under development for acute kidney injury (AKI) and acute pancreatitis. Such a focus on CRAC channels stems from comprehensive research indicating their crucial involvement in various inflammatory and immunologic diseases.
The paper titled "Combination of Orai1 Inhibitor CM5480 with Specific Therapy Mitigates Pulmonary Hypertension and Its Cardiac Dysfunction" was co-authored by Sudarshan Hebbar, M.D., Chief Medical Officer at CalciMedica, and Kenneth A. Stauderman, Ph.D., the company's Chief Scientific Officer. Significant contributions came from the research team at Inserm, France's National Institute of Health and Medical Research, under the guidance of Professor Marc Humbert, a prominent authority in the field of PAH.
PAH remains a rare and debilitating condition characterized by the progressive constriction and thickening of pulmonary arteries, which leads to heightened pulmonary artery pressure and resistance. Such pathological changes can result in adverse outcomes such as right ventricular hypertrophy and dysfunction, culminating in right ventricular failure and potentially, death. Current treatments primarily target various signaling pathways associated with the disease, leaving room for innovative strategies that directly address the underlying mechanisms.
Previous studies corroborate that the dysregulation of calcium entry via CRAC channels significantly contributes to the pathogenesis of PAH and associated right ventricular dysfunction (RVD). Moreover, research indicates an elevated expression of Orai1 among patients suffering from pulmonary veno-occlusive disease, supporting the importance of this pathway in disease management.
Dr. Humbert noted the pressing challenge in PAH therapy: "Despite recent advancements, the quest for effective PAH treatment continues as we seek novel therapeutic options. Our findings suggest CRAC channel inhibition may unveil new strategies to enhance patient outcomes."
In the experimental design, CM5480 was administered in an animal model exhibiting pulmonary hypertension induced by monocrotaline (MCT). The study's findings revealed that CM5480, utilized in both monotherapy and in conjunction with existing treatments such as ambrisentan and sildenafil, led to a remarkable reduction in key clinical parameters, including right ventricular systolic pressure (RVSP), pulmonary vascular resistance (PVR), and right ventricular hypertrophy. Notably, combination therapies yielded significantly enhanced therapeutic benefits compared to individual treatment regimens.
Dr. Antigny emphasized, "Given the complexity of PAH, optimal treatment strategies will likely involve a multi-faceted approach to effectively manage combinatorial signaling pathway dysregulation."
Beyond its implications for PAH, the study hints at broader applications of CRAC channel inhibition for conditions like sepsis-associated RVD, which is prevalent in a substantial cohort of AKI patients. With a remarkable threefold increase in mortality associated with RVD, Dr. Hebbar highlighted the potential clinical implications for the ongoing KOURAGE trial, further exploring the benefits of CRAC channel inhibition in severe AKI with acute respiratory failure.
CalciMedica is committed to advancing innovative CRAC channel therapies targeting a range of inflammatory and immunologic conditions, aspiring to provide essential therapeutic options where few exist. The promising outcomes of CM5480 reaffirm the company's dedication to pioneering much-needed advances in the realm of pulmonary arterial hypertension and beyond.
For more information about CalciMedica and their ongoing research efforts, visit CalciMedica's website.
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