Designing Clinical Trials to Address Asthma and COPD Flare-Ups

Acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) remain among the most dangerous and costly events in respiratory medicine. 

These sudden flare-ups can rapidly escalate into medical emergencies, often leading to emergency department visits, hospitalizations and, in severe cases, death. 

Despite decades of progress in chronic disease management with multiple biologic therapies available, acute exacerbations continue to represent a major unmet need, with limited therapeutic options specifically designed to intervene once an exacerbation is started. 

To explore why this gap persists and how clinical insights are shaping new approaches, Xtalks spoke with Barry Quart, CEO and Director of Connect Biopharma. The clinical-stage company is focused on developing therapies for acute exacerbations of inflammatory diseases, including asthma and chronic obstructive pulmonary disease (COPD), an area that has been difficult to address both scientifically and operationally. This is an area where no biologic therapy currently exists and Connect is the first company to enter this space addressing acute exacerbations of inflammatory respiratory diseases.

Dr. Quart brings more than three decades of leadership experience in biotechnology and drug development, having overseen the advancement of multiple FDA-approved therapies. 

In this conversation, he shares why acute exacerbations have remained so challenging to study and how advances in immunology have clarified key inflammatory drivers. He also discusses what it takes to design clinical trials in fast-moving, real-world care settings.

Why Acute Exacerbations Are So Difficult to Study

Although acute exacerbations are a well-recognized clinical problem, Dr. Quart emphasizes that the challenges in this space are not rooted in a lack of scientific understanding.

“The difficulty really is more practical than it is scientific,” he explains. “I think we understand fairly well the underlying causes of patients having acute exacerbations.”

From a biological standpoint, the inflammatory pathways that drive exacerbations are increasingly well characterized. The real hurdle lies in conducting clinical research during a medical emergency. 

Patients experiencing chest tightness and difficulty breathing typically attempt to manage symptoms with rescue inhalers at home. When those treatments fail, anxiety escalates and patients seek urgent or emergency care.

Emergency departments, however, are not optimized environments for traditional clinical trial workflows. They operate around the clock, are highly dynamic and often lack dedicated research staff during overnight hours. Unlike scheduled clinic visits, there is no predictable window in which patients can be identified, consented and enrolled.

“It’s much more difficult to conduct clinical studies in patients entering the emergency department for a potentially life-threatening emergency,” Dr. Quart says. “It’s not like setting up an appointment to go see the clinician to enroll a patient. So, it takes a lot of additional effort to be able to do a study in an emergency room setting. That’s really the biggest obstacle here.” 

Dr. Quart mentions that each year, millions of patients experience exacerbations, and according to the Asthma and Allergy Foundation of America, approximately 1 million presented to emergency departments in the U.S. alone for asthma-related treatment needs. Many more seek care through urgent care centers or physicians’ offices, stressing the need for broader patient-capture strategies.

To address this unmet need, Dr. Quart describes an approach that extends beyond emergency departments by identifying patients across multiple care settings and pre-screening individuals who are at high risk for future exacerbations. 

By obtaining baseline information and informed consent in advance, researchers can move more quickly to randomization when an exacerbation occurs, a different model from traditional chronic disease trials.

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The Science Behind Acute Asthma and COPD Flares

Advances in immunology have clarified the biological cascades that drive acute respiratory exacerbations. These events can be triggered by allergens, cigarette smoke or viral infections, particularly in asthma, where both allergic and non-allergic mechanisms contribute.

“We understand a lot more now in terms of those different cascades,” Dr. Quart notes, describing a process that begins with an external trigger and progresses through immune activation, airway inflammation, mucus production and airflow limitation.

Importantly, these insights extend beyond bronchoconstriction. Cytokines such as interleukin-13 (IL-13) not only contribute directly to airway narrowing but can also reduce the effectiveness of beta-agonist bronchodilators, the mainstay of rescue therapy. 

“The bronchodilator that the patient has in their inhaler is not going to work as well when you have excessive amounts of IL-13 circulating,” he explains.

Together, these findings have shaped  Connect’s approach to treating acute exacerbations, accenting upstream inflammatory signaling rather than downstream symptom control. Targeting interleukin-4 receptor alpha (IL-4Rα), which mediates IL-4 and IL-13 signaling, may address multiple contributors to airway obstruction by reducing direct bronchoconstriction and restoring responsiveness to beta-agonists.

How Respiratory Clinical Trials Are Evolving

For chronic asthma and COPD, trial methodologies have remained relatively stable over the past decade. 

These studies are typically conducted through pulmonologists and allergists, with standardized treatment approaches guided by international frameworks such as the Global Initiative for Asthma (GINA). The widespread adoption of these guidelines enables global trial execution, allowing sponsors to recruit patients across regions such as Eastern Europe and Latin America with confidence in consistent standards of care.

Acute exacerbation trials, however, demand an entirely different approach. Patients must be identified at the moment symptoms worsen, often outside traditional research sites. Timing becomes critical, and trial infrastructure must be flexible enough to operate in urgent and emergency care environments.

Competition also plays a major role in shaping trial feasibility. While many companies are pursuing chronic COPD therapies, leading to intense competition for eligible patients, acute exacerbations remain relatively underexplored.

As a result, acute exacerbations are an unmet medical need, with few therapies specifically designed to intervene at the point of highest risk for patients.

Endpoint Design and Patient Capture Challenges

Designing endpoints for respiratory trials presents certain challenges, particularly when exacerbation reduction is the outcome of interest. 

Regulatory agencies typically expect sponsors to demonstrate a reduction in exacerbation rates, but baseline event rates in control arms are often low, averaging around one exacerbation per patient per year.

As Dr. Quart explains, even meaningful relative reductions of 50% to 60% translate into small absolute differences, such as reducing one event per year to half an event per year. Detecting statistical significance under these conditions requires large patient populations, which increases recruitment demands.

As a result, patient identification and enrollment become the main constraints on trial feasibility. Rather than biology or endpoint sensitivity, Dr. Quart emphasizes that access to enough eligible patients is often the rate-limiting factor in respiratory clinical research.

Lessons from Three Decades in Drug Development

Reflecting on his career, Dr. Quart states that drug development has become much more complex, data-intensive and costly. Regulatory interactions have evolved substantially, shifting from paper-based submissions that once filled warehouses to more streamlined, yet far more information-heavy, digital processes.

Throughout these changes, he emphasizes that the defining strength of biotech remains its agility. “The hallmark of biotech is being nimble, moving quickly and being willing to take risks that ‘large pharma’ frequently won’t take,” he explains.

When those risks succeed, they drive much of the innovation that fuels the broader pharmaceutical ecosystem. Many therapies ultimately marketed by large pharmaceutical companies originate in smaller biotech organizations willing to pursue unproven ideas at the cutting edge of science.

As insight into inflammatory cascades deepens and clinical trial designs evolve to reflect real-world care, respiratory medicine may be closer to addressing a long-standing gap. Acute exacerbations remain a critical focus, given both their clinical severity and their substantial burden on patients as well as healthcare systems.