Autobahn Therapeutics, Inc., a biotechnology company developing restorative treatments for people affected by neuropsychiatric disorders, today reported new nonclinical data on the antidepressant mechanism of action for elunetirom, its lead investigational therapy in Phase 2 development for adjunctive treatment of bipolar depression and major depressive disorder (MDD). The data show that elunetirom rapidly increased the number of synaptic connections between neurons and enhances the cellular energy machinery that neurons depend on to build and sustain those connections. Together, these findings provide a cellular framework for the rapid onset and robust magnitude of antidepressant effects observed in Autobahn’s Phase 2 AMPLIFY-BD clinical trial in bipolar depression.

A manuscript presenting these results, titled “Elunetirom, a brain-targeted TRβ prodrug, promotes neuronal plasticity and mitochondrial biogenesis-related signaling in primary neuronal cultures,” is currently under peer review and has been posted to the bioRxiv preprint server. The manuscript is available at https://doi.org/10.64898/2026.07.21.739927.

Thyroid hormone has a long-recognized role in mood regulation, and non-selective thyroid hormone therapies such as liothyronine (T3) and levothyroxine (T4) have shown benefit as augmentation strategies in depression. Their broader adoption, however, has been limited primarily by cardiovascular, skeletal, and metabolic effects and by the associated monitoring burden. As a brain-directed prodrug, elunetirom was designed to address those limitations by preferential distribution to the central nervous system, where it is converted into the receptor-active thyromimetic LL-340001 by fatty acid amide hydrolase (FAAH), an enzyme enriched in the brain.

“There is a substantial body of evidence that depression involves impairments in both synaptic plasticity and cellular bioenergetics, which are usually discussed as separate problems requiring separate solutions,” said Stephen M. Stahl, M.D., Ph.D., Professor of Psychiatry at the University of California San Diego and a co-author of the manuscript. “What is notable about these recent results is that a single mechanism appears to engage both. Elunetirom does what a thyroid receptor agonist ought to do developmentally, which is promote neurite growth and synapse formation. Strikingly, it does so in mature neurons, on a timescale of hours rather than weeks, and while increasing the cell’s energy-producing capacity rather than drawing it down. It also preserves synapses under amyloid challenge, which suggests the mechanism is not only constructive but protective. What excites me is the prospect of a brain-penetrant thyroid hormone receptor agonist for the treatment of mood disorders that acts where it needs to, without the cardiac and skeletal exposure and associated monitoring burden that have limited the approach historically.”

Key Findings

Nonclinical studies evaluated elunetirom and LL-340001 in primary rodent cortical and hippocampal neuronal cultures, with brain-derived neurotrophic factor (BDNF), the brain’s principal neurotrophic growth factor, as the positive control. Key findings are as follows:

  • Rapid and sustained synaptogenesis: In mature hippocampal neurons, elunetirom significantly increased the neurite network and the number of synapses per neuron within 24 hours, with effects persisting through 72 hours and comparable in magnitude to BDNF.

  • Enhanced bioenergetic capacity: LL-340001 increased the number of functional mitochondria, the structures that generate cellular energy, and raised ATP content, alongside increases in nuclear PGC-1α and NRF2, transcription factors that govern mitochondrial production and oxidative stress defense. These indicate engagement of the mitochondrial biogenesis program that supports the substantial energy demands of synaptic remodeling.

  • Synaptic protection under stress: When mature neurons were challenged with amyloid-β, a protein fragment that drives synapse loss, LL-340001 preserved synapse number to a degree comparable to BDNF, indicating defense of existing connections.

  • A distinct route to neuroplasticity: The increase in cortical neuron number was attenuated by a TrkB antagonist, implicating BDNF-linked signaling, and was not blocked by a 5-HT2A antagonist, the receptor pathway required for the effects of psychedelics. Conversely, the antagonist blocked psilocin in the same experiment, confirming the block was effective.

Additional findings, including effects on neurite growth and branching in developing cortical neurons, are described in the manuscript.

“These experiments provide valuable mechanistic insight into the cellular rationale for the speed and magnitude of response we observed with elunetirom in AMPLIFY-BD, where patients improved significantly by the second week of treatment,” said Jason Harris, Ph.D., Chief Scientific Officer of Autobahn Therapeutics and corresponding author of the manuscript. “The structural changes observed were both rapid and durable, with synapse number elevating within 24 hours and deepening out to 72 hours, which is distinct from what we’ve seen with neurotransmitter-based mechanisms. Seeing the mitochondrial and ATP changes emerge in the same neurons gives us a clear account of how those connections are built and then sustained. Importantly, these effects did not depend on 5-HT2A signaling, which sets elunetirom apart from classic psychedelics. As the field looks for ways to capture the rapid, pro-plastic benefits of newer antidepressant approaches without the complexity of supervised in-clinic dosing, we believe elunetirom’s oral, once-daily profile and novel thyroid hormone receptor mechanism could offer a compelling new option for patients with MDD and bipolar depression.”

Elunetirom is the first CNS thyroid hormone receptor agonist to receive Fast Track designation from the U.S. Food and Drug Administration for the adjunctive treatment of bipolar depression. Positive topline clinical results in the Company’s Phase 2 AMPLIFY-BD trial in patients with bipolar depression show that adjunctive elunetirom achieved a clinically meaningful 16.8-point mean reduction in HAMD-17 total score at Week 6 (p<0.001), with a 75% response-50 rate and 50% remission rate and statistically significant improvement observed as early as Week 2. Elunetirom was generally safe and well tolerated, with no severe or serious treatment-related adverse events. Autobahn plans to present full results from the AMPLIFY-BD trial at an upcoming medical conference in the second half of 2026.

Autobahn is also evaluating elunetirom as an adjunctive treatment for MDD in its ongoing Phase 2 AMPLIFY trial (NCT06633016), with topline data expected in the third quarter of 2026.

About Elunetirom

Elunetirom (ABX-002) is an investigational, oral, once daily, brain-penetrant small molecule prodrug that targets CNS thyroid hormone receptors (CNS-TRs). Elunetirom is believed to uniquely boost energy and plasticity in the brain through improving mitochondrial health, increasing cellular energy production, and driving neuroplastic changes in the CNS, offering a potentially fundamentally different mechanism to treat depression and other CNS disorders. Elunetirom is designed to enhance beneficial neurobiological activity at CNS-TRs while also reducing the liabilities of peripheral thyroid hormone receptor activity from the administration of synthetic thyroid hormone (e.g., triiodothyronine, T3), a treatment which has shown efficacy in numerous placebo-controlled human studies across MDD and bipolar disorder depression. In nonclinical and clinical studies, elunetirom has demonstrated optimized PK properties, target engagement in brain regions associated with depression, and a favorable safety and tolerability profile. Elunetirom has been granted Fast Track designation by the U.S. Food and Drug Administration for the adjunctive treatment of bipolar depression and is being evaluated in clinical studies as a potential adjunctive treatment for MDD and bipolar depression.

About Autobahn Therapeutics

Autobahn Therapeutics, Inc., is a biotechnology company developing a portfolio of neuropsychiatric clinical candidates leveraging its brain-targeting chemistry platform. Autobahn aims to unlock new therapeutic opportunities through precision tuning of CNS exposure, pursuing validated clinical and biologic targets, and guiding development with biomarkers. The company’s pipeline is led by elunetirom, a CNS thyroid hormone receptor (CNS-TR) agonist being developed as a potential adjunctive treatment for people with major depressive disorder and bipolar disorder depression, including those with atypical depression, a highly prevalent and underserved subpopulation of depression. For more information, visit www.autobahntx.com.

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