Rezpeg AD Maintenance Data: Phase IIb Signal Promising, But Phase III Proof Still Absent

Nektar's Rezpeg Shows Sustained Efficacy in Atopic Dermatitis Phase IIb

Nektar Therapeutics presented data from the maintenance period of the Phase IIb REZOLVE-AD study for rezpegaldesleukin (rezpeg) in atopic dermatitis (AD) at EADV 2026. Patients receiving monthly or quarterly rezpeg for up to 52 weeks showed sustained disease control, with a meaningful proportion achieving 75% and 90% improvement in eczema severity and itch reduction. Full skin clearance was observed in 22% (monthly) and 18% (quarterly) of patients at week 52. The safety profile was favorable and consistent with prior studies. Nektar plans to initiate a Phase III program for rezpeg in AD and alopecia areata.

• Nektar's rezpegaldesleukin (rezpeg) demonstrated sustained disease control and significant efficacy in the Phase IIb REZOLVE-AD study's maintenance period. At 52 weeks, a substantial proportion of patients achieved 75% and 90% improvement in eczema spread and severity, alongside reduced itch. Specifically, 22% of monthly-dosed patients and 18% of quarterly-dosed patients achieved full skin clearance, highlighting rezpeg's potential for long-term benefits in atopic dermatitis.
• The safety profile of rezpeg was reported as favorable and consistent with previous studies during the maintenance period, with no new safety signals identified. This positive outcome supports Nektar's strategic decision to advance rezpeg into a Phase III program for atopic dermatitis. Additionally, the company intends to initiate a Phase III trial for rezpeg in alopecia areata early next year, expanding its potential therapeutic applications.
• William Blair analysts noted that the EADV readout provides further evidence of rezpeg's "material durability advantage over current standard-of-care options" in AD. However, they also highlighted a potential concern regarding high levels of injection site reactions compared to placebo, which could "pose an overhang on rezpeg’s target product profile." This suggests a mixed but generally positive outlook on its competitive standing.

Nektar and Pfizer Deliver Strong Atopic Dermatitis Efficacy

Recent clinical research across biologics and JAK inhibitors has continued to expand the evidence base for moderate-to-severe atopic dermatitis, with studies evaluating both efficacy benchmarks and comparative safety profiles. The following table summarizes key findings from several recent studies.

Evommune's EVO301: A Novel IL-18 Approach in Atopic Dermatitis

Research into atopic dermatitis (AD) has expanded well beyond conventional immunosuppression, with multiple novel molecular targets now under active investigation across the inflammatory, neuronal, and barrier-function axes of disease pathogenesis.

• JAK/STAT pathway inhibition: Both topical and oral JAK inhibitors have emerged as significant therapeutic modalities. Ruxolitinib cream, a selective JAK1/2 inhibitor formulated as an oil-in-water emulsion, delivers targeted local inhibition of cytokine-driven inflammatory signaling directly to the skin. Upadacitinib, engineered for selectivity toward JAK1, has been approved for moderate-to-severe RA and is under investigation in AD and other inflammatory indications. A retrospective cohort study using the TriNetX network found that topical ruxolitinib users had significantly lower incidences of arterial thrombosis and tuberculosis compared to oral JAK inhibitor users, and demonstrated decreased risk of all-cause mortality, cerebrovascular accidents, and venous thromboembolism compared to controls.

• Type 2 inflammatory cytokine cascade: Dupilumab, a monoclonal antibody targeting the IL-4 receptor α subunit, established proof of concept for biologics in AD and is approved for moderate-to-severe or severe AD in children, adolescents, and adults. Subsequent drug development has focused on IL-4, IL-13, and their downstream JAK signaling as primary targets, with several additional monoclonal antibodies under investigation.

• IL-31 and pruritus signaling: IL-31 and its receptor have been identified as key mediators of pruritus in AD. Elevated IL-31 levels have been reported in tissue and serum of patients with atopic dermatitis, prurigo nodularis, and psoriasis. Nemolizumab, a humanized monoclonal antibody targeting the IL-31 receptor, is the only agent in this class to have successfully completed late-stage clinical studies to date.

• TRP ion channels — TRPM3, TRPA1, and TRPV1: Transient receptor potential (TRP) channels represent an emerging neuronal target class for AD-associated itch. Sphingosylphosphorylcholine (SPC), found at elevated levels in the stratum corneum of AD patients, induces itch via activation of TRPM3 and TRPA1 in sensory neurons; TRPM3 and TRPA1 antagonists significantly reduced SPC-induced scratching behaviors in an AD mouse model, with TRPM3 identified as playing a critical role in spontaneous scratching. TRPV1, which affects multiple pathways involved in pruritus and skin barrier function, is also under investigation, with early trials data suggesting safety of TRPV1 antagonists, though efficacy assessment in AD remains pending.

• IL-33 signaling pathway: IL-33, a member of the IL-1 cytokine family released by epithelial and endothelial cells in response to pro-inflammatory stimuli and cell damage, activates NF-κB signaling and induces phosphorylation of ERK1/2, JNK, p38, and PI3K/AKT modules. Aberrant IL-33 signaling has been implicated in the pathogenesis of atopic dermatitis, positioning the IL-33/IL-33R axis as a potential therapeutic target.

• Broader T helper cell subtypes and cytokine targets: Recognizing the contributions of Th1 and Th22 cells alongside the Th2 axis, and the specific role of IL-31 in pruritus generation, the landscape of potential therapeutic targets in AD has widened considerably, with multiple systemic agents targeting these pathways currently under investigation.

Shaping the Future of Atopic Dermatitis Treatment

The atopic dermatitis (AD) treatment landscape has undergone substantial expansion beyond topical corticosteroids, driven by a growing body of phase 3 trial data and real-world evidence. Topical nonsteroid therapies — specifically the calcineurin inhibitors pimecrolimus and tacrolimus, and the PDE4 inhibitor crisaborole — established an early foundation, demonstrating efficacy in lesion clearance and symptom management with low systemic absorption and no demonstrated increase in malignancy risk across 69 clinical trials. More recently, 1.5% ruxolitinib cream, a selective JAK1/JAK2 inhibitor, has entered the topical space; a network meta-analysis across 12 randomized controlled trials in a systemic-eligible moderate AD subgroup found no statistically significant differences between ruxolitinib cream and systemic agents — including dupilumab, upadacitinib, and abrocitinib — on IGA 0/1, EASI-75, and Itch NRS4, with point estimates numerically favoring ruxolitinib cream for IGA 0/1 and EASI-75.

In the systemic arena, dupilumab has accumulated long-term efficacy and safety data across the full age spectrum. In adolescents, 52-week open-label data showed EASI reductions of −85% ± 12% (2 mg/kg) and −84% ± 20% (4 mg/kg) from baseline, with nasopharyngitis and AD exacerbation as the most common treatment-emergent adverse events. In children aged 6 months to 5 years, a phase 3 open-label extension demonstrated that 96.6%, 79.3%, and 58.6% of patients achieved at least 50%, 75%, or 90% EASI improvement, respectively, by week 52, with 36.2% reaching IGA 0/1. Tralokinumab, an IL-13 inhibitor, has added further depth to the biologic class: pooled data from ECZTRA 1 and 2 (n = 1,596) showed progressive improvement through week 52, with EASI-75 rates rising from 37.6% to 61.8% and EASI-90 from 20.4% to 37.3% across all patients initiated on tralokinumab. Real-world data from a single-center retrospective study of 37 adults corroborated these findings, with 93% (28/30) achieving IGA 0/1 at 1 year and no adverse events reported through follow-up.

Oral JAK inhibitors — upadacitinib and abrocitinib — have emerged as high-efficacy options, particularly for severe and difficult-to-treat disease. A post hoc analysis of the phase 3 JADE COMPARE trial demonstrated that abrocitinib 200 mg achieved significantly greater IGA 0/1, EASI-75, and EASI-90 responses versus placebo (nominal p < 0.05) across all severe and/or difficult-to-treat subgroups, with time to PP-NRS4 response of 4.5–6.0 days — shorter than dupilumab (8.0–11.0 days). An open-label extension of the Heads Up trial further showed that patients switching from dupilumab to upadacitinib 30 mg experienced incremental clinical improvements within 4 weeks, including those who had not achieved adequate responses on dupilumab. However, the comparative safety profile of oral JAKi warrants careful consideration: a propensity score–matched cohort study of 938 patients per arm found significantly higher risks of herpes simplex (HR = 1.64, 95% CI = 1.03–2.61), herpes zoster (HR = 2.51, 95% CI = 1.14–5.52), acne (HR = 2.09, 95% CI = 1.54–2.84), neutropenia (HR = 4.02, 95% CI = 1.91–8.47), and hyperlipidemia (HR = 1.45, 95% CI = 1.09–1.92) with oral JAKi versus dupilumab. FAERS-based disproportionality analyses have further identified novel signals — including sepsis, appendicitis, and septic shock — for both upadacitinib and abrocitinib, underscoring the need for continued long-term pharmacovigilance as these agents assume a larger role in the treatment algorithm.

Rezpeg's Sustained AD Efficacy: A New Chapter for IL-2 in Autoimmunity

The recent data from Nektar Therapeutics on rezpegaldesleukin (rezpeg) in atopic dermatitis (AD) marks a significant moment for a novel therapeutic approach. The Phase IIb REZOLVE-AD study demonstrated sustained disease control over 52 weeks, with a meaningful proportion of patients achieving substantial improvements in eczema severity and itch, alongside a favorable safety profile. This sustained efficacy is particularly crucial for a chronic, debilitating condition like AD, where long-term management is paramount.

Rezpeg operates through a distinct mechanism as a regulatory T cell (Treg) pathway agonist, leveraging low-dose interleukin-2 (IL-2) to promote Treg expansion and restore immune tolerance. This stands apart from many existing biologics that primarily target type 2 inflammation. In a competitive landscape, where agents like dupilumab have established strong efficacy and long-term safety, rezpeg's unique mechanism could offer a differentiated option, especially for patients who may not respond optimally to current therapies.

The company's decision to advance rezpeg into Phase III for both AD and alopecia areata (AA) is strategically sound. Research indicates a clear association between AD and AA, and IL-2 therapy has shown promise across various autoimmune diseases. This dual indication strategy could broaden rezpeg's market potential and capitalize on its foundational immune-modulating properties.

However, the path forward is not without its challenges. While Phase IIb data are encouraging, a network meta-analysis of AD biologics highlighted that evidence for emerging therapies like rezpeg is currently limited to smaller trials, leading to lower certainty in comparative efficacy rankings. The upcoming Phase III program will be critical to validate these sustained benefits in a larger, more diverse patient population and to generate the extensive long-term safety data necessary for a chronic treatment. Successfully navigating these trials and demonstrating clear differentiation will be key to rezpeg's potential to reshape treatment paradigms in AD and AA.