Centanafadine ‘Clinically Meaningful' for Adult ADHD

Medscape

2 days ago

LOS ANGELES — The novel norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) centanafadine (Otsuka Pharmaceutical Co., Ltd.) is effective and 'clinically meaningful' for adult attention-deficit/hyperactivity disorder (ADHD), new research suggested.
In a combined analysis of two phase 3 trials with a total of 859 adults, more patients who received the NDSRI had at least an 18-point improvement at week 6 on the ADHD Investigator Symptom Rating Scale (AISRS) total scores compared with patients on placebo.
Additionally, a significantly greater percentage of the active treatment groups showed improvement in the measure's hyperactivity/impulsivity and inattention subscales.
Lenard A. Adler, MD
But we weren't just interested in statistically significant change but in change 'that means something,' said principal investigator Lenard A. Adler, MD, director of the Adult ADHD program and professor of psychiatry at the New York University (NYU) Grossman School of Medicine, New York City.
'In other words: What do we know is a significant amount of change in patients receiving a compound? That's always a question because we want to get patients well and not just better,' Adler told Medscape Medical News .
The findings were presented on May 19 at the American Psychiatric Association (APA) 2025 Annual Meeting.
A high-dose, pediatric version of the drug was similarly effective for both children and adolescents in two additional phase 3 trials also presented at the meeting by Adler and colleagues.
'Gives a Benchmark'
Centanafadine 'is a triple reuptake inhibitor, so it's not a classical stimulant,' said Adler. 'It's a compound that offers a unique profile.'
Investigators pooled data from two identically designed phase 3 trials looking at the drug in patients with a primary diagnosis of ADHD. Together, this included 859 adult patients, with a mean age of 35 years (52% men; 80.3% White).
The mean baseline total score on the semi-structured AISRS scale was 38.8 ('moderately ill'), with the mean AISRS inattention score 21.6 ('severely ill') and the mean AISRS hyperactivity/impulsivity score 17.2 ('moderately ill').
The AISRS is conducted as an interview between patient and clinician.
'We also recorded data on clinicians' global impression of severity and global impression of change and then used those as anchors to look at the clinically meaningful within-patient change for the AISRS,' co-investigator Caroline Ward, PhD, director of the Global Clinical Development at Otsuka Pharmaceutical Companies, told Medscape Medical News.
All participants were randomly assigned to receive centanafadine at 200 mg (n = 287) or 400 mg (n = 287) or a matching placebo (n = 285).
Results showed that the mean change on the AISRS total score at week 6 was −12.1 and −12.5 for the centanafadine 200 mg and 400 mg groups, respectively, vs −8.1 for the placebo group ( P = .002 and .0009).
In addition, 24% of the 200 mg group and 25.4% of the 400 mg group achieved an 18-point or greater improvement in AISRS total score from baseline to week 6 compared with 15.4% of the placebo group (ratio of response rate [RR], 1.70; P = .002 and RR, 1.71; P = .001, respectively).
A 10-point or greater improvement on the AISRS inattention subscale was achieved by 26.1% of the 200 mg group and 23.3% of the 400 mg group compared with 16.5% of the placebo group (RR, 1.71; P = .001 and RR, 1.45; P = .03, respectively); and an 8-point or greater improvement on the hyperactivity/impulsivity subscale was achieved by 26.5% and 28.6% of the 200 mg and 400 mg groups, respectively, compared with 20% of the placebo group (RR, 1.38; P = .03 and RR, 1.47; P = .01, respectively).
The 200 mg and 400 mg groups also reached the 'clinically meaningful within-patient change AISRS threshold' for the first time earlier than the placebo group ( P = .0006 and P < .0001, respectively).
Looking at meaningful change 'gives clinicians a benchmark,' said Adler.
Pediatric Safety and Efficacy
The investigators also presented results from two other randomized phase 3 trials that assessed the drug in children between the ages of 6 and 12 years (n = 480; 58% boys) and adolescents between 13 and 17 years (n = 459; 59% boys). Of these, 77% and 81%, respectively, completed their studies. All were from the United States and Canada.
The adolescents received high-dose centanafadine (328.8 mg once daily), low-dose centanafadine (164.4 mg once daily), or placebo for 6 weeks. The children received a placebo or a high or low dose of centanafadine, with doses based on their weight.
A larger number of children who received high-dose centanafadine had an 18-point or greater improvement at week 6 on the ADHD Rating Scale–5 (ADHD-RS-5) total score compared with the children who received placebo (34.5% vs 23.3%; P = .03), with even stronger effects found in the adolescents (47.7% vs 31.7%; P = .004).
A greater number of the high-dose active treatment group vs the placebo group also had at least a 10-point improvement in ADHD-RS-5 inattention subscale scores (children, P = .03; adolescents, P = .003) and at least an 8-point improvement in hyperactivity/impulsivity subscale scores ( P = .04 and .03, respectively).
In addition, the mean change from baseline to week 6 on the ADHD-RS-5 total score was −16.3 for the children receiving the high-dose drug vs −10.8 for those receiving placebo ( P = .0008) and was −18.5 vs −14.2 in the adolescents ( P = .0006).
When assessing caregiver-rated improvements, investigators found that a greater number of children and adolescents receiving high-dose centanafadine vs placebo achieved at least a 14-point improvement on the Conners 3–Parent Short Inattention T-scores ( P = .02 and .001, respectively) and at least a 13-point improvement on the Conners 3–Parent Short Hyperactivity/Impulsivity T-scores ( P = .02 and .007, respectively).
Most treatment-emergent adverse events were deemed to be mild to moderate. The most common adverse events in the high-dose centanafadine group were decreased appetite and rash in the children and decreased appetite, rash, nausea, and headache in the adolescents.
Ward reported that data from these studies, along with some they conducted previously and some that are ongoing, will be part of a package they're preparing to send to the US Food and Drug Administration in the near future. Altogether, 'it tells a nice story,' she said.
Real-World Data
Commenting for Medscape Medical News, Soonjo Hwang, MD, associate professor of psychiatry at the University of Nebraska Medical Center, Omaha, Nebraska, noted that among treatments already available for ADHD, the most well-known are stimulant medications, which 'are purely' dopaminergic reuptake inhibitors.
Soonjo Hwang, MD
'That said, norepinephrine, dopamine, and serotonin have a close relationship with each other in the brain. So, if you inhibit one, it will have an impact on the others as well,' said Hwang, who was not involved with the new research.
He pointed out that centanafadine has a similar profile to other medication groups, such as antidepressants, that have been assessed previously for ADHD.
'In terms of the mechanism, it's similar to some we've had in the past. Still, it is really important for us to have new tools to treat this disorder because we currently have limited options,' Hwang said.
He noted that being 'clinically meaningful' is a concept worth thinking about.
'This was a randomized-controlled clinical trial that [focused] towards more real-world data. And it's important to have data on how the medication performs in a real-world situation before launching it to market,' he said.
Hwang added that he'd also like to know, moving forward, how well the medication works in patients with comorbidities, which is common in those with ADHD.