‘Unexpectedly high’ placebo response derails darvadstrocel for Crohn’s perianal fistulas
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Key takeaways:
- A single dose of darvadstrocel showed no “clinically meaningful” benefit over placebo for complex perianal fistulas and Crohn’s disease.
- Darvadstrocel was well-tolerated and comparable to placebo for safety.
WASHINGTON — Darvadstrocel demonstrated “no statistically significant or clinically meaningful” benefit vs. placebo for complex perianal fistulas and Crohn’s disease, according to ADMIRE-CD II trial data presented at Digestive Disease Week.
“Complex Crohn’s perianal fistulas are a serious complication of Crohn’s disease that occur in up 28% of patients within 20 years of diagnosis,” Laura E. Raffals, MD, professor and associate chair of faculty development in the division of gastroenterology and hepatology at the Mayo Clinic, told attendees. “The ADMIRE-CD study showed efficacy of darvadstrocel vs. placebo for complex Crohn’s perianal fistulas with a combined remission of 50% vs. 34% at week 24 — [here, we present] results from the ADMIRE-CD II study.”
To assess the benefit of darvadstrocel (Alofisel, Takeda Pharmaceuticals) as a potential therapy for complex Crohn’s perianal fistulas, researchers randomly assigned adult patients (n = 568; mean age, 38.1 years; 44.2% women) to a single dose of darvadstrocel or placebo over 24 weeks with a follow-up period up to 52 weeks.
The primary efficacy endpoint of ADMIRE-CD II was combined remission at 24 weeks, which included closure of all treated external openings that were draining at baseline despite gentle finger compression and an absence of collections greater than 2 cm as confirmed by MRI. Secondary efficacy endpoints included combined remission at 52 weeks, clinical remission at 24 and 52 weeks and time to clinical remission at 24 weeks.
According to trial results, at 52 weeks, combined remission was achieved by 41% of patients in the darvadstrocel group and 39.7% of the placebo group (change, 1.3%; 95% CI –6.8 to 9.3).
At 24 weeks, 49.8% of patients in the darvadstrocel group achieved clinical remission vs. 47% in the placebo group (change, 2.7%; 95% CI –5.5 to 10.9) with no significant difference between the groups at 52 weeks: 43.1% for darvadstrocel and 41.4% for placebo (change, 1.6%; 95% CI –6.5 to 9.7)
“There was no significant difference in time to clinical remission between the darvadstrocel and placebo groups,” Raffals noted.
The researchers reported that placebo response rates were higher than observed in previous trials, especially during the second half of the study, possibly due to changes in concomitant treatment patterns and the frequency with which biologics are prescribed for complex Crohn’s perianal fistulas in the United States vs. the European Union. Based on post-hoc analyses, the researchers speculated that the COVID-19 pandemic may have had uncertain effects on host immunity in this patient population.
Raffals and colleagues also noted that patients enrolled in ADMIRE-CD II may have had more severe disease compared with those in its predecessor trial, with a larger proportion of patients receiving immunosuppressives and monoclonal antibodies (95.8% in ADMIRE-CD II vs. 78.8% in ADMIRE-CD).
“Treatment of complex Crohn’s perianal fistulas with a single dose of darvadstrocel showed no statistically significant or clinically meaningful differences in key efficacy endpoints compared with placebo, with an unexpectedly high response rate in the placebo group,” Raffals said. “Treatment with darvadstrocel was well-tolerated, and no new safety signals observed during this study.”
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Serclova Z, et al. Efficacy and safety of darvadstrocel treatment in patients with complex perianal fistulas and Crohn’s disease: Results from the global ADMIRE-CD II phase 3 study. Presented at: Digestive Disease Week; May 18-21, 2024; Washington (hybrid).
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