FDA Issues Complete Response Letter for Cingulate's Once-Daily ADHD Drug CTx-1301

The FDA has issued a complete response letter (CRL) for Cingulate Inc’s New Drug Application (NDA) for CTx-1301 (dexmethylphenidate HCl), an investigational once-daily treatment for attention-deficit/hyperactivity disorder (ADHD).¹ According to the announcement from Cingulate, the agency's feedback was confined to chemistry, manufacturing, and controls (CMC) information requests and did not identify any concerns related to the drug's clinical safety or efficacy.

The CRL comes after the FDA accepted the NDA for review in October 2025 and set a Prescription Drug User Fee Act target action date of May 31, 2026. Although the letter signals that the drug will not advance to approval at this time, Cingulate characterized the response as focused and resolvable.

"We are encouraged that the FDA's response was limited to specific information requests related to CMC and did not currently identify any issues related to the clinical safety or efficacy of CTx-1301," Shane J. Schaffer, CEO of Cingulate, said in the statement.¹ "Our immediate priority is to complete the CMC work already underway with our manufacturing partner; we believe the outstanding requests will be addressed quickly as we move efficiently toward resubmission."

Schaffer also emphasized the company's financial footing, noting that Cingulate holds nearly $30 million in cash reserves—a position the company believes is sufficient to resolve the CMC issues, complete resubmission, and sustain precommercial activities into 2027.

Phase 3 Data Back Submission

Cingulate had a successful pre-NDA meeting in April 2025 and completed phase 3 clinical trials in both adult (NCT05631626) and pediatric (NCT05286762; NCT05924594) cohorts (ages 6 and older).²

Data from these trials demonstrated that CTx-1301 achieved statistically significant improvements in ADHD symptoms across multiple metrics. Investigators noted large clinical effect sizes that were maintained from the morning into the afternoon and evening. Furthermore, CTx-1301 exhibited a favorable safety profile; the incidence of treatment-emergent adverse events was notably lower in the active treatment group (9%) compared with the placebo group (30%).

Pediatric Phase 3 Fixed-Dose Study

The pediatric and adolescent clinical trial assessed the efficacy of once-daily CTx-1301 over a 5-week period in patients aged 6 to 17.³ The primary efficacy end point measured the mean change from baseline to week 5 in the Attention-Deficit/Hyperactivity Disorder Rating Scale 5 total score. Across all evaluated fixed doses, the treatment demonstrated statistically significant improvements in ADHD symptoms, a finding achieved despite using less than one-third of the study's originally planned subject population.

The breakdown of the pediatric data highlights dose-dependent improvements and robust statistical outcomes:

• 18.75-mg dose: Achieved a statistically significant improvement (P = .018) and a mean effect size of 0.737 compared with the placebo.
• 25-mg dose: Demonstrated continued efficacy (P = .011) and an increased mean effect size of 0.782.
• 37.5-mg dose: Yielded the most prominent reduction in symptoms (P = .001) and the largest mean effect size of 1.185.
• Overall metrics: The cumulative trial data produced a total overall mean effect size of 0.901 compared with the placebo arm. From a safety perspective, the profile aligned with the traditional stimulant class, displaying no unexpected or serious treatment-emergent adverse events.

Adult Phase 3 Dose-Optimization Study

The adult study focused on evaluating the clinical onset and sustained duration of the medication within an adult laboratory classroom setting.⁴ The trial enrolled 21 adults between the ages of 18 and 55 with ADHD. Following a 5-week dose-optimization period where subjects were titrated to optimized doses ranging from 25 mg to 50 mg, participants were randomly assigned in a 1:1 ratio to receive either their tailored dose or a placebo for 7 days. On the final day of the study, participants completed a rigorous, 17-hour laboratory visit involving multiple Permanent Product Measure of Performance (PERMP) math tests to objectively track active symptom control.

The results from the adult trial highlighted the medication's extended-release performance:

• PERMP scores and effect sizes: Adults randomized to active treatment showed substantial improvements in PERMP performance, tracking an individual assessment effect size ranging from 0.88 to 2.60, with a high overall average effect size of 1.79 compared with the placebo arm.
• Onset and duration milestones: The treatment generated a notable effect size of 1.41 at the 30-minute mark, establishing a rapid onset of clinical action. Efficacy remained consistent across the day, concluding with an effect size of 0.98 at the 16-hour postdose mark. For context, historical meta-analyses of existing long-acting adult stimulants average an effect size of roughly 0.73 (ranging from 0.5 to 0.9).
• Statistical outcomes: While tracking individual windows demonstrated strong symptom reduction, the global trend toward statistical significance for PERMP ratings over the entire 16-hour testing window recorded a final value of P = .089. Similar to the pediatric cohort, the multicore formulation proved to be well-tolerated with an expected stimulant safety profile.

What’s Next for CTx-1301?

CMC-related CRLs are among the most common reasons the FDA declines to approve an NDA on first review.¹ Unlike clinical holds, they typically do not require new efficacy or safety trials—instead, the company must provide additional documentation or data on the manufacturing process, formulation stability, or quality controls. Cingulate said it plans a prompt resubmission once the CMC work with its manufacturing partner is finalized.

The company has not disclosed a projected resubmission timeline, but the absence of clinical concerns positions CTx-1301 as a candidate still on track for potential approval pending resolution of the manufacturing questions.

References

1. Cingulate receives complete response letter from FDA for CTx-1301. News release. Cingulate. June 2, 2026. Accessed June 3, 2026. https://www.cingulate.com/news-releases/news-release-details/cingulate-receives-complete-response-letter-fda-ctx-1301
2. Kuntz L. FDA accepts NDA for CTx-1301 for treatment of ADHD. Psychiatric Times. October 14, 2025. Accessed May 27, 2026. https://www.psychiatrictimes.com/view/fda-accepts-nda-for-ctx-1301-for-treatment-of-adhd
3. Efficacy results announced from Cingulate’s phase 3 pediatric study of CTx-1301 (dexmethylphenidate) for ADHD. News release. Cingulate. May 20, 2025. Accessed May 27, 2026. https://www.cingulate.com/news-releases/news-release-details/efficacy-results-announced-cingulates-phase-3-pediatric-study
4. Cingulate announces detailed trial results from phase 3 adult efficacy and safety trial of CTx-1301 (dexmethylphenidate) for ADHD. News release. Cingulate. September 11, 2023. Accessed May 27, 2026. https://www.cingulate.com/news-releases/news-release-details/cingulate-announces-detailed-trial-results-phase-3-adult