First-in-Class Oral PKM2 Modulator Shows Early Efficacy in Atopic Dermatitis

Sitryx Therapeutics announced positive topline results from a Phase 1b trial of SYX-5219, a first-in-class oral pyruvate kinase M2 (PKM2) modulator, in adults with moderate to severe atopic dermatitis (AD). The investigational therapy demonstrated improvements over placebo across measures of skin disease severity and itch after 6 weeks of treatment, according to the company.¹

The randomized, double-blind, placebo-controlled trial included 35 adults with moderate to severe AD at sites in the United States and Europe. Participants were randomized 2:1 to receive SYX-5219 or placebo for 6 weeks, followed by a 14-day off-treatment follow-up period.

According to Sitryx, SYX-5219 was safe and well tolerated during the 6-week treatment period, with pharmacokinetic and target-engagement findings consistent with observations from earlier studies in healthy volunteers.¹

Improvements in Disease Severity and Itch

Differences between SYX-5219 and placebo were observed across clinical end points beginning at day 8, with separation increasing throughout treatment.

At 6 weeks, the placebo-adjusted change in total Eczema Area and Severity Index (EASI) score was approximately 28%. The difference in Peak Pruritus Numerical Rating Scale (PP-NRS) itch score compared with placebo was approximately 48%.

Investigators also observed an increasing number of patients achieving at least a 1-point improvement in validated Investigator Global Assessment (vIGA) over time.

The findings represent early proof of concept for targeting PKM2, an enzyme involved in cellular metabolism, as a potential therapeutic approach in inflammatory skin disease.

“The improvements in skin disease severity and itch address two of the most important burdens for people living with atopic dermatitis,” Ravi Rao, head of R&D and chief medical officer of Sitryx, said in a statement.¹

Targeting Immune Cell Metabolism

Unlike therapies directed at an individual inflammatory cytokine or signaling pathway, SYX-5219 is being developed to alter immune cell metabolism through modulation of PKM2.

PKM2 plays a role in regulating cellular metabolism, and modulation of the enzyme may alter the activity of T lymphocytes and other inflammatory cells. Sitryx is investigating whether this approach can produce broader immunomodulatory effects while supporting restoration of immune balance and skin barrier function.

Earlier clinical development of SYX-5219 included a Phase 1a program in healthy volunteers. Sitryx previously reported pharmacokinetic, pharmacodynamic, and immunomodulatory findings from that program before advancing the therapy into patients with AD.²

“We have provided the first human validation for a differentiated oral therapy, demonstrating activity across multiple clinical endpoints and biomarkers in patients with atopic dermatitis,” Iain Kilty, chief executive officer of Sitryx, said in a statement.¹

Biomarker Changes Correlate With Clinical Activity

The Phase 1b trial also evaluated biomarkers associated with atopic disease.

Reductions in several AD-related biomarkers, including CCL-17/TARC and CCL-11/eotaxin, significantly correlated with improvements in disease activity, according to the company. Exploratory analyses also showed decreases in serum interleukin-13 (IL-13) and immunoglobulin E (IgE).

Larger biomarker decreases were observed among patients with comorbid asthma, a finding Sitryx said could support further investigation of PKM2 modulation in asthma and other inflammatory diseases.

The combination of target engagement, clinician-assessed skin improvement, patient-reported itch improvement, and biomarker changes provides preliminary clinical support for PKM2 modulation as an approach to inflammatory disease. However, the findings come from a small, early-stage trial, and larger and longer studies will be needed to characterize the therapy's efficacy, durability, and safety.

“Despite advances in treatment, many people with atopic dermatitis still need alternative options to achieve better control of their disease,” Alan Irvine, MD, DSc, professor of dermatology at Trinity College Dublin, president of the International Eczema Council, and principal investigator of the trial, said in a statement. “There is a particular need for effective, safe oral therapies and treatments that act through new biological pathways, broadening the choices available to patients and clinicians.”¹

Phase 2 Planned for 2027

Sitryx is finalizing the design of a Phase 2 trial evaluating SYX-5219 in adults with moderate to severe AD, with initiation expected in the first half of 2027.

The company also plans to evaluate SYX-5219 in additional autoimmune and inflammatory diseases. Full results from the Phase 1b study are expected to be presented at a forthcoming scientific congress and submitted for peer-reviewed publication.¹

If subsequent trials confirm the Phase 1b findings, SYX-5219 could represent a mechanistically distinct addition to the growing range of systemic treatments being investigated for moderate to severe AD. For now, the results provide early clinical evidence supporting PKM2 and immune cell metabolism as potential therapeutic targets in inflammatory skin disease.

References

1. Sitryx Therapeutics. Sitryx reports positive Phase 1b results for first-in-class oral PKM2 modulator SYX-5219 in patients with moderate to severe atopic dermatitis. Published October 13, 2026. Accessed October 13, 2026.
2. Sitryx Therapeutics. First-in-class oral PKM2 modulator SYX-5219 Phase 1a trial data to be presented at SID 2026. Published May 13, 2026. Accessed October 13, 2026.