Nancy A. Melville

June 09, 2017

MIAMI – Medications in development for the treatment of attention-deficit/hyperactivity disorder (ADHD) target specific behaviors, such as impulsive aggression, and genes that involve the glutamatergic network, new research shows.

In the first of two studies presented here at the American Society of Clinical Pharmacology (ASCP) Annual Meeting, researchers reported on improvements in the management of impulsive aggression in children with ADHD with long-term therapy, lasting more than 6 months, of extended-release molindone (SPN-810, Supernus) as an adjunct to stimulant monotherapy.

Previous studies have suggested that more than 50% of children with ADHD exhibit impulsive aggression at baseline, and the symptom is often unresponsive to ADHD medications, said presenter Toyin Adewole, MD, an employee of Supernus Pharmaceuticals, in presenting the findings in a Pharmaceutical Pipeline session at the meeting.

"Impulsive aggression is often refractory to ADHD-targeted therapy, and guidelines recommend adjunctive aggression-targeted therapy when impulsive aggression persists despite ADHD treatment. There is currently no FDA-approved medication specifically for use as adjunctive therapy to treat refractory impulsive aggression in children with ADHD," she said.

Previous research has shown that immediate-release adjunctive molindone improves disruptive and aggressive behavior in children. The current study was an open-label extension of the double-blind, placebo-controlled study. Assessment of the overall clinical response was conducted for a period of up to 6 months.

Study participants were between the ages of 6 and 12 years and had been diagnosed with ADHD with aggression, as determined by having a score of 24 or higher on the Retrospective-Modified Overt Aggression Scale (R-MOAS).

Of the 78 patients enrolled, 52 (67%) completed the study. Withdrawal of consent (11.5%) was the most common reason for failure to complete the study.

In the double-blind study, median changes in R-MOAS scores from baseline were -31.5 for patients who received the maintenance dose of 18 mg/day, -25.0 for the group that received 27 mg/day, and -27.0 for the group that received 36 mg/day. These changes were maintained at 6 months in the 18- and 36-mg/day groups. For patients who received 27 mg/day, there was an increase of 10 points in R-MOAS scores in the extension period.

Treatment-related adverse events increased with dose and ranged from 13% in the 9-mg/day group to 33% in the 36-mg/day group. The most common adverse events believed to be treatment related included sedation (12%), weight gain (10%), and increased appetite (9%).

Two patients developed extrapyramidal symptoms, including dyskinesia (n = 1) and dystonia (n = 1). Symptoms resolved either on their own or with a dose reduction.

Adverse events resulted in seven patients discontinuing treatment. These adverse events were aggression, weight gain, and tachycardia.

"SPN-810 was generally well tolerated, and there was a relatively low rate of discontinuation due to adverse events," Dr Adewole said.

In commenting on the study, Melvin D. Oatis, MD, a psychiatrist and clinical supervisor at the Child Study Center, New York University School of Medicine, New York City, noted the need to clarify the role of impulsive aggression in ADHD.

"It's important to be careful to separate impulsiveness in ADHD with impulsive aggression, because aggression is not a symptom of ADHD," he told Medscape Medical News.

He added that psychotherapy should be a key aspect of treating impulsive aggression.

"If the child is displaying aggression, they should be receiving therapy such as behavioral modification to better understand how to express their anger in an appropriate way.

"This medication is also associated with a number of potential side effects, so I would always recommend starting with behavioral therapy and optimize the course of treatment for ADHD before moving on to something else," Dr Oatis said.

A Potential Genetic Pathway

The session also featured results from another ADHD drug – the novel glutamate modulator drug AEVI-001 (Aevi Genomic Medicine). In a multicenter phase 2 study, the drug failed to meet its primary endpoint of a greater reduction of symptoms, as determined using total score on the ADHD Rating Scale (ADHS-RS), in comparison with placebo in children and adolescents with mutations in metabotropic glutamate receptors. However, some encouraging findings were reported in subanalyses.

Results on key prespecified parameters did show significantly greater responses with AEVI-001 (n = 46) compared to placebo (n = 50), including proportion of patients who had a 30% or greater reduction in ADHD-RS-5 total score (70% in the AEVI-001 group vs 42% in placebo; P < .05); a CGI-I score of 1 or 2 (56.5% vs 32%; P < .05); and composite of the two (56.5% vs 32%; P < .05), reported presenter Liza A. Squires, MD, head of neuroscience with AEVI Genomic Medicine.

Importantly, results from post hoc analyses showed significantly greater responses in patients with mutations in nine key genes of interest involving glutamatergic networks.

A subset analysis of the patients who had the identified genes of interest (n = 43) showed an improvement in ADHD-RS-5 total score change in comparison with the group that received placebo that was apparent at week 1, using an optimized dose of up to 400 mg BID. The improvement was significant through week 6 (P < .005).

Dr Squires noted that the most prevalent of the nine genes was the contactin 4 gene (CNTN4), which was present in 19% of the randomized sample of adolescents with ADHD.

"Contactin 4 is a cell-adhesion molecule which is important in neuronal connectivity and is important in development and throughout the lifespan," Dr Squires explained.

There was a trend favoring the AEVI-001 group over placebo in patients carrying the CNTN4 mutation (P = .09) in the ADHD-RS-5 total score change by endpoint and visit, but the difference was significant compared to placebo when the uncorrected Wilcoxan rank sum test was used (P = .03), Dr Squires said.

"We found that predictors of treatment response were having mutations in the nine-gene subset. CNTN4 mutations were the most prevalent and were associated with the most robust clinical response, and the clinically meaningful response in the nine-gene subset was largely attributable to the CNTN4 subgroup," she said.

Adverse events were considered mild, with fatigue among the most common, and the drug was well-tolerated, Dr Squires said.

A separate study conducted by the Aevi researchers in collaboration with the Center for Applied Genomics at the Children's Hospital of Philadelphia found that among 1013 children and adolescents with ADHD, 26% of children and 20% of adolescents tested positive for the CNTN4 mutation. Those patients were significantly more likely to demonstrate disruptive behaviors, as well as problems involving anger control and inappropriate movements, according to parent reports.

Dr Oatis commented that the findings could have value, but the clinical utility may be limited.

"It's helpful to look at markers showing variability in ADHD, because it's always good to have additional information, but this is clearly going to only be a subset of the greater ADHD population, and the question I would have is how cost-effective would this be. It warrants far more investigation, but I applaud the researchers for looking at another pathway that might be helpful," he said.

Dr Adewole is an employee of Supernus. Dr Squires is an employee of Aevi Genomic Medicine. Dr Oatis is on the speaker's bureau for Neos. He disclosed no financial relationships related to the studies.

American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting. Abstracts 3001014 and 3000860, presented May 31, 2017.


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