Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (Macaca fascicularis)

Bowman, Christopher J.; Evans, Mark; Cummings, Thomas; Oneda, Satoru; Butt, Mark T.; Hurst, Susan; Gremminger, Jessica-lyn; Shelton, David L.; Kamperschroer, Cris; Zorbas, Mark

doi:10.1016/j.reprotox.2014.10.004

Cited by 15 publications

(11 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the low likelihood of off-target toxicity, one species should be sufficient for safety demonstration and a full definitive developmental toxicity may not be warranted if only confirming an expected effect. In this case (based on other considerations), the Sponsor conducted definitive studies in pregnant cynomolgus monkeys and confirmed the literaturebased effects on the developing nervous system and reduced growth and survival of offspring (Bowman et al, 2015). Potentially important details: Although mAbs have been shown to transfer to the fetus prenatally, other large molecules or even Fab fragments are less likely to cross the placenta into the fetal circulation and thus the "ADME confi-dence" for those molecules may dictate limited embryo-fetal risk if the target is only expressed in the embryo (and not the placenta (Miller et al, 2003;Wakefield, Stephens, Foulkes, Nesbitt, & Bourne, 2011 sufficient using rat alone.…”

Section: Scenariosupporting

confidence: 69%

“…One example is an antinerve growth factor (NGF) mAb intended to treat chronic back pain. There is strong literature supporting the critical role NGF has in pregnancy and development, homozygous gene knockout mice are not viable after weaning and (not surprisingly) numerous effects are observed on the developing nervous system when an "anti-NGF state" is induced in rodents (Bowman et al, 2015;Butt et al, 2014). However, because risk tolerance is lower, the expression database information and the literature base is a good start, but alone were considered insufficient due to degree of target inhibition and target coverage necessary to induce effects that might be relevant for humans.…”

Section: Scenariomentioning

confidence: 99%

See 1 more Smart Citation

Goldilocks’ Determination of What New In Vivo Data are “Just Right” for Different Common Drug Development Scenarios, Part 1

Bowman

Chapin

2016

Birth Defects Research Pt B

View full text Add to dashboard Cite

As alternative models and scientific advancements improve the ability to predict developmental toxicity, the challenge is how to best use this information to support safe use of pharmaceuticals in humans. While in vivo experimental data are often expected, there are other important considerations that drive the impact of developmental toxicity data to human risk assessment and product labeling. These considerations include three key elements: (1) the drug's likelihood of producing off-target toxicities, (2) risk tolerance of adverse effects based on indication and patient population, and (3) how much is known about the effects of modulating the target in pregnancy and developmental biology. For example, there is little impact or value of a study in pregnant monkeys to inform the risk assessment for a highly specific monoclonal antibody indicated for a life-threatening indication against a target known to be critical for pregnancy maintenance and fetal survival. In contrast, a small molecule to a novel biological target for a chronic lifestyle indication would warrant more safety data than simply in vitro studies and a literature review. Rather than accounting for innumerable theoretical possibilities surrounding each potential submission's profile, we consolidated most of the typical situations into eight possible scenarios across these three elements, and present a discussion of these scenarios here. We hope that this framework will facilitate a rational approach to determining what new information is required to inform developmental toxicity risk of pharmaceuticals in context of the specific needs of each program while reducing animal use where possible.

show abstract

Section: Scenariosupporting

confidence: 69%

Section: Scenariomentioning

confidence: 99%

Goldilocks’ Determination of What New In Vivo Data are “Just Right” for Different Common Drug Development Scenarios, Part 1

Bowman

Chapin

2016

Birth Defects Research Pt B

View full text Add to dashboard Cite

show abstract

“…Additional concern comes from the growth factor role of NGF in development. In pregnant cynomolgus monkeys intravenous tenezumab increased stillbirth and infant mortality, decreased infant growth with changes in the peripheral sympathetic and sensory nervous system including developmental neurotoxicity 263,264 . This risk, as well as the possibility of some neurotoxicity in adults will need to be carefully monitored and excluded.…”

Section: Challenges and Considerations In The Clinical Development Ofmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

285

246

View full text Add to dashboard Cite

Acute and chronic pain complaints, while very common, are generally poorly served by existing therapies. The unmet clinical need reflects the failure in developing novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms coupled with the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities to develop new therapeutic strategies and revisit existing targets, including modulating ion channels, enzymes and GPCRs.

show abstract

“…2,42 These sensory ganglia usually are sampled when there is a possibility to be targeted by a test article. 43 –46 Autonomic ganglia generally are obtained for evaluation only as they occur within the walls of hollow nonneural organs sampled as part of the protocol-specified tissue list.…”

Section: Resultsmentioning

confidence: 99%

Nervous System Sampling for General Toxicity and Neurotoxicity Studies in Rabbits

Pardo

Rao²,

Morrison

et al. 2020

Toxicol Pathol

View full text Add to dashboard Cite

Although manuscripts for multiple species recommending nervous system sampling for histopathology evaluation in safety assessment have been published in the past 15 years, none have addressed the laboratory rabbit. Here, we describe 2 trimming schemes for evaluating the rabbit brain in nonclinical toxicity studies. In both schemes, the intact brain is cut in the coronal plane to permit bilateral assessment. The first scheme is recommended for general toxicity studies (tier 1) in screening agents where there is no anticipated neurotoxic potential; this 6-section approach is consistent with the Society of Toxicologic Pathology (STP) “best practice” recommendations for brain sampling in nonrodents ( Toxicol Pathol 41: 1028-1048, 20131). The second trimming scheme is intended for dedicated neurotoxicity studies (tier 2) to characterize known or suspected neurotoxicants where the nervous system is a key target organ. This tier 2 strategy relies on coronal trimming of the whole brain into 3-mm-thick slices and then evaluating 12 sections. Collection of spinal cord, ganglia, and nerve specimens for rabbits during nonclinical studies should follow published STP “best practice” recommendations for sampling the central nervous system1 and peripheral nervous system ( Toxicol Pathol 46: 372-402, 20182).

show abstract

Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (Macaca fascicularis)

Cited by 15 publications

References 39 publications

Goldilocks’ Determination of What New In Vivo Data are “Just Right” for Different Common Drug Development Scenarios, Part 1

Goldilocks’ Determination of What New In Vivo Data are “Just Right” for Different Common Drug Development Scenarios, Part 1

Breaking barriers to novel analgesic drug development

Nervous System Sampling for General Toxicity and Neurotoxicity Studies in Rabbits

Contact Info

Product

Resources

About