Heart disease is the principal cause of death and disability for both men and women in the US, accounting for 40% of all annual deaths. African American populations are disproportionately burdened with metabolic diseases, due in part to cholesterol metabolism deficiencies. Elevated low density lipoprotein (LDL) cholesterol levels and inflammation promote atherogenic conditions which lead to heart disease. Proprotein convertase subtilisin/kexin-9 (PCSK9) is a biomarker which enhances athrogenic progression by controlling the number of LDL receptor molecules expressed at the plasma membrane. PCSK9 indirectly regulates LDL-cholesterol levels. Previous reports show some patients do not respond well to general anti-cholesterolemic treatments. We believe this is due to altered PCSK9 activity, which is currently not being evaluated. We have developed a novel assay to detect active PCSK9. A1AT is a SERPIN family member whose primary objective is inhibition of proteases. Specific levels of A1AT are required to maintain metabolic homeostasis. Based on this, we hypothesized that a specific ratio between A1AT serum levels and PCSK9 activity levels would eliminate statin intolerance/resistance, regulating LDL-cholesterol metabolism congruently. Using this novel active PCSK9 detection assay, we provide evidence that A1AT interacts with PCSK9 in the medium of C3A hepatic-like cells, preventing the formation of PCSK9/LDL receptor complexes in vitro. There was an approximate 20% inhibition in PCSK9-LDL receptor complex formation when liver cells were treated with recombinant A1AT (rA1AT). A dose dependent response analysis proved 200ng/ml of rA1AT had an 46% reduction in PCSK9 activity. We determined PCSK9 activty and A1AT levels correlate with key diabetic factors in humans, suggesting that A1AT could effect diabetes progression.
What is patient-centricity? In some contexts, it has been associated with targeting therapies based on biomarkers or enabling healthcare access. There has been a surge in patient-centricity publications, and in many cases for the biopharmaceutical industry, patient engagement is used to endorse pre-held assumptions at a specific moment in time. Rarely is patient engagement used to drive business decisions. Here we describe an innovative partnership between Alexion, AstraZeneca Rare Disease and patients that allowed a deeper understanding of the biopharmaceutical stakeholder ecosystem and an empathic understanding of each patient’s and caregiver’s lived experience. Alexion’s decision to build patient-centricity frameworks resulted in the formation of two unique organisation design platforms: STAR ( S olutions T o A ccelerate R esults for patients) and LEAP ( L earn, E volve, A ctivate and deliver for P atients) Immersive Simulations. These interconnected programmes required cultural, global, and organisational shifts. STAR generates global patient insights that are embedded in drug candidate and product strategies while helping to establish enterprise foundational alignment and external stakeholder engagement plans. LEAP Immersive Simulations produce detailed country-level patient and stakeholder insights that contribute to an empathetic understanding of each patient’s lived experience, support country medicine launches and provide ideas to have a positive impact along the patient journey. Combined, they deliver integrated, cross-functional insights, patient-centric decision making, an aligned patient journey, and 360° stakeholder activation. Throughout these processes, the patient is empowered to dictate their needs and validate the proposed solutions. This is not a patient engagement survey. This is a partnership where the patient co-authors strategies and solutions.
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