Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy After Single and Multiple Dosings of LY3016859 in Healthy Subjects and Patients With Diabetic Nephropathy. Issue 7 (31st January 2018)

• Record Type: Journal Article
• Authors: Sloan‐Lancaster, Joanne; Raddad, Eyas; Deeg, Mark A.; Eli, Michelle; Flynt, Amy; Tumlin, James
• Is Part Of: Clinical pharmacology in drug development. Volume 7:Issue 7(2018)
• Page Start: 759
• Page End: 772
• Publication Date: 2018-01-31
• Subjects: diabetic nephropathy -- epiregulin -- transforming growth factor α; Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.436
• Languages: English
• ISSNs: 2160-7648

Abstract

Abstract: 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.