Nektar Launches Phase 3 ZENITH AD Program for First-in-Class T-Reg Biologic Rezpegaldesleukin in Moderate-to-Severe Atopic Dermatitis
核心洞察
Nektar Therapeutics has initiated the first two global registrational trials in the Phase 3 ZENITH AD program evaluating rezpegaldesleukin, a first-in-class regulatory T-cell biologic, in patients aged 12 and older with moderate-to-severe atopic dermatitis (搜索).
The program includes three 510-patient randomized, double-blind, placebo-controlled trials, with ZENITH AD-3 enrolling treatment-experienced patients beginning in September 2026.
Initial Phase 3 topline data are expected in mid-2028, with a Biologics License Application submission targeted for 2029.
Nektar Therapeutics (Nasdaq: NKTR) has announced the initiation of the first two global registrational trials in the Phase 3 ZENITH AD program for rezpegaldesleukin, a first-in-class regulatory T-cell (T-reg) biologic, in patients 12 years of age and older with moderate-to-severe atopic dermatitis (搜索). The program includes three global, randomized, double-blind, placebo-controlled trials designed to support both U.S. and European registration.
"Initiating our Phase 3 program in atopic dermatitis (搜索) takes us one step closer to bringing this important regulatory T-cell-targeted mechanism to patients," said Howard W. Robin, President and Chief Executive Officer of Nektar Therapeutics. "We designed a robust registrational program in atopic dermatitis from our compelling Phase 2b data, and we expect initial data from ZENITH AD in mid-2028."
ZENITH AD Program Design and Endpoints
The ZENITH AD global registrational program is targeting enrollment of a total of 1,530 patients with moderate-to-severe atopic dermatitis (搜索) across North America, Europe, and Asia-Pacific. The first two trials, ZENITH AD-1 and ZENITH AD-2, will enroll biologic and systemic JAK inhibitor treatment-naive patients, while ZENITH AD-3, set to begin in September 2026, will enroll patients with prior systemic biologic and/or JAK inhibitor treatment experience. Each of the three pivotal studies will enroll 510 patients.
Each trial includes a 24-week blinded induction period in which patients are randomized 2:1 to receive rezpegaldesleukin 24 micrograms per kilogram or placebo administered subcutaneously every two weeks. Patients who achieve an EASI-75 (Eczema Area and Severity Index 75) and/or IGA 0/1 (Investigator's Global Assessment of Atopic Dermatitis (搜索) of 0 or 1) response at Week 24 advance to a 28-week blinded maintenance period and are re-randomized 2:2:1 to monthly dosing, quarterly dosing, or placebo. Patients not meeting the threshold enter an open-label treatment escape arm.
The primary endpoint of the ZENITH AD studies is IGA 0/1 response at Week 24, with EASI-75 response at Week 24 as a key secondary endpoint. For registration in jurisdictions outside the U.S., the co-primary endpoints are IGA 0/1 response and EASI-75 response at Week 24. Other key secondary endpoints include EASI-90 and Itch Numeric Rating Scale (NRS), with a 4-point or greater reduction from baseline, along with several patient-reported outcomes.
Phase 2b Data Supporting the Registrational Program
The Phase 3 program is based on clinically meaningful efficacy and favorable safety data observed in a 393-patient Phase 2b study. Notably, the study demonstrated an up to five-fold increase in EASI-100 between 16 and 52 weeks with monthly and quarterly maintenance dosing, suggesting deepening disease control over time.
"Many patients on currently available therapies for atopic dermatitis (搜索) fail to achieve adequate disease control or lose response over time, leaving a major unmet need for a more durable treatment option," said Mary A. Tagliaferri, M.D., Chief Medical Officer of Nektar Therapeutics. "By using a novel agonist approach to restore T-reg function upstream of the inflammatory pathways that drive atopic dermatitis, we believe rezpegaldesleukin offers an important differentiated approach to treating this chronic disease."
Dr. Tagliaferri further noted that the Phase 2b data demonstrated rapid and strong-onset EASI-75 and Itch-NRS response, as well as control of asthma symptoms in patients with self-reported comorbid asthma. Given that approximately 25% of patients with moderate-to-severe atopic dermatitis (搜索) have comorbid asthma, the ZENITH AD program includes a prespecified assessment of asthma control through the ACQ-5 (Asthma Control Questionnaire-5) in patients with a history of asthma at baseline.
Mechanism of Action and Regulatory Status
Rezpegaldesleukin targets the interleukin-2 (IL-2) receptor complex to preferentially stimulate the proliferation of regulatory T-cells, thereby restoring immune balance. This mechanism addresses the underlying immune system imbalance in autoimmune and chronic inflammatory conditions, where a failure of the body's self-tolerance mechanisms enables the formation of pathogenic T lymphocytes that attack healthy cells.
In February 2025, the U.S. FDA granted Fast Track designation for rezpegaldesleukin for the treatment of adult and pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis (搜索) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. In July 2025, the FDA granted a second Fast Track designation for rezpegaldesleukin for the treatment of severe alopecia areata (搜索) in adults and pediatric patients 12 years of age and older who weigh at least 40 kg.
Broader Development Pipeline
Beyond atopic dermatitis (搜索), Nektar plans to initiate a single registrational Phase 3 trial in alopecia areata (搜索) in early 2027, based on data from a randomized, placebo-controlled Phase 2b study. Additionally, initial data from a Phase 2 study of rezpegaldesleukin in Type 1 diabetes (搜索) are expected in 2027. The ZENITH AD program and the Phase 3 registrational trial in alopecia areata were designed following completion of End-of-Phase 2 meetings with the FDA and scientific advice from the European Medicines Agency (EMA).
Atopic dermatitis (搜索), the most common type of eczema, affects approximately 30 million people in the United States and is characterized by a defect in the skin barrier that allows allergens and other irritants to enter the skin, leading to an immune reaction and inflammation. Initial Phase 3 topline data from the ZENITH AD program are expected in mid-2028, with a Biologics License Application submission targeted for 2029.