Etokimab trial highlights IL-33 targeting as potential new AD therapy

Patients with moderate to severe atopic dermatitis who received the immunoglobulin G1 anti–interleukin-33 monoclonal antibody etokimab showed significant disease improvement 29 days after receiving a single systemic administration, according to results from a recent proof-of-concept, phase IIa study.

“Most of the focus for IL-33 pathway inhibition has been on the type 2 cytokine axis because of significant supporting genetic and functional data in both human and murine systems,” Yi-Ling Chen, a DPhil student at the University of Oxford (England), and colleagues wrote in Science Translational Medicine. “Our findings might also provide a further dimension to explain how etokimab, by inhibiting IL-33, could provide such a rapid and persistent clinical benefit as described in this report.”

In their study, 12 patients with moderate to severe AD received etokimab in a single intravenous dose of 300 mg. Prior to receiving etokimab, patients received a placebo dose and then underwent saline or house dust mite intraepidermal challenge, with researchers obtaining blister samples 1 day after challenge following placebo administration and again after patients received etokimab.

At 29 days, 83% of patients reached rapid and sustained clinical benefit under Eczema Area and Severity Index (EASI ) 50 and 33% in EASI 75, including peripheral eosinophil reduction. There also was significant reduction in skin neutrophil infiltration after patients received etokimab and then house dust mite challenge, compared with after they received placebo, .

“These findings open new therapeutic possible applications of etokimab to sterile neutrophilic disease as well as other inflammatory diseases with a clear neutrophilic involvement such as neutrophilic asthma,” the researchers said. “This first-in-class experimental medicine study has shown that in vivo in human tissue IL-33 has key upstream effects which broadly influence different and relevant inflammatory cascades and thus widen the potential of this treatment to a larger than anticipated group of diseases.

“Although excellent previous studies have demonstrated in vitro and in murine models that IL-33 is involved in neutrophil migration, the translation here to human tissue immunology shows that IL-33 plays a dominant role and effects are in part likely to be mediated instead by CXCR1,” concluded Ms. Chen and colleagues. “Therefore, specific IL-33 therapeutic intervention is not targeting a redundant system and is worthy of further investigation.”

This study was funded by AnaptysBio, which was responsible for the conception and design of the study. AnaptysBio also helped in part to analyze and interpret the data from the study, and approved it for submission. Dr. Ogg reported having served on an advisory board, as a consultant, or holds equity in Eli Lilly, Novartis, Janssen, Orbit Discovery, and UCB Pharma. Ms. Marquette and Dr. Londei reported being employees of AnaptysBio.

SOURCE: Chen Y-L et al. Sci Transl Med. 2019. doi: 10.1126/scitranslmed.aax2945.

Patients with moderate to severe atopic dermatitis who received the immunoglobulin G1 anti–interleukin-33 monoclonal antibody etokimab showed significant disease improvement 29 days after receiving a single systemic administration, according to results from a recent proof-of-concept, phase IIa study.

“Most of the focus for IL-33 pathway inhibition has been on the type 2 cytokine axis because of significant supporting genetic and functional data in both human and murine systems,” Yi-Ling Chen, a DPhil student at the University of Oxford (England), and colleagues wrote in Science Translational Medicine. “Our findings might also provide a further dimension to explain how etokimab, by inhibiting IL-33, could provide such a rapid and persistent clinical benefit as described in this report.”

In their study, 12 patients with moderate to severe AD received etokimab in a single intravenous dose of 300 mg. Prior to receiving etokimab, patients received a placebo dose and then underwent saline or house dust mite intraepidermal challenge, with researchers obtaining blister samples 1 day after challenge following placebo administration and again after patients received etokimab.

At 29 days, 83% of patients reached rapid and sustained clinical benefit under Eczema Area and Severity Index (EASI ) 50 and 33% in EASI 75, including peripheral eosinophil reduction. There also was significant reduction in skin neutrophil infiltration after patients received etokimab and then house dust mite challenge, compared with after they received placebo, .

“These findings open new therapeutic possible applications of etokimab to sterile neutrophilic disease as well as other inflammatory diseases with a clear neutrophilic involvement such as neutrophilic asthma,” the researchers said. “This first-in-class experimental medicine study has shown that in vivo in human tissue IL-33 has key upstream effects which broadly influence different and relevant inflammatory cascades and thus widen the potential of this treatment to a larger than anticipated group of diseases.

“Although excellent previous studies have demonstrated in vitro and in murine models that IL-33 is involved in neutrophil migration, the translation here to human tissue immunology shows that IL-33 plays a dominant role and effects are in part likely to be mediated instead by CXCR1,” concluded Ms. Chen and colleagues. “Therefore, specific IL-33 therapeutic intervention is not targeting a redundant system and is worthy of further investigation.”

This study was funded by AnaptysBio, which was responsible for the conception and design of the study. AnaptysBio also helped in part to analyze and interpret the data from the study, and approved it for submission. Dr. Ogg reported having served on an advisory board, as a consultant, or holds equity in Eli Lilly, Novartis, Janssen, Orbit Discovery, and UCB Pharma. Ms. Marquette and Dr. Londei reported being employees of AnaptysBio.

SOURCE: Chen Y-L et al. Sci Transl Med. 2019. doi: 10.1126/scitranslmed.aax2945.

Patients with moderate to severe atopic dermatitis who received the immunoglobulin G1 anti–interleukin-33 monoclonal antibody etokimab showed significant disease improvement 29 days after receiving a single systemic administration, according to results from a recent proof-of-concept, phase IIa study.

“Most of the focus for IL-33 pathway inhibition has been on the type 2 cytokine axis because of significant supporting genetic and functional data in both human and murine systems,” Yi-Ling Chen, a DPhil student at the University of Oxford (England), and colleagues wrote in Science Translational Medicine. “Our findings might also provide a further dimension to explain how etokimab, by inhibiting IL-33, could provide such a rapid and persistent clinical benefit as described in this report.”

In their study, 12 patients with moderate to severe AD received etokimab in a single intravenous dose of 300 mg. Prior to receiving etokimab, patients received a placebo dose and then underwent saline or house dust mite intraepidermal challenge, with researchers obtaining blister samples 1 day after challenge following placebo administration and again after patients received etokimab.

At 29 days, 83% of patients reached rapid and sustained clinical benefit under Eczema Area and Severity Index (EASI ) 50 and 33% in EASI 75, including peripheral eosinophil reduction. There also was significant reduction in skin neutrophil infiltration after patients received etokimab and then house dust mite challenge, compared with after they received placebo, .

“These findings open new therapeutic possible applications of etokimab to sterile neutrophilic disease as well as other inflammatory diseases with a clear neutrophilic involvement such as neutrophilic asthma,” the researchers said. “This first-in-class experimental medicine study has shown that in vivo in human tissue IL-33 has key upstream effects which broadly influence different and relevant inflammatory cascades and thus widen the potential of this treatment to a larger than anticipated group of diseases.

“Although excellent previous studies have demonstrated in vitro and in murine models that IL-33 is involved in neutrophil migration, the translation here to human tissue immunology shows that IL-33 plays a dominant role and effects are in part likely to be mediated instead by CXCR1,” concluded Ms. Chen and colleagues. “Therefore, specific IL-33 therapeutic intervention is not targeting a redundant system and is worthy of further investigation.”

This study was funded by AnaptysBio, which was responsible for the conception and design of the study. AnaptysBio also helped in part to analyze and interpret the data from the study, and approved it for submission. Dr. Ogg reported having served on an advisory board, as a consultant, or holds equity in Eli Lilly, Novartis, Janssen, Orbit Discovery, and UCB Pharma. Ms. Marquette and Dr. Londei reported being employees of AnaptysBio.

SOURCE: Chen Y-L et al. Sci Transl Med. 2019. doi: 10.1126/scitranslmed.aax2945.