Rezpegaldesleukin's Early Treg Signal in AD: Emma Guttman-Yassky, MD

More than 50% of adults with atopic dermatitis report inadequately controlled disease despite current biologics targeting type 2 inflammation.¹ Oral JAK inhibitors act on broader pathways but carry a boxed warning many patients and dermatologists prefer to avoid. Rezpegaldesleukin is an IL-2 receptor agonist designed to selectively expand regulatory T cells (Tregs) rather than block a single cytokine axis.

In the phase 2b REZOLVE-AD trial (NCT06136741), rezpegaldesleukin 24 μg/kg every 2 weeks produced statistically significant improvements across primary and secondary endpoints after a 16-week induction phase compared with placebo.² A biomarker sub-study presented as a late-breaking oral at EADV Congress 2026 analyzed 100 patients, 59 on rezpegaldesleukin and 41 on placebo. Blood and lesional tape strips were collected at baseline and at weeks 2 and 4 and evaluated by RNA-seq and Olink proteomics.¹

By week 2, rezpegaldesleukin significantly upregulated Treg and T-cell activation markers, including ICOS, CD3D/E, CTLA4, FOXP3, IL2RA, and IL2RB, versus both baseline and placebo.¹ Week 2 changes in IL-10 (R=-0.621, P<.0001), CCL17 (R=0.524, P<.0001), and TGFB1 (R=-0.573, P<.0001) each predicted week 16 EASI exclusively in the rezpegaldesleukin arm, with no comparable correlations in the placebo arm (all |R|≤0.30, P≥.06).¹

Rezpegaldesleukin also reduced fibrosis-associated transcripts, including POSTN, COL15A1, ELN, COL16A1, COL1A1, and LUM, alongside markers across the Th1, Th2, Th17, and Th22 axes (all P<0.05).¹ Clinically, the mean EASI reduction reached 64.3% at week 16, with 42.4% of patients achieving EASI75 and significant separation from placebo as early as week 2 across EASI-50/75/90, IGA 0/1, and itch outcomes.¹

Emma Guttman-Yassky, MD, PhD, Waldman Professor of Dermatology and Immunology at the Icahn School of Medicine at Mount Sinai, led the biomarker sub-study. In the following interview, Guttman-Yassky discusses how rezpegaldesleukin's regulatory T-cell mechanism differs from existing AD therapies and what the earliest molecular changes revealed.

HCPLive: Despite biologics and JAK inhibitors, why do so many AD patients still have uncontrolled disease?

Emma Guttman-Yassky, MD, PhD: Atopic dermatitis is a heterogeneous disease, and while we have good treatments now, they either target one pathway, like the Th2 pathway, or they're oral JAK inhibitors that act on more pathways. The issue with oral medications, particularly JAK inhibitors, is the black box warning, so many dermatologists and many patients don't want to go there. When we give patients Th2-targeting biologics, we will miss some patients because of the heterogeneity of the disease.

HCPLive: IL-2 can stimulate both regulatory and effector T cells. How is this molecule designed to favor Tregs?

Emma Guttman-Yassky, MD, PhD: It's all about the dosing. The dosing is key here. We did the biomarker study, and interestingly, the biomarkers showed even greater differentiation from placebo, because typically, when you look at the skin, it tells you things earlier than the clinical results, and we saw things much, much earlier. In fact, even at week 2 we saw meaningful data, and based on week 2 biomarkers, we could predict week 16 responses.

HCPLive: Can you expand on what the skin showed at the molecular level within the first 2 weeks?

Emma Guttman-Yassky, MD, PhD: We saw significant modulation of many markers, including Th2 markers. We also saw increases in some Treg markers, and some of these, such as CCL17 and Treg markers like TGF-beta and IL-10, were significantly correlated with the clinical improvement at week 16.

[Fibrosis-associated markers also fell, which] matters because in atopic dermatitis you have hyperplasia, and hyperplasia involves some fibrosis. We also know fibroblasts can produce inflammatory markers and are important. In general, we believe fibrosis is important in atopic dermatitis and in other diseases, so we're excited about the potential of this drug for other indications.

HCPLive: Blood markers at week 2 tracked with EASI at week 16. Do you see potential there for predicting response?

Emma Guttman-Yassky, MD, PhD: Yes, we think that's a very nice feature that we sometimes see, where early responses can predict later responses, and I can see how this could shorten trials in the future and save money.

HCPLive: Is there anything else from the EADV data you think is important to know?

Emma Guttman-Yassky, MD, PhD: Just that, interestingly, when you look at the clinical data, you saw large placebo responses, but when you looked at the biomarker data, you saw much smaller placebo responses. This is the amazing thing about biomarkers: they're objective, and for companies it's important to do this, because it can increase the delta between your drug and placebo and really get that differentiation.

HCPLive: Looking forward, what would you want to learn from phase 3 studies, and does the same biology apply to alopecia?

Emma Guttman-Yassky, MD, PhD: We also looked at pathways relevant to alopecia, and we saw they were modulated. I'm very excited about alopecia and this drug. I'd also like to learn what happens when you stop the drug after a year, or after prolonged use, and see when the disease actually comes back. Maybe it will take some time.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Silverberg JI, Guttman-Yassky E, et al. REZOLVE-AD: 16-week induction results of rezpegaldesleukin in moderate-to-severe atopic dermatitis. Lancet. Published online August 25, 2026. doi:10.1016/S0140-6736(26)01143-8

2. Manson M, Manzo Margiotta F, Del Duca E, et al. Multi-omic profiling identifies early molecular responses to rezpegaldesleukin, a novel regulatory T cell-inducing therapy, in atopic dermatitis [abstract LB-219]. Presented at: EADV Congress 2026; September 30-October 3, 2026; Vienna, Austria.