ARCADIA trials: A win for nemolizumab in atopic dermatitis

In the phase III ARCADIA 1 and 2 trials, the investigational, first-in-class interleukin-31-Rα antagonist nemolizumab delivered early, rapid, and sustained improvements in the core signs and symptoms of atopic dermatitis (AD) in patients with moderate-to-severe disease.

“In these two identical trials, nemolizumab was associated with significant improvements in pruritus, skin lesions, and sleep disturbance in adults and adolescents with moderate-to-severe AD at week 16,” said lead investigator Professor Jonathan Silverberg from George Washington University School of Medicine and Health Sciences, Washington, DC, US, at EADV 2023.

 

Lesion improvements

IGA success* improvements at week 16 with nemolizumab vs placebo were highly significant and consistent in the full** (35.6 percent vs 24.6 percent; p=0.0003 [ARCADIA 1] and 37.7 percent vs 26.0 percent; p=0.0006 [ARCADIA 2]) and severe pruritus** cohorts (35.5 percent vs 21.4 percent; p=0.0002 and 36.7 percent vs 22.0 percent; p=0.0008, respectively). These suggest that more than a third of patients on nemolizumab achieved clearance or near-clearance of skin lesions.

There were also significant and clinically meaningful EASI-75*** responses with nemolizumab at week 16, both in the full (43.5 percent vs 29.0 percent; p<0.0001 [ARCADIA 1] and 42.1 percent vs 30.2 percent; p=0.0006 [ARCADIA 2]) and severe itch cohorts (41.6 percent vs 23.8 percent; p<0.0001 and 41.1 percent vs 25.0 percent; p=0.0004, respectively). [EADV 2023, abstract 6614]

 

Itch improvement as early as day 1

The ≥4-point reduction in PP-NRS^# was evident as early as week 1. The separation of nemolizumab from placebo continued to widen out to week 16 (48.6 percent vs 20.5 percent; p≤0.0001), with no clear evidence of plateau, suggesting that there would be ongoing efficacy beyond week 16, noted Silverberg. There was an even higher degree of efficacy for the severe itch cohort (52.5 percent vs 21.4 percent; p≤0.0001).

The results held up in ARCADIA 2 as well, in both the full cohort (48.1 percent vs 20.6 percent) and severe itch subgroup (57.8 percent vs 24.4 percent; p≤0.0001 for both).

“The improvement in itch was seen as early as day 1,” stressed Silverberg. Again, the separation of the two arms continued to widen out through week 16 (p≤0.0001 at all timepoints). The rates were consistent in the full (-56.1 percent vs -30.6 percent [ARCADIA 1] and -55.6 percent vs -30.2 percent [ARCADIA 2]) and severe itch cohorts (-55.5 percent vs -27.9 percent and -57.0 percent vs -30.3 percent, respectively).

 

Sleep disturbance, safety

More nemolizumab vs placebo recipients had ≥4-point improvement in SD-NRS^## at week 16 in both ARCADIA 1 (44.2 percent vs 22.4 percent [overall] and 49.4 percent vs 24.9 percent [severe itch]) and 2 (38.4 percent vs 19.9 percent and 49.8 percent vs 25.9 percent, respectively; p<0.0001 for all).

Rapid responses were also seen in terms of percent change from baseline in weekly average SD NRS (p≤0.0001 across all timepoints in both the full and severe itch cohorts of both trials).

There were no major signals for serious or severe adverse events. “Overall, nemolizumab had a very reassuring safety profile,” said Silverberg.

 

Targets three most burdensome AD symptoms

In total, the two studies had 1,728 adult and adolescent participants. They had a topical therapy run-in phase for 4 weeks and were then randomized 2:1 to nemolizumab 30 mg Q4W with concomitant background TCS/TCI^### (60-mg loading dose) or placebo for 16 weeks.

“By targeting the neuroimmune cytokine IL-31, these data demonstrate that nemolizumab significantly and quickly improves three of the most burdensome symptoms of these conditions: itch, skin lesions, and sleep disturbance,” said Silverberg.

 

Key takeaways

Both trials met their coprimary and all key secondary endpoints. Taken together, the results extend the efficacy and safety findings from the phase IIb study of nemolizumab in this patient setting.

“These studies have several very important key take-home messages. I think it does more than extend – the studies refine our understanding of how this drug works,” said Silverberg. “We are seeing improvements in the severe itch population, which is quite impressive, and we are seeing improvements in lesions, not just on itch.”

“These important results highlight nemolizumab’s potential to be an effective and convenient treatment for the millions of people globally who live with [AD],” said Galderma CEO Dr Flemming Ørnskov, in a press release.

The US FDA has granted Breakthrough Therapy designation for nemolizumab in December 2019 for the treatment of itch associated with prurigo nodularis.