Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers

  • Michael E. RothenbergEmail author
  • Michael Tagen
  • Jae H. Chang
  • Janel Boyce-Rustay
  • Michel Friesenhahn
  • David H. Hackos
  • Avis Hains
  • Dan Sutherlin
  • Michael Ward
  • William Cho
Original Research Article


Background and Objective

Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that NaV1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel NaV1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects.


This phase I, randomized, double-blind, placebo-controlled study assessed GDC–0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2–270 mg (seven cohorts) and 45–540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15–540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined.


Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred.


GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.



The authors thank all the volunteers who participated in this study. They also thank Dr. Isabella Szeto and the clinical site staff at INC Research Toronto, Inc. (Toronto, ON, Canada) for their assistance in performing this trial, Robert Paul for early clinical development leadership, and Dinah Misner for toxicology support. Editing and writing support was provided by Deborah Solymar (Genentech, Inc.) and was funded by Genentech, Inc.

Compliance with Ethical Standards

Conflicts of interest

Michael E. Rothenberg, Michael Tagen, Jae H. Chang, Janel Boyce-Rustay, Michel Friesenhahn, David H. Hackos, Avis Hains, Dan Sutherlin, Michael Ward, and William Cho were employees of Genentech, Inc., a member of the Roche group, at the time this study was performed, and owned Roche stock and/or options at the time of their employment. Michael Tagen is currently an independent scientific consultant. Michael Ward is currently an employee of Alector, Inc., South San Francisco, CA, USA.


This study was funded by Genentech, Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the site’s Institutional Review Board.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

40261_2019_807_MOESM1_ESM.docx (103 kb)
Supplementary material 1 (DOCX 103 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Michael E. Rothenberg
    • 1
    Email author
  • Michael Tagen
    • 1
  • Jae H. Chang
    • 1
  • Janel Boyce-Rustay
    • 1
  • Michel Friesenhahn
    • 1
  • David H. Hackos
    • 1
  • Avis Hains
    • 1
  • Dan Sutherlin
    • 1
  • Michael Ward
    • 1
  • William Cho
    • 1
  1. 1.Genentech, Inc.South San FranciscoUSA

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