ELUNETIROM, A FIRST-IN-CLASS, BRAIN-TARGETING, ANTIDEPRESSANT CANDIDATE IN PH2 DEVELOPMENT, TRIGGERS ROBUST BIOENERGETIC AND NEUROPLASTIC IMPROVEMENTS IN PRECLINICAL STUDIES

Background

Impaired neuroplasticity, synaptic loss, and dysfunctional mitochondria in the cortical and limbic regions of the brain are hallmarks of many neuropsychiatric disorders. The thyroid hormone, T3, drives neuroplasticity during pre-and postnatal development via upregulation of both brain-derived neurotrophic factor (BDNF) expression and mitochondrial activation. T3 acts on nuclear hormone receptors to directly stimulate neuritogenesis and synaptogenesis and supports the increased energy demands of the growing neurons. While T3 has shown benefit in the adjunctive treatment of major depressive disorder (MDD), it is underutilized primarily due to concern for adverse cardiac effects. We designed the braintargeting thyroid hormone receptor agonist prodrug, elunetirom, to be CNS targeting and, potentially, act like T3 as an antidepressant but without the undesirable side-effects of T3. In a phase 1 study of elunetirom, no CNS dissociative or clinically meaningful adverse cardiac effects were observed at any of the dose levels explored.

Methods

The effects of elunetirom and its active metabolite were examined in a series of in vitro and in vivo assays relevant to neuroplasticity and the treatment of major depressive disorder and bipolar depression. Cortical and hippocampal neurons were isolated from Wistar rat embryos. All experimental protocols in animal studies were approved by the appropriate Institutional Animal Care and Use Committee and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Analysis of variance (ANOVA) was performed on the resulting data; Fisher’s test was used for pairwise comparisons, and p value ≤ 0.05 was considered significant.

Results

Elunetirom and it’s active metabolite demonstrated significant effects on measures of neuroplasticity and mitochondrial health in primary rat neuronal cultures. In a primary culture of cortical neurons, the active metabolite showed significant increases in number of neurons, neurite length, number of roots, and number of neurite extremities. In a primary culture of mature hippocampal neurons, elunetirom also significantly increased markers of mitochondrial biogenesis and synaptogenesis, even in the presence of the neuronal insult amyloid ꞵ 1-42. In all experiments, elunetirom’s and its active metabolite’s effects were comparable to those achieved with the positive control BDNF (50 ng/mL).

Conclusions

Elunetirom is a brain-targeting thyroid hormone receptor agonist prodrug that is in Phase 2 clinical development for MDD and bipolar depression. Elunetirom drives robust neuroplastic effects and improves mitochondrial health in brain neurons. Preclinical and clinical data suggest that elunetirom has the potential to have a rapid and enduring antidepressant effect in humans without cardiac side effects. These potential therapeutic effects are the result of direct actions on the genes that drive restorative bioenergetics and neuroplasticity in brain (e.g., Ppargc1a → PGC-1α protein, Nfe2l2 → NRF2 protein, Bdnf → BDNF protein ).