Stimulants, amphetamines, and methylphenidates are the first-line treatment for moderate to severe attention-deficit/hyperactivity disorder (ADHD) across the seven major markets (7MM*). Non-stimulants are mainly utilized as second-line therapies due to their lack of efficacy. However, stimulants are highly controlled substances, and prescriptions are often restricted to 30 days. This creates a demand for non-stimulants with stimulant comparable efficacy in the ADHD space in 7MM, says GlobalData, a leading data and analytics company.

Lorraine Palmer, Pharma Analyst at GlobalData, comments: “Stimulant use comes with some practical issues, for example, ensuring the safe storage of stimulant medication by patients who are using it at university was listed as a concern by key opinion leaders (KOLs) interviewed by GlobalData.”

Three out of the four agents currently in late-stage development are non-stimulants, which include Axsome Therapeutics Inc’s solriamfetol, Otsuka’s centanafadine, and Neurocentria Inc’s L-Threonate Magnesium Salt. KOLs believe that these agents are unlikely to become first-line therapies without efficacy comparable to stimulants. Thus far, there have been no head-to-head trials.

In contrast, KOLs stated that despite the oversaturation of the stimulant market, Cingulate Inc’s CTx-1301 (dexmethylphenidate; currently in Phase III) has the potential to become a competitive first-line treatment if it can provide 16 hours of therapeutic coverage per dose. This would meet an unmet need identified by KOLs across the 7MM, coverage into the evening. It would also make it the longest lasting stimulant currently in the market, alongside Takeda’s Mydayis ER (mixed amphetamine salts), which provides coverage for up to 16 hours.

Palmer continues: “CTx-1301 has a lot of potential due to its impressive coverage. KOLs have stated it might become their ‘go-to’. However, with a long duration of action comes the potential for sleep disturbances such as delayed sleep onset. Since poor compliance of ADHD medication is consistently raised as a concern by KOLs, the development of a drug that provides coverage into the evening without affecting sleep is a key unmet need.”

While some have a long duration of action, the lack of dosing flexibility with non-stimulants is an issue raised by KOLs. Taking a medication break for the weekend is possible with stimulants but more difficult with non-stimulants, as it can take weeks for therapeutic benefit to be seen, and consistent dosing is required. The development of non-stimulants that allow for more flexible dosing is therefore an unmet need. If addressed, the resulting non-stimulant would have a competitive edge over other marketed non-stimulants.

Palmer concludes: “A further competitive edge for pipeline non-stimulants would be to address the symptoms of co-morbidities common with ADHD, such as autism spectrum disorder and emotional instability. Otsuka’s centanafadine might have an edge as a serotonin–norepinephrine–dopamine reuptake inhibitor in Phase II trials for major depressive disorder.”

*7MM countries- France, Germany, Italy, Spain, the UK, the US, and Japan