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, E.; Jiang, Guangliang; Jan, C.

doi:10.1016/j.joca.2019.05.028

Cited by 37 publications

(17 citation statements)

References 41 publications

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“…A single intra-articular injection of the TrkA inhibitor GZ389988A has been shown to modestly improve osteoarthritis knee pain at 8 weeks. 197 In contrast, treatment with the oral TrkA inhibitor ASP7962 at a dose of 100 mg BID failed to improve pain and function in patients with knee osteoarthritis after 4 weeks of treatment. 198 Finally, a Phase 1 trial of LEVI-04, an injectable p75NTR fusion protein designed to bind excess NGF, is currently recruiting healthy volunteers and patients with knee OA (NCT03227796).…”

Section: Future Perspectivesmentioning

confidence: 97%

<p>Nerve Growth Factor Signaling and Its Contribution to Pain</p>

Barker¹,

Mantyh²,

Arendt-Nielsen³

et al. 2020

JPR

155

104

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Nerve growth factor (NGF) is a neurotrophic protein essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development. A substantial body of evidence, based on both animal and human studies, demonstrates that NGF plays a pivotal role in modulation of nociception in adulthood. This has spurred development of a variety of novel analgesics that target the NGF signaling pathway. Here, we present a narrative review designed to summarize how NGF receptor activation and downstream signaling alters nociception through direct sensitization of nociceptors at the site of injury and changes in gene expression in the dorsal root ganglion that collectively increase nociceptive signaling from the periphery to the central nervous system. This review illustrates that NGF has a well-known and multifunctional role in nociceptive processing, although the precise signaling pathways downstream of NGF receptor activation that mediate nociception are complex and not completely understood. Additionally, much of the existing knowledge derives from studies performed in animal models and may not accurately represent the human condition. However, available data establish a role for NGF in the modulation of nociception through effects on the release of inflammatory mediators, nociceptive ion channel/receptor activity, nociceptive gene expression, and local neuronal sprouting. The role of NGF in nociception and the generation and/or maintenance of chronic pain has led to it becoming a novel and attractive target of pain therapeutics for the treatment of chronic pain conditions.

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Section: Future Perspectivesmentioning

confidence: 97%

<p>Nerve Growth Factor Signaling and Its Contribution to Pain</p>

Barker¹,

Mantyh²,

Arendt-Nielsen³

et al. 2020

JPR

155

104

View full text Add to dashboard Cite

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“…Two studies using TrkA inhibitors have also been published recently. One showed limited success after intra-articular delivery, 51 and a second oral agent study failed to reach its primary endpoint. 104 Neither agent confirmed direct target engagement.…”

Section: The Course Of Pain In Human Osteoarthritismentioning

confidence: 99%

Peripheral pain mechanisms in osteoarthritis

Vincent

2020

Pain

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There is a well-established historical observation that structural joint damage by plain X-ray correlates poorly with symptomatic disease in osteoarthritis (OA). This is often attributed to the inability to visualise soft-tissue pathology within the joint and the recognition of heterogeneous patient factors that drive central pain sensitisation. A major issue is the relative paucity of mechanistic studies in which molecular pathogenesis of pain is interrogated in relation to tissue pathology. Nonetheless, in recent years, three broad approaches have been deployed to attempt to address this: correlative clinical studies of peripheral and central pain outcomes using magnetic resonance imaging, where soft-tissue processes can be visualised; molecular studies on tissue from patients with OA; and careful molecular interrogation of preclinical models of OA across the disease time course. Studies have taken advantage of established clinical molecular targets such as nerve growth factor. Not only is the regulation of nerve growth factor within the joint being used to explore the relationship between tissue pathology and the origins of pain in OA, but it also provides a core model on which other molecules present within the joint can modulate the pain response. In this narrative review, how molecular and pathological tissue change relates to joint pain in OA will be discussed. Finally, a model for how tissue damage may lead to pain over the disease course will be proposed.

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“…In 2019, two randomised controlled trials targeting high affinity nerve growth factor receptor (TrkA), the receptor through which NGF signals, were published. 139 , 140 In one study, 139 215 participants were randomly assigned to receive twice daily oral dosing with ASP7962, placebo or naproxen for 4 weeks. The study failed to meet its primary endpoint (WOMAC pain subscore).…”

Section: Targeting Nerve Growth Factor To Treat Osteoarthritis Painmentioning

confidence: 99%

“…The study failed to meet its primary endpoint (WOMAC pain subscore). 139 A second study 140 randomly assigned 104 participants to intraarticular GZ389988A or placebo. This study did show improved pain outcomes of the drug compared with placebo, although the effect size was small and of questionable clinical value.…”

Section: Targeting Nerve Growth Factor To Treat Osteoarthritis Painmentioning

confidence: 99%

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Of mice and men: converging on a common molecular understanding of osteoarthritis

Vincent

2020

The Lancet Rheumatology

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Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Molecular interrogation of disease through ex-vivo tissue analysis, in-vitro studies, and preclinical models have radically reshaped the knowledge landscape. Inflammation in osteoarthritis appears to be distinct from that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism. Nerve growth factor has emerged as a robust target in osteoarthritis pain in phase 2–3 trials. These studies, both positive and negative, align well with those in preclinical surgical models of osteoarthritis, indicating that pathogenic mechanisms identified in mice can lead researchers to valid human targets. Several novel candidate pathways are emerging from preclinical studies that offer hope of future translational impact. Enhancing trust between industry, basic, and clinical scientists will optimise our collective chance of success.

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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

Cited by 37 publications

References 41 publications

<p>Nerve Growth Factor Signaling and Its Contribution to Pain</p>

<p>Nerve Growth Factor Signaling and Its Contribution to Pain</p>

Peripheral pain mechanisms in osteoarthritis

Of mice and men: converging on a common molecular understanding of osteoarthritis

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