8-K: Nektar Therapeutics' Novel Atopic Dermatitis Drug Achieves All Primary and Key Secondary Endpoints in Phase 2b Trial

Nektar Therapeutics today announced statistically significant positive topline results from its Phase 2b REZOLVE-AD clinical trial for rezpegaldesleukin in moderate-to-severe atopic dermatitis, validating its novel T-regulatory cell mechanism.

Summary

• Nektar Therapeutics reported positive topline results from its global Phase 2b REZOLVE-AD clinical trial for rezpegaldesleukin in 393 patients with moderate-to-severe atopic dermatitis.
• The trial met its primary endpoint, demonstrating a statistically significant mean improvement in Eczema Area and Severity Score (EASI) from baseline at week 16 for all three rezpegaldesleukin dose arms (24 g/kg q2w, 18 g/kg q2w, and 24 g/kg q4w) compared to placebo (p<0.001).
• All three dose arms also achieved statistical significance at week 16 for key secondary endpoints including EASI-75 (75% reduction in EASI), EASI-50 (50% reduction in EASI), and mean percent improvement in Body Surface Area (BSA) score.
• The high (24 g/kg q2w) and middle (18 g/kg q2w) dose arms achieved statistical significance for vIGA-AD 0/1 (validated Investigators Global Assessment for Atopic Dermatitis) and Itch Numerical Rating Score (NRS) reductions.
• The high dose (24 g/kg q2w) additionally achieved statistical significance on EASI-90 (90% reduction in EASI).
• Similar efficacy responses were observed in both severe (baseline vIGA-AD of 4) and moderate (baseline vIGA-AD of 3) patients.
• Translational blood biomarker data showed robust on-target and dose-dependent pharmacological activity, with up to a 6-fold increase in total Tregs in the high dose arm, correlated with reductions in key T helper 2 (Th2) inflammatory markers (IL-19, TARC/CCL17, periostin, and MDC/CCL22).
• The safety profile over the 16-week induction period was consistent with previously reported results, with local injection site reactions (ISRs) being the most common treatment-emergent adverse events (69.7% of treated patients), predominantly mild or moderate (99.6%), and leading to discontinuation in less than 1% of patients.
• No increased risk of conjunctivitis, oral ulcers, or infections, including oral herpes, was observed in the rezpegaldesleukin arms.

Sentiment

Score: 8

Explanation: The clinical trial results for rezpegaldesleukin in atopic dermatitis are highly positive, meeting all primary and multiple key secondary endpoints with statistical significance. The drug's novel T-regulatory cell mechanism is validated, showing robust pharmacological activity and a consistent safety profile. This strong data supports advancement to Phase 3 and positions the drug favorably in a large market with unmet needs, indicating significant potential for the company.

Positives

• The trial met its primary endpoint of mean improvement in EASI score from baseline at week 16 for all three rezpegaldesleukin dose arms versus placebo (p<0.001).
• All three dose arms achieved statistical significance for key secondary endpoints: EASI-75, EASI-50, and mean percent improvement in Body Surface Area (BSA) score.
• The high (24 g/kg q2w) and middle (18 g/kg q2w) dose arms achieved statistical significance for vIGA-AD 0/1 and Itch NRS (≥4-point reduction).
• The high dose (24 g/kg q2w) achieved statistical significance on EASI-90.
• Rapid onset of EASI reduction and magnitude of itch improvement were observed, showing potential differentiation.
• Similar efficacy responses were observed in severe patients (baseline vIGA-AD of 4) as in moderate patients (baseline vIGA-AD of 3).
• Robust on-target and dose-dependent pharmacological activity was demonstrated, with up to a 6-fold increase in total Tregs in the high dose arm.
• Reduction of key T helper 2 (Th2) inflammatory markers (IL-19, TARC/CCL17, periostin, and MDC/CCL22) was observed, validating the mechanism.
• The safety profile was consistent with previously reported results, with no new safety concerns identified.
• The most common adverse events, injection site reactions (ISRs), were largely mild or moderate (99.6%) and self-resolving, with a very low discontinuation rate (<1%) due to ISRs.
• There was no increased risk of conjunctivitis, oral ulcers, or infections, including oral herpes, in the rezpegaldesleukin arms.

Negatives

• Injection site reactions (ISRs) were common, observed in 69.7% of all rezpegaldesleukin-treated patients, although mostly mild or moderate.
• The low dose (24 g/kg q4w) did not achieve statistical significance for vIGA-AD 0/1, EASI-90, or Itch NRS.
• Other treatment-emergent adverse events (TEAEs) more commonly observed (>5%) in the study treatment arms (n=320) versus placebo (n=73) included eosinophilia (7.8% vs. 2.7%), pyrexia (6.3% vs 2.7%), headache (6.3% vs. 4.1%), and arthralgia (5.0% vs 1.4%).

Risks

• Statements regarding the therapeutic potential of rezpegaldesleukin are based on preclinical and clinical findings and observations and are subject to change as research and development continue.
• Rezpegaldesleukin is an investigational agent, and its continued research and development are subject to substantial risks, including negative safety and efficacy findings in future clinical studies, despite positive earlier findings.
• Rezpegaldesleukin is in clinical development, and the risk of failure is high and can unexpectedly occur at any stage prior to regulatory approval.
• The timing of the commencement or end of clinical trials and the availability of clinical data may be delayed or unsuccessful due to regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, changing standards of care, evolving regulatory requirements, clinical trial design, clinical outcomes, competitive factors, or delay or failure in ultimately obtaining regulatory approval in one or more important markets.
• A Fast Track designation does not increase the likelihood that rezpegaldesleukin will receive marketing approval in the United States.
• Patents may not issue from the Company's patent applications for its drug candidates, patents that have issued may not be enforceable, or additional intellectual property licenses from third parties may be required.
• Certain other risk factors are described in the Risk Factors and Management's Discussion and Analysis of Financial Condition and Results of Operations sections of the Company's most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q, and any other future SEC filings.

Future Outlook

Nektar Therapeutics plans to submit the 16-week induction results from the REZOLVE-AD trial for presentation at a medical conference later in 2025. The company expects to report full 52-week data from the REZOLVE-AD trial in early 2026 and 52-week off-study treatment durability data in early 2027. Top-line Phase 2b data for rezpegaldesleukin in alopecia areata are anticipated in the fourth quarter of 2025 (December 2025). The company also plans an End of Phase 2 Meeting with the FDA to discuss the Phase 3 development plan for rezpegaldesleukin in atopic dermatitis. Beyond atopic dermatitis and alopecia areata, Nektar sees potential for expansion into vitiligo and other skin-related immune conditions, with a Phase 2 study for Type 1 diabetes starting in 2025, and a second T regulatory cell mechanism (TNFR2 agonist antibody) planned to enter the clinic in 2026, with potential for development in Crohn's Disease, UC, and MS.

Management Comments

• Prof. Jonathan Silverberg, MD, PhD, MPH, Professor of Dermatology at George Washington University School of Medicine and Health Sciences, stated: "These data from REZOLVE-AD show a fast onset of both EASI response and itch relief within the first few doses of rezpegaldesleukin treatment, which are important metrics for physicians as they assess treatment options in atopic dermatitis. This shows the advantage of a broad-based Treg mechanism over other immune-modulation approaches in development to treat the disease. Additionally, we don't see any increased risk of incidence of conjunctivitis, oral herpes, or oral ulcers with this mechanism of action as we do with other mechanisms."
• Prof. David Rosmarin M.D., Chair, Department of Dermatology and Associate Professor of Dermatology, Indiana University School of Medicine, commented: "These REZOLVE-AD results present a new therapeutic hypothesis for treatment of dermatological diseases and the investigators are looking forward to rezpegaldesleukin advancing in development in atopic dermatitis. With the establishment of this efficacy profile in the dermatological setting of atopic dermatitis, we are also eager to see the upcoming results from the ongoing REZOLVE-AA study in patients with severe to very-severe alopecia areata."
• Howard W. Robin, President and CEO of Nektar Therapeutics, said: "We believe that the REZOLVE-AD study results clearly demonstrate that Nektar has established a new biology and harnessed the promise of Tregs as an important potential therapeutic modality to treat inflammatory skin disorders and other autoimmune conditions. These compelling efficacy findings are further boosted by the translational data that show, for the first time, that rezpegaldesleukin also reduced key markers of Th2 inflammation in atopic dermatitis. With this validation in atopic dermatitis, we also look forward to reporting results in the fourth quarter of this year for rezpegaldesleukin in alopecia areata."

Industry Context

Atopic dermatitis (AD) is a widespread chronic autoimmune condition affecting approximately 30 million people in the United States and 220 million globally, with a significant portion suffering from moderate-to-severe disease. Despite the market leader, Dupixent, exceeding $10.5 billion in annual sales, there remains a high unmet need for new therapies, particularly those offering a potential for remittive effect, as about 50% of patients fail on existing treatments. Rezpegaldesleukin, with its novel T-regulatory cell (Treg) mechanism, aims to address this by restoring immune system balance, differentiating it from other immune-modulation approaches. This mechanism, which enhances Treg numbers and reduces proinflammatory cytokines, offers a new therapeutic hypothesis for inflammatory skin disorders and other autoimmune conditions, potentially providing a first-in-class treatment option in a large and underserved market.

Comparison to Industry Standards

• **EASI LS Mean % reduction from baseline (Placebo)**: Rezpegaldesleukin's q2w arms (61% for 24 g/kg q2w, 58% for 18 g/kg q2w) are comparable to Amlitelimab (58%/61%) and Rocatinlimab (62%), but lower than Dupilumab (68%), Tralokinumab (72%), and Lebrikizumab (69%).
• **EASI-75 (Placebo)**: Rezpegaldesleukin's q2w arms (42% for 24 g/kg q2w, 46% for 18 g/kg q2w) are comparable to Amlitelimab (40%) and Rocatinlimab (44%/40%), but lower than Dupilumab (52%), Lebrikizumab (48%), and Nemolizumab (46%).
• **vIGA-AD Responders (0/1) (Placebo)**: Rezpegaldesleukin's q2w arms (20% for 24 g/kg q2w, 26% for 18 g/kg q2w) are comparable to Rocatinlimab (19%/15%) and Amlitelimab (22%), but lower than Dupilumab (30%), Lebrikizumab (45%), and Nemolizumab (37%).
• **EASI-90 (Placebo)**: Rezpegaldesleukin's high dose (25% for 24 g/kg q2w) is comparable to Dupilumab (28%) and Lebrikizumab (30%), and higher than Tralokinumab (15%), Nemolizumab (16%), Rocatinlimab (19%/12%), and Amlitelimab (18%).
• **Itch NRS ≥4 pt Responders (Placebo)**: Rezpegaldesleukin's high dose (42% for 24 g/kg q2w) is comparable to Dupilumab (41%) and Rocatinlimab (37%/46%), but lower than Lebrikizumab (67%).
• Overall, rezpegaldesleukin's q2w arms demonstrate similar efficacy responses to the OX40/OX40L class (Rocatinlimab and Amlitelimab) across key endpoints like EASI-75 and vIGA-AD 0/1 at Week 16, positioning it competitively within the novel immune-modulator landscape.

Stakeholder Impact

• **Shareholders**: The positive clinical trial results are highly likely to increase investor confidence and potentially lead to a significant positive impact on the company's share price, indicating strong progress in its lead drug candidate.
• **Patients (Atopic Dermatitis)**: The announcement offers a new, potentially first-in-class therapeutic option for moderate-to-severe atopic dermatitis, addressing a high unmet medical need with a novel mechanism of action, rapid onset of effect, and a favorable safety profile.
• **Healthcare Providers**: The data presents a new therapeutic hypothesis and a differentiated treatment approach for atopic dermatitis, providing physicians with a promising new tool for managing the disease.
• **Employees**: Positive clinical trial outcomes can boost employee morale, validate their work, and potentially lead to further investment in research and development, securing future opportunities within the company.
• **Competitors**: The successful validation of a novel Treg-based mechanism could intensify competition in the atopic dermatitis market and influence future drug development strategies by other pharmaceutical companies.

Next Steps

• Nektar management will host a conference call and live webcast on June 24, 2025, to review the results.
• The Company plans to submit the REZOLVE-AD 16-week induction results for presentation at a medical conference later in 2025.
• An End of Phase 2 Meeting with the FDA is planned to review the Phase 3 development plan for rezpegaldesleukin in atopic dermatitis.
• Top-line Phase 2b data for rezpegaldesleukin in alopecia areata are expected in the fourth quarter of 2025 (December 2025).
• Full 52-week data from the REZOLVE-AD trial are expected in early 2026.
• 52-week off-study treatment durability data from the REZOLVE-AD trial are expected in early 2027.
• Phase 2 study for rezpegaldesleukin in Type 1 diabetes is starting in 2025.
• A second T Regulatory Cell Mechanism (TNFR2 agonist antibody) is planned to enter the clinic in 2026 (IND).

Key Dates

Recommendation

Keywords

Nektar Therapeutics, NKTR, rezpegaldesleukin, REZPEG, atopic dermatitis, eczema, clinical trial, Phase 2b, REZOLVE-AD, immunology, regulatory T-cells, Tregs, IL-2 pathway agonist, EASI, vIGA-AD, Itch NRS, BSA, biomarkers, Th2 inflammation, alopecia areata, biotechnology, drug development, dermatology