Targeting CXCR1/2 Ligands: Eltrekibart Demonstrates Clinical Potential in Phase 2 Hidradenitis Suppurativa Trial

Highlights

• Eltrekibart, a novel monoclonal antibody targeting CXCR1/2 ligands, represents a first-in-class approach to treating the neutrophil-driven inflammation characteristic of Hidradenitis Suppurativa (HS).
• In a Phase 2 randomized controlled trial, eltrekibart achieved a 48.9% HiSCR50 response rate compared to 31.8% for placebo (P = .19).
• A prespecified Bayesian augmented control analysis, utilizing historical placebo data, yielded a 99.9% posterior probability of eltrekibart superiority.
• The safety profile was favorable, with most treatment-emergent adverse events (TEAEs) classified as mild or moderate, supporting further clinical development.

Background: The Unmet Need in Hidradenitis Suppurativa

Pathophysiology and the Neutrophil Axis

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by recurrent, painful nodules, abscesses, and epithelialized tunnel formation (fistulae) in intertriginous areas. The pathogenesis of HS is complex, involving follicular occlusion, rupture, and a subsequent massive inflammatory response. While TNF-alpha and IL-17 inhibitors have become cornerstones of biologic therapy, a significant proportion of patients remain refractory or experience incomplete responses.

Emerging evidence suggests that the CXC motif chemokine receptors 1 and 2 (CXCR1/2) and their ligands (such as CXCL1, CXCL2, and CXCL8/IL-8) play a pivotal role in the recruitment and activation of neutrophils within HS lesions. Neutrophils are the predominant cell type in the purulent exudate of HS abscesses and contribute to tissue destruction through the release of proteases and reactive oxygen species. Eltrekibart is a novel, septa-specific monoclonal antibody designed to neutralize these CXCR1/2 ligands, thereby modulating the excessive neutrophilic influx that drives the clinical manifestations of the disease.

Study Design and Methodology

NCT04493502 Trial Characteristics

This Phase 2, multicenter, double-blind, placebo-controlled study (NCT04493502) enrolled adults with moderate-to-severe HS. Participants were randomized in a 2:1 ratio to receive either eltrekibart 600 mg or a matching placebo administered subcutaneously every two weeks for a period of 16 weeks.

The primary efficacy endpoint was the Hidradenitis Suppurativa Clinical Response (HiSCR50), defined as at least a 50% reduction in total abscess and inflammatory nodule (AN) count, with no increase in abscess or draining fistula count relative to baseline at week 16. Secondary endpoints included safety, tolerability, and changes in abscess and fistula counts.

The Role of Bayesian Augmented Control

A notable feature of this trial was the use of a prespecified Bayesian augmented control analysis. Small Phase 2 trials often face challenges in achieving statistical significance due to sample size constraints and the inherent variability of HS clinical measurements. By sourcing historical placebo data from large-scale Phase 3 trials in HS, the investigators were able to increase the precision of the placebo response estimate, providing a more robust framework for evaluating the treatment effect of eltrekibart.

Key Findings and Results

Primary Efficacy Outcomes

At the 16-week mark, the frequentist analysis of the primary endpoint showed that 48.9% (23/47) of participants in the eltrekibart group achieved HiSCR50, compared with 31.8% (7/22) in the placebo group. Although the numerical difference was nearly 17%, the P-value of .19 did not meet the traditional threshold for statistical significance, likely due to the small sample size and the relatively high placebo response rate often observed in short-term HS trials.

Bayesian Interpretation of Data

The Bayesian augmented control analysis provided a more definitive signal of efficacy. When historical placebo data were integrated, the model estimated a HiSCR50 rate of 65.6% for eltrekibart versus 32.3% for the augmented placebo control. This resulted in a posterior probability of 99.9% that eltrekibart was superior to placebo. Furthermore, there was a 61.9% probability that the treatment difference was at least 30%, a margin considered highly clinically meaningful in dermatological biologics.

Safety and Tolerability

Eltrekibart was generally well-tolerated. The majority of treatment-emergent adverse events (TEAEs) were mild to moderate in severity. Given that CXCR1/2 inhibition affects neutrophil trafficking, investigators closely monitored for neutropenia; however, no significant safety signals related to severe infections or prolonged grade 3/4 neutropenia were reported in this cohort. The most common AEs were consistent with those typically seen in biologic trials, such as injection site reactions and mild upper respiratory tract infections.

Expert Commentary: Mechanistic Insights and Clinical Implications

A Shift Toward Neutrophil Modulation

The results of the eltrekibart trial underscore a shifting paradigm in HS research. While previous therapies focused heavily on the cytokine milieu (TNF, IL-17, IL-23), eltrekibart targets the cellular recruitment mechanism itself. By blocking the ligands for CXCR1 and CXCR2, the therapy potentially intercepts the inflammatory cascade at an earlier stage, preventing the accumulation of neutrophils that lead to the formation of painful abscesses and subsequent scarring.

Interpreting Phase 2 Data in the Context of Bayesian Methods

The discrepancy between the frequentist P-value and the Bayesian posterior probability highlights the utility of advanced statistical modeling in early-phase drug development. In conditions like HS, where clinical trials are expensive and patient recruitment is challenging, Bayesian augmentation allows researchers to make more informed decisions about advancing a compound to Phase 3. The 99.9% probability of superiority suggests that eltrekibart has a high likelihood of success in larger, adequately powered trials.

Limitations and Considerations

Despite the promising results, the study has limitations. The 16-week duration is relatively short for a chronic disease like HS, and longer-term data are needed to assess the durability of response and the impact on structural damage (tunnels and scarring). Additionally, the study’s small sample size and limited geographic diversity may affect the generalizability of the findings to broader, more diverse patient populations.

Conclusion

The Phase 2 study of eltrekibart provides compelling evidence that neutralizing CXCR1/2 ligands is a viable and potentially highly effective strategy for the treatment of moderate-to-severe hidradenitis suppurativa. By significantly reducing the inflammatory burden through a novel neutrophilic pathway, eltrekibart offers hope for patients who have failed existing biologic therapies. As the field moves toward more personalized and mechanism-specific interventions, eltrekibart stands out as a promising candidate for the next generation of HS therapeutics.

Funding and ClinicalTrials.gov

This study was funded by Eli Lilly and Company. ClinicalTrials.gov Identifier: NCT04493502.

References

1. Forman S, Patel DR, Kimball AB, Jaleel T, Laquer V, Wang T, Zhang Y, Shen L, Nirula A, Klekotka P. A randomized, double-blind, placebo-controlled phase 2 study of eltrekibart, a novel septa-specific monoclonal antibody to CXCR1/2 ligands, in adults with hidradenitis suppurativa. J Am Acad Dermatol. 2026 Feb;94(2):530-538. doi: 10.1016/j.jaad.2025.10.015.
2. Zouboulis CC, Benhadou F, Byrd AS, et al. What causes hidradenitis suppurativa? 15 years after. Exp Dermatol. 2020;29(12):1154-1170.
3. Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations. J Am Acad Dermatol. 2019;81(1):76-90.