Sanofi and Regeneron’s COPD drug candidate itepekimab met its primary endpoint in one phase 3 study but failed in a second trial.
RT’s Three Key Takeaways
- AERIFY-1 Success: The AERIFY-1 Phase 3 trial showed a statistically significant 27% reduction in moderate or severe COPD exacerbations at week 52 with itepekimab compared to placebo.
- AERIFY-2 Variability: The AERIFY-2 trial did not meet its primary endpoint, though some early benefits were observed, likely impacted by unexpectedly low exacerbation rates during the COVID-19 pandemic.
- Consistent Safety Profile: Itepekimab demonstrated a consistent and comparable safety profile across both dosing regimens and trials, with no concerning safety signals or impact from anti-drug antibodies.
The AERIFY-1 phase 3 study evaluating itepekimab in former smokers with inadequately controlled COPD met the primary endpoint of a statistically significant reduction in moderate or severe acute exacerbations compared to placebo of 27% at week 52, a clinically meaningful benefit. However, the AERIFY-2 phase 3 study did not meet the same primary endpoint, although a benefit was seen earlier in the trial, according to a press release from Sanofi and Regeneron.
Itepekimab is a fully human monoclonal antibody that binds to and inhibits interleukin-33 (IL33), an initiator and amplifier of broad inflammation in COPD. IL33 is thought to be involved in different types of inflammation and is particularly elevated in the lungs of former smokers. Itepekimab is being jointly developed by Sanofi and Regeneron under a global collaboration agreement and is currently in clinical development programs for CRSwNP (phase 3), non-cystic fibrosis bronchiectasis (phase 2), and CRSsNP (phase 2).
In the studies, patients were randomized to receive itepekimab every two weeks (AERIFY-1: n=375; AERIFY-2: n=326), every four weeks (AERIFY-1: n=377; AERIFY-2: n=303), or placebo (AERIFY-1: n=375; AERIFY-2: n=324), which was added to inhaled triple or double standard-of-care therapy. The primary endpoint analysis for AERIFY-1 and AERIFY-2 was the reduction in the annualized rate of acute moderate or severe COPD exacerbations with itepekimab treatment.
The table below summarizes the reductions in moderate or severe exacerbations (itepekimab compared to placebo) through weeks 24 and 52:
| | AERIFY-1 | AERIFY-2 | ||
| Week 24 | Week 52 | Week 24 | Week 52 | |
| Itepekimab every two weeks | 30% | 27%a | 18% | 2% |
| Itepekimab every four weeks | 34% | 21%a | 21% | 12% |
a Formal significance testing was only performed at 52 weeks in the Phase 3 trials, with significance achieved for both the every two-week arm and every four-week arm in AERIFY-1
The total number of exacerbations were lower than prospectively anticipated, decreasing the power of both trials. Enrollment largely occurred during the time of the global COVID pandemic, which could have contributed to the overall lower exacerbation rates.
“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, MD, PhD
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, and we remain committed to discussing these data with regulatory agencies to evaluate our path forward.”
The safety profile of itepekimab was consistent across dosing regimens, and adverse events (AEs) were generally comparable between treatment and placebo groups. In AERIFY-1, the overall rates of AEs were 67% and 68% for itepekimab every two weeks and every four weeks, respectively, compared to 68% for placebo. In AERIFY-2, the overall rates of AEs were 64% and 71% for itepekimab every two weeks and every four weeks, respectively, compared to 64% for placebo. In AERIFY-1, the rate of serious infections was 7% for each itepekimab arm, compared to 10% for placebo. In AERIFY-2, the rate of serious infections was 10% and 7% for itepekimab every two weeks and every four weeks, respectively, compared to 7% for placebo. AEs leading to death were 1% for each itepekimab arm compared to 2% for placebo in AERIFY-1, and 3% for each itepekimab arm compared to 2% for placebo in AERIFY-2. Anti-drug antibodies were rare and had no apparent impact on itepekimab drug levels.
“COPD is a particularly complex disease, and novel approaches are needed to address the multiple underlying biological disease driver,” said George D. Yancopoulos, M.D., Ph.D, Board co-Chair, President and Chief Scientific Officer at Regeneron. “We are proud of our work in this challenging treatment landscape, bringing Dupixent – the first-ever biologic medicine for COPD – to certain patients who previously had very limited options remaining. We are encouraged by the initial results from AERIFY-1 and are carefully reviewing the results from both itepekimab trials to inform next steps. We remain committed to our broader itepekimab development program. The learnings will be invaluable as we continue to advance itepekimab in respiratory diseases with unmet need.”
Sanofi and Regeneron are reviewing the data and will discuss with regulatory authorities to evaluate next steps.
