Cingulate's CTx-1301 for ADHD: FDA Alignment on NDA Filing
Cingulate Inc. announced that it received positive feedback from the FDA regarding its pre-New Drug Application (NDA) meeting for CTx-1301, a novel on...
Breakthrough Clinical Results
Cingulate Inc. announced that it received positive feedback from the FDA regarding its pre-New Drug Application (NDA) meeting for CTx-1301, a novel once-daily dexmethylphenidate formulation for Attention Deficit/Hyperactivity Disorder (ADHD). The FDA's feedback aligns with Cingulate's plan to submit the NDA this summer. CTx-1301 utilizes Cingulate's proprietary Precision Timed Release™ (PTR™) technology to deliver three releases of medication throughout the day, aiming to provide all-day efficacy. The FDA's acceptance of the nonclinical safety data and the proposed approach to the integrated safety and efficacy summaries are key milestones. Cingulate expects a 24-month shelf life for all dosage strengths at launch.
Key Highlights
- FDA feedback aligns with plans to submit NDA for CTx-1301 this summer.
- CTx-1301 is a novel once-daily dexmethylphenidate formulation for ADHD.
- FDA accepted nonclinical safety data and the proposed approach to integrated summaries.
- CTx-1301 aims to provide all-day efficacy with a unique three-release delivery system.
Incidence and Prevalence
Global ADHD Prevalence and Incidence:
The prevalence and incidence of ADHD vary depending on the population studied (children, adolescents, adults, or across the lifespan) and the methodology used. Here's a summary of the latest estimates from different studies, focusing on global figures:
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Children and Adolescents: A 2024 umbrella review (PMID: 37495084) encompassing 13 systematic reviews and over 3 million participants estimated the global prevalence of ADHD in children and adolescents at 8.0% (95% CI 6.0-10.0%). This review also highlighted that the prevalence is twice as high in boys (10%) compared to girls (5%). Another meta-analysis (PMID: 37081447) found a slightly lower prevalence, with 7.6% in children aged 3-12 and 5.6% in adolescents aged 12-18.
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Adults: A 2023 umbrella review (PMID: 37708807) of adult ADHD, including 5 systematic reviews and over 21 million participants, reported a pooled prevalence of 3.10% (95% CI 2.60-3.60%). A separate study (PMID: 33692893) adjusting for the 2020 global demographic structure estimated the prevalence of persistent adult ADHD (childhood onset) at 2.58% and symptomatic adult ADHD (regardless of onset) at 6.76%. This translates to approximately 140 million and 366 million affected adults globally, respectively.
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Across the Lifespan: The Global Burden of Disease (GBD) study (PMID: 37684322) provides estimates for ADHD across the lifespan. In 2019, the GBD estimated the global age-standardized incidence at 0.061% (95% UI 0.040-0.087) and prevalence at 1.13% (95% UI 0.831-1.494). However, the authors of this study suggest that the GBD may have underestimated the true prevalence, particularly in children and adolescents, due to methodological limitations and data imputation for countries lacking prevalence data. Their re-analysis of data prior to 2013 showed a prevalence in children/adolescents of 5.41%, considerably higher than the GBD estimate.
Trends and Variability:
Several studies note an increasing trend in ADHD diagnoses, particularly in adults. However, the GBD study reports a slight decrease in global age-standardized prevalence and incidence between 1990 and 2019. It's important to recognize that prevalence estimates can vary significantly due to methodological differences between studies, including diagnostic criteria, source of information, and impairment requirements. For example, a 2024 systematic review and meta-analysis (PMID: 39381949) found substantial variability in prevalence estimates depending on the type of study (register, survey, or clinical studies). Therefore, caution is needed when comparing estimates across different studies.
Key Considerations:
- Methodological variations: Differences in diagnostic criteria, data collection methods, and study populations can significantly influence prevalence estimates.
- Underdiagnosis/Underestimation: ADHD may be underdiagnosed in certain populations, particularly girls and minority racial/ethnic groups. The GBD estimates may also underestimate the true prevalence.
- Comorbidity: ADHD frequently co-occurs with other conditions, such as anxiety, depression, and autism spectrum disorder, which can complicate diagnosis and treatment.
- Further research: More research is needed to refine prevalence estimates, particularly in low- and middle-income countries, and to better understand the causes and long-term impacts of ADHD.
Economic Burden
ADHD Economic Burden (USA & Europe)
Several studies from PubMed provide estimates of the economic burden of ADHD in the USA and Europe, varying based on the scope, methodology, and year of the study. Here's a summary of some of the most recent and comprehensive findings:
USA:
- Children and Adolescents: A 2020 study estimated the total annual societal excess costs associated with ADHD at $19.4 billion for children ($6,799 per child) and $13.8 billion for adolescents ($8,349 per adolescent). Education costs were the primary driver, followed by direct healthcare and caregiver costs.
- Adults: A 2019 study estimated the total societal excess cost attributable to adult ADHD at $122.8 billion ($14,092 per adult). The largest cost components were unemployment, productivity loss, and healthcare services.
- Overall: A 2011 review estimated the annual national incremental costs of ADHD to range from $143 billion to $266 billion. Most costs were incurred by adults, primarily due to productivity and income losses. For children and adolescents, healthcare and education were the largest cost categories.
Europe:
- A 2013 Danish study found that adults with ADHD had considerably lower disposable income, paid less tax, received more state benefits, and had higher costs for health, social care, and crime. The total average cost difference was 20,134 more than their siblings without ADHD.
- A 2014 Dutch study estimated the annual national ADHD-related costs to be between 1,041 and 1,529 million. Education was the largest cost category, followed by healthcare and social services.
- A 2017 study comparing the burden of ADHD in Europe and the US found a greater impact on psychosocial functioning, work productivity impairments, and healthcare resource use in Europe.
Key Cost Drivers:
Across both regions, key cost drivers include:
- Direct Healthcare Costs: Medications, therapy, and other medical services.
- Indirect Costs: Lost productivity due to unemployment, absenteeism, and presenteeism.
- Education Costs: Special education services, tutoring, and other educational supports.
- Societal Costs: Costs related to the criminal justice system, social services, and reduced quality of life.
Limitations and Considerations:
- Methodological Variations: Studies use different methodologies, making direct comparisons challenging.
- Data Sources: Variations in data sources (e.g., claims data, surveys) can affect cost estimates.
- Comorbidities: The presence of comorbid conditions can significantly influence costs.
- Undiagnosed/Untreated ADHD: Many individuals with ADHD remain undiagnosed or untreated, leading to potential underestimation of the true economic burden.
Conclusion:
ADHD imposes a substantial economic burden on both the USA and Europe. While estimates vary, the costs are significant across all age groups and affect multiple sectors of society. Further research with standardized methodologies and comprehensive cost assessments is needed to fully understand the economic impact of ADHD and inform resource allocation decisions.
Drug used in other indications
Dexmethylphenidate (d-MPH), the d-isomer of methylphenidate, is primarily used to treat Attention-Deficit/Hyperactivity Disorder (ADHD). However, research suggests its potential efficacy for other conditions. Several studies have explored its use in treating fatigue associated with various conditions, and cognitive impairment in specific populations.
1. Sarcoidosis-Associated Fatigue:
A double-blind, randomized, placebo-controlled, crossover trial investigated d-MPH's effectiveness in treating fatigue in sarcoidosis patients. Ten patients receiving systemic sarcoidosis therapy were enrolled. Significant improvement in fatigue was reported with d-MPH (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], p < 0.001; Fatigue Assessment Score [FAS], p < 0.02). Forced vital capacity (FVC) also improved after 8 weeks of d-MPH (p < 0.01), but the 6-minute walk distance did not change significantly. The study suggests d-MPH may be a potential treatment option for sarcoidosis-associated fatigue.
Intervention Model: Double-blind, randomized, placebo-controlled, crossover trial.
2. Chemotherapy-Related Fatigue and Cognitive Impairment:
A randomized, double-blind, placebo-controlled, parallel-group study evaluated D-MPH for treating chemotherapy-related fatigue and cognitive impairment in 154 cancer patients. D-MPH significantly improved fatigue symptoms (FACIT-F, P=0.02; Clinical Global Impression-Severity scores, P=0.02) without affecting hemoglobin levels. However, cognitive function did not improve significantly. A higher rate of drug-related adverse events and discontinuations was observed in the D-MPH group. The study suggests D-MPH may improve fatigue in cancer patients treated with chemotherapy, but further research is needed to confirm these findings and explore the risk-benefit ratio.
Intervention Model: Randomized, double-blind, placebo-controlled, parallel-group study.
3. Cancer-Related Fatigue:
Another study examined the effects of D-MPH on cancer-related fatigue. While the specific details of the study design are not provided, the results indicated significant improvement in fatigue symptoms. However, the study also noted a higher rate of adverse events and discontinuations in the D-MPH group, suggesting the need for further research to balance potential benefits with risks.
Intervention Model: Not specified, but likely a randomized controlled trial.
In summary, while dexmethylphenidate is primarily indicated for ADHD, research suggests its potential for treating fatigue associated with sarcoidosis and cancer, and possibly chemotherapy-related fatigue. However, further research is needed to confirm these findings, optimize treatment strategies, and fully understand the drug's risk-benefit profile in these patient populations.
