New LEVEL UP Period 2 Data Shows Patients Who Switched From Dupilumab to Upadacitinib Achieved Higher Treatment Targets in AD

In a panel discussion at Fall Clinical 2024 in Las Vegas, Nevada, Christoper Bunick, MD, PhD, joined colleagues Brad Glick, DO, MPH, and Alexandra Golant, MD, in a CME satellite symposium titled, "Is EASI 75 Good Enough or Can We Do Better? Elevating Efficacy and Long-Term Safety With JAK Inhibitors in Moderate-to-Severe Atopic Dermatitis."¹

Bunick, associate professor of dermatology and translational biomedicine at the Yale University School of Medicine in New Haven, Connecticut, and Dermatology Times’ 2024 Winter Editor in Chief, reviewed the latest results of period 2 data from the phase 3b/4 LEVEL UP study², a head-to-head comparison of dupilumab vs upadacitinib for the treatment of adults and adolescents with moderate to severe atopic dermatitis.

In LEVEL UP period 1, upadacitinib demonstrated superiority vs. dupilumab in primary and all secondary end points throughout 16 weeks. Period 2 is a 16-week extension study to assess outcomes in patients who didn’t achieve adequate response. In period 2, dupilumab patients who didn’t achieve adequate response (not meeting EASI 75) at week 16 of period 1, entered period 2 and were switched to upadacitinib 15mg once daily up to week 32.

Overall, of the patients who switched from dupilumab to upadacitinib in period 2, 79.6%, 58.7%, and 19.9% of patients achieved an EASI 75, EASI 90, and EASI 100, respectively for skin lesion improvement, and 60.2% and 37% achieved a 4-point reduction in itch (WP NRS=>4), and little or no itch (WO-NRS 0/1), respectively.

In LEVEL UP, patients were randomized to receive a upadacitinib 15mg starting dose or dupilumab per its label dose for 16 weeks (period 1), with a 16-week extension period to 32 weeks (period 2) for patients who did not achieve at least a 75% reduction in EASI 75 from baseline at week 16.

Background and Methods

In total, 355 patients moved on to period 2. Of the total patients, 208 received dupilumab in period 1 and then switched to upadacitinib in period 2, and 147 patients continued with upadacitinib 30mg. In the group of patients who switched from dupilumab to upadacitinib (n=208), 47.6% (n=99) of patients escalated to upadacitinib 30mg in period 2 starting at week 20. The other 109 patients were never dose escalated.

Week 32 demonstrated 16 weeks after the switch from dupilumab to upadacitinib, and week 20 was 4 weeks after the switch from dupilumab to upadacitinib.

Results

Selected end points for the patients who switched from dupilumab to upadacitinib in period 2 and their results included:

• EASI 75 at week 32, among patients who did not achieve EASI 75 at week 16
  • Achieved by 79.6% of patients who switched
• EASI 90 at week 32, among patients who did not achieve EASI 75 at week 16
  • Achieved by 58.7% of patients who switched
• EASI 100 at week 32, among patients who did not achieve EASI 75 at Week 16
  • Achieved by 19.9% of patients who switched
• WP-NRS improvement ≥ 4 at week 32, among patients with baseline WP-NRS ≥ 4 and did not achieve WP-NRS reduction ≥ 4 at week 16 (∆WP-NRS≥4 )
  • Achieved by 60.2% of patients who switched
• WP-NRS 0/1 at week 32, among patients with baseline WP-NRS > 1 and did not achieve WP-NRS 0/1 at week 16
  • Achieved by 37.0% of patients who switched
• EASI 90 and WP-NRS 0/1 at week 32, among patients who did not simultaneously achieve EASI 90 and WP-NRS 0/1 at week 16
  • Achieved by 26.8% of patients who switched

Patients who switched from dupilumab to upadacitinib demonstrated improved responses as early as 4 weeks post-switch (week 20), with increased responses by 16 weeks post-switch (week 32). Additionally, patients who switched had improvements in measures of itch and most patients achieved ∆WP-NRS≥4 by week 20. The proportion of patients who achieved WP-NRS 0/1 increased by 4 weeks post-switch (week 20), with even more increases by week 32.

In total, 26.8% of patients reached the stringent end point of simultaneous achievement of both EASI 90 and WP-NRS 0/1 by 16 weeks post-switch from dupilumab to upadacitinib (week 20, week 32) with response rates recorded as early as 4 weeks post-switch.

The week 20 results included patients who received upadacitinib 15mg due to dose escalations not occurring until week 20 or later if protocol criteria were met. The week 32 results include patients who received upadacitinib15mg and patients who were dose escalated to receive upadacitinib 30mg. The efficacy measures for patients who escalated to upadacitinib30mg showed that a “proportion of patients achieved clinically meaningful improvements in both skin and itch outcomes after continuing treatment.”

“It’s really important to understand this trial because it’s raising the standard of care for atopic dermatitis,” said Bunick in his presentation.

Safety

Regarding safety, the proportions of patients with treatment-emergent adverse events (TEAEs) were similar for both the patients who switched from dupilumab to upadacitinib and the patients who dose escalated to upadacitinib 30mg. The most frequently reported TEAEs were nasopharyngitis, acne, upper respiratory tract infection, and atopic dermatitis. Additionally, one patient reported serious pneumonia in the dupilumab to upadacitinib group; 2 patients who dose escalated to upadacitinib 30mg and 1 patient who switched from dupilumab had opportunistic infections (not including tuberculosis and herpes zoster), and all were non-serious events of eczema herpeticum that did not lead to study discontinuation.

Most notably in safety, no malignancies; adjudicated major adverse cardiac events; adjudicated venous thromboembolic events; adjudicated gastrointestinal perforations; or active tuberculosis were reported in either treatment group.

“Treatment of moderate to severe atopic dermatitis with upadacitinib (UPA) in patients who received dupilumab (DUPI) for 16 weeks but did not achieve an adequate response demonstrated improved efficacy in skin (EASI 75, EASI 90, and EASI 100) and itch (WP-NRS 0/1 & ∆WP-NRS≥4) end points, as well as simultaneous achievement of both EASI 90 and WP-NRS 0/1 after switching to UPA...These findings indicate that UPA may address an unmet medical need in patients with moderate-to-severe AD who do not achieve an adequate response while taking DUPI,” concluded Bunick et al.

The switch study in LEVEL UP period 2 provides practice-informing evidence that is aligned with the AHEAD treat-to-target recommendations. Based on the AHEAD recommendations, clinicians should aim for optimal treatment targets for skin clearance and itch relief, and that treatment response can be considered inadequate if the agreed targets are not met within 3 to 6 months; treatment modification or escalation should then be considered.

References

1. Bunick CG, Glick B, Golant A. Is EASI 75 good enough or can we do better? Elevating efficacy and long-term safety with JAK inhibitors in moderate-to-severe atopic dermatitis. Presented at: 2024 Fall Clinical Dermatology Conference; October 24-27, 2024; Las Vegas, Nevada.
2. Buick CG, Magnolo N, Moore A, et al. Switching from dupilumab to upadacitinib in adults and adolescents with moderate-to-severe atopic dermatitis and inadequate response to dupilumab: efficacy and safety results from the phase 3b/4 LEVEL UP study. Presented at: 2024 Fall Clinical Dermatology Conference; October 24-27, 2024; Las Vegas, Nevada.