A groundbreaking interleukin (IL)-2 receptor agonist and regulatory T-cell (Treg) proliferator, known as rezpegaldesleukin, has demonstrated substantial improvements in managing atopic dermatitis, along with encouraging secondary effects for patients dealing with coexisting asthma, according to findings from the phase IIb REZOLVE-AD clinical trial.
Strong Results in Eczema Control
The trial’s primary measure of success focused on the Eczema Area and Severity Index (EASI), which tracks the extent and intensity of skin lesions. Across various treatment groups receiving rezpegaldesleukin, patients experienced EASI score reductions ranging from 53% to 61% over a 16-week period. This marked a clear dose-dependent response, significantly outperforming the 31% improvement observed in those receiving placebo. All comparisons achieved statistical significance with P-values less than 0.001. These results were presented by James R. Treat, MD, from the Children’s Hospital of Philadelphia, during a session at the American College of Allergy, Asthma & Immunology annual meeting.
Approximately one-quarter of the study participants also suffered from comorbid asthma. In this subgroup, scores on the five-question Asthma Control Questionnaire (ACQ-5) showed notable declines with rezpegaldesleukin, particularly in the two highest-dose regimens. The improvements translated to placebo-adjusted reductions of 0.5 to 0.6 points, reaching statistical significance (P less than 0.05). For individuals who reported poorly controlled asthma at baseline, the benefits were even more pronounced, with placebo-adjusted ACQ-5 score drops of 1.0 to 1.4 points across the different dose levels (P less than 0.05 to 0.01).
Validating a Novel Mechanism
Dr. Treat emphasized that this represents the first substantial clinical investigation to confirm the regulatory T-cell mechanism of action and the therapeutic promise of rezpegaldesleukin, an IL-2 pathway agonist, specifically in patients with moderate-to-severe atopic dermatitis. He shared these insights during the late-breaking abstract presentation at the conference.
Nicole Chase, MD, from the University of Minnesota School of Medicine in Minneapolis, who had no involvement in the research, drew parallels to dupilumab, a medication already approved for both moderate-to-severe asthma and eczema. She acknowledged the positive outcomes but viewed them as consistent with existing therapies in the field. In discussions with medical reporters, she pointed out that while rezpegaldesleukin clearly surpassed placebo, certain alternative treatments deliver superior enhancements in the Investigator Global Assessment (IGA) scores and potentially equivalent relief from itch symptoms.
Dr. Chase also highlighted the competitive landscape of eczema treatments, noting that many current options act more swiftly. She observed that the peak efficacy for rezpegaldesleukin’s primary endpoint appears around week 16, with response curves gradually ascending over that timeframe. This timeline, she suggested, aligns with the drug’s underlying biology, which aims to recalibrate an overactive immune response by bolstering the system’s natural regulatory functions.
Debating Speed Versus Sustained Efficacy
Jonathan Silverberg, MD, PhD, MPH, a co-author of the study from George Washington University School of Medicine and Health Sciences in Washington, D.C., offered a different perspective. He argued that the prolonged improvement trajectory is actually a key advantage. What stood out to him was the consistent upward trajectory in the treatment response curves, showing no signs of leveling off. He described these as among the most compelling long-term efficacy profiles observed to date in atopic dermatitis trials.
Although phase III studies may yield varying results, as seen with other candidates in this therapeutic area, Dr. Chase appreciated the value of additional choices. Dr. Silverberg concurred, stressing that despite the availability of multiple biologic options for atopic dermatitis, significant gaps remain in patient care. In his own practice, he regularly encounters individuals whose eczema and asthma remain inadequately managed by existing interventions.
Trial Design and Key Secondary Outcomes
The core findings from the REZOLVE-AD trial were first unveiled at the recent European Academy of Dermatology and Venereology Congress in Paris. This study involved randomizing 393 adults with moderate-to-severe atopic dermatitis to receive subcutaneous self-injections of rezpegaldesleukin at one of three dosing schedules—24 µg/kg every 2 weeks, 18 µg/kg every 2 weeks, or 24 µg/kg every 4 weeks—or matching placebo every 2 weeks. Following the 16-week evaluation of primary and secondary outcomes, responsive participants entered a blinded maintenance phase, where they were re-randomized to the same dose administered every 4 or 12 weeks, extending through week 52. This long-term portion remains in progress.
Beyond the primary endpoint, all secondary measures at 16 weeks supported the drug’s efficacy:
- EASI-75, defined as at least 75% improvement in lesion extent and severity from baseline—a threshold deemed clinically meaningful—was achieved by 34% to 46% of rezpegaldesleukin patients versus 17% on placebo (all P less than 0.05 to 0.001).
- EASI-90, indicating at least 90% improvement, occurred in 17% to 25% versus 9% (P less than 0.05, limited to the highest-dose group).
- Itch Numerical Rating Scale response, requiring a reduction of 4 or more points on a 0-10 scale, was seen in 23% to 42% versus 16% (P less than 0.05 to 0.01 for higher doses).
- The validated Investigator Global Assessment for Atopic Dermatitis rated skin as “clear” or “almost clear” in 19% to 26% versus 8% (P less than 0.05 to 0.01 for higher doses).
Improvements continued to strengthen through 24 weeks among those on the 24 µg/kg every 2 weeks regimen advancing to phase III, with mean EASI changes reaching 72% from baseline and EASI-75 rates hitting 60%.
Safety Profile and Future Directions
Regarding safety, treatment-emergent adverse events affected 85.6% of patients on the highest-dose rezpegaldesleukin, compared to 57.5% on placebo. Serious events were rare, occurring in 1% versus 0%. The most frequent issue was injection site reactions, reported in 76% of cases but generally mild. Other notable events included pyrexia in roughly 10%, eosinophilia in about 16%, lymphadenopathy in around 7%, musculoskeletal and connective tissue issues in approximately 18%, and nervous system disorders—primarily headaches—in about 10%. Importantly, there were no elevated risks for conjunctivitis, oral ulcers, asthma exacerbations, infections, or major cardiovascular incidents relative to placebo.
Looking ahead, a phase III pivotal trial is being planned for moderate-to-severe atopic dermatitis, incorporating specific evaluations of its impact on comorbid asthma. Dr. Treat highlighted that the FDA has awarded Fast Track designation to rezpegaldesleukin, streamlining its regulatory review for treating patients aged 12 and older with moderate-to-severe atopic dermatitis inadequately responsive to topical prescription therapies.
