Development of Pain Therapies Targeting Nerve Growth Factor Signal Transduction and the Strategies Used to Resolve Safety Issues

The Journal of Toxicological Sciences (J. Toxicol. Sci.) 1 Vol.43, No.1, 1-10, 2018 Review Development of pain therapies targeting nerve growth factor signal transduction and the strategies used to resolve safety issues Patrice Bélanger1, Christine R. West2 and Mark T. Brown2 1Pfizer Inc, 10646 Science Center Drive, San Diego, CA 92121 USA 2Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340 USA [Recommended by Ikuo Horii] (Received December 18, 2017; Accepted December 21, 2017) ABSTRACT — Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpect- ed joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in ani- mals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learn- ings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety. Key words: Nerve growth factor antibody, Tanezumab, Fasinumab, Fulranumab INTRODUCTION monoclonal antibodies (mAbs) binding to NGF rep- resents a novel approach to the treatment of chron- A large unmet medical need exists for the development ic pain using a mechanism-based approach (Hefti et al., of safe and effective therapeutics for treatment of chron- 2006; Woolf and Max, 2001). For example, tanezumab ic pain (Institute of Medicine, 2011). Therapeutic agents (Pfizer Inc.), fulranumab (Janssen Pharmaceuti- commonly used in the management of chronic pain cals LLC), and fasinumab (Regeneron Pharmaceuti- include nonsteroidal anti-inflammatory drugs (NSAIDs) cals Inc. and Teva Pharmaceuticals Inc.) are mAbs tar- and opioids (Kissin, 2010). These compounds have lim- geted against NGF that have been investigated for ited effectiveness and issues of dependence, tolerabili- treatment of chronic pain conditions, including osteoar- ty, and overall safety have been associated with standard thritis (OA), chronic low back pain (CLBP), and can- pain therapies (Bjordal et al., 2004). cer pain (Balanescu et al., 2014; Brown et al., 2012, One approach to selecting appropriate new targets for 2013; Ekman et al., 2014; Gimbel et al., 2014; Katz et the development of potential pain treatments is through al., 2011; Kivitz et al., 2013; Lane et al., 2010; Mayorga the identification of intracellular signals involved in the et al., 2016; Nagashima et al., 2011; Sanga et al., 2013, pain transduction pathway. For example, nerve growth 2016; Schnitzer et al., 2015, 2011; Sopata et al., 2015; factor (NGF) has been identified as an important key Spierings et al., 2013; Tiseo et al., 2014). In 2010, the mediator in the pain pathway. The development of NGF US Food and Drug Administration (FDA) placed a partial clinical hold on the clinical development of all NGF Correspondence: Patrice Bélanger (E-mail: patrice.belanger@pfizer.com) Vol. 43 No. 1 2 P. Bélanger et al. antibodies due to adverse events initially described as receptors, tropomyosin-related kinase A (trkA; high affin- osteonecrosis (Janssen Research and Development LLC, ity) and p75 (low affinity) (Mantyh et al., 2011). These 2012; Pfizer Inc., 2012; Regeneron Pharmaceuticals receptors are expressed on the peripheral terminals of Inc. and Arthritis Advisory Committee Meeting, 2012). A-delta and unmyelinated C-fibers (Bennett et al., 1998; Despite these initial reports, blinded external adjudica- Hefti et al., 2006; Mantyh et al., 2011). When bound, tion analyses determined that tanezumab treatment was the NGF:trkA complex is internalized into the fibers and not associated with an increase in osteonecrosis but was transported to cell bodies in dorsal root ganglia where it associated with an increase in rapidly progressive OA activates transcription factors that control expression of (RPOA) (Hochberg et al., 2016; Pfizer Inc., 2012). Based modulators involved in pain signaling. These include a on these findings, and clinical analyses which identi- number of receptors and ion channels at the membrane fied a number of risk mitigation procedures intended to surface, including transient receptor potential vanilloid reduce the risk of RPOA with tanezumab (Hochberg et 1 (TRPV1), acid-sensing ion channels 2 and 3, endothe- al., 2016; Pfizer Inc., 2012), the FDA lifted the joint safe- lin receptors, bradykinin receptors, voltage-gated sodi- ty partial clinical hold on tanezumab in 2012. A second um, and calcium channels, delayed rectifier potassium class-wide partial clinical hold was implemented by FDA currents, increased synthesis of peptides (e.g. substance P in December 2012 due to nonclinical data showing mor- and calcitonin gene-related peptide [CGRP]) and putative phologic changes in the sympathetic nervous system. In mechanotransducers (Delcroix et al., 2003; Kendall et 2015, FDA lifted the partial clinical hold on tanezumab al., 1995; Mantyh et al., 2011; Miller and Kaplan, 2001; due to a number of new nonclinical studies and clinical Woolf, 1996). data analyses undertaken to understand how inhibition of Tissue NGF levels are increased in pain states, includ- NGF impacts sympathetic nervous system safety (Pfizer ing inflammatory pain (McMahon, 1996; Wu et al., Inc., 2015). Although the clinical development of tanezu- 2007), leading to both peripheral sensitization of nocic- mab was stopped for over 4 years in total due to the two eptors and central sensitization of dorsal horn neurons partial clinical holds, tanezumab clinical trials resumed in responding to noxious stimuli (McMahon, 1996) (see July 2015 and include clinical risk mitigation measures Fig. 1). In studies investigating administration of NGF, related to joint safety and sympathetic nervous system injection of NGF caused behavioral hyperalgesia in rats safety that were agreed to with FDA. To share our learn- and long-lasting pain sensitivity in humans (Dyck et al., ings from the rigorous evaluation of clinical and nonclini- 1997; Lewin et al., 1994; Svensson et al., 2003). Con- cal safety, we herein review the rationale for targeting the versely, blocking NGF activity via administration of NGF NGF signal transduction pathway for treatment of chronic antibody or Trk A immunoglobulin G (IgG) fusion pro- pain, nonclinical and clinical studies of NGF mAbs, and tein decreased pain-related behavior in animal models strategies used to evaluate safety concerns associated with (Shelton et al., 2008; Zahn et al., 2004). NGF-antibody these agents to remove the partial clinical holds. treatment significantly reduced bone cancer pain-related behaviors in animal models of early and late stage cancer NGF BIOLOGY AND ROLE IN PAIN SIGNALING (Halvorson et al., 2005; Sevcik et al., 2005). Administra- tion of NGF antibody also reversed established hyperal- NGF was first isolated and described based on obser- gesia in a rodent model of autoimmune arthritis (Shelton vations of increased production of nerve fibers in tumors et al., 2005). Thus, blockade of NGF is a promising ther- grafted onto chick embryos (Bueker, 1948). NGF has a apeutic approach for treatment of chronic pain (Mantyh et key role in the developing nervous system, where it pro- al., 2011). motes growth and development of specific populations of Tanezumab is a humanized IgG2Δa mAb targeted primary sensory and sympathetic neurons and contacts against NGF with high selectivity and specificity for NGF with their targets (Mantyh et al., 2011). NGF is also crit- that is currently in development for treatment of chron- ical for survival of these neurons since NGF inhibition ic pain (Abdiche et al., 2008; Mantyh et al., 2011). Tane- during development leads to a marked loss of sensory zumab binds NGF and inhibits NGF interaction with its and sympathetic neurons due to an increase in the magni- receptors (Abdiche et al., 2008; Mantyh et al., 2011). Ful- tude of naturally occurring cell death (Gorin and Johnson, ranumab and fasinumab are recombinant, fully human, 1979; Levi-Montalcini and Booker, 1960). NGF mAbs that bind to NGF and have also been stud- In the adult, NGF is no longer required for survival ied in patients with chronic pain (Mayorga et al., 2016; of primary sensory or sympathetic neurons, but it has a Sanga et al., 2013, 2016; Tiseo et al., 2014). Based on role in pain signaling through the binding of NGF to its current published data, there do not appear to be substan- Vol. 43 No. 1 3 NGF antibodies Fig. 1. NGF levels increase in response to tissue damage, inflammation and in chronic pain states. Short term, NGF increases expression of TrkA receptors and channels at the membrane surface resulting in immediate heat-hypersensitivity. Long term there is retrograde

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