While investigators did not meet their primary endpoint in the study, results in former smokers within the trial were promising and prompted further research on the subgroup.
Chronic obstructive pulmonary disease (COPD) global prevalence has been alarming over recent years, with an estimated 3 million people dead due to the disease annually as recently as 2017. The number represented a 17.5% increase from the previous decade, as well as a roughly 13% increase in premature loss of life.
A phase 2 trial from the LugenClinic in Grosshansdorf, Germany assessed the safety and efficacy of the human IgG4 monoclonal antibody itepekimab on patients with moderate-to-severe COPD.
While the primary endpoint of the study was not met, the investigative team did gather promising data on the itepekimab’s impact on the exacerbations and lung function of former smokers with COPD, and a pair of ongoing phase 3 clinical trials are currently being conducted to confirm the efficacy and safety of the drug on that subgroup.
COPD has been characterized by persistent respiratory symptoms, shortness of breath, sputum production, and airflow limitation. Investigators, led by Professor Klaus Rabe, MD, noted the exacerbations associated with COPD are often associated with increased morbidity, hospital admission, and mortality.
While approved therapies such as smoking cessation has been known to improve lung function in patients, the exacerbations they have often persist.
Recently, the association between interleukin 33 (IL-33) and asthma has been considered in approaches to COPD management. Studies of loss-of-function in IL-33 suggested a strong support for a protective effect of an IL-33 blockade in asthma, which was confirmed in phase 2 of the itepekimab trials.
Additionally, researchers proposed a role for IL-33 in COPD, as previous studies showed that serum IL-33 levels were found to be associated with exacerbation history.
Investigators from the Grosshansdorf study performed a series of human genetic association studies to assess whether genetic variants within IL-33 pathways were associated with COPD in patients.
The investigators conducted a randomized, placebo-controlled, phase 2A trial to assess the efficacy and safety of itepekimab in patients with moderate-to-severe COPD.
A total of 437 previously genotyped participants were included in the study, 54% of whom were women and 46% were men. The individuals were genotyped as part of a prior collaboration between DiscovEHR and the Regeneron Genetics Center and Geisinger Health System (GHS).
Eligibility criteria included an age range of 40-75 years, current or former smokers with a history of at least 10 pack-years, and a diagnosis of COPD for at least 1 year based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.
From there, participants were randomly assigned to either the itepekimab or placebo group. The study was comprised of a screening period (10 days to 4 weeks), treatment period (24-52 weeks) and a post-treatment safety follow-up period (20 weeks).
Participants in the itepekimab group were given 300 mg of the antibody administered as 2 injections of 150 mg. The injections were given to participants every 2 weeks, and patients continued background controller medication throughout.
Researchers defined the primary objective as the assessment of the effect of itepekimab on the annualized rate of moderate-to-severe acute exacerbations of COPD during the 24-52 week treatment period.
Secondary objectives included change in prebronchodilator FEV1 from baseline to weeks 16–24, change in postbronchodilator FEV1 from baseline to week 24, time to first moderate-to- severe acute exacerbations of COPD (up to 52 weeks) and adverse events through the post-treatment follow-up period (up to 72 weeks).
The researchers noted that while the primary and secondary endpoints were not significantly different for either treatment group, benefits in acute exacerbations in former smokers treated with itepekimab were accounted for.
Additionally, the study showed that the effects observed for acute exacerbations and FEV1 during the treatment period persisted during the 20-week post-treatment follow-up period. This suggested sustained efficacy of itepekimab and confirmed the previously observed preferential efficacy in the former smoker subgroup on the reduction of exacerbations.
While treatment adverse events for the itepekimab and placebo groups were about the same (78% and 80%, respectively), the antibody did reduce the annual rate of acute exacerbations by 19%.
Rabe and colleagues noted that this was the first study to demonstrate a potential benefit for biological therapy in terms of exacerbation rate and lung function for former smokers with COPD, and believed a stronger focus on this subgroup in the study could be beneficial.
“Inhibition of IL-33 with itepekimab might be effective and well tolerated in these patients,” the investigators wrote. “Two phase 3 clinical studies are being conducted to confirm and better understand the potential of this novel therapy in COPD.”
The study, “Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomized, double-blind, phase 2a trial,” was published online in The Lancet Respiratory Medicine.