SUN-010 A Phase 1 Double-Blind, Randomized, Placebo-Controlled, Single And Multiple Ascending Dose Study Of The Safety, Pharmacokinetics, And Pharmacodynamics Of The Novel Thyromimetic ABX-002 In Healthy Adult Participants

Abstract Disclosure: B.B. Franey: None. A. Heldreth: Takeda, General Electric. H.D. Smith: None. J.A. Everett: None. A.D. Barry: None. J. Harris: None. J. Zhou: BlossomHill Therapeutics, Inc. T.S. Scanlan: T.S.S is a founder of and advisor to Autobahn Therapeutics. J.A. Vivian: None. G. Davar: None. Major depressive disorder (MDD) is one of the leading causes of disability, impacting 280 million people around the world. The current standard of care for MDD is the use of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs). However, more than 50% of patients receiving SSRI/SNRIs will have an inadequate response to their antidepressant therapy (ADT), resulting in the need to switch treatments or augment current treatment with additional pharmaceutical agents. Two such augmentation agents are the thyroid hormones (TH) triiodothyronine (T3) and thyroxine (T4). While T3 and T4 have demonstrated efficacy as adjunctive treatments for MDD, these hormones have a very narrow therapeutic range limited by peripheral side effects. ABX-002 is a novel CNS-targeted thyromimetic exerting its effects through the active metabolite and thyroid hormone beta-receptor (TRβ) preferring agonist, LL-340001. With its preferential CNS distribution, ABX-002 may augment the clinical response of patients with MDD who have had an inadequate response to their ADT. ABX-002 and the active metabolite, LL-340001, were studied for safety, tolerability, pharmacokinetics, and pharmacodynamics in a Phase 1/First-in-Human study in healthy adult participants. For both the single ascending dose (SAD) and multiple ascending dose (MAD) portions of the study, ABX-002 was safe and well-tolerated up to the highest doses tested of 150 μg and 5.6 μg, respectively. All 48 participants completed the study, and no serious adverse events (AEs) were reported. Most AEs reported were mild (Grade 1) in severity. There were no changes of clinical relevance observed in laboratory testing, vital signs, physical/ophthalmic examination, electrocardiogram (ECG), or electroencephalogram parameters.TH class-related effects were evaluated with analysis of heart rate, systolic/diastolic blood pressure, ECG/24h Holter monitoring, and thyroid function testing. There was no appreciable difference identified in heart rate or blood pressure between those receiving ABX-002 vs. placebo. Additionally, T4, T3, and thyroid stimulating hormone (TSH) remained within normal range across cohorts, except for a mild transient reduction of TSH at the 150 μg dose in the SAD. Clinical evidence of CNS target-engagement after administration of ABX-002 was demonstrated in the MAD; there were modest, tolerable, and reversible mood-altering effects at 5.6 μg, consistent with overtreatment of thyroid hormone medication. ABX-002 is being developed as an adjunctive treatment for MDD and bipolar depression. With its favorable safety and tolerability profile observed to date, preferential CNS distribution, and TRβ selectivity, ABX-002 has the potential to differentiate from TH and standard of care ADT, while augmenting the clinical response of patients who have failed to respond adequately to their current therapies. Presentation: Sunday, July 13, 2025