Abstract
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.
Methods
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.
Results
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.
Conclusion
GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.
Similar content being viewed by others
Change history
23 July 2019
A Correction to this paper has been published: https://doi.org/10.1007/s40261-019-00832-2
References
Institute of Medicine. Relieving pain in America, a blueprint for transforming prevention, care, education and research. Washington, DC. The National Academies Press; 2011. http://books.nap.edu/openbook.php?record_id=13172&page=1. Accessed 31 Jan 2019.
Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16:821–47.
Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res. 2015;8:105–18.
Morgan MM, Christie MJ. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol. 2011;164:1322–34.
Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care. 2016;54:901–6.
Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and opioid-involved overdose deaths–United States, 2013–2017. MMWR Morb Mortal Wkly Rep. 2019;67:1419–27.
Wood JN, Boorman JP, Okuse K, Baker MD. Voltage-gated sodium channels and pain pathways. J Neurobiol. 2004;61:55–71.
McKerrall SJ. Sutherlin DP (2108) Nav1.7 inhibitors for the treatment of chronic pain. Bioorg Med Chem Lett. 2018;28:3141–9.
Cummins TR, Howe JR, Waxman SG. Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J Neurosci. 1998;18:9607–19.
Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–8.
Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, et al. Loss-of-function mutations in the NaV1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet. 2007;71:311–9.
Weiss J, Pyrski M, Jacobi E, Bufe B, Willnecker V, Schick B, et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature. 2011;472:186–90.
Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004;41:171–4.
Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci. 2004;24:8232–6.
Fischer TZ, Waxman SG. Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann N Y Acad Sci. 2010;1184:196–207.
Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39.
Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA. 2010;107:5148–53.
Bankar G, Goodchild SJ, Howard S, Nelkenbrecher K, Waldbrook M, Dourado M, et al. Selective NaV1.7 antagonists with long residence time show improved efficacy against inflammatory and neuropathic pain. Cell Rep. 2018;24:3133–45.
Cao L, McDonnell A, Nitzsche A, Alexandrou A, Saintot PP, Loucif AJ, et al. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci Transl Med. 2016;8:335–56.
McDonnell A, Collins S, Ali Z, Iavarone L, Surujbally R, Kirby S, et al. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain. 2018;159:1465–76.
Sutherlin, D. Books of Abstracts, 254th ACS National Meeting and Exposition, Washington, DC, August 20–24, 2017; American Chemical Society: Washington, DC, 2017 (MEDI-253).
Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania smell identification test: a rapid quantitative olfactory function test for the clinic. Laryngoscope. 1984;94:176–8.
Columbia-Suicide Severity Rating Scale. The Columbia Lighthouse Project. 2016. http://www.cssrs.columbia.edu.
Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Inf J. 1995;29:1039–48.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17:1278–83.
Hummel J, McKendrick S, Brindley C, French R. Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Pharm Stat. 2009;8:38–49.
Hingorani P, Karnad DR, Rohekar P, Kerkar V, Lokhandwala YY, Kothari S. Arrhythmias seen in baseline 24-hour Holter ECG recordings in healthy normal volunteers during phase 1 clinical trials. J Clin Pharmacol. 2016;56:885–93.
Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21:69–72.
de Lera RM, Kraus RL. Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. J Med Chem. 2015;58:7093–118.
Schild JH, Kunze DL. Differential distribution of voltage-gated channels in myelinated and unmyelinated baroreceptor afferents. Auton Neurosci. 2012;172:4–12.
Morinville A, Fundin B, Meury L, Juréus A, Sandberg K, Krupp J, et al. Distribution of the voltage-gated sodium channel Nav1.7 in the rat: Expression in the autonomic and endocrine systems. J Comp Neurol. 2007;504(6):680–9.
Han C, Hoeijmakers JG, Liu S, Gerrits MM, te Morsche RH, Lauria G, et al. Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy. Brain. 2012;135(Pt 9):2613–28.
Emanuel EJ, Bedarida G, Macci K, Gabler NB, Rid A, Wendler D. Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. BMJ. 2015;350:h3271.
Ahn HS, Black JA, Zhao P, Tyrrell L, Waxman SG, Dib-Hajj SD. Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons. Mol Pain. 2011;7:32.
Gordon CJ. The mouse thermoregulatory system: its impact on translating biomedical data to humans. Physiol Behav. 2017;179:55–66.
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Funding
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.
Additional information
The original version of this article was revised: A few entries were incorrect in Table 2.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rothenberg, M.E., Tagen, M., Chang, J.H. et al. 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. Clin Drug Investig 39, 873–887 (2019). https://doi.org/10.1007/s40261-019-00807-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40261-019-00807-3