*Result*: Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.

*Background and Objective: Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.
Methods: Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).
Results: The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.
Conclusions: The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V<subscript>c</subscript>) than male sex, and DPNP was associated with lower V<subscript>c</subscript> than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC<subscript>50</subscript>).
Trail Registry: ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.
(© 2025. The Author(s).)*

*Declarations. Funding: This work was funded by Eli Lilly and Company, who also sponsored the original studies, medical writing support, and open-access publication of the manuscript. Conflict of interest: Douglas James and Jason Bailey are full-time employees of Eli Lilly and Company and/or one of its subsidiaries and are minority holders of company stock. Jan-Stefan van der Walt, Julia Winkler, and Rik Schoemaker are full-time employees of Occams Coöperatie UA, Amstelveen, the Netherlands. At the time the study was conducted, Jan-Stefan van der Walt was a full-time employee of Eli Lilly and Company, Indianapolis, IN, USA, and was a minority holder of company stock. Ethics approval: All studies included in this analysis were approved by appropriate ethics committees and were conducted in accordance with the principles of the Declaration of Helsinki and the International Council on Harmonisation Good Clinical Practice guidelines. Consent to participate: Written informed consent was obtained from all participants of the studies included in this analysis. Consent for publication: Not applicable. Availability of data and material: Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org . Code availability: Not applicable. Author contributions: J.-S.v.d.W. conceived and designed the study. J.B. was responsible for scientific oversight of immunogenicity and biomarker sample analysis. D.E.J., J.W., and R.S. analyzed the data. D.E.J., J.-S.v.d.W., J.B., J.W., and R.S. interpreted the data. D.E.J., J.B., and J.-S.v.d.W. drafted the manuscript. J.W. and R.S. critically revised the manuscript for important intellectual content. All authors read and approved the final version of the manuscript.*