A Randomized, Placebo-controlled Trial of the Analgesic Efficacy and Safety of the p38 MAP Kinase Inhibitor, Losmapimod, in Patients With Neuropathic Pain From Lumbosacral Radiculopathy

Ostenfeld, Thor; Krishen, Alok; Lai, Robert; Bullman, Jonathan; Green, Jonathan; Scholz, Joachim; Kelly, M.

doi:10.1097/ajp.0000000000000122

Cited by 38 publications

(30 citation statements)

References 49 publications

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“…Potent small-molecule inhibitors of Nav1.7 channels have been found 153–155 , most notably a class of sulfonamide compounds that can be made highly selective for Nav1.7 channels over other sodium channels, and even selective for human Nav1.7 channels over those from other species 156 . Clinical trials of several of these compounds are underway (Table 2), including the Icagen/Pfizer compound PF-05089771 which completed Phase II trials for wisdom tooth removal and primary erythromelalgia 250 , and two compounds (GDC-276 and GDC-0310) developed by Xenon Pharmaceuticals which are being tested in Phase I trials in collaboration with Genentech 251 .…”

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

“…It is uncertain if the trial failed because of a lack of adequate target engagement or differences between chronic (years) lumbosacral radiculopathy and much more acute animal models of neuropathic pain (days/weeks) 251 . Because the preclinical data was not aligned with the patient cohort tested, the significance of the failed trial for other pain types is uncertain, which is true for most neuropathic pain trials..…”

Section: Challenges and Considerations In The Clinical Development Ofmentioning

confidence: 99%

See 1 more Smart Citation

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

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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

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

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

282

246

View full text Add to dashboard Cite

show abstract

“…In the domain of chronic back pain, the Standardized Evaluation of Pain (StEP), which consists of 6 interview questions and 10 physical tests, has been used to evaluate the neuropathic components of spinal pain and to distinguish axial LBP from back pain with signs of a radiculopathy [212]. Indeed, StEP has recently been applied as part of a screening neurological examination to evaluate participant eligibility in an RCT focused on patients with radiculopathy-related neuropathic pain [187]. Other validated tools such as the Michigan Neuropathy Screening Instrument are also increasingly used to assess specific neuropathic conditions (e.g., distal peripheral neuropathy in diabetes) [34].…”

Section: Phenotypic Domainsmentioning

confidence: 99%

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations

Edwards

Dworkin

Turk

et al. 2016

Pain

Self Cite

304

261

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There is tremendous inter-patient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine”, or personalized pain therapeutics (i.e., empirically-based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain, and the success rates for putative analgesic drugs in Phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

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“…Phosphorylation of p38 or extracellular signal-regulated kinase (ERK)-1/2, another MAPK, is necessary for the development and perpetuation of mechanical hypersensitivity, as observed in models of chronic neuropathic6 and acute-to-chronic postoperative pain 3,7,8. Although p38 inhibition has demonstrated some efficacy in neuropathic pain in humans,9,10 its role in this condition remains unclear 11…”

Section: Introductionmentioning

confidence: 99%

Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice

Skopelja-Gardner

Saha

Alvarado-Vázquez

et al. 2017

JPR

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Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) and its substrates (extracellular signal-regulated kinase [ERK] and p38) play an important role in pathophysiological mechanisms of acute postoperative and chronic neuropathic pain in the spinal cord. This study aimed to understand the role of MKP-3 and its target MAPKs at the site of surgical incision in nociceptive behavior. Wild-type (WT) and MKP-3 knockout (KO) mice underwent unilateral plantar hind paw incision. Mechanical allodynia was assessed by using von Frey filaments. Peripheral ERK-1/2 and p38 phosphorylation were measured by Western blot. Cell infiltration was determined using hematoxylin and eosin histological staining. Peripheral phosphorylated ERK-1/2 (p-ERK-1/2) inhibition was performed in MKP-3 KO mice. In WT mice, mechanical hypersensitivity was observed on postoperative day 1 (0.69±0.17 g baseline vs 0.13±0.08 g day 1), which resolved normally by postoperative day 12 (0.46±0.08 g, N=6). In MKP-3 KO mice, this hypersensitivity persisted at least 12 days after surgery (0.19±0.06 g; N=6). KO mice displayed higher numbers of infiltrating cells (51.4±6 cells/0.1 mm2) than WT mice (8.7±1.2 cells/0.1 mm2) on postoperative day 1 (vs 5–6 cells/0.1 mm2 at baseline) that returned to baseline 12 days after surgery (10–12 cells/0.1 mm2). In WT mice, peripheral p-p38 and p-ERK-1/2 expression increased (5- and 3-fold, respectively) on postoperative days 1 and 5, and returned to basal levels 7–12 days after surgery (N=3 per group). Peripheral p-p38 levels in MKP-3 KO mice followed a similar expression pattern as WT mice. Peripheral p-ERK-1/2 levels in MKP-3 KO mice remained elevated 12 days after surgery (2.5-fold, N=3 per group). Administration of PD98059 (MEK inhibitor, N=8, vehicle N=9) reduced p-ERK-1/2 expression in the incised tissue and blocked hypersensitivity in MKP-3 KO mice (N=6). The findings of this study suggest that MKP-3 is pivotal for normal resolution of acute postoperative allodynia, through the regulation of peripheral p-ERK-1/2.

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A Randomized, Placebo-controlled Trial of the Analgesic Efficacy and Safety of the p38 MAP Kinase Inhibitor, Losmapimod, in Patients With Neuropathic Pain From Lumbosacral Radiculopathy

Abstract: Losmapimod could not be differentiated from placebo in terms of analgesia. The lack of response could reflect insufficient losmapimod levels in the spinal cord or differences between lumbosacral radiculopathy and animal models of neuropathic pain.

Cited by 38 publications

References 49 publications

Breaking barriers to novel analgesic drug development

Breaking barriers to novel analgesic drug development

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations

Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice

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