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Clin Pharmacol Drug Dev. 2018 Sep;7(7):759-772. doi: 10.1002/cpdd.436. Epub 2018 Jan 31.

Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy After Single and Multiple Dosings of LY3016859 in Healthy Subjects and Patients With Diabetic Nephropathy.

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Chorus, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
PharPoint Research, Inc., Durham, NC, USA.
Nephrology Associates, Chattanooga, TN, USA.


Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF-α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo. Pharmacokinetics, pharmacodynamics, anti-LY antibodies, and change in proteinuria and albuminuria were evaluated. Single and multiple doses of LY administered 3 weeks apart were well tolerated. Pharmacokinetics were nonlinear in healthy subjects and patients with DN, indicating target-mediated drug disposition. Epiregulin level increased in both studies, and TGF-α levels increased in the TGAB study, consistent with target engagement; however, LY treatment did not significantly reduce proteinuria or albuminuria in patients with DN. There was no obvious effect of LY on the disease-related biomarkers monocyte chemoattractant protein-1, synaptopodin, or transferrin. Although LY administration resulted in a high frequency of anti-LY antibodies, pharmacokinetics, target engagement, and efficacy were not impacted.


diabetic nephropathy; epiregulin; transforming growth factor α


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