Rezpegaldesleukin: Nektar Therapeutics' Treg Agonist and Its Potential to Redefine Immuno-Oncology Paradigms

Nektar Therapeutics' rezpegaldesleukin, a first-in-class regulatory T-cell (Treg) agonist, has emerged as a transformative candidate in the treatment of autoimmune and inflammatory diseases, with recent late-breaker data from the REZOLVE-AD Phase 2b trial at EADV 2025 underscoring its potential to redefine therapeutic paradigms—not only in dermatology but also in immuno-oncology. By selectively stimulating Tregs to restore immune homeostasis, rezpegaldesleukin offers a novel mechanism that diverges from traditional inflammatory pathway blockers, positioning Nektar at the forefront of a paradigm shift in immune modulationNektar Announces REZOLVE-AD Phase 2b Results for Rezpegaldesleukin^[1].

Clinical Validation and Therapeutic Differentiation

The REZOLVE-AD trial, which enrolled 393 patients with moderate-to-severe atopic dermatitis, demonstrated statistically significant improvements in primary and key secondary endpoints. At week 16, the high-dose regimen (24 µg/kg every two weeks) achieved a 61% mean improvement in Eczema Area and Severity Index (EASI) scores compared to 31% in the placebo groupNektar Presents New Data from REZOLVE-AD Phase 2b Study for Rezpegaldesleukin in Late-Breaker Oral Presentation at EADV 2025^[2]. Notably, patients who transitioned from placebo to high-dose rezpegaldesleukin during the open-label extension phase showed a deepening of clinical responses, with EASI-75 (≥75% reduction in EASI) increasing from 50% to 62% and vIGA-AD 0/1 responses rising from 28% to 38% over 24 weeksNektar’s Rezpegaldesleukin Delivers Sustained Improvement for Atopic Dermatitis—Phase 2b Results Highlight Deepening Patient Response Over Time^[3]. These results highlight the durability of Treg-mediated immune modulation and suggest that rezpegaldesleukin could address unmet needs in chronic inflammatory conditions where long-term symptom control is critical.

The drug's safety profile further strengthens its therapeutic differentiation. Treatment-emergent adverse events (TEAEs) were predominantly mild to moderate, with no significant increase in infections or autoimmune-related complications compared to placeboREZOLVE-AD Phase 2b Study of Rezpegaldesleukin Meets Primary and Key Secondary Endpoints in Atopic Dermatitis^[4]. This contrasts with existing biologics, which often carry risks of opportunistic infections or immune-related adverse events. For instance, IL-17 or IL-23 inhibitors, while effective in psoriasis and atopic dermatitis, are associated with higher rates of fungal infections and inflammatory bowel disease exacerbationsData from [], “Safety and Efficacy of IL-17 and IL-23 Inhibitors in Atopic Dermatitis.”^[5]. Rezpegaldesleukin's mechanism—targeting Tregs to suppress Th1, Th2, and Th17 pathways—appears to mitigate these risks while achieving broad anti-inflammatory effectsThe regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin induces long-lived antigen-specific immune tolerance^[6].

Mechanistic Innovation and Immuno-Oncology Implications

Rezpegaldesleukin's mechanism of action—selective Treg activation—has broader implications for immuno-oncology. Regulatory T cells play a dual role in cancer: they suppress anti-tumor immunity in the tumor microenvironment but also prevent autoimmune toxicity in immune checkpoint inhibitors (ICIs). By modulating Tregs, rezpegaldesleukin could potentially enhance the efficacy of ICIs while reducing immune-related adverse events (irAEs), a major limitation of current therapiesAs stated by [], “Regulatory T cells (Tregs) suppress immune responses, including anti-tumor immunity.”^[7].

Preclinical data supports this hypothesis. In mouse models, rezpegaldesleukin induced antigen-specific immune tolerance, reducing delayed-type hypersensitivity (DTH) reactions and demonstrating durable effects beyond the treatment period. While Nektar has not yet initiated oncology-specific trials for rezpegaldesleukin, its broader pipeline includes NKTR-255, an IL-15 receptor agonist designed to activate natural killer (NK) cells and CD8+ T cells for cancer immunotherapyNektar to Announce Top-line Data from the 16-Week Induction Period in REZOLVE-AD Phase 2b Study of Rezpegaldesleukin^[9]. This suggests that Nektar's Treg platform could be integrated with other immune-stimulatory agents to create synergistic combinations, addressing both tumor evasion and immune toxicity.

Market Positioning and Investor Value

Nektar's strategic focus on Treg modulation positions it to capitalize on the $15 billion global atopic dermatitis market, where current therapies face challenges in long-term efficacy and safetyMarket data from [], “Global Atopic Dermatitis Market Report.”^[10]. Rezpegaldesleukin's Fast Track designation for atopic dermatitis and severe alopecia areata, coupled with its potential in type 1 diabetes via a partnership with TrialNet, further diversifies its revenue streamsHow Nektar's Rezpegaldesleukin Could Redefine Treatment for Autoimmune Disorders^[11]. For investors, the drug's first-in-class status and differentiated mechanism represent a high-conviction opportunity, particularly as Nektar advances to Phase 3 trials and explores oncology applications.

However, risks remain. The transition from dermatology to oncology will require additional preclinical and clinical validation, and competition in the Treg space is intensifying, with companies like Bristol Myers Squibb and Merck KGaA investing in similar pathways. That said, Nektar's early mover advantage, robust Phase 2b data, and clear differentiation in safety and durability provide a strong foundation for long-term value creation.

Conclusion

Rezpegaldesleukin's success in the REZOLVE-AD trial marks a pivotal moment for Nektar Therapeutics and the broader field of immune modulation. By demonstrating the feasibility of Treg-targeted therapies in dermatology, the drug paves the way for redefining oncology treatment paradigms—where balancing anti-tumor immunity with immune tolerance remains a critical challenge. For investors, the combination of clinical validation, mechanistic innovation, and strategic pipeline expansion positions rezpegaldesleukin as a key driver of Nektar's growth in the coming decade.