A multiple-dose toxicity study of tanezumab in cynomolgus monkeys

Abstract

Nerve growth factor (NGF) is an important mediator of pain and hyperalgesia and has become a target of novel analgesic therapeutics. Tanezumab is a humanized IgG₂ antibody that binds NGF with high affinity and specificity. In a study to assess the toxicity and pharmacokinetic properties of tanezumab in adult, male and female, cynomolgus monkeys following weekly intravenous administration of 1, 10, or 30 mg/kg for up to 26 weeks (followed by an 8-week recovery period), tanezumab was well tolerated with no macroscopic or microscopic effects on those brain, spinal cord, nerve, or ganglia sections evaluated. One fifth of tanezumab-treated monkeys developed an antibody response to tanezumab that prevented maintenance of tanezumab exposure between dosing. In the antibody-negative animals, accumulation of tanezumab was observed; steady state was achieved approximately 8 weeks after the first dose of study drug, and exposure to tanezumab was approximately dose proportional with no observed difference between male and female animals. One monkey died during the study; this monkey had findings suggestive of hypersensitivity reaction. The favorable toxicity and pharmacokinetic profile of tanezumab seen in this study supports its further evaluation for the treatment of pain in clinical practice.

Introduction

Nerve growth factor (NGF) has been known to play a role in the development of the nervous system since its discovery some 50 years ago (Cohen, 1960, Levi-Montalcini and Booker, 1960). However, since the early 1990s various roles for NGF in mature adults have also been proposed, including a role in the modulation of neuronal structure and function. It has, moreover, been shown to be an important mediator of pain and hyperalgesia (Della Seta et al., 1994, Lewin et al., 1993, McMahon et al., 1995, Woolf et al., 1994). These findings suggested that NGF may be a viable target of novel analgesic therapeutics. Consequently, there have been several attempts to develop new pain treatments based on NGF antagonism (Hefti et al., 2006, Watson et al., 2008).

Tanezumab is a humanized IgG₂ antibody that has been shown to bind NGF with high affinity and specificity and block binding to both of its known receptors, trkA and p75 (Abdiche et al., 2008). In animal models of arthritis, bone cancer, bone fracture, complex regional pain syndrome, and post-operative pain, tanezumab and its murine precursor, muMab911, have been associated with improvements in pain-related behaviors, with no effect on normal pain sensitivity in naïve animals (Koewler et al., 2007, Sabsovich et al., 2008, Sevcik et al., 2005, Shelton et al., 2008, Shelton et al., 2005). Moreover, the efficacy of tanezumab in reducing pain-related behaviors in some animal models was comparable to, or greater than that achieved with morphine sulfate and superior to that achieved with non-steroidal anti-inflammatory drugs (Halvorson et al., 2005, Jimenez-Andrade et al., 2007, Koewler et al., 2007, Sevcik et al., 2005).

This paper reports the design and results of the most extensive tanezumab non-clinical toxicology study conducted to date – a 26-week multiple dose study with an 8-week recovery period, conducted in cynomolgus monkeys. This study is part of the preclinical safety program conducted before a clinical trial program can be initiated to evaluate the use of tanezumab in humans. Cynomolgus monkeys were chosen as the test species for the program because NGF in this species has identical sequence homology to that in humans and in both species tanezumab binds with high affinity to a common epitope as determined by Plasmon Resonance Binding. Administration to monkeys also presents the opportunity to evaluate possible safety considerations following repeated chronic administration of tanezumab, while minimizing the chances of a universal anti-drug antibody (ADA) response. Tanezumab dose selection (1, 10, and 30 mg/kg) was based on tanezumab exposures observed in a previous 4-week multiple-dose study in the same species, at the same doses, in which the highest dose employed resulted in plasma exposure to drug that was at least 100 times greater than the plasma exposure achieved with the dose anticipated for use in clinical practice. Tanezumab was administered by the intravenous (IV) route in the current study as this is an intended route of administration in humans. The objectives of this study were to assess the potential toxicity of tanezumab and to evaluate its pharmacokinetic (PK) properties in adult monkeys following multiple-dose, weekly, IV administration of 1, 10, and 30 mg/kg for up to 26 weeks.