The novel orexin-2 receptor agonist ALKS 7290 (Alkermes) showed promise for treating adult attention-deficit hyperactivity disorder (ADHD) in early research, topline results from a phase 1B proof-of-concept study suggest.

The findings from the trial showed what the company called “clinically meaningful” improvement in symptoms of ADHD from baseline to day 14 after treatment with a 20- or 50-mg dose of the drug. Improvements, as measured on the Adult ADHD Investigator Symptom Rating Scale (AISRS), were seen as early as day 6.

ADHD severity scores were also improved on the Clinical Global Impression-Severity scale (CGI-S). Additionally, both doses of the novel medication were well tolerated, with no serious treatment-emergent adverse events (TEAEs), the company reported, noting that this is “the first clinical evidence” on the effects of any orexin receptor agonist for treatment of ADHD.

“I’m pretty excited about this class of medication because there’s an unmet public health need for these patients, especially for a non-stimulant,” Michael Halassa, MD, PhD, professor of psychiatry and biomedical engineering at Virginia Tech, Roanoke, told Medscape Medical News.

Halassa was not involved with the current study but has written earlier about a possible role for this drug class in patients with ADHD.

Although this was a small, early study, “there were several things that made the results believable,” including the use of multiple clinical scales, Halassa said, adding that he’s now looking forward to seeing what a phase 2 study may find.

Targeting the Orexin System

Orexin is a neuropeptide that is produced in the lateral hypothalamus and interacts with multiple pathways and neural circuits pertaining to attention, cognition, and mood. ALKS 7290 targets the orexin system.

In the phase 1B double-blind, parallel-group study, the primary outcomes were safety and tolerability in 50 adults with ADHD (mean baseline AISRS total score, 39; median CGI-S score at baseline, 4.0-5.0) and in 88 healthy volunteers. Exploratory efficacy endpoints in just the participants with ADHD included changes on the AISRS and the CGI-S at day 14.

During the 14 days of inpatient treatment, those with ADHD were randomly assigned to receive ALKS 7290 at a total daily dose of 20 mg (n = 20) or 50 mg (n = 20) in split doses or matching placebo (n = 10).

Severity scores on the AISRS were reduced by 14 points from baseline to day 14 for the 20-mg dose of the novel drug and by 19 points for the 50-mg dose. Improvements were also observed at day 6, which was the first assessment time for post-treatment scores.

“Clinically meaningful improvements were [also] observed across AISRS Inattentive and Hyperactivity/Impulsivity subscales,” the company reported.

Phase 2 Study Now Enrolling

As with the AISRS, improvements in CGI-S scores were observed by day 6. At day 14, median score reductions of 1.0 and 2.0 were observed for the 20-mg and 50-mg doses, respectively.

Treatment effects were also shown across several cognitive domains, including working memory, processing speed, and attention.

Additionally, both doses of ALKS 7290 were well tolerated, with most TEAEs deemed to be mild. The most common of these were insomnia, dizziness, change in sustained attention, and constipation. There were no significant changes in hepatic or renal parameters, ECGs, or vital signs.

None of the participants receiving the novel drug dropped out of the study, but two members of the placebo group did withdraw.

The drug was also well tolerated in healthy volunteers who received single- and multiple-ascending doses.

“These data provide early evidence supporting the potential of the orexin pathway to influence the brain’s neural networks that are linked to ADHD,” Greg Mattingly, MD, associate clinical professor of psychiatry at the Washington University School of Medicine, St. Louis, said in the release.

The company noted that a phase 2 study is now enrolling and it hopes to provide data on around 312 participants in 2027. The primary outcome for that study will be AISRS total score change from baseline to week 4 vs placebo.

Potential Treatment Alternative

Halassa said there has been worry in the field about giving stimulants to patients with psychotic disorders and comorbid ADHD because they can worsen psychotic symptoms.

“So if this class of medication ends up showing long-term efficacy without psychotic symptoms, then this could potentially be a great alternative for the types of patients I care for,” he said.

“It’s possible that at least one of these compounds in this class of medication will have a favorable profile,” Halassa added.

He noted that although he would have liked to have seen more detailed data, especially about the ECG findings, this was a study with exploratory endpoints. “And as far as exploration is concerned, I found it pretty compelling,” he concluded.

The study was funded by Alkermes. Halassa reported no relevant financial relationships.