FRONTIER-2 Study Evaluates Safety and Efficacy of Tozorakimab in Patients with AD

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An exploratory phase 2a study evaluated the safety and efficacy of tozorakimab in patients with moderate to severe atopic dermatitis (AD).¹ Improvements in response rates and a reduction in pruritus were observed in the FRONTIER-2 study, specifically in patients taking 600 mg of tozorakimab. Tozorakimab is a high-affinity human monoclonal antibody that neutralizes interleukin-33, a broad-acting alarmin cytokine that is over-expressed in the keratinocytes of patients with AD.

The randomized, placebo-controlled, double-blind study (NCT04212169) was conducted from December 2019 to September 2022 at 32 centers across Australia, Germany, Poland, Spain, the United Kingdom, and the United States. 113 patients were randomized 3:1:1:3 to receive either placebo, tozorakimab 60 mg, tozorakimab 300 mg, or tozorakimab 600 mg by subcutaneous injection once every 4 weeks for 4 doses.

The participants were between the ages of 18 and 65 and had remained symptomatic, despite the previous use of topical therapy. They also had an Investigator's Global Assessment (IGA) score of 3 or greater, an Eczema Area and Severity Index (EASI) score of 16 or greater, and body surface area of involvement (BSA) of 10% or greater.

The primary endpoint was the change in EASI score percentage from baseline to week 16 in patients treated with tozorakimab versus placebo. The secondary outcomes included patients achieving ≥75% reduction from baseline in EASI score and an IGA score of clear or almost clear.

Researchers observed no statistically significant difference in EASI change between placebo and tozorakimab groups from baseline to week 16. However, the proportion of EASI-75 and IGA 0/1 responders at Week 16 was numerically higher in the tozorakimab 600 mg group than in the placebo group (EASI-75: 18.2% vs. 7.1%, p = 0.094; IGA 0/1: 9.1% vs. 1.8%, p = 0.113). 

In the 600 mg group, a higher percentage of patients achieved a reduction of at least 3 points of daily peak pruritus numerical rating compared to placebo (21.8% vs. 16.1%, respectively). Additionally, serum pharmacokinetics were dose-dependent, and immunogenicity incidence was low.

Overall, tozorakimab was well tolerated with no major safety concerns. Most patients, in both the placebo and tozorakimab groups, experienced one or more mild or moderate treatment-emergent adverse events. Nonetheless, the proportion of patients was numerically higher in the placebo group (66.1%). 

Two patients in the tozorakimab 600 mg group discontinued treatment due to these effects. The most common adverse effects were injection site reaction, nasopharyngitis, and other infections. These results are consistent with what was observed in similar studies involving anti-IL-33 or anti-ST2 antibodies in AD treatment.²

The investigators noted several study limitations, including the study design and the fluctuating symptomatic nature of AD. Further research with more frequent administration over a duration longer than 16 weeks is recommended. Tozorakimab is currently under investigation in other conditions including chronic obstructive pulmonary disease and asthma.

“According to a small porcine distribution study, only 5% of the systemic available product is expected to be distributed to the skin compared to other organs like lungs, where distribution was found to be approximately 20%,” the authors wrote. “To achieve optimum distribution in AD, higher doses of tozorakimab may be needed compared with respiratory diseases, particularly as IL-33 is locally acting cytokine.It is uncertain what higher doses may achieve in terms of efficacy, but longer-term studies with a higher dose may be necessary to explore full efficacy potential.”

References

1. Silverberg JI, Mustapa MN, Reid F, et al. Efficacy and safety of tozorakimab in moderate-to-severe atopic dermatitis: A Phase 2a randomized controlled trial (FRONTIER-2). J Eur Acad Dermatol Venereol. Published online November 13, 2024. doi:10.1111/jdv.20388

2. Maurer M, Cheung DS, Theess W, et al. Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis. J Allergy Clin Immunol. 2022;150(6):1517-1524. doi:10.1016/j.jaci.2022.08.015