The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials

Abstract

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician's Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25^bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control.

Fig. 1. CONSORT diagrams.

a CONSORT diagram for Phase 1b trial of REZPEG in PsO patients. b CONSORT diagram for Phase 1b trial of REZPEG in AD patients. AD atopic dermatitis, AE adverse event, GCP Good Clinical Practice, ISR injection site reaction, PsO psoriasis.

Fig. 2. REZPEG-induced pharmacokinetics and pharmacodynamics.

REZPEG concentration in a, PsO and b, AD patients, shown as mean ± SEM. CD25^bright Tregs measured in c, PsO and d, AD patients. CD4 + T cells in e, PsO and f, AD patients. CD8 + T cells in g, PsO and h, AD patients. All measurements performed using peripheral blood samples from patients treated with placebo (grey circles), 12 μg/kg (blue circles) or 24 μg/kg (red circles) REZPEG administered once every 2 weeks for 12 weeks. Pharmacodynamic data shown as mean fold change from baseline ± SEM. Number of samples at each time point provided in Supplementary Tables 6 (PsO) and 7 (AD). AD atopic dermatitis; PsO psoriasis; SEM standard error of the mean; Tcons conventional T cells; Tregs regulatory T cells. Source data are provided as a Source Data file.

Fig. 3. REZPEG efficacy in PsO patients.

Reduction in PASI scores from baseline in patients with PsO after 12 weeks of 24 μg/kg REZPEG treatment (red circles) compared to placebo (grey circles) administered once every 2 weeks for 12 weeks. Data shown as mean percent change from baseline ± SEM. Number of subjects at each time point shown in Supplementary Table 8. PASI, psoriasis area and severity index; PsO, psoriasis; SEM, standard error of the mean. Source data are provided as a Source Data file.

Fig. 4. AD investigator-assessed efficacy outcomes.

a EASI score mean % change from baseline ± SEM. b BSA score mean % change from baseline ± SEM. c, Proportion of EASI-75 patients whose EASI score decreased by at least 75% relative to baseline. d Proportion of EASI-90 patients whose EASI score decreased by at least 90% relative to baseline. e Proportion of vIGA-AD responders, patients with a post-baseline vIGA-AD score of 0 or 1 and a ≥ 2-point improvement from baseline. Red, REZPEG 24 µg/kg; blue, REZPEG 12 µg/kg; grey, placebo. For continuous endpoints using observed data (a and b), number of subjects at each time point shown in Supplementary Table 9. All responder data shown as % of adjusted ITT populations. BSA, body surface area; EASI, Eczema Area and Severity Index; ITT, intention to treat; NRI, non-responder imputation; SEM, standard error of the mean, vIGA-AD, Validated Investigator Global Assessment for Atopic Dermatitis. Source data are provided as a Source Data file.

Fig. 5. AD off-treatment extended efficacy outcomes through week 48.

Proportion of week 19 EASI-50 responders maintaining a, EASI-50, decrease in EASI score by at least 50% relative to baseline; b, EASI-75, decrease in EASI score by at least 75% relative to baseline; c, EASI-90, decrease in EASI score by at least 90% relative to baseline; d, vIGA-AD score of 0 or 1 and a ≥ 2-point improvement from baseline; e DLQI score reduction by ≥ 4 points among patients with baseline score ≥ 4. f POEM score reduction by ≥ 4 points among patients with baseline score ≥ 4. g itch NRS score reduction by ≥ 4 points among patients with baseline score ≥ 4. Red, REZPEG 24 µg/kg; blue, REZPEG 12 µg/kg; grey, placebo. DLQI, Dermatology Life Quality Index; NRI, non-responder imputation; NRS, numeric rating scale; POEM, Patient-Oriented Eczema Measure; vIGA-AD, Validated Investigator Global Assessment for Atopic Dermatitis. Source data are provided as a Source Data file.

Fig. 6. AD patient-reported outcomes.

a DLQI mean % change from baseline ± SEM. b POEM mean % change from baseline ± SEM. c, Proportion with post-baseline DLQI score reduced by ≥ 4 points among patients with baseline score ≥ 4. d Proportion with post-baseline POEM score reduced by ≥ 4 points among patients with baseline score ≥ 4. e Proportion with post-baseline itch NRS scale reduced by ≥ 4 points among patients with baseline score ≥ 4. Red, REZPEG 24 µg/kg; blue, REZPEG 12 µg/kg; grey, placebo. For continuous endpoints using observed data (a and b), number of subjects at each time point shown in Supplementary Table 9. All responder data shown as % of adjusted ITT populations. DLQI, Dermatology Life Quality Index; ITT, intention to treat; NRI, non-responder imputation; NRS, numeric rating scale; POEM Patient-Oriented Eczema Measure; SEM standard error of the mean. Source data are provided as a Source Data file.

Fig. 7. Serum proteomic biomarker analysis.

a Dose-dependent volcano plots of the serum proteins showing the -log10(p-value) vs fold-change in protein expression in response to REZPEG treatment compared to placebo. Data were fitted with a linear mixed model with multiple testing correction using Benjamini-Hochberg. Statistical comparisons were made between treatment and placebo using the Tukey method. Proteins with a statistically significant treatment-based change (threshold p < 0.05) are indicated by red circles; those with non-significant changes are indicated by teal circles. b Example line charts of differentially-detected serum proteins over the 12-week REZPEG treatment induction period shown as Log2 fold change (FC) in expression from baseline ± SEM. Red, REZPEG 24 µg/kg; blue, REZPEG 12 µg/kg; grey, placebo. Number of samples at each time point provided in Supplementary Table 10. CCL, CC motif chemokine ligand; CD160, cluster of differentiation 160; CX3CL1, C-X3-C motif chemokine ligand 1 (fractalkine); FASLG, Fas ligand; GNLY, granulysin; IL, interleukin; ITGB2, integrin beta 2 (CD18); Log2(FC), Log2 fold change; LTA, lymphotoxin alpha; NCR1, natural cytotoxicity triggering receptor 1 (NKp46); RRM2, ribonucleotide reductase regulatory subunit M2; SEM, standard error of the mean; TNFRSF4, tumor necrosis factor receptor superfamily member 4 (CD134, OX40). Source data are provided as a Source Data file.