A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients

Abstract

Objective:

Secondary hyperparathyroidism (SHPT) is a frequent complication of chronic kidney disease. We evaluated AMG 416, a long-acting peptide agonist of the calcium-sensing receptor, to assess its safety, tolerability, and efficacy and to determine a safe and effective starting dose for subsequent phase 2 studies. The study was not designed to titrate AMG 416 dosing to achieve a specific PTH treatment goal.

Research design and methods:

This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation study designed to evaluate the safety and efficacy of AMG 416 administered thrice weekly by IV bolus at the end of hemodialysis for up to 4 weeks. Eligible subjects were enrolled in one of three cohorts and treated with 5 mg of AMG 416 or placebo for 2 weeks (Cohort 1) or 5 or 10 mg of AMG 416 or placebo for 4 weeks (Cohorts 2 and 3). The primary endpoint was mean percentage change from baseline in PTH during the efficacy assessment phase (EAP) in Cohorts 2 and 3.

Results:

Analysis of the primary endpoint showed that treatment with AMG 416 at 10 mg (Cohort 2) and 5 mg (Cohort 3) for up to 4 weeks resulted in mean 49.4% and 33.0% reductions from baseline in PTH during the efficacy assessment phase, respectively (p < 0.05 for both cohorts compared to placebo group within the cohort). A substantial proportion of subjects treated with AMG 416 achieved PTH ≤300 pg/mL and ≥30% reduction in PTH from baseline in both cohorts. The observed decreases in serum-corrected calcium were well tolerated and serum phosphate levels also tended to decrease.

Conclusions:

The present clinical findings support the continued development of AMG 416 as a treatment for SHPT in hemodialysis patients.

Keywords: :

• AMG 416
• Calcium-sensing receptor
• Chronic kidney disease
• Hemodialysis
• Secondary hyperparathyroidism

Transparency

Declaration of funding

This work was supported by KAI Pharmaceuticals, a wholly owned subsidiary of Amgen, Thousand Oaks, CA, USA.

Declaration of financial/other relationships

G.B. and S.H. have disclosed that they were employees of KAI Pharmaceuticals, a wholly owned subsidiary of Amgen, Thousand Oaks, CA, at the time this study was conducted. K.J.M and G.A.B. have disclosed that they were consultants and served on advisory boards of Amgen Inc.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.

Acknowledgments

The authors wish to thank the investigators, staff, and patients who participated in the study. David Martin PhD, Todd Okamoto PharmD (formerly Amgen Inc.) and Holly Tomlin MPH (employee and stockholder, Amgen Inc.) assisted in the preparation of the manuscript. Karen Pickthorn PhD was involved in the research and earlier drafts of this manuscript. Andy Vick of Seventh Wave Laboratories assisted in conducting the analyses. All authors contributed to the development of this manuscript and approved the final draft.

Previous presentation: The original work presented in this manuscript was sponsored by KAI Pharmaceuticals Inc., a wholly owned subsidiary of Amgen Inc. It has not been presented elsewhere except in abstract form at the American Society of Nephrology 2011 and at the European Renal Association – European Dialysis and Transplant Association in May 2012.

Notes

*Sensipar and Mimpara are registered trade names of Amgen Inc., Thousand Oaks, CA, USA