Neflamapimod (INN - generic name - for drug previously code named VX-745)
The investigational drug neflamapimod specifically inhibits the intra-cellular enzyme p38 mitogen activated protein kinase alpha (MAPK alpha). Neflamapimod was discovered through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals, and was licensed by EIP Pharma for development in central nervous system (CNS) disorders.
In an animal pharmacology study conducted by EIP Pharma in Aged Rats with identified cognitive deficit neflamapimod improved cognitive performance (p=0.007) and demonstrated an anti-inflammatory effect in the brain. The Aged Rat model was chosen as to evaluate neflamapimod because the cognitive deficits in that mode had previously been documented to be due to inflammation-induced synaptic dysfunction. These data from that study combined with dose response data in prior animal and clinical studies, have been utilized to identify doses that are highly likely to have pro-cognitive activity in human brain. The predicted doses are 5- fold lower than the dose that demonstrated anti-inflammatory activity and was well tolerated in rheumatoid arthritis, consistent with the drug preferentially distributing to the brain in animals. Importantly, these dose levels provide a sufficient therapeutic window relative to the toxicity findings in long-term animal studies that had led to the discontinuation of the development program in rheumatoid arthritis.
Neflamapimod was also tested in aged transgenic mice that overproduce amyloid-precursor protein (APP) and develop amyloid plaque. In this model, neflamapimod appeared to decrease amyloid plaque burden in the hippocampus, a finding that provided the rationale for utilizing PET amyloid scanning as a biomarker of drug effect in one of the two phase 2a clinical studies.
More recently, neflamapimod was also studied in an induced-stroke model in rats: transient ischemia of sufficient duration was induced such that significant neurologic disability developed without mortality and the neurologic disability did not substantially reverse during follow-up without therapy. These rats were then treated with vehicle (controls) or nelfamapimod. Six weeks of neflamapimod treatment, starting at 48-hours after stroke, led to substantial improvement on multiple parameters of neurologic function compared to vehicle controls (p<0.001 for each of global neurologic scores, motor- and sensory-specific tests). As recovery after stroke is dependent on neuronal and synaptic plasticity, these results further confirm that neflamapimod is active in reversing impaired synaptic plasticity.
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Alam, J. Selective brain-targeted antagonism of p38 MAPK alpha reduces hippocampal IL-1 beta Levels and improves Morris Water Maze performance in Aged Rats. Journal of Alzheimer's Disease 2015; 48:219-227.
Alam J, Blackburn K, Patrick D. Neflamapimod: Clinical phase 2b-ready oral small molecule inhibtior of p38 alpha to reverse synaptic dysfunction in early Alzeimer's disease.
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