Evaluation of the Safety and Efficacy of NE3107, a Safe, Orally Bioavailable, Blood-Brain Barrier-Permeable Anti-Inflammatory and Insulin-Sensitizing Agent for Treatment of Long COVID

Background: An estimated 18,000,000 adults and 24,000 to 42,000 Veterans in the U.S. suffer from Long COVID, a condition occurring in people months after infection with the causative agent of the COVID-19 pandemic, SARS CoV-2 virus. Symptoms, including fatigue, cognitive dysfunction and sleep disturbances, are debilitating and there are no non-pharmacological or pharmacological therapies effective for treatment. Increasing evidence points to persisting inflammation in the periphery and central nervous system contributing to symptoms in at least 50% of patients. Evidence strongly suggests that persisting circulating viral spike protein drives this inflammatory signaling via stimulation of toll-like receptors (TLR) 2 and 4. NE3107, a chemical derivative of naturally occurring human adrenal sterol beta-androstenetriol (beta-AET), is an orally available, safe, insulin-sensitizer that has shown anti-inflammatory activity in murine models of TLR-driven inflammation including Parkinson's disease (PD). Our current understanding of the mechanism of action of NE3107 is that it binds the MAP kinase ERK, likely in a compartmentalized spatiotemporal scaffold (TPL2/MEK/ERK) that directs pro-inflammatory signaling downstream of TLR engagement. Given the blood-brain-barrier permeability of NE3107 and its ability to inhibit the TLR4/TPL2/MEK/ERK pathway that plays a key role in amyloidβ-mediated activation of microglia, neuroinflammation and insulin resistance in Alzheimer's Disease (AD), NE3107 is currently being evaluated in a phase 3 trial in AD. In a phase 2a 3-month study in 23 subjects with cognitive decline due to degenerative dementia, NE3107 resulted in significant improvements in cognition correlated with a reduction in inflammatory cytokine tumor necrosis factor (TNF). PRMRP Topic Area: The proposed project relates to Long-COVID under the Neuroscience topic Neuroinflammatory responses to emerging viral diseases. The research project addresses the PRMRP strategic goal to develop and evaluate novel treatments, strategies, or therapeutic targets for associated neurological diseases and psychological conditions, which may include repurposing existing drugs. Hypothesis/Objective(s): The Phase 2b study is designed to test that NE3107 will be safe and well-tolerated and result in improvement in symptoms of fatigue, sleep disorders and cognitive impairment in Long COVID patients. NE3107, which is blood-brain-barrier-permeable, is anti-inflammatory but not immunosuppressive, and possesses unique attributes for targeting the mechanisms underlying the neurological symptoms of Long COVID. NE3107 has a good safety profile to date and has a low risk for drug:drug interactions, which may be important should viral persistence prove to be a contributing factor to chronic inflammation. Specific Aims: To determine whether treatment with NE3107 (20 mg BID) for 3 months is safe and effective in improving fatigue, cognitive impairment and sleep disorders in Long COVID patients. To determine if effectiveness is associated with a change in biomarkers predicted/shown to be impacted by insulin-sensitizing anti-neuroinflammatory activity of NE3107. This includes biomarkers of neuronal injury (NfL), neuroinflammation (GFAP), glycemic control and peripheral inflammation (IL-6 and TNF). Study Design: A phase 2b randomized (1:1), placebo-controlled, multicenter trial conducted with 200 patients with Long COVID randomized to treatment with NE3107 (20 mg BID) or matching placebo for 3 months. The selected dosage, 20 mg (1 x 20 mg capsule) 2X daily, is what is currently being evaluated in our on-going phase 3 clinical study in AD. Clinical Impact: The successful completion of this study will provide the basis for an "end of phase 2" meeting with the FDA to seek guidance and agreement on a phase 3 clinical development program to support filing of a New Drug Application for NE3107 for the treatment of Long COVID. Depending on the persuasiveness of the data from the proposed study, it can potentially support a request for an Emergency Use Authorization from FDA. NE3107 has the potential to be the first FDA approved pharmacological therapy for outpatient treatment of Long COVID. Military Relevance: Prolonged COVID symptoms have a profound impact on an individual's ability to work. Apart from the obvious impact of common symptoms of fatigue and cognitive dysfunction on the ability of active military to perform their duties, the burden in terms of health care and costs is significant: Those with Long COVID can be considered by the DOD to be medically retired and qualify for full retirement benefits, including full health care and a monthly payment. The economic benefit of a treatment for debilitating symptoms of this condition would thus be enormous, and research and funding of treatment options for Long COVID is extremely significant for the military. Less