ALKS 7290: First OX2R Agonist Signal in ADHD, But Phase 1 Proof-of-Concept Cannot Carry Pivotal Weight

Alkermes' ALKS 7290 Shows Clinical Proof-of-Concept in Adult ADHD

Alkermes plc reported positive topline results from a phase 1 proof-of-concept study for ALKS 7290, a novel, investigational orexin 2 receptor (OX2R) agonist for Attention-Deficit Hyperactivity Disorder (ADHD). The study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics in 88 healthy volunteers and 50 adults with ADHD. ALKS 7290 was generally well tolerated across all tested doses. In adult ADHD participants, the drug demonstrated dose-dependent, clinically meaningful improvements on exploratory endpoints, including the Adult ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression-Severity Scale (CGI-S), by day 14 of treatment. These findings mark the first clinical evidence for an orexin receptor agonist in ADHD and support the dose range for the ongoing phase 2 study (NCT07755410), which is currently enrolling and expects data in 2027.

• ALKS 7290 demonstrated clinically meaningful improvements in ADHD symptoms, as measured by the AISRS and CGI-S scales. At day 14, median reductions from baseline in AISRS total scores were 14.0 points for the 20 mg dose and 19.0 points for the 50 mg dose. Similarly, CGI-S scores showed median reductions of 1.0 point for 20 mg and 2.0 points for 50 mg, indicating a shift from moderately or markedly ill to mildly ill.
• The investigational drug, ALKS 7290, was generally well tolerated across all doses tested in both healthy volunteers and adults with ADHD. No serious treatment-emergent adverse events (TEAEs) were reported, and most TEAEs were mild in severity. The most common TEAEs included insomnia, pollakiuria, dizziness, and constipation. No clinically significant findings were observed in hepatic or renal parameters, vital signs, or ECGs, and no participants discontinued treatment in the ALKS 7290 groups.
• ALKS 7290 is a novel, oral orexin 2 receptor (OX2R) agonist, targeting the orexin system which regulates wakefulness, attention, cognition, and mood. These positive phase 1b results provide the first clinical evidence of an orexin receptor agonist's effects in ADHD, supporting the potential of this pathway as a new therapeutic approach. An ongoing phase 2 study (NCT07755410) is currently enrolling approximately 312 adults with ADHD to further evaluate its safety and efficacy, with data anticipated in 2027.

Unlocking New Pathways: Orexin 2 Receptor Agonism in ADHD

The nicotinic acetylcholine receptor (nAChR) system represents a well-characterized emerging therapeutic target in ADHD research. Stimulation of nAChRs — particularly those containing the β2 and α7 subunits, encoded by CHRNB2 and CHRNA7 respectively — has been associated with improvements in attention, working memory, and executive processes mediated by the prefrontal cortex (PFC). The PFC integrates cortical and subcortical inputs to execute cognitive functions directly implicated in ADHD symptomatology, and nicotinic agonist exposure has been reported to enhance these PFC-mediated processes. Mutations in CHRNB2 and CHRNA7 have further been associated with cognitive deficits in humans, reinforcing the relevance of this receptor system as a therapeutic entry point.

Glutamatergic synapses constitute another area of active investigation in neurodevelopmental disorders including ADHD. Dysfunction of glutamatergic transmission — involving α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), N-methyl-d-aspartate receptors (NMDARs), and metabotropic glutamate receptors (mGluRs) — has been identified as a shared pathogenic mechanism across neurodevelopmental disorders affecting learning, sociability, and mood. Deregulation of major scaffolding proteins that govern glutamate receptor positioning and functioning further contributes to synaptic dysfunction, supporting glutamatergic synapses as a potential therapeutic target to ameliorate patient symptomatology across this disease continuum.

The noradrenaline transporter and its inhibition — exemplified by atomoxetine — also continues to attract research interest alongside nAChR-directed approaches. Neuroimaging data indicate that nicotine produces pronounced upregulation of activation in bilateral prefrontal and left parietal cortex during successful response inhibition, with individual effects correlated with trait impulsivity, implicating the nAChR in the neural basis of impulsivity relevant to ADHD. The knowledge base does not have sufficient information on this aspect regarding orexin 2 receptor agonism specifically as an emerging ADHD therapeutic target.

ALKS 7290 Trial Design: From Phase 1b to Ongoing Phase 2

Several randomized controlled trials and pilot studies have examined ADHD interventions across pediatric and adult populations, spanning pharmacological, neurofeedback, behavioral, and cognitive approaches. The studies below represent a cross-section of trial designs, populations, and endpoint frameworks used to evaluate ADHD treatment efficacy.

Orexin Agonism: A Novel Path for Adult ADHD Treatment

The recent positive topline results for ALKS 7290 in a Phase 1 proof-of-concept study for adult Attention-Deficit Hyperactivity Disorder (ADHD) mark a significant moment for the field. As the first clinical evidence for an orexin 2 receptor (OX2R) agonist in ADHD, this development introduces a novel mechanism of action that could reshape treatment paradigms. Current pharmacological options for ADHD, including stimulants like mixed amphetamine salts and non-stimulants such as extended-release guanfacine, have well-established efficacy in addressing core symptoms like inattention, impulsivity, and hyperactivity. However, these treatments are not universally effective or well-tolerated, leaving a substantial unmet need.

ALKS 7290's ability to demonstrate dose-dependent, clinically meaningful improvements on key exploratory endpoints like the Adult ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression-Severity Scale (CGI-S) in adult ADHD participants is encouraging. This suggests that modulating the orexin system, known for its role in arousal and wakefulness, could offer a distinct therapeutic pathway. The general tolerability observed in this early study is also a positive signal, although the long-term safety profile, particularly regarding potential class-specific adverse events like hypersalivation reported with other orexin agonists, will require careful monitoring in subsequent trials.

Strategically, this positions ALKS 7290 to potentially differentiate itself in a crowded market by offering a novel approach. However, the path forward is not without its challenges. The efficacy observed in Phase 1 must be rigorously validated in larger Phase 2 and 3 studies to demonstrate a compelling benefit-risk profile against existing, highly effective treatments. The ongoing Phase 2 study, with data anticipated in 2027, will be critical in determining whether this promising early signal translates into a truly impactful new option for adults living with ADHD.