Two experimental medications are advancing toward potential approval for attention-deficit/hyperactivity disorder (ADHD), each taking a different approach to improve treatment outcomes. Cingulate’s CTx-1301 and Otsuka’s centanafadine have both undergone recent FDA review, representing distinct strategies for addressing limitations in current therapies.
CTx-1301: A New Delivery System for an Established Drug
Developed under the 505(b)(2) pathway, the treatment aims to optimize drug delivery rather than introduce a new active compound. Traditional stimulant formulations often require multiple daily doses, leading to rebound effects when medication wears off.
The new system releases active medication three times daily with a single dose, targeting rapid onset and all-day effectiveness. This profile distinguishes CTx-1301 from immediate- and extended-release stimulant formulations by maintaining therapeutic coverage throughout the day while reducing symptom fluctuations.
The FDA accepted Cingate’s New Drug Application (NDA) in October, with a target PDUFA action date of May 31. However, in early June, the agency issued a complete response letter requesting additional chemistry, manufacturing, and controls information. The company is working to address these concerns.
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A Phase 3 study (CTx-1301-005) evaluated the treatment in 103 pediatric patients aged 6 to 17 with ADHD. Participants received doses ranging from 18.75 mg to 37.5 mg daily after titration from 12.5 mg. The primary endpoint—change in ADHD-RS-5 total score—was met, and the safety profile matched other stimulant agents.
A separate Phase 3 trial (CTx-1301-022) assessed 21 adults in a laboratory classroom setting. While the study did not meet its primary efficacy endpoint, CTx-1301 showed improvement trends in performance measures compared to placebo, with no insomnia reports.
Centanafadine: A Novel Nonstimulant Approach
Centanafadine, now FDA-approved, works as a norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI). As a triple reuptake inhibitor, it represents a first-in-class nonstimulant option with broader neurochemical activity than existing alternatives, potentially avoiding stimulant-related abuse liability.
The FDA granted priority review to Otsuka’s NDA in January, setting a mid-summer PDUFA target date. Centanafadine is indicated for children, adolescents, and adults as a once-daily extended-release capsule.
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In children aged 6 to 12, 480 participants received weight-based dosing or placebo for six weeks. The high dose showed statistically significant improvement on ADHD-RS-5 scores compared to placebo, while the low dose did not.
In adolescents aged 13 to 17, 459 participants received 164.4 mg or 328.8 mg daily. The higher dose achieved significant improvement versus placebo, though the lower dose did not meet the primary endpoint.
Two adult studies enrolled 466 and 440 participants respectively, using 200 mg or 400 mg daily dosing. Both trials showed statistically significant improvements in AISRS total scores and CGI-S ratings compared to placebo, with the medication well-tolerated across all studies.
Pediatric and Adult Trial Designs and Dosing Protocols
The Phase 3 trial CTx-1301-005 enrolled 103 pediatric patients aged 6 to 17 with ADHD. Participants received CTx-1301 at doses of 18.75 mg, 25 mg, or 37.5 mg once daily. Treatment began at 12.5 mg and was titrated weekly to reach the target dose. Efficacy was measured after 5 weeks, with at least 2 weeks at the assigned dose.
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A total of 459 participants were randomized in the adolescent study, with 451 included in the efficacy analysis. Participants received once-daily centanafadine at 164.4 mg or 328.8 mg, or placebo for 6 weeks. The 328.8 mg dose showed statistically significant improvement compared to placebo at week 6, while the 164.4 mg dose did not meet the primary endpoint.
Two Phase 3 adult studies (NCT03605680 and NCT03605836) enrolled 466 and 440 participants respectively. In study 1, 446 participants received double-blind treatment, with 348 completing the study. In study 2, 430 participants received treatment during the double-blind period, and 336 completed the trial. Participants were randomly assigned to receive centanafadine 200 mg or 400 mg daily as sustained-release tablets or placebo.
Addressing Manufacturing Concerns and Future Outlook
The complete response letter issued to Cingate in June centered on chemistry, manufacturing, and controls information, indicating areas where the FDA sought further clarification before proceeding with approval. This type of request is not uncommon during the review process, particularly for applications relying on the 505(b)(2) pathway, which requires demonstration of bioequivalence and therapeutic equivalence alongside novel delivery mechanisms.
Broader Implications for ADHD Treatment Innovation
The divergent paths taken by CTx-1301 and centanafadine reflect evolving priorities in ADHD drug development, particularly the focus on improving daily adherence and minimizing side effects through smarter formulations or alternative mechanisms of action. While stimulants remain first-line treatments, their limitations, including short duration of action and potential for misuse, have driven interest in both optimized delivery systems and nonstimulant alternatives.