Centanafadine: A Novel Approach to Adult ADHD*


An effective treatment for adult attention deficit hyperactivity disorder (ADHD) has to address lack of focus, inattention and disorganization, as well as impaired executive function.

Neurovance’s centanafadine (CTN, formerly EB-1020) is a novel triple reuptake inhibitor that modulates norepinephrine, dopamine and, to a lesser extent, serotonin reuptake. Our intent is to improve focus, attention and executive function.

“We believe that CTN is among the first of a new generation of triple reuptake inhibitors in advanced development for ADHD and Phase 2B study results are critical to establishing the dose range and regulatory path forward for centanafadine. Based on previous data we have shown, CTN has an efficacy profile approaching that of amphetamines yet with human trial results suggesting less risk of abuse.”
~Anthony A. McKinney, Founder and Chief Development Officer of Neurovance

Mechanism of Action

NOREPINEPHRINE (NE): In preclinical studies, CTN has its most potent effect on norepinephrine. The ability to focus is often attributed to norepinephrine.

DOPAMINE (DA): In preclinical studies, CTN also increases dopamine activity. Increased DA activity in the CNS has been associated with improved attention and problem-solving activity, as well as potentially leading to a faster speed of onset and improved cognition.

SEROTONIN (5-HT): CTN features a modest effect on serotonin. Increasing serotonin is thought to be related to relief of anxiety and depression that may accompany ADHD. An effect on serotonin may also moderate on-off effects and improve overall tolerability.

Centanafadine May Be an Effective and Well-Tolerated Medication with Less Abuse Potential

SAFETY: Results from a human abuse liability (HAL) study suggest less risk of abuse and diversion for CTN compared to stimulants used to treat ADHD. When the dose is increased beyond the therapeutic range or when blood levels rise rapidly, subjects experienced an acute onset of aversion and disliking, a distinct profile, which may serve to limit abuse and diversion. If this profile is confirmed through development, then CTN could qualify for less restrictive scheduling than C-II of the Controlled Substances Act.

EFFICACY: Results from a Phase 2b trial demonstrate that CTN sustained release (SR) in adults with ADHD, met both the primary and secondary endpoints. Though this trial was not a head-to-head trial, the study showed that CTN at 400 mg demonstrated an effect size of 0.6, within the range of the pivotal trials of approved stimulants, the most frequently prescribed drugs in the US for ADHD. The 400 mg dose was generally well tolerated with rates of insomnia and loss of appetite less than typically seen with amphetamines for ADHD. Neurovance will use the data from this trial to support an FDA regulatory package with the goal of initiating phase 3 trials in 2017.

Specifically, this was a 3-week placebo-controlled crossover Phase 2b trial in 85 adult ADHD patients conducted at 4 US sites and designed to provide efficacy and safety data for CTN given twice daily. Patients receiving CTN 400 mg had a -15.1 point change from baseline in the primary endpoint vs. a -8.1 point change observed with placebo, resulting in a statistically significant difference of -7.0 (p<0.001) and an effect size of 0.6. Effect size is a well-accepted statistical method to enable comparisons with medications across trials. Stimulants generally have effect sizes higher than non-stimulants.

Previous results from a pilot phase 2a clinical trial of CTN SR adult patients with ADHD suggested a robust treatment effect. The data showed a statistically significant improvement from baseline in ADHD symptoms on the ADHD-Rating Scale-IV (ADHD-RS-IV), the primary outcome measure, in a range similar to that reported in previously published trials with stimulants. CTN SR appeared to be well tolerated at the doses studied.

Comparison to Current Treatments

ADHD is a large $12b market dominated by a single therapeutic class, stimulants, which have important limitations (tolerability, patient adherence, C-II scheduling).

Stimulants can be highly effective; however, they can be abused. They can also be diverted to non-medical use and can cause side effects such as sleeplessness and weight-loss. Because of the potential for abuse their use is highly regulated as Schedule II Controlled Substances.

Non-stimulant medications such as atomoxetine, a norepinephrine reuptake inhibitor, are not controlled substances, however, non-stimulants generally have significantly had lower efficacy than the stimulants. Centanafadine is a unique non-stimulant with stimulant-like efficacy but low risk of abuse.