Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 May;64(5):757-767.
doi: 10.1007/s40262-025-01506-3. Epub 2025 Apr 23.

Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain

Douglas E James  1 , Jason Bailey  2 , Jan-Stefan van der Walt  3   4 , Julia Winkler  4 , Rik Schoemaker  4
Affiliations
Clinical Trial

Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain

Douglas E James et al. Clin Pharmacokinet. 2025 May.

Abstract

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 (Vc) than male sex, and DPNP was associated with lower Vc than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC50).

Trail registry: ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Model schematic for the final PK and PK-PD model
Fig. 2
Fig. 2
Forest plot for single covariate effects on fold change in fepixnebart Cav with 95% confidence intervals. ADA occurrence of antidrug antibodies during treatment, Cav average concentration over 24 h, DPNP diabetic peripheral neuropathic pain relative to chronic low back pain, GFR body surface area adjusted glomerular filtration rate using the six-variable Modification of Diet in Renal Disease Study equation, OA osteoarthritis knee pain relative to chronic low back pain, SEX females relative to males. Red lines indicate the limits associated with 0.8- to 1.25-fold change in Cav. Continuous covariates (age, GFR) are scaled to estimate the fractional change across 95% of the covariate range
Fig. 3
Fig. 3
Linear scale (a) and log scale (b) of the VPC for fepixnebart (LY3016859) using the final population PKPD model (run321). Red lines: observed fepixnebart quantiles (2.5th, 50th, 97.5th). Black lines: median of fepixnebart quantiles (2.5th, 50th, 97.5th) across simulated trials. Blue and red shaded areas: 95% of the fepixnebart quantiles (2.5th, 50th, 97.5th) across simulated trials. Red circles: observations
Fig. 4
Fig. 4
Linear scale (a) and log scale (b) of the VPC for epiregulin using the final population PKPD model (run321). Red lines: observed epiregulin quantiles (2.5th, 50th, 97.5th). Black lines: median of epiregulin quantiles (2.5th, 50th, 97.5th) across simulated trials. Blue and red shaded areas: 95% of the epiregulin quantiles (2.5th, 50th, 97.5th) across simulated trials. Red circles: observations
Fig. 5
Fig. 5
Simulated profiles of fepixnebart (a), epiregulin (b), and target engagement for the phase 2 dose regimen (c). Red line: median time profile. Blue area: 90% of the simulated concentrations (from the 5th to the 95th percentile)
See this image and copyright information in PMC

References

    1. Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, Kerns R, Von Korff M, Porter L, Helmick C. Prevalence of chronic pain and high-impact chronic pain among adults—United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67:1001–6. 10.15585/mmwr.mm6736a2. - PMC - PubMed
    1. Kersten C, Cameron MG. Cetuximab alleviates neuropathic pain despite tumour progression. BMJ Case Rep. 2012;2012:1–6. 10.1136/bcr.12.2011.5374. - PMC - PubMed
    1. Kersten C, Cameron MG, Laird B, Mjåland S. Epidermal growth factor receptor-inhibition (EGFR-I) in the treatment of neuropathic pain. Br J of Anaesth. 2015;115(5):761–7. 10.1093/bja/aev326. - PubMed
    1. Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res. 2003;284:2–13. 10.1016/s0014-4827(02)00105-2. - PubMed
    1. Roepstorff K, Grandal MV, Henriksen L, Knudsen SL, Lerdrup M, Grøvdal L, Willumsen BM, van Deurs B. Differential effects of EGFR ligands on endocytic sorting of the receptor. Traffic. 2009;10(8):1115–27. 10.1111/j.1600-0854.2009.00943.x. - PMC - PubMed

Publication types

MeSH terms

Associated data