Efficacy of a novel, locally delivered TrkA inhibitor in preclinical models of OA and joint pain

Flannery, Carl R.; Moran, Nicholas; Blasioli, Dominick J.; Donahue, Kathleen; Kane, Jeffrey; Gladysheva, Tatiana; Dagher, Ramzi; Fang, Robert C.; Vardanyan, A. V.; Bangari, Dinesh S.; Ho, Chiu‐Ming; Bourque, Andrea; Santos, Mara Lisiane dos; Philbrook, M.; Matthews, G.

doi:10.1016/j.joca.2015.02.100

Cited by 9 publications

(9 citation statements)

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“…Another TrkA inhibitor (GZ389988) has been developed by Sanofi, formulated for IA administration to control OA pain. In the rat MIA model, a single IA injection of GZ389988 resulted in more normal weight‐bearing for four weeks without any significant histopathological changes in joint tissues compared with placebo 103 . Interestingly, IA injection into the contralateral joint had no effect on the ipsilateral limb joint pain, suggesting that IA injection does not result in substantial systemic exposure, which may limit the risk of AEs.…”

Section: Monoclonal Antibodies Targeting Ngfmentioning

confidence: 99%

Anti‐nerve growth factor monoclonal antibodies for the control of pain in dogs and cats

et al. 2019

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Nerve growth factor (NGF) is essential for the survival of sensory and sympathetic neurons during development. However, in the adult, NGF and its interaction with tropomyosin receptor kinase A receptor (TrkA) has been found to play a critical role in nociception and nervous system plasticity in pain conditions. Thus, various monoclonal antibody (mAb) therapies targeting this pathway have been investigated in the development of new pharmacotherapies for chronic pain. Although none of the mAbs against NGF are yet approved for use in humans, they look very promising for the effective control of pain. Recently, species-specific anti-NGF mAbs for the management of osteoarthritis (OA)-associated pain in dogs and cats has been developed, and early clinical trials have been conducted. Anti-NGF therapy looks to be both very effective and very promising as a novel therapy against chronic pain in dogs and cats. This review outlines the mechanism of action of NGF, the role of NGF in osteoarthritis, research in rodent OA models and the current status of the development of anti-NGF mAbs in humans. Furthermore, we describe and discuss the recent development of species-specific anti-NGF mAbs for the treatment of OA-associated pain in veterinary medicine.

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Section: Monoclonal Antibodies Targeting Ngfmentioning

confidence: 99%

Anti‐nerve growth factor monoclonal antibodies for the control of pain in dogs and cats

et al. 2019

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“…GZ389988A is insoluble in water and has been formulated as an aqueous suspension for intra-articular (IA) injection, aiming at sustaining pain reduction and reducing systemic exposure. In rat models of OA and joint pain, GZ389988 showed a significant relief of local knee pain 28 .…”

Section: Introductionmentioning

confidence: 94%

“…GZ389988 was tested in animal OA models, and a 4-week efficacy was observed (the entire observation period due to limitations of animal models 28 ). With this, it was predicted hypothetically that the duration of efficacy in humans could be around 2.5 months.…”

Section: Assessmentsmentioning

confidence: 99%

Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: a randomized, double-blind and placebo-controlled study

Krupka

Jiang

Jan

2019

Osteoarthritis and Cartilage

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Objective: This trial evaluated the efficacy and safety of GZ389988A, a tropomyosin receptor kinase A (TrkA) inhibitor, in subjects with painful knee osteoarthritis (OA). Method: In this single center, double-blind, placebo-controlled and randomized trial, 104 subjects with moderate-to-severe knee OA pain were enrolled to receive a single intra-articular (IA) injection of either GZ389988A or placebo. Efficacy measures were assessed over 12 weeks and included walking pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] A1), overall knee pain, WOMAC A, B, C and total score, Patient Global Impression of Change (PGIC), OMERACT-OARSI responder rate and rescue medication use. Adverse events (AEs) were monitored up to 24 weeks. Results: The primary efficacy endpoint was met with a between-group difference of À7.49 (VAS 0e100) on WOMAC A1 changes over 4 weeks (P < 0.05 favoring GZ389988A). The secondary outcome on WOMAC A1 changes over 12 weeks had a between-group difference of À6.78 (P ¼ 0.064). Among weekly assessments, statistically significant greater improvement in the GZ389988A group was observed in WOMAC A1, overall knee pain and/or WOMAC A at weeks 2e5. Although not statistically significant, improvements over placebo on pain and WOMAC C persisted over 12 weeks. Greater AE incidence was observed in the GZ389988A group including transient and self-limited injection joint inflammatory reactions with a spike of acetaminophen intake within the first week post-injection. Conclusion: IA injection of TrkA inhibitor GZ389988A in knee OA subjects reduced pain with a numerically functional gain and an acceptable safety profile. (ClinicalTrials.gov, NCT02845271).

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“… Reversion of the weight-bearing asymmetry of rats with MIA after 7 days from TrkAd5 inhibitor treatment. Adverse effects were not evaluated Flannery 2015 20 Pain assessment Rat model of MIA Anti-NGF mAb 9 mg/kg, 2 days after MIA induction (s.c.) Reversion of the rat MIA model burrowing deficit after 3 days from mAb treatment. Adverse effects were not evaluated Bryden 2015 21 Pain and joint assessment Rat model of OA Anti-NGF mAb AS2886401-00 0.3 or 1 mg/kg on day 3 (i.v.)…”

Section: In Vivo Preclinical Studies On the Effects Of Anti-ngf Mabs In Animal Models Of Chronic Pain: An Updatementioning

confidence: 99%

“…Similar findings were presented by Flannery et al in a rat mono-iodoacetate (MIA) model. 20 Bryden et al demonstrated that a subcutaneous injection of anti-NGF mAb, in a rat MIA model, reversed deficits in burrowing compared to non-treated mice. 21 To date, few preclinical studies conducted on animal models of chronic pain have assessed both pain and joint changes after anti-NGF mAb treatment.…”

Section: In Vivo Preclinical Studies On the Effects Of Anti-ngf Mabs In Animal Models Of Chronic Pain: An Updatementioning

confidence: 99%

The Role of Anti-Nerve Growth Factor Monoclonal Antibodies in the Control of Chronic Cancer and Non-Cancer Pain

Bimonte¹,

Cascella²,

Forte³

et al. 2021

JPR

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Nerve growth factor (NGF) belongs to the neurotrophin family and plays a fundamental role in the endurance of sensory and sympathetic neurons during embryogenesis. NGF, by interacting with tropomyosin receptor kinase A receptor (TrkA), modulates the pain pathway through the enhancement of the neurotrophic and nociceptor functions. Moreover, it has been demonstrated that NGF is upregulated in patients with chronic pain syndromes, which are difficult to treat. Thus, new non-pharmacological approaches, based on the use of different species-specific monoclonal antibodies (mAbs) targeting the NGF pathway, have been tested for the treatment of chronic pain in preclinical and clinical studies. With regard to preclinical investigations, anti-NGF mAbs have been used for the management of osteoarthritis (OA) and chronic low back pain animal models, with encouraging results. Moreover, anti-NGF mAb therapy is effective in animal models of neuropathic cancer pain. As regards patients with OA, although phase II and phase III clinical trials with tanezumab led to pain reduction, the safety was not observed in all these patients. Here, we review the preclinical and clinical studies on anti-NGF mAb therapy in chronic syndromes, dissect the role of NGF in pain transduction, and highlight the use of anti-NGF mAbs in humans.

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Efficacy of a novel, locally delivered TrkA inhibitor in preclinical models of OA and joint pain

Cited by 9 publications

References 0 publications

Anti‐nerve growth factor monoclonal antibodies for the control of pain in dogs and cats

Anti‐nerve growth factor monoclonal antibodies for the control of pain in dogs and cats

Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: a randomized, double-blind and placebo-controlled study

The Role of Anti-Nerve Growth Factor Monoclonal Antibodies in the Control of Chronic Cancer and Non-Cancer Pain

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