Mimecan and a Functional Fragment Hereof as a Novel Regenerative Agent for COPD

Presented by: L. Van Der Koog

COPD is characterized by progressive airflow limitation and emphysema development, associated with enhanced tissue destruction and defective repair. At present, there is no pharmacological treatment that reactivates lung repair.

Objective: The study aimed to identify proteins within the secretome of lung fibroblasts that can promote regeneration in alveolar epithelial progenitors.

Method: Proteomics analysis was conducted on MRC5 lung fibroblast secretomes. Epithelial progenitors (CD31-/CD45-/Epcam+) from mice or human COPD IV patients were co-cultured with lung fibroblasts in Matrigel to generate lung organoids. After 14 days, organoid number and size were determined, as was the number of differentiated alveolar organoids. Single-cell RNA sequencing was conducted on mouse lungs exposed to escalating durations of cigarette smoke, while immunostaining was employed to quantify mimecan expression in human lung tissue.

Result: 

• 12 potential drug targets were identified from the 41 distinct growth factors and cytokines found within the MRC5 secretome.
• These candidates were subsequently tested for regenerative potential in murine lung organoids. Among the tested ligands, mimecan (MC001) exhibited an exceptionally potent regenerative effect compared to the other recombinant proteins.
• Both MC001 and MC002, a functional fragment of mimecan, promoted the formation of organoids in murine models in a concentration-dependent manner, regardless of the presence of 5% cigarette smoke extract (CSE) or 0.5 ng/mL transforming growth factor-ß (TGF-ß). Additionally, exposure to CSE and TGF-ß reduced the proportion of alveolar organoids, an effect that was reversed by the addition of MC001 or MC002.
• Treatment with MC001 or MC002 also increased the number of organoids derived from epithelial cells obtained from COPD IV patients.
• Single-cell RNA sequencing demonstrated that prolonged exposure to cigarette smoke results in decreased mimecan expression in the lungs of mice, primarily originating from fibroblasts.
• Immunostaining analysis revealed a significant reduction in mimecan expression in the parenchyma and overall lung tissue of both current and ex-smokers.

Proteomics-guided drug discovery strategy also identified osteoglycin to have an exceptionally strong regenerative potential in the lung organoid model, and the expression was reduced in lung tissue exposed to cigarette smoke. The study stated that an active fragment of osteoglycin enhanced lung function parameters in elastase-induced lung injury. However, further studies are needed to establish its potential.

Conclusion: By employing a proteomics-guided approach centered on the secretome of lung fibroblasts, mimecan and a functional fragment of mimecan were identified as innovative therapeutic candidates for promoting regeneration in COPD. 

Impact of Mepolizumab on Airway Remodelling in Severe Eosinophilic Asthma (REMOMEPO)

Presented by: Camille Taillé

Chronic inflammation in asthma induces structural changes in airways, which leads to lung impairment and other clinical manifestations. The role of IL-5 and eosinophils in the development of airway remodeling is well established, thus blocking IL-5 would impact airway remodeling. Mepolizumab, an IL-5 antagonist, is approved for the treatment of severe eosinophilic asthma.

Objective: This prospective observational study aimed to assess airway changes, assessed by Broncho-alveolar lavage (BAL) and bronchial biopsies obtained during fiberoptic bronchoscopy (FOB), which was performed at inclusion and after 6 and 12 months of mepolizumab treatment.

Inclusion: Adult >18 years, with severe uncontrolled eosinophil asthma according to French recommendations (eosinophil blood count >300/mm3 in the previous year, >2 exacerbations, despite optimal step 4-5 therapy, including daily use of steroids), and no previous treatment with benralizumab or mepolizumab were enrolled.

Result: 

• Paired baseline and 12-month BAL and bronchial biopsies were obtained in 23 patients with 47.8% females.
• Upon treatment with mepolizumab, the Asthma Control Test (ACT) score increased from 15.0 to 20.0 (ACT score >19 indicates well-controlled asthma), while the annual exacerbations rate decreased from 4.0 to 1.0 after 12 months.
• Reticular basement membrane (RBM) thickening was reduced in patients with mepolizumab from 3.3µm to 1.9µm, and smooth muscle area was reduced from 14.4 [8.8-22.7] % to 6.4 [4.5-13.1]%, at 12 months. 
• 72% of the patients had "excellent response" or "good response" by their physician, as per the Global Evaluation of Treatment Effectiveness (GETE) score, and had thicker RBM at inclusion
• No modification was observed in the number of vascular sections, and no correlation was found between pre-BD FEV1 and remodeling parameters.
• In biopsies, the number of eosinophils infiltrating the mucosa decreased at 12 months from 62.1 to 49.1, while in the BAL, mepolizumab decreased eosinophils from 4.7 to almost nil (0.3).

Conclusion: 12-month treatment with mepolizumab led to a significant reduction in RBM thickness and airway smooth muscle content. This reduction in airway inflammation was associated with a marked decrease in bronchial remodeling in severe asthma patients. These results provide new insights into the efficacy of mepolizumab in eosinophilic asthma.

Effect of Dupilumab on Pulmonary Vascular Volume in Patients with Moderate-to-Severe Asthma

Presented by: A. A. Mappanasingam

DUPIXENT (dupilumab), a non-immunosuppressive monoclonal antibody, targets interleukin-4 and interleukin-13 pathways, effectively reducing type 2 inflammation in moderate-to-severe asthma patients aged 6 and older, including those with an eosinophilic phenotype or corticosteroid dependence. In the retrospective analysis, CT assessments revealed that a lower relative volume of small peripheral pulmonary vasculature is linked to greater asthma severity, poorer control, and reduced lung function. Dupilumab was shown to reduce airway mucus and improve airflow, assessed by 129Xe ventilation MRI. In a single-center retrospective study of 27 adults with uncontrolled moderate-to-severe asthma, 19 received dupilumab and eight received a placebo every 2 weeks for 16 weeks. Chest CT scans at Week 0 and Week 16 measured pulmonary vascular volumes using open-source software. Results indicated that IL-4 antagonism with dupilumab caused a shift in pulmonary blood volume toward smaller vessels, improving patient outcomes and clinical measures. Ongoing research aims to determine if these vascular changes are due to airway morphology alterations or a separate biologically relevant mechanism independent of the airways.

Novel Role of the Chromatin Remodeling Protein HMGN5 in Driving COPD Susceptibility

 

Presented by: A. Jeridi

The chromatin remodeling protein High Mobility Group Nucleosome Binding Domain 5 (HMGN5) is crucial in COPD pathogenesis. HMGN5 binds to the nucleosomal core particle of chromatin, competing with histone H1, and thereby altering chromatin structure and function. Transcriptomic analysis of COPD patients showed significantly reduced HMGN5 expression in the lungs compared to healthy individuals. scRNAseq data and immunofluorescence analysis identified HMGN5 in proliferative ATII cells in both humans and mice. B6 mice exposed to porcine pancreatic elastase (PPE) showed reduced Hmgn5 expression at Day 28. HMGN5 deficient mice exhibited more severe lung function impairment and greater evidence of emphysema compared to wild-type controls following PPE exposure. Mechanistically, in vitro studies revealed that downregulating HMGN5 with siRNA in A549 cells significantly delayed cell proliferation and sensitized the cells to ferroptotic cell death by upregulating ACSL4 and downregulating SLC7A11 and GPX4, which protect against ferroptosis. This downregulation crucially delayed organoid development from pmATII cells lacking HMGN5 due to siRNA knockdown. In COPD lungs, the absence of HMGN5 impairs epithelial cell proliferation and sensitizes these cells to ferroptotic cell death, driving the development and progression of emphysema in patients and mice. This data suggests a novel causal link between chromatin dynamics and emphysema development through increased ferroptosis and impaired cell proliferation, highlighting potential new therapeutic avenues for halting emphysema progression.

Industry Theatre: What Can the Future Hold for Your Patients With Severe Asthma?

Presented by: AstraZeneca

Objective: AstraZeneca presented 5-Year Safety and Efficacy Data of FASENRA from the MELTEMI study. FASENRA (benralizumab) is a monoclonal antibody that binds directly to the IL-5 receptor alpha on eosinophils and attracts natural killer cells to induce rapid and near-complete depletion of eosinophils. It is approved as an add-on maintenance treatment for severe eosinophilic asthma. 

Study Design: MELTEMI is a Phase III, open-label, safety extension study in adults with severe asthma who completed one of three Phase III, randomized, double-blind, placebo-controlled predecessor trials (SIROCCO, CALIMA, ZONDA), enrolled in the BORA extension trial, and transitioned to the MELTEMI open-label extension (n=447). Around 86% completed the study. 

Results:

• According to post hoc sub-analysis, in the SIROCCO trial, a 51% reduction in the annual asthma exacerbation rate was observed in patients treated with FASENRA + standard of care, compared to placebo + SOC, while in CALIMA a 28% reduction was observed. Annual exacerbation rates remained consistent over 5 years, and around ≥75% of FASENRA dosing arm patients experienced zero exacerbations each year, while 59% had zero exacerbations across the extension study period.
• In ZONDA, treatment with FASENRA led to a 75% reduction in OCS doses, which are given for exacerbation management to reduce resolution time and prevent relapse but are associated with side effects. 
• FASENRA also showed a consistent long-term safety profile as observed in previous Phase III studies. Adverse events and serious adverse events did not increase over time

Conclusion: MELTEMI integrated analysis reaffirmed findings from the SIROCCO, CALIMA, ZONDA, and BORA trials. These data demonstrated that among patients with severe, uncontrolled eosinophilic asthma receiving benralizumab for up to 5 years, long-term eosinophil depletion was not associated with an increased risk of a serious infection or any new safety signals, and the reductions in bEOS levels and asthma exacerbations rates observed in preceding studies were maintained through long-term follow-up. These findings further support the long-term safety and efficacy of benralizumab for achieving and maintaining asthma control in patients with severe, uncontrolled eosinophilic asthma.

AstraZeneca also presented a case study of severe eosinophilic asthma and stated that eosinophils are more than biomarkers or predictors of treatment response, as they form important targets for severe asthma with acute exacerbation.

Industry Theatre: Should we be targeting eosinophils regardless of allergic status in patients with severe eosinophilic asthma?

Presented by: GSK

A 44-year-old asthma patient with total IgE levels of 260 kU/L and a blood eosinophil count of 215 cells/μL is currently on high-dose ICS/LABA therapy and uses SABA as needed. Elevated IgE levels alone are not sufficient to indicate allergic asthma, as they can also result from non-allergic pathways and non-atopic conditions. According to the Global Initiative for Asthma (GINA), elevated baseline blood eosinophils are a predictive biomarker for exacerbation risk and response to biologics in severe asthma, while baseline IgE does not predict response to biologics. Blood eosinophil levels of ≥150 cells/μL can indicate eosinophilic asthma, with greater variability in eosinophil count associated with a higher risk of hospitalization or ED visits. Eosinophils can also contribute to non-allergic airway inflammation in asthma, driven by factors such as pollution and microbes, through eosinophilic inflammation and the release of IL-5. Common features of patients with severe eosinophilic asthma include elevated blood eosinophils, low lung function, frequent severe exacerbations in the prior year, dependence on oral corticosteroids, adult-onset asthma, and nasal polyps. According to the GINA report, these features can predict a favorable response to biologics targeting IL-5. NUCALA (mepolizumab) is the only anti-IL-5 therapy approved for severe eosinophilic asthma, as well as for chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). NUCALA, a humanized monoclonal antibody, targets IL-5 by binding to it and blocking its interaction with the alpha chain of the IL-5 receptor complex, thereby inhibiting IL-5 signaling and reducing the production and survival of eosinophils.

The reduction in exacerbations was evaluated in both a controlled clinical trial and a real-world study: MENSA and REALITI-A. The MENSA clinical trial demonstrated a significant 61% reduction in exacerbations requiring hospitalization or emergency department visits. In the REALITI-A study, there was a 76% reduction in exacerbations requiring hospitalization or emergency department visits in the first year post-NUCALA and a 79% reduction in the second year.

A one-year interim sub-group analysis evaluated exacerbation reduction across different blood eosinophil counts. The results showed a 66% reduction in exacerbations for patients with baseline blood eosinophil counts of <150 cells/μL, 65% for counts of 150 to <300 cells/μL, 67% for counts of 300 to <500 cells/μL, and 75% for counts of ≥500 cells/μL. Additionally, the same analysis revealed exacerbation rates by allergic status: a 71% reduction in exacerbations for allergic patients and a 67% reduction for non-allergic patients one-year post-NUCALA.

In the first 24 weeks of the MENSA and SIRIUS studies, adverse reactions occurred in ≥3% of patients treated with NUCALA and in 5% of those receiving a placebo. The reported adverse reactions included headache, injection site reactions, back pain, fatigue, influenza, urinary tract infections, upper abdominal pain, eczema, pruritus, and muscle spasms.

The COLUMBA study, a 4.5-year open-label investigation into the safety and efficacy of NUCALA, found that its long-term safety and immunogenicity profiles were consistent with those observed in controlled asthma trials. The study also demonstrated a 61% reduction in the annual exacerbation rate 4.5 years post-exposure when NUCALA was used alongside asthma controller therapy.

When managing severe asthma with systemic steroids, GINA advises that low-dose maintenance oral corticosteroids (OCS) should only be considered after ruling out other add-on treatments, due to their significant side effects. Patients on shorter OCS regimens (<30 days) exhibited higher rates of all three adverse events assessed: approximately double the risk of fractures, triple the risk of venous thromboembolism, and five times the risk of sepsis.

In the SIRIUS trial, before randomization, OCS doses were reduced during the optimization phase to establish the lowest dose necessary to maintain asthma control. In a real-world study, the daily maintenance OCS dose in a subgroup of OCS-dependent patients was reduced by 75% at weeks 45-64 and eliminated at weeks 81-104. Additionally, 57% of these patients were able to eliminate maintenance OCS use entirely.

In summary, NUCALA (mepolizumab) demonstrates significant efficacy in reducing asthma exacerbations and maintaining long-term safety across various studies, particularly in patients with severe eosinophilic asthma. Additionally, it helps reduce or eliminate the need for maintenance of oral corticosteroids, mitigating their associated risks. This supports NUCALA's role in effective asthma management.

Industry Theatre: How Would You Address Eosinophilic + Allergic Inflammation in Severe Asthma?

Presented by: AstraZeneca/Amgen

Tezspire is a first-in-class biologic for severe asthma that targets the epithelial cytokine thymic stromal lymphopoietin (TSLP) at the top of the inflammatory cascade. It is the first and only biologic to consistently and significantly reduce asthma exacerbations across Phase II and III clinical trials, which included a large population of patients with severe asthma regardless of important biomarkers such as blood eosinophil counts, allergic status, and fractional exhaled nitric oxide (FeNO). This means that, Tezspire works in people irrespective of biomarkers, making it the only treatment option for those with low blood eosinophil count and non-atopic asthma. Additionally, it may be the right treatment for many patients who have a combination of allergic and eosinophilic asthma.

In their previous results, Tezspire consistently demonstrated statistically significant reductions in exacerbations across two pivotal trials (Pathway 71%, Navigator 56%). Furthermore, the company continued to receive data from post-hoc analysis of pooled PATHWAY and NAVIGATOR data, estimated 79% reductions in exacerbations and 93% reduction in hospitalizations, urgent care or ED visits due to exacerbations.

Industry Supported Evening Symposia - Epithelial Cytokines: Connecting the Dots in Severe Asthma, Nasal Polyps, and COPD

Presented by: Amgen/AstraZeneca

Objective: AstraZeneca presented data detailing the science of endothelial cytokines and the role of various endothelial alarmins in the pathophysiology of severe asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and COPD as drivers of inflammation. The focus on research about the role of endothelial cytokines in airway diseases has gained impetus only recently, with the role of TSLP in ILC2 activation discovered in 2016.

Results: Asthma

• According to data from an ongoing observational CHRONICLE study in the US, among the various triggers that activate the epithelium, 8 are the most commonly reported in patients with severe asthma, and include air/weather change, viral infection, allergies, physical activity, etc. These were identified based on self-administered questionnaires to adults with severe asthma.
• Airway epithelim has a role in immune responses with epithelial cytokine activating airway inflammation and even driving structural changes. 
• Epithelial cell-derived mediators including the alarmin cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) have emerged as key players in propagating asthma pathogenesis, and they have distinct and overlapping effects on a broad range of cells. Release of these alarmins leads to the downstream production of type 2 cytokines, most notably IL-4, IL-5, and IL-13, etc. from multiple effector cells, which then initiate recruitment of eosinophils, DCs, ILC2s, basophils, T cells, and other immune cells, leading to inflammation, exacerbation risk, AHR, airway remodeling, etc.  
• With increased focus on asthma research, it is also established that severe asthma has overlapping biomarker profiles indicating multiple activated pathways with nearly 2/3 of patients having ≥2 biomarkers elevated.
• Data from studies establish that TSLP levels in serum are associated with exacerbation risks in severe asthma, with high serum TSLP associated with nearly 8.7-fold higher odds of exacerbation.

The data validates that endothelial cytokines, released in response to environmental exposure, act at the top of the inflammatory cascade, initiating downstream response, leading to airway inflammation and hyper-responsiveness. Thus, IL-25, IL-33, and TSLP are linked to asthma pathogenesis and pathophysiology and may prove to be novel targets for therapeutic interventions.

CRSwNP:

Cytokines play a central role in CRSwNP, particularly in the maintenance of the inflammatory response and the recruitment of eosinophils. According to the Unified Airway Model, upper and lower airways are linked by a similar process, manifesting in different parts of the airway.

Data also suggests that geographies with a higher prevalence of upper airway diseases also have a higher prevalence of lower airway diseases. Both have the same phenotype and pathophysiologic mechanism, for example, both severe asthma and CRSwNP have eosinophil, IL-5, IL-5, and IL-13 involvement.

TSLP, IL-25, and IL-33 are produced as the first line of defense against infections and stimulations in the airway epithelium, thus leading to potent augmentations of allergic inflammations and exerting effects as "bridges" linking innate and adaptive airway mucosal immunities. These released by the epithelium, drive type 2 inflammation, and are potential therapeutic targets for CRSwNP.

COPD

COPD is growing with disease prevalence and mortality not having improved even in 2021. Neurotrophic inflammation though is the predominant endotype associated with COPD, around 20-60% exhibit type-2 inflammation.

• Epithelial-driven inflammation has a role in COPD pathophysiology leading to increased risk of exacerbation, airway remodeling, airwall thickness, etc. In COPD, endothelial cytokines, TSLP, IL-33, and IL-25 impact innate and adaptive immune cells to drive various inflammatory responses (type1, type2, type3).
• Study data also establishes that blood eosinophil count is higher in severe asthma compared to COPD.
• IL-33 is significantly associated with the risk of exacerbation, and correlated with smoking history, but is negatively related to FEV1 (%).
• TSLP drives COPD by impacting various immune and non-immune cells like T cells, smooth muscle cells, fibroblasts, etc. COPD and smoking history are associated with elevated TSLP levels.
• Results from Bronchoalveolar lavage fluid analysis, establish that TSLP levels are elevated in Asthma and COPD patients, with TSLP levels being about three times higher in COPD patients. Elevated TSLP also impacts IL-25 levels significantly.

 

AstraZeneca demonstrated that TSLP and IL-33 significantly initiate downstream response and contribute to COPD clinical manifestation. Additional research is needed to further elucidate the mechanism and role in COPD treatment.