IL-15 Blockade Plus Phototherapy Shows Promise in Vitiligo

Key Takeaways

• Ordesekimab did not meet the primary endpoint at Week 24 but demonstrated significantly greater repigmentation when combined with phototherapy.
• IL-15 blockade depleted cytotoxic CD8+ memory T cells, with this biologic effect correlating with clinical response.
• Findings support a combination approach in vitiligo, targeting immune suppression alongside repigmentation with phototherapy.

Targeting IL-15 with ordesekimab in combination with narrowband ultraviolet B (nbUVB) phototherapy led to greater repigmentation in patients with non-segmental vitiligo, according to results from a randomized, placebo-controlled trial presented by Brett King, MD, PhD, at the American Academy of Dermatology (AAD) 2026 Annual Meeting.

Vitiligo pathogenesis is driven by cytotoxic CD8+ T cells, particularly tissue-resident memory T cells dependent on IL-15 signaling.

“The hypothesis here is that blocking IL-15 will reduce frequencies of hotter reactive CD8+ T resident memory cells in the scan, interrupting the positive feedback loop and possibly allowing for melanocyte recovery,” Dr. King said. 

In the trial (NCT04338581), 60 participants were randomized 2:1 to ordesekimab or placebo for 10 weeks, with the primary endpoint of F-VASI35 at Week 24. The primary endpoint was not met, with 6 of 40 patients in the ordesekimab group and 1 of 19 in the placebo group achieving F-VASI35 (P = .411).

However, after initiation of nbUVB in nonresponders, clinically meaningful differences emerged. At later time points, significantly more patients receiving ordesekimab achieved F-VASI50 at Week 36 and F-VASI75 and T-VASI35 at Week 48 compared with placebo (P < .05).

“Vitiligo treatment is truly a two-step process; you have to suppress inflammation, but you need light to stimulate repigmentation.” 

Phototherapy adherence also influenced outcomes. Patients receiving sufficient nbUVB (≥15 weeks with ≥2 sessions weekly) had higher response rates, with significant differences observed for F-VASI50 and F-VASI75 at Week 48.

Mechanistic analyses supported the clinical findings. Ordesekimab led to durable depletion of cytotoxic CD8+ memory T cells through Week 48, despite dosing only through Week 10.

“Depletion of CD8 T cells was strongly correlated with ordesekimab treatment,” Dr. King said. 

The treatment was well tolerated, with no major safety signals reported.