Novel Therapeutic Option Striking Multiple Downstream Inflammatory Pathways Associated with Uncontrollable Asthma

JoAnn Filipov, Mercer University College of Pharmacy

Despite established standard of care therapies, literature suggests that patients diagnosed with moderate-to-severe asthma experience frequent exacerbations and significant lung function limitations due to uncontrolled asthma. [1] A proposed molecular mechanism in asthma is the type 2 (T2) inflammatory pathway, characterized by elevated levels of blood eosinophils, serum IgE, and fractional exhaled nitric oxide (FENO). [2] Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine central for regulation of T2 immunity.  It has been identified as a potential therapeutic target for its ability to activate various cell types, such as basophils, mast cells, innate lymphoid cells, natural killer T cells, and neutrophils, across a broad patient population. [3]

Tezepelumab is an investigational human IgG2 monoclonal antibody. It binds to TSLP to prevent TSLP-receptor interaction. [4] This mechanism prevents the release of cytokines via immune cells targeted by TSLP early in the inflammation cascade. [5] It has been suggested that tezepelumab could be an adjunct therapy for patients with a history of asthma exacerbations and uncontrolled asthma who have failed previous therapies. [6]

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A Controlled Trial of Erenumab for Episodic Migraine

Shawn Yee, Mercer University College of Pharmacy

Migraine is a common neurological disorder that is ranked top 10 in terms of global disease burden. [1] The term migraine can be categorized into either episodic (< 15 migraine or headache days per month) or chronic (≥ 15 headache days per month, with ≥ eight days of migraine days). [2] Patients with debilitating or frequent migraines are eligible for preventative treatment; however, none of these options target the pathophysiologic pathways involved in migraines. [3]

Erenumab is a fully human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor, which is involved in migraine pathophysiology of the trigeminovascular system. [3] There are other monoclonal antibodies targeting CGRP, such as fremanezumb that have shown safety and efficacy in migraine prevention. Erenumab in particular, has also demonstrated efficacy in reducing the number of migraine days per month at doses ranging from 70 mg to 140 mg per month in a prior phase II trial. [3,4] Below is the summary of a phase III trial. [3]

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Sirukumab for Rheumatoid Arthritis: the Phase III SIRROUND-D Study

Shawn Yee, Mercer University College of Pharmacy

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. Disease-modifying antirheumatic drug (DMARD) therapy, such as methotrexate (MTX) is commonly used for the treatment of RA. However, for patients unresponsive or refractory to this therapy, a newer treatment with monoclonal antibodies (mAb) is being further studied. [1]

One of the proposed underlying mechanisms of RA includes the activity of interleukin-6 (IL-6) in the joints, where higher levels of IL-6 is associated with joint damage and inflammation. [1,2] Therefore, inhibiting the activity of IL-6 with drug therapy is thought to improve RA symptoms and overall disease progression. [1] Previous studies analyzing the effect IL-6 receptor antagonism with monoclonal antibodies such as tocilizumab and sarilumab found success with improving RA outcomes, and showed reduction in RA symptoms, improved physical function and reduced the rate of RA progression. [3,4,5,6]

In a previous phase II trial, sirukumab (selective IL-6 cytokine human mAb), showed efficacy in patients refractory to MTX therapy. [7] The phase III trial is summarized below. [1]

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Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

Sandy Liu, Mercer University College of Pharmacy

A 2016 guideline from the American College of Cardiology stated that the inability to achieve a 30%-50% low-density lipoprotein cholesterol (LDL-C) reduction with statins and/or dietary interventions may necessitate the initiation of the following medications: ezetimibe, bile acid sequestrants and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.  [1]

Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 by binding to low-density lipoprotein receptors on hepatocyte surfaces to promote LDL-receptor degradation within the liver, thereby lowering LDL-C levels. [2]

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