Insulin-sensitizing NE3107 in Improving Sleep and Fatigue in Subjects With Traumatic Brain Injury

A growing body of literature recognizes neuroinflammation as a pivotal contributor to the pathogenesis of TBI. A surge of inflammatory cytokines and chemokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), often follows TBI, leading to a complex cascade of secondary events that ultimately result in neuronal damage and long-term consequences.

It has been shown that patients with mild TBI have higher plasma inflammatory cytokine levels than those without TBI at both 24 hours and 6 months following initial injury.The activation of these inflammatory mediators has been demonstrated in both cerebrospinal fluid (CSF) and serum of TBI patients. Elevated levels of TNF-α in CSF and serum have been associated with injury severity and unfavorable outcomes in TBI.

IL-1, IL-6, and TNF-α induce the extracellular signal-regulated kinase (ERK) pathway, promoting neuroinflammation. Furthermore, NF-kB, a crucial transcription factor in the inflammatory response, plays a significant role in amplifying neuroinflammation post-TBI, mediating the expression of several inflammatory cytokines and contributing to neuronal apoptosis and cognitive impairment.

Neuroinflammation's contribution to sleep disturbances, fatigue, and cognitive impairment has been increasingly recognized. These inflammatory cytokines may influence the hypothalamic-pituitary-adrenal (HPA) axis and disrupt sleep architecture, leading to sleep disturbances and fatigue. Further, they are known to induce synaptic alterations and neuronal apoptosis, contributing to cognitive impairment.

Chronic, low-grade inflammation often ensues post-TBI, contributing to the persistent and potentially insidious process leading to long-term impairment and diminished quality of life.

Apart from neuroinflammation, intracranial insulin resistance, another secondary consequence of TBI, plays a significant role in the pathogenesis of TBI. Insulin resistance has been observed in TBI patients, and it's linked to worse outcomes. In mouse models, induced TBI has been shown to demonstrate reduced glucose uptake in mice brains on positron emission tomography (PET) scans, consistent with the insulin resistance that has been seen in TBI patients. Insulin resistance may exacerbate neuroinflammation, disrupt synaptic plasticity, and contribute to cognitive deficits, further compounding the injury's impact.

If these symptoms remain untreated, they can significantly impair quality of life, limiting independent living and reducing the ability to perform daily activities. They can also predispose individuals to mental health disorders such as depression and anxiety and lead to a higher risk of chronic diseases and premature death.

Currently, there is no therapeutic option to halt or fully reverse the sequelae from traumatic brain injuries or the attendant neurophysiological deterioration. Other conditions with similarly limited-to-no available and effective treatment strategies, including Alzheimer's disease, share an overlapping deteriorative quality relating to neuroinflammation and even reduced insulin functioning. A promising area of research among traumatic brain injury and Alzheimer's treatment is investigating the use of insulin synthesizers; this study group has also initiated a project involving NE3107 among patients with Alzheimer's disease (IND 159271). In addition to IND 159271, several Phase 3 studies had been previously initiated and/or completed with compounds such as Semaglutide, a hormone that stimulates insulin signaling, Metformin, an insulin synthesizer , and NE3107, an anti-inflammatory insulin-sensitizing agent.

In this study, the drug under investigation is NE3107 (17a-ethynyl0androst-5-ene-3b, 7b, 17b-triol). NE3107 is a small, blood-brain permeable molecule with anti-inflammatory and insulin-sensitizing properties. The mechanism of action for NE3107 involves selective inhibition of inflammatory mediators.