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The COPD Foundation is calling for a change in clinical trial design that would test experimental therapies in subsets of patients.
As many as 30 million people in the United States are estimated to have chronic obstructive pulmonary disease (COPD), although approximately half don’t have a diagnosis. Until the COVID-19 pandemic, COPD was consistently the fourth leading cause of death in the U.S. Diagnosis and treatment is complicated by the fact that COPD is really something of an umbrella category for lung disease that is characterized by difficulty breathing. The two most common conditions that fit under the COPD rubric include emphysema and chronic bronchitis.
The current treatment choices for COPD are varied and complicated, mirroring the condition itself. But in broad strokes, they can be grouped into three main medication categories:
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends bronchodilators as first-line treatment for COPD and preferably a LABA or LAMA. Treatment with bronchodilators can include LABA or LAMA alone or a combination of the two.
Some of the combination therapies include Anoro Ellipta (umeclidinium and vilanterol), Duaklir Pressair (aclidinium bromide and formoterol fumarate) and Stiolto Respimat (tiotropium and olodaterol).
Ruth Tal-Singer, Ph.D., president and chief scientific officer of the COPD Foundation, a nonprofit organization that promotes COPD research and improved care, explains that the proponents of the LABA-LAMA combinations argue that pairing the medications often produces the best outcome. But there is an opposing “minimalist” school of thought, says Tal-Singer, that argues that “these are drugs, and you want to minimize the number of drugs people are on.”
There are many forks in the COPD treatment road. Patients whose COPD flares up can be treated with ICS in combination with a LABA. Triple inhaled therapy is an option for people whose COPD doesn’t respond to the ICS-LABA combination. That’s a large group: About 1 in every 3 patients with COPD end up on triple inhaled therapy within a year of diagnosis.
The FDA approved the first triple inhaled therapy, GlaxoSmithKline’s Trelegy Ellipta, in 2017. Trelegy Ellipta is a combination of fluticasone furoate, an inhaled corticosteroid; umeclidinium, a LAMA; and vilanterol, a LABA. AstraZeneca’s tripe therapy product, Breztri Aerosphere, was approved last year. Breztri Aerosphere is a combination of budesonide, an inhaled corticosteroid; glycopyrrolate, a LAMA; and formoterol fumarate, a LABA.
The GOLD strategy makes note of the fact that COPD is complex and multifaceted, which means a one-size-fits-all treatment approach (is that ever a good idea?) is an especially bad one. As a result, the COPD Foundation and others are steering COPD research and care toward a precision-medicine strategy that would tailor treatment to selected subsets of patients based on lung imaging and other factors that matter to patients.
A more tailored approach to research and clinical trials is not entirely uncharted territory; the GOLD strategy suggests calibrating treatment to the various manifestations of COPD and their future risk of exacerbations. But it is taking hold in the research agenda in a new way. For example, the phase 3 RELIANCE study is designed by researchers in collaboration with patients and caregivers to promote individualized treatment plans for patients with COPD who are at risk for exacerbations. The study is comparing two approved treatments used to reduce COPD exacerbations: azithromycin, the antibiotic, and roflumilast, an oral, anti-inflammatory, in more than 3,000 patients.
The trial is an exciting development in the move toward precision medicine, but Tal-Singer says that, as a whole, the current state of clinical trial design for COPD creates a challenge in bringing different kinds of treatments to market. New treatments have been introduced in recent years, but a pharmaceutical treatment with a novel mechanism of action hasn’t been approved since 2011 when the FDA OK’d oral roflumilast for a subset patients. Based on traditional regulatory expectations, clinical trials testing potential new COPD treatments have often lumped COPD patients together. “If you study everyone with a disease that is so complex, the chance of failure is quite high,” says Tal-Singer.
Ideally, researchers wanting to test a potential new treatment could conduct a smaller trial of subpopulations of patients based on their symptoms and clinical characteristics. This approach has been adopted by COPD360Net, a network of COPD Foundation-accredited care centers. Tal-Singer is the chair of the network’s executive committee. The network sets its focus on advancing the development of new treatments or the repurposing of existing ones. Its goals include organizing clinical trials that target specific COPD subpopulations, identifying new endpoints, and adopting a mostly remote, digital approach to conducting trials.
Another area of clinical trial design concern highlighted by Tal-Singer is the stage of disease in which patients are typically given experimental treatments. A treatment that has failed in trials of patients with severe disease may actually show benefit if tested in patients while they have an earlier stage of disease. However, there’s a challenge with this, notes Tal-Singer. Even if the patient exhibits abnormalities based on lung imaging or has certain symptoms of illness, they may not yet be considered “sick” with COPD, typically excluding them from clinical trials. But there is a study underway that is taking a different approach. The phase 2 RETHINC study is examining whether current or former smokers’ normal breathing tests could benefit from bronchodilator treatment. Data from the study are expected to reported this year.
Jaime Rosenberg is a freelance writer based in Jersey City, New Jersey.