Sanofi and Regeneron announced mixed results from two pivotal phase 3 trials evaluating itepekimab, an investigational IL-33 inhibitor, in former smokers with inadequately controlled chronic obstructive pulmonary disease (COPD). While the AERIFY-1 study achieved its primary endpoint with clinically meaningful benefits, the AERIFY-2 trial failed to demonstrate statistical significance despite early positive signals.
AERIFY-1 Demonstrates Clinical Benefit
The AERIFY-1 trial successfully met its primary endpoint, showing a statistically significant 27% reduction in moderate or severe acute exacerbations at week 52 compared to placebo. The study enrolled 1,127 adults aged 40-85 years who were former smokers with moderate-to-severe COPD, defined as those who had not smoked for at least six months.
Patients were randomized to receive itepekimab every two weeks (n=375), every four weeks (n=377), or placebo (n=375), administered subcutaneously in addition to standard-of-care inhaled therapy. Both dosing regimens achieved formal significance testing at 52 weeks, with the every-two-week arm showing a 27% reduction and the every-four-week arm demonstrating a 21% reduction in exacerbations.
AERIFY-2 Falls Short of Primary Endpoint
In contrast, the AERIFY-2 trial, which enrolled 953 patients with similar demographics and design, did not meet the primary endpoint. Despite showing promising early results with an 18% reduction in exacerbations at week 24 for the every-two-week dosing, the benefit diminished to only 2% by week 52. The every-four-week arm showed a 21% reduction at week 24 but only 12% at week 52.
The total number of exacerbations across both trials was lower than prospectively anticipated, decreasing the statistical power of the studies. Enrollment largely occurred during the COVID-19 pandemic, which may have contributed to the overall lower exacerbation rates observed.
Safety Profile Remains Consistent
Itepekimab demonstrated a favorable safety profile consistent across dosing regimens and comparable to placebo. In AERIFY-1, overall adverse event rates were 67% and 68% for the every-two-week and every-four-week arms respectively, compared to 68% for placebo. AERIFY-2 showed similar patterns with rates of 64% and 71% for itepekimab arms versus 64% for placebo.
Serious infection rates were generally low across both studies. In AERIFY-1, serious infections occurred in 7% of patients in each itepekimab arm compared to 10% in the placebo group. AERIFY-2 showed rates of 10% and 7% for the itepekimab arms versus 7% for placebo. Deaths were infrequent, occurring in 1% of each itepekimab arm versus 2% for placebo in AERIFY-1, and 3% for each itepekimab arm versus 2% for placebo in AERIFY-2.
Mechanism and Development Program
Itepekimab is a fully human monoclonal antibody developed using Regeneron's VelocImmune technology that binds to and inhibits interleukin-33 (IL-33), an initiator and amplifier of broad inflammation in COPD. IL-33 is particularly elevated in the lungs of former smokers and is thought to be involved in different types of inflammation.
"While we are encouraged by the results of AERIFY-1, the results of both studies merit further exploration to have a full understanding of the data and the role that IL33 plays in this complex disease," said Houman Ashrafian, Executive Vice President, Head of Research and Development at Sanofi. "Certain people with COPD are in desperate need of new treatment options, especially those who continue to experience exacerbations despite being on maximal therapy."
Broader Clinical Development
The AERIFY program includes two additional ongoing trials: AERIFY-3, a phase 2 mechanistic study assessing the impact of itepekimab on airway inflammation in COPD patients, and AERIFY-4, a phase 3 study evaluating long-term safety. Beyond COPD, itepekimab is currently being evaluated in phase 3 trials for chronic rhinosinusitis with nasal polyps and phase 2 studies for non-cystic fibrosis bronchiectasis and chronic rhinosinusitis without nasal polyps.
George D. Yancopoulos, Board co-Chair, President and Chief Scientific Officer at Regeneron, emphasized the complexity of COPD treatment: "COPD is a particularly complex disease, and novel approaches are needed to address the multiple underlying biological disease drivers. We are encouraged by the initial results from AERIFY-1 and are carefully reviewing the results from both itepekimab trials to inform next steps."
Regulatory Path Forward
Both companies are reviewing the complete dataset and plan to discuss the findings with regulatory authorities to evaluate next steps for potential approval. The mixed results present a complex regulatory scenario, with one successful trial demonstrating clinical benefit while the second failed to replicate these findings at the primary endpoint timepoint.
Detailed results from both trials will be presented at a future medical meeting, providing the scientific community with comprehensive data to better understand the role of IL-33 inhibition in COPD treatment and the factors that may have contributed to the divergent outcomes between the two studies.
