Rezpegaldesleukin

iStock, Anzhelika Poltavets Despite falling short of its primary Phase II objective, Nektar plans to push its T cell stimulator rezpeg into Phase III development. Nektar Therapeutics’ investigational IL-2 agonist rezpegaldesleukin was unable to significantly ease disease severity in a mid-stage study of patients with alopecia areata. The Phase II failure seems not to have deterred the California-based company, however, which in its Tuesday news release insisted that rezpegaldesleukin, or rezpeg, achieved its “target product profile” and said the asset will move forward to late-stage development next year. Nektar’s confidence appears to come from what it claims are enrollment issues, which in turn led to rezpeg’s miss. Specifically, the biotech said that four patients were enrolled in the Phase IIb REZOLVE-AA study despite having “major study eligibility violations that should have disqualified them.” Nektar did not specify what these disqualifying issues were. Still, the company noted that removing these patients from the analysis would result in the trial’s success. In a note to investors on Tuesday, analysts at William Blair were also bullish on rezpeg’s potential in this indication. “We believe rezpegaldesleukin exhibits clinical activity in alopecia areata, despite missing statistical significance on the primary endpoint,” they wrote, likewise alluding to potential improvements in efficacy over the long term. “Since there is not a noticeable plateau, it is conceivable that the proportion of patients achieving less than 20% hair loss could increase with longer follow-up,” the analysts continued. Shares of Nektar dipped 7% to $49.16 at market close Tuesday. In the overall analysis, REZOLVE-AA found that a 24-µg/kg dose of rezpeg treatment decreased mean scores on the Severity of Alopecia Tool (SALT) by 28.2% at 36 weeks, while an 18-µg/kg dose led to a 30.3% drop. Placebo comparators, on the other hand, saw an 11.2% reduction in SALT scores over the same time period. The treatment effects of both dose strengths were not statistically significant. Excluding the four problematic patients, however, was enough to push rezpeg past the statistical bar. The higher- and lower-dose arms saw a 29.6% and 30.4% SALT drop, respectively, while placebo scores decreased by 5.7%. P-values for the respective rezpeg arms were 0.049 and 0.042. Still, the William Blair analysts conceded that “rezpeg’s efficacy is not competitive with low-dose JAK inhibitors.” Even when excluding the four patients with problematic enrollment, the placebo-corrected percentage of participants achieving SALT scores below 20 ranged from 8.1% to 8.9%, the firm explained, which “is lower than management’s expectations of about 15%.” Nektar plans to present full REZOLVE-AA findings at a medical conference next year, while data from the ongoing 16-week extension phase will come in during the second quarter of 2026 .

Nektar Therapeutics blamed the missed endpoint on four patients who were enrolled in the trial in error, all of whom “did not meet major study eligibility criteria at baseline.” \n Nektar Therapeutics is planning to bring its interleukin-2-targeting drug candidate into a phase 3 trial for severe alopecia areata, even after the asset narrowly missed the main goal of a midstage trial.The biotech said the miss occurred because four of the patients were enrolled erroneously, all of whom “did not meet major study eligibility criteria at baseline,” according to a Dec. 16 company release.When those patients were excluded, Nektar’s candidate rezpegaldesleukin did meet the study’s goal, significantly reducing the severity of scalp hair loss by about 30% compared to 6% for placebo, the biotech said.“These four cases were adjudicated by three medical monitors that were blinded to this study, who all determined in unison that these four patients should never have been enrolled to the trial,” Mary Tagliaferri, M.D., Nektar’s chief medical officer, said in a Dec. 16 conference call about the results. “We then did this analysis and clearly demonstrated a very clear efficacy meeting our target product profile.”The phase 2 Rezolve AA trial enrolled a total of 92 patients, including the four who were later excluded, and randomized them to receive 18 milligrams per kilogram of rezpeg, 24 mg per kg of rezpeg or placebo. One of the inappropriately enrolled patients was in the placebo arm and had been diagnosed with alopecia areata less than six months before entering the study, a period when the autoimmune disease is usually unstable.“When patients don\'t have stable disease, you can have a higher placebo rate” and spontaneous regrowth of hair, David Rosmarin, M.D., a dermatologist at the Indiana University School of Medicine, said on the conference call. Excluding such patients “is routine in all alopecia areata studies” to ensure that hair regrowth seen in the trial is being caused by treatment.In a larger phase 3 trial, Rosmarin added, a patient with an abnormally large placebo effect “would be a blip on the screen.”Analysts from William Blair agreed that rezpeg “exhibits clinical activity in alopecia areata,” according to a Dec. 16 note, while adding the efficacy seen so far is lower than that seen in low-dose JAK inhibitors, three of which are approved for severe alopecia areata.However, Rosmarin and two other dermatologists on the call noted that patients can be uncomfortable with JAK inhibitors due to their black box warnings and requirements for consistent monitoring.“There are a lot of dermatologists and patients who are scared to use JAK inhibitors,” Jonathan Silverberg, M.D., Ph.D., a dermatologist at the George Washington University School of Medicine and Health Sciences, said on the call. “The field sorely needs a clean biologic without the laboratory monitoring or boxed warnings.” Rezpeg commonly caused injection-site reactions like redness or swelling, 87% of which were mild and none of which led to a discontinuation, Nektar CMO Tagliaferri said during the call. One patient who received rezpeg discontinued treatment due to an adverse event, and, overall, rezpeg led to no increased risk of major cardiovascular events, thrombosis, acne or oral herpes, she added.Rezpeg is designed to target interleukin-2 receptors in order to boost the activity of regulatory T cells (Tregs), a rare population of immune cells that calm the self-destructive immune response typical of autoimmune diseases like alopecia. The discoverers of Tregs were awarded the Nobel Prize in Physiology or Medicine this October, and numerous biotechs are striving to turn the potent cells into new therapies.Nektar is also testing rezpeg in phase 2 trials in atopic dermatitis and Type 1 diabetes. The biotech announced in June that the molecule had notched a win in the atopic dermatitis trial, though with lower efficacy than Regeneron and Sanofi’s blockbuster Dupixent.Rezpeg has a dramatic history—it used to be part of a collaboration with Eli Lilly before the pharma handed it back to Nektar in 2023 after growing unimpressed with the candidate’s efficacy. However, Nektar accused the drugmaker of botching its analysis of the phase 1b data from patients with atopic dermatitis and psoriasis in a manner that misrepresented rezpeg’s potential.Nektar chose to sue Lilly in August 2023, and Lilly countersued in March 2024. As of now, the case is still making its way through the district court of Northern California.