Comments on “Safety and pharmacology of AMY109, a long-acting anti–interleukin-8 antibody, for endometriosis: a double-blind, randomized phase 1 trial”

We commend Wang et al. (1) for conducting the first-in-human study of AMY109, a novel anti–interleukin-8 (IL-8) antibody, which represents a significant advance in developing nonhormonal therapies for endometriosis. Although their trial establishes a foundation of safety and pharmacokinetics, several important aspects require deeper exploration to ensure that AMY109 achieves true clinical utility.

The investigators report frequent upper respiratory tract infections but conclude that causality with AMY109 was uncertain. However, IL-8 is a key neutrophil chemoattractant, central to mucosal immunity. In CXCR2-deficient mouse models, impaired IL-8 signaling delays wound healing and reduces neutrophil infiltration (2). Clinical immunology data also highlight IL-8’s evolving role in epithelial barrier defense against respiratory and gastrointestinal pathogens (3). Thus, even mild upper respiratory tract infections observed in this small trial may be early indicators of a real susceptibility risk when IL-8 is chronically suppressed. With endometriosis affecting approximately 190 million women globally, many of whom undergo repeated surgeries or long-term therapies, vigilance is essential. Larger phase 2–3 trials should integrate structured infectious disease monitoring with pathogen identification to confirm whether AMY109 compromises host defense.

An important observation was that AMY109 did not disrupt menstrual cycles, a notable advantage over hormonal therapies that often impair ovulation. However, reproductive outcomes remain unclear. Increased IL-8 levels in follicular fluid and endometrial tissue have been linked to implantation and pregnancy success, suggesting a physiological role in endometrial receptivity (4). Targeting IL-8 may, therefore, carry unintended consequences for women actively pursuing fertility. Given that infertility is a major clinical burden of endometriosis, it is crucial that future studies assess oocyte quality, implantation rates, and pregnancy outcomes alongside pain reduction.

The trial assessed pharmacodynamics using plasma IL-8 levels but did not explore peritoneal or lesion-level cytokine changes. This is a critical gap because endometriosis is driven by localized peritoneal inflammation. Peritoneal macrophages secrete IL-8, sustaining lesion growth, angiogenesis, and innervation (5). Without direct tissue biomarker analysis, it remains uncertain whether AMY109 meaningfully alters the inflammatory microenvironment that drives disease progression. Incorporating peritoneal fluid assays, lesion biopsies, and imaging biomarkers in subsequent trials will help determine whether systemic IL-8 suppression translates into local therapeutic benefit.

Wang et al. (1) observed modest reductions in pain scores with AMY109; however, outcomes were not clearly different from placebo. This raises questions about patient selection. Prior network analyses have shown that subsets of women with high baseline peritoneal IL-8 or macrophage-driven inflammation exhibit distinct disease biology (5). Enriching future trials with biomarker-positive patients could reveal stronger efficacy signals and help avoid the risk of underestimating therapeutic potential. Such precision-medicine approaches are now standard in oncology and may accelerate progress in gynecology as well.

The phase 1 results of AMY109 are an important milestone in the development of nonhormonal therapies for endometriosis. Nonetheless, infection risk, reproductive safety, and tissue-specific pharmacodynamics remain unanswered questions that must be prioritized in upcoming trials. Furthermore, biomarker-guided enrichment could optimize patient selection and clarify the true therapeutic value of AMY109. Addressing these factors will ensure that this promising biologic evolves into a clinically meaningful option for women with endometriosis worldwide.

CRediT Authorship Contribution Statement

Shashank Dokania: Conceptualization, Writing – original draft, Writing – review & editing. Parth Aphale: Supervision, Writing – original draft, Writing – review & editing. Himanshu Shekhar: Writing – review & editing.

Declaration of Interests

S.D. has nothing to disclose. P.A. has nothing to disclose. H.S. has nothing to disclose.