Daxdilimab Shows Rapid, Significant Improvements in Discoid Lupus in Phase 2 Trial

Daxdilimab demonstrated significant and rapid improvements in disease activity among patients with moderate to severe discoid lupus erythematosus (DLE), according to phase 2 findings presented at the 2026 European Academy of Dermatology and Venereology (EADV) Congress in Vienna, Austria.

The investigational human IgG1 monoclonal antibody targets immunoglobulin-like transcript 7 (ILT7), a cell-surface protein expressed on plasmacytoid dendritic cells (pDCs). Binding to ILT7 results in targeted reductions of pDCs in tissue and blood. These cells are increased in lesional skin in cutaneous lupus erythematosus and are associated with type I interferon biology, making them a potential therapeutic target.

“The main takeaway is that this was a phase 2 trial that looked at [daxdilimab], which is actually an antibody against ILT7, and it works by depleting pDCs,” Victoria Werth, MD, professor of dermatology at the University of Pennsylvania, told Dermatology Times at EADV.

Werth explained that pDCs contribute to the production of pro-inflammatory cytokines, including type I interferons, providing the rationale for targeting the cells in DLE.

Rapid Improvements in Disease Activity

The multicenter, randomized, double-blind, placebo-controlled trial enrolled adults aged 18 to 75 years with chronic, moderate-to-severe, treatment-refractory DLE for at least 6 months. Eligible patients had active disease at baseline, defined as a Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A) score of 8 or greater, without systemic features.

Seventy-two patients were randomized 1:1:1 to low-dose daxdilimab (n=24), high-dose daxdilimab (n=23), or placebo (n=25). Treatment was administered every 4 weeks from day 1 through week 20, with efficacy assessed at week 24. The primary endpoint was mean change from baseline in CLASI-A score at week 24. Secondary endpoints included achievement of at least a 50% reduction in CLASI-A (CLASI-50) and a Cutaneous Lupus Activity Investigator’s Global Assessment (CLA-IGA) score of 0 or 1.

Both doses met the primary and secondary endpoints, with improvements becoming evident as early as week 4 and continuing through the 24-week study period.

“The response rate was very rapid,” Werth said. “The improvement occurred by 4 weeks, but continued to improve over the 24 weeks of the study.”

At week 24, the least-squares mean difference in change from baseline in CLASI-A versus placebo was –6.0 with low-dose daxdilimab (90% CI, –8.7 to –3.2; P=.0005) and –5.7 with high-dose daxdilimab (90% CI, –8.5 to –2.9; P=.0012).

CLASI-50 response rates were 61.7% with low-dose daxdilimab and 62.1% with high-dose daxdilimab, compared with 23.7% with placebo. CLA-IGA 0/1 responses were achieved by 60.3% and 51.6% of patients in the low- and high-dose groups, respectively, versus 8.9% with placebo.

Werth noted that responses were also observed across additional measures evaluated in the study, including CLASI-70 and measures of low disease activity. More importantly, she said, the magnitude of improvement was clinically visible.

“We know a CLASI-50 is significant from a patient perspective,” Werth said. “But when you actually look at the patients who got treated and some of the photography, you can really see the improvement is quite dramatic.”

Addressing an Unmet Need in Cutaneous Lupus

DLE is the most common form of chronic cutaneous lupus erythematosus and is characterized by erythematous, scaly lesions that frequently affect the scalp, face, and ears. Disease progression can result in permanent scarring, alopecia, and facial disfigurement, contributing to substantial effects on quality of life.

Werth emphasized that the findings are particularly notable given the limited therapeutic options available specifically for cutaneous lupus.

“There’s a need for new treatments for discoid lupus and for cutaneous lupus in general,” she said. “There has not been a single approved drug in like 80 years, and so we’re still stuck with many of the old therapies.”

For patients with refractory disease, Werth said the goal is not only to expand treatment options, but to identify therapies capable of producing substantial improvement quickly while maintaining an acceptable safety profile.

Safety Findings

Daxdilimab was well tolerated through week 24, with no serious adverse events or deaths reported. Treatment-related adverse events occurred in 58.3% of patients receiving low-dose daxdilimab, 56.5% receiving high-dose daxdilimab, and 60.0% receiving placebo. One patient in the high-dose group discontinued treatment because of arthralgia.

“There really was no safety signal that was meaningful,” Werth said, noting that diarrhea occurred in a small number of patients and that no cases of herpes zoster were observed during the study.

The latter finding was particularly reassuring, she explained, because of concerns surrounding infection when therapeutically interfering with interferon pathways.

Potential Role of pDC-Targeted Therapy

The findings also provide further support for pDCs as a therapeutic target in cutaneous lupus. Daxdilimab reduces pDC numbers by targeting ILT7, representing one approach to interfering with the cells and their downstream inflammatory activity.

According to Werth, the combination of early efficacy and the safety findings raises the possibility that pDC-targeting therapies could ultimately be considered relatively early in the treatment pathway if their benefits are confirmed in further studies.

“I think [daxdilimab] and pDC-targeting drugs in general could fit very early in a cascade because of the rapidity of action and also the relative safety profile,” she said. “I think that drug and other pDC-targeting drugs will be very interesting in the future.”

Investigators concluded that the improvements across primary and secondary efficacy endpoints, alongside the observed safety profile, support both the continued development of daxdilimab in moderate-to-severe DLE and the role of pDCs in DLE pathogenesis.

References

1. Werth V, Merola JF, Chong B, et al. Daxdilimab in moderate-to-severe discoid lupus erythematosus: Efficacy and safety results from a phase 2, randomised, placebo-controlled trial. Presented at: European Academy of Dermatology and Venereology (EADV) Congress; September 30–October 3, 2026; Vienna, Austria.
2. Drenkard C, et al. Arthritis Care Res (Hoboken). 2019;71(1):95-103.
3. Karnell JL, et al. Sci Transl Med. 2021;13(595):eabf8442.