Logo Image
News|Articles|June 2, 2026

FDA Issues CRL for CTx-1301 in ADHD Over CMC Concerns

Fact checked by: Tim Smith
Listen
0:00 / 0:00

Key Takeaways

  • A complete response letter for CTx-1301 was driven by CMC information requests, with FDA feedback not identifying deficiencies in clinical safety or efficacy.
  • Adult phase 3 dose-optimization data met the PERMP primary endpoint and favored active treatment on AISRS and CGI-S, with large effect sizes across the assessment window.
SHOW MORE

The FDA declined to approve Cingulate's once-daily ADHD therapy CTx-1301, citing CMC information requests with no clinical safety or efficacy concerns identified.

The US Food & Drug Administration (FDA) has issued a complete response letter (CRL) for CTx-1301 (dexmethylphenidate HCl), declining to approve the investigational once-daily ADHD treatment at this time, according to an announcement from Cingulate on June 2, 2026.

Key Takeaways

  • The FDA issued a CRL for CTx-1301 (dexmethylphenidate HCl), a once-daily ADHD treatment, citing Chemistry, Manufacturing, and Controls (CMC) information requests
  • No concerns were raised regarding clinical safety or efficacy
  • Two pivotal phase 3 studies—one in adults, one in children and adolescents—demonstrated meaningful improvements on validated ADHD symptom scales
  • CTx-1301 uses a multi-core tablet design to deliver three timed drug releases over 12–16 hours
  • Cingulate says CMC work is already underway and resubmission is the immediate priority

FDA Cites CMC Requests, Raises No Clinical Concerns

The FDA's letter cited requests for additional Chemistry, Manufacturing, and Controls (CMC) information. The agency did not identify any concerns related to the clinical safety or efficacy of CTx-1301.

“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,” said Cingulate CEO Shane J. Schaffer.

The decision follows an FDA review of 2 pivotal phase 3 studies demonstrating clinically meaningful improvements in validated ADHD symptom scales across both pediatric and adult populations, with a tolerability profile consistent with the broader methylphenidate class and no serious treatment-emergent adverse events reported in either trial.2,3

Phase 3 Data Supported Efficacy Across Age Groups

The adult dose-optimization trial (CTx-1301-022) was a single-center, double-blind, randomized, placebo-controlled, parallel-group study in 21 adults aged 18 to 55 years with ADHD.4 Following 5-week dose-optimization phase titrating participants to between 25 mg and 50 mg, participants were randomized to CTx-1301 or placebo. The primary endpoint (the Permanent Product Measure of Performance (PERMP)_ was met, with effect sizes ranging from 0.88 to 2.60 across the active-day assessment window. The Adult ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression–Severity (CGI-S) also favored active treatment.

The pediatric fixed-dose study (CTx-1301-005) was a randomized, double-blind, placebo-controlled trial in children and adolescents aged 6 to 17 years.5 CTx-1301 produced dose-dependent improvements on the ADHD Rating Scale 5 (ADHD-RS-5), CGI-Improvement (CGI-I), and CGI-S, with the 37.5 mg dose producing the largest observed effect size. Safety findings were consistent with the methylphenidate class, and no unexpected adverse events were reported.

About CTx-1301

CTx-1301 is a once-daily, multi-core tablet that delivers 3 precisely timed releases of active drug over the course of a single dose. Data supports its onset within the first hour post-dose and sustained efficacy through approximately 12 to 16 hours. CTx-1301’s active ingredient—dexmethylphenidate, the pharmacologically active d-threo-enantiomer of methylphenidate—has been FDA-approved in immediate- and extended-release forms since 2001 and 2005, respectively.6,7

ADHD affects an estimated 20 million people in the US, including 8 million children and 12 million adults.2 Stimulants remain the gold-standard pharmacologic treatment, supported by decades of data and endorsed by major clinical guidelines, including those from the American Academy of Pediatrics. However, current extended-release formulations may not provide symptom control through late afternoon and evening, often requiring booster doses that add dosing complexity and may disrupt sleep.8

Dexmethylphenidate exerts its therapeutic effect primarily by blocking dopamine and norepinephrine transporters in prefrontal cortical and subcortical circuits involved in attention regulation and impulse control.9 As the more pharmacologically active enantiomer of methylphenidate, it provides symptom relief at lower absolute doses than racemic formulations.

“Our immediate priority is to complete the CMC work already underway with our manufacturing partner,” Schaffer continued. “We believe the outstanding requests will be addressed quickly as we move efficiently toward resubmission.”

References

  1. Cingulate Receives Complete Response Letter from FDA for CTx-1301 - Cingulate Inc. Cingulate Inc. Published 2026. Accessed June 2, 2026. https://www.cingulate.com/news-releases/news-release-details/cingulate-receives-complete-response-letter-fda-ctx-1301
  2. Cingulate Inc. FDA accepts Cingulate's new drug application for CTx-1301 in attention-deficit/hyperactivity disorder (ADHD) and sets a May 31, 2026 PDUFA date. News release. October 14, 2025. https://www.globenewswire.com/news-release/2025/10/14/3166151/0/en/fda-accepts-cingulate-s-new-drug-application-for-ctx-1301-in-attention-deficit-hyperactivity-disorder-adhd-and-sets-a-may-31-2026-pdufa-date.html
  3. Cingulate Inc. Cingulate presents positive phase 3 results for CTx-1301 demonstrating statistically significant efficacy and entire active-day symptom control. News release. October 28, 2025. https://www.globenewswire.com/news-release/2025/10/28/3172555/0/en/Cingulate-Presents-Positive-Phase-3-Results-for-CTx-1301-Demonstrating-Statistically-Significant-Efficacy-and-Entire-Active-Day-Symptom-Control.html
  4. ClinicalTrials.gov. Phase 3 efficacy and safety study in adults with ADHD using CTx-1301 (CTx-1301-022). NCT05631626. https://clinicaltrials.gov/study/NCT05631626
  5. Kang J. Novel Dexmethylphenidate Formulation Improves Pediatric ADHD Symptoms. MPR. Published May 20, 2025. Accessed May 29, 2026. https://www.empr.com/news/novel-dexmethylphenidate-formulation-improves-pediatric-adhd-symptoms/
  6. Liu F, Minami H, Silva RR. Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder. Neuropsychiatr Dis Treat. 2006;2(4):467-473. doi:10.2147/nedt.2006.2.4.467
  7. McGough JJ, Pataki CS, Suddath R. Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder. Expert Rev Neurother. 2005;5(4):437-441. doi:10.1586/14737175.5.4.437
  8. Wolraich ML, Hagan JF Jr, Allan C, et al; Subcommittee on Children and Adolescents with Attention-Deficit/Hyperactive Disorder. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019;144(4):e20192528. https://doi.org/10.1542/peds.2019-2528
  9. Dexmethylphenidate - an overview | ScienceDirect Topics. www.sciencedirect.com. https://www.sciencedirect.com/topics/neuroscience/dexmethylphenidate

Related to this article

View more