FDA approves Otsuka’s Simtriyo as first-in-class NDSRI for ADHD treatment

USA—The US Food and Drug Administration (FDA) has approved Otsuka Pharmaceutical’s once-daily extended-release capsule Simtriyo (centanafadine) to treat attention-deficit/hyperactivity disorder (ADHD) in patients aged six years and older.

The approval makes Simtriyo the first norepinephrine, dopamine, serotonin reuptake inhibitor (NDSRI) for ADHD and gives Otsuka what Jefferies analysts described as its “next major CNS launch.”

In a July 26 note, the analysts said the treatment could become a blockbuster in the large but underpenetrated ADHD market.

However, Simtriyo must undergo a controlled-substance review by the US Drug Enforcement Administration (DEA) before Otsuka can launch it in the US.

The review is a standard process for central nervous system drugs with stimulant properties and can take up to three months.

The DEA’s classification could significantly influence Simtriyo’s commercial prospects.

A Schedule II designation, similar to that assigned to widely used ADHD medicines such as Adderall and Vyvanse, could limit uptake.

In contrast, a lower classification could give Simtriyo an advantage in the competitive ADHD market.

During an investor question-and-answer session in April, Otsuka said it was uncertain whether Simtriyo would require a DEA review.

However, Jefferies analysts noted that the FDA appears to view the treatment as a stimulant because of its dopaminergic activity.

Potential to expand non-stimulant ADHD treatment

Simtriyo works by blocking the reuptake of norepinephrine, dopamine and serotonin, thereby increasing the availability of these neurotransmitters in brain pathways involved in attention and behavior.

ADHD is a chronic neurodevelopmental disorder that can affect attention, impulse control and behavior.

According to the Centers for Disease Control and Prevention (CDC), the condition affects about seven million children and 15.5 million adults in the US.

Although stimulants remain the most commonly prescribed ADHD treatments, many patients discontinue therapy or switch between medicines because of inadequate efficacy, side effects or changing needs throughout their lives.

Jefferies analysts therefore said the ADHD market could support multiple treatment classes, giving Simtriyo an opportunity to expand the non-stimulant segment rather than compete directly with established products such as Qelbree and Strattera.

Otsuka has set a peak sales target of more than ¥100 billion (US$610 million) for Simtriyo.

The company acquired the drug through its 2017 purchase of Neurovance for US$100 million upfront, with an additional US$150 million available in potential development and regulatory milestone payments.

Positive Phase 3 results support approval

Simtriyo demonstrated efficacy in four Phase 3 clinical trials.

The drug significantly improved ADHD symptoms compared with placebo, based on the ADHD Rating Scale-5 (ADHD-RS-5) in two pediatric trials and the Adult ADHD Investigator Symptom Rating Scale (AISRS) in two adult studies.

The most common adverse reactions included rash and decreased appetite among children aged six to 12 years.

Adolescents aged 13 to 17 years commonly experienced decreased appetite, nausea, rash, headache and abdominal pain.

In adults, the most frequently reported adverse reactions were headache, decreased appetite, insomnia, nausea, dry mouth and diarrhea.

In June, Otsuka also reported positive topline Phase 3b results showing that Simtriyo significantly outperformed placebo on the AISRS among patients with ADHD and comorbid anxiety.

“The approval of Simtriyo introduces a novel mechanism of action and expands the range of options available to healthcare professionals and patients,” said Lenard Adler, director of the adult ADHD program at NYU Langone Health and an investigator in the centanafadine studies.

The approval comes less than a year after the FDA declined to approve Otsuka and partner Lundbeck’s Rexulti as part of a combination treatment for post-traumatic stress disorder because of mixed clinical trial results.

Simtriyo further expands Otsuka’s CNS portfolio, which includes Rexulti and Abilify Maintena, atypical antipsychotics approved for schizophrenia and other neurological conditions.

Jefferies analysts said the ADHD treatment could also benefit from Otsuka’s established US commercial infrastructure and broad network of community-based prescribers.