ALKS 7290, Alkermes' (Nasdaq: ALKS) oral orexin 2 receptor (OX2R) agonist, produced dose-dependent reductions in attention-deficit hyperactivity disorder (ADHD) symptom scores in a small proof-of-concept study, according to the company. The results represent the first clinical evidence of an orexin receptor agonist producing measurable effects on ADHD symptoms, according to Alkermes, and provide a mechanistic rationale for advancing the drug into a larger efficacy study.
The Phase Ib proof-of-concept study enrolled 50 adults with ADHD in a double-blind, placebo-controlled, parallel-group design. Following a two-week washout of existing ADHD medications, participants were randomized 4:1 to receive ALKS 7290 at a total daily dose of 20 mg (n=20) or 50 mg (n=20), administered in split doses, or placebo (n=10) for 14 days of inpatient treatment. The study's primary objective was safety and tolerability; changes on clinical scales were exploratory endpoints, and the study was not powered to detect statistically significant differences between groups.
At day 14, median reductions from baseline on the Adult ADHD Investigator Symptom Rating Scale (AISRS) — a 54-point clinician-administered measure — were 14.0 points for the 20 mg dose and 19.0 points for the 50 mg dose, against a baseline median of approximately 39. On the Clinical Global Impression-Severity scale, median reductions were 1.0 and 2.0 points for the respective doses, representing a shift to "mildly ill" from "moderately or markedly ill." Improvements on both measures were observed as early as day 6. EEG-based biomarkers and cognitive performance tests showed treatment effects across processing speed, working memory, and attention, which Alkermes said informed dose selection for Phase II. No serious treatment-emergent adverse events were reported; the most common adverse events occurring in 10% or more of treated participants were insomnia, pollakiuria, dizziness, change in sustained attention, micturition urgency, and constipation. There were no discontinuations among ALKS 7290-treated participants.
ALKS 7290 activates OX2R, a receptor through which orexin regulates wakefulness and neural circuits involved in attention and cognition. The mechanism is distinct from currently approved ADHD therapies, which include dopaminergic and noradrenergic stimulants, norepinephrine-targeting non-stimulants, and α2-adrenergic agonists. More recently, Otsuka's Simtriyo (centanafadine), a norepinephrine, dopamine, and serotonin reuptake inhibitor, received FDA approval in July 2026. If the early signal translates into later-stage efficacy, ALKS 7290 could represent a new pharmacological approach to ADHD.