Watch and Learn More About DUPIXENT
DR. LAREN TAN: OCS-DEPENDENT ASTHMA PATIENT CASE
[DUPIXENT is indicated as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma. Limitation of use: DUPIXENT is not indicated for the relief of acute bronchospasm or status asthmaticus.]
Let’s go through a hypothetical case. Let’s go through this case of a 52-year old female with adult-onset asthma who’s frequently on oral corticosteroids. Every time that we’ve tried to take her off oral corticosteroids it’s led to worsening of symptoms and also another exacerbation. She definitely wants to stop oral corticosteroids because of weight gain, but she fears having another exacerbation. Because of her asthma, she avoids social activities due to other symptoms and like a lot of asthmatics that we actually see, she also reports that she’s got nasal polyps. [Patient profile is representative and is not an actual DUPIXENT patient.] Other information that is important to know is that she’s had two severe exacerbations in the past year, she’s got poor lung function with an FEV1 of 58%, she was diagnosed with asthma at the age of 23 with nasal polyps at age 38, and her asthma is still uncontrolled with an ACT score of 15 despite being on maximum inhaled corticosteroids, long acting beta agonist and also leukotriene receptor antagonist. She’s had multiple courses of oral corticosteroids over the last 6 months and she continues to use nasal irrigation along with intranasal corticosteroids for nasal polyps. And even then, you can see that she’s not exactly doing well. Biomarkers that was actually done blood eosinophils of 140 with a total serum IgE of 405. So when we look at her we realize that because she is oral corticosteroid dependent, this would definitely be a patient that we would want to consider putting on DUPIXENT. In addition to that even despite her eosinophils being 140 because she’s OCS dependent, that is something to think about as to why she would actually benefit from DUPIXENT.
DR. LAREN TAN: MOA BREAKDOWN
The mechanism of action for DUPIXENT is unique. It is the only fully human IgG-4 monoclonal antibody that binds to Interleuken-4 receptor alpha. And we can say it’s the subunit shared by IL-4 and IL-13 receptors. As you can see in the picture in the diagram, Type 1 receptor has an IL-4 receptor alpha and also a gamma chain subunit. How is that different from a Type II receptor? Well for Type II receptors there’s an IL-4 receptor alpha and also at least in the Type II receptor side, an IL-13 receptor alpha 1. Now, in order for self-signaling to occur both of these subunits actually need to come together. And they will come together only when IL-4 actually binds to IL-4 receptor alpha at least in the Type 1 receptor and for Type II IL-4 and IL-13 needs to bind to get to each of the corresponding subunits. DUPIXENT works by binding or blocking also the IL-4 receptor alpha therefore, IL-4 does not have the ability to actually bind on to that specific subunit. [The mechanism of DUPIXENT action in asthma has not been definitively established.] DUPIXENT’s able to decrease multiple biomarkers. Biomarkers that we see commonly in Type 2 inflammation. It’s able to decrease IgE by up to 70% and fractional exhaled nitric oxide of up to 35%. Other biomarkers that are not commercially available currently right now were also decreased like eotaxin-3, TARC, and periostin. [Correlations between DUPIXENT pharmocodynamics data and efficacy endpoints have not been established]
Type 2 inflammation occurs in up to 50% to 84% of adult patients with asthma and plays an important role in the pathogenesis of asthma.
The Type 2 inflammatory pathway encompasses both allergic and eosinophilic inflammation.
Disruption of airway epithelium barrier functions along with allergen uptake by dendritic cells and activation of T cells help drive Type 2 inflammation in asthma. There are multiple cell types and mediators involved in Type 2 inflammation—including IL-4 and IL-13. IL-4 drives Th2 cell differentiation and mediates the production of Type 2 cytokines.
IL-4 and IL-13 play an important role in class switching of B cells to produce IgE, a key component of allergic inflammation.
IL-13 mediates goblet cell hyperplasia and increased mucus secretion and promotes airway obstruction, bronchial hyperreactivity, smooth muscle hypertrophy, airway remodeling, and stimulation of nitric oxide synthase to produce nitric oxide.
IL-4 and IL-13 drive the trafficking of eosinophils to sites of inflammation and IL-5 mediates the differentiation of eosinophils in bone marrow, which contributes to eosinophilic inflammation.
IL-4 and IL-13 are two key cytokines that contribute to allergic and eosinophilic inflammation.
DUPIXENT is indicated as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma. DUPIXENT is not indicated for the relief of acute bronchospasm or status asthmaticus.
DUPIXENT is the first and only dual inhibitor of IL-4 and IL-13 signaling, impacting two of the sources that mediate allergic and eosinophilic inflammation.
[The mechanism of dupilumab action in asthma has not been definitively established.]
In the inflammatory process, IL-4 binds the IL-4Rα subunit, and IL-13 binds the IL-13Rα1 subunit, which is the same as the IL-4Rα subunit.
DUPIXENT binds to IL-4Rα, blocking IL-4 and IL-13 intracellular signaling; this results in reduced expression of proinflammatory cytokines, ultimately leading to decreased total and specific IgE, decreased FeNO, and a transient increase in blood eosinophils.
DUPIXENT blocks the IL-4/IL-13 pathway and decreases markers of Type 2 inflammation, including IgE, in which there was up to 70% reduction in total IgE from baseline and a reduction in eosinophilic lung inflammation, despite the presence of normal or increased blood eosinophil levels. DUPIXENT also reduced levels of FeNO by blocking IL-13, which is responsible for stimulating nitric oxide synthase to produce nitric oxide.
Based on a study of the general asthma population approximately 7 out of 10 asthma patients had an eosinophilic phenotype or an overlap of eosinophilic and allergic phenotypes.
DUPIXENT is indicated for patients (12 plus years) with moderate-to-severe asthma with an eosinophilic phenotype and is the only biologic indicated for an OCS-dependent asthma population, regardless of phenotype.
DUPIXENT is a novel biologic that inhibits IL-4 and IL-13 signaling, two of the sources of inflammation in asthma.