Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Health
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ORIGINAL RESEARCH ARTICLE
Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post‑Menopausal Women Maureen G. Conlan1 · Erik F. J. de Vries2 · AWJM Glaudemans2 · Yamei Wang3 · Steven Troy4
© The Author(s) 2020
Abstract Background and Objectives Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/ antagonist activity that is being developed as a treatment option for ER+ breast cancer. Methods Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. Results In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5–6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. Conclusions These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.
Key Points Elacestrant, an oral SERD, is safe and well tolerated at oral doses up to 500 mg per day Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13318-020-00635-3) contains supplementary material, which is available to authorized users. * Maureen G. Conlan [email protected] 1
Department of Oncology Clinical Development, Radius Health, Inc., 950 Winter Street, Waltham, MA 02451, USA
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
2
3
Department of Biostatistics, Radius Health, Inc., 950 Winter Street, Waltham, MA, USA
4
Department of Clinical Pharmacology, Radius Health, Inc., 950 Winter Street, Waltham, MA, USA
Robust ERα occupancy (75–90%) is observed at elacestrant doses of 200 mg to 500 mg daily Elacestrant’s bioavailability and long t1/2 support a oncedaily oral dosing
1 Introduction Breast cancer continues to be the most commonly diagnosed malignancy among women [1], and approximately 75% of all breast ca
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