Breakthrough Clinical Results
Dyne Therapeutics announced that the FDA granted Breakthrough Therapy Designation to DYNE-101 for treating myotonic dystrophy type 1 (DM1). This follows a Type C meeting where Dyne and the FDA agreed to use video hand opening time (vHOT) as the primary endpoint for Accelerated Approval. New data from the Phase 1/2 ACHIEVE trial showed sustained improvements in vHOT and other endpoints at 12 months, supporting vHOT as an early indicator of clinical benefit. Dyne submitted a revised protocol for the ACHIEVE trial's Registrational Expansion Cohort, aiming to enroll 60 participants and include US sites. The company expects to complete enrollment in Q4 2025 and submit for Accelerated Approval in late 2026.
Key Highlights
- FDA granted Breakthrough Therapy Designation to DYNE-101 for DM1.
- Revised ACHIEVE trial protocol submitted with vHOT as the primary endpoint for Accelerated Approval.
- New data shows sustained improvement in vHOT and other endpoints at 12 months.
- Registrational Expansion Cohort of ACHIEVE trial to enroll 60 participants, including US sites.
Incidence and Prevalence
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy. Estimating global incidence and prevalence is challenging due to variations in study methodologies, case ascertainment, and geographic distribution. While older estimates suggested a prevalence of approximately 1 in 8000, more recent data and regional studies suggest higher figures in some populations.
Prevalence:
- A frequently cited prevalence figure is 13/100,000. However, studies have shown significant variations. For example, a study in western Sweden found a prevalence of 17.8/100,000, while another in the Saguenay-Lac-Saint-Jean region of Quebec, Canada, reported a prevalence of 158/100,000 in 2010. This high prevalence in specific regions is likely due to founder effects. A study in Taiwan found a minimal prevalence of 0.46/100,000. A systematic review of studies published between 1960 and 2013 estimated the prevalence of all muscular dystrophies combined to be between 19.8 and 25.1 per 100,000 person-years, with myotonic dystrophy ranging from 0.5 to 18.1 per 100,000. Another systematic review from 1985 to 2011 estimated a pooled prevalence of 8.26 per 100,000 for myotonic dystrophy. A study in Iceland found a prevalence of 28.2/100,000, including a high prevalence of the congenital form (7.9/100,000). A study in Belgrade, Serbia, found a prevalence of 5.3/100,000 in 2002. A study in Navarre, Spain, found a prevalence of 35.90/100,000 in 2016. A 2017 study estimated 9,004,610 prevalent cases globally.
Incidence:
- Incidence data is less readily available than prevalence data. A study in Belgrade, Serbia, reported an average annual incidence rate of 2.0/1,000,000. The 2017 study estimated 234,710 incident cases globally.
Key Factors Affecting Estimates:
- Case ascertainment: Studies vary in how they identify cases, leading to differences in reported prevalence. Some studies rely on hospital records, while others use population-based screening. Mild or late-onset cases may be missed in some studies.
- Geographic variation: DM1 prevalence differs significantly between regions, likely due to founder effects and genetic drift.
- Diagnostic criteria: Variations in diagnostic criteria can also affect prevalence estimates.
Conclusion:
The prevalence and incidence of DM1 vary considerably based on geographic location and study methodology. While some regional prevalences are very high, a global estimate is difficult to ascertain with precision. More research with standardized methodologies is needed to better understand the true global burden of DM1.
Emerging End Points
Clinical Trials and Endpoints in Myotonic Dystrophy Type 1 (DM1)
Recent publications highlight several key endpoints emerging in DM1 clinical trials, reflecting the multisystemic nature of the disease. These endpoints can be broadly categorized into:
1. Muscle Function and Strength:
- 6-Minute Walk Test (6MWT): This remains a commonly used endpoint to assess functional capacity and ambulation. One study found no significant effect of mexiletine on 6MWT at 6 months.
- Muscle Strength: Measures like grip strength are used to evaluate muscle weakness, a core symptom of DM1. One study explored the relationship between CTG repeat length and grip strength, finding a statistically significant but not clinically meaningful correlation. Another study found that hand training significantly increased hand function in a small group of DM1 patients.
- Myotonia: Objective measures of myotonia, such as grip relaxation time, are being used. Mexiletine showed a positive effect on objectively measured hand grip myotonia, but this was not reflected in patient-reported myotonia.
- Timed Up & Go (TUG): This test assesses mobility and balance, which are often affected in DM1. One study found the Mini-BESTest, a balance assessment tool, to be valid in DM1 and correlated with TUG.
- Motor Performance: Pre-clinical studies in mouse models use measures like rotarod performance to assess motor function. One study found that exercise improved motor performance in a DM1 mouse model.
2. Patient-Reported Outcomes (PROs):
- Myotonic Dystrophy Health Index (MDHI): This DM1-specific PRO measure assesses the impact of the disease on various aspects of daily life.
- Individualized Neuromuscular Quality of Life (INQoL): This questionnaire captures the impact of neuromuscular diseases on quality of life. One study found that DM1 is associated with a substantial disease burden across many life domains, as measured by the INQoL.
- Fatigue Severity Scale: This scale measures the severity of fatigue, a common symptom in DM1. One study found that psychological distress and muscle impairment correlated with fatigue in DM1. Another study found this scale to be responsive to change in DM1 patients.
- Daytime Sleepiness Scale: This scale assesses daytime sleepiness, another frequent DM1 symptom. One study found this scale to be responsive to change in DM1 patients. Another study explored factors influencing daytime sleepiness and fatigue, finding associations with CTG repeat number, psychological distress, depression, muscle impairment, sleep duration, BMI, and hypothyroidism.
- Canadian Occupational Performance Measurement (COPM): This tool assesses self-perceived occupational performance and satisfaction. One small study found a positive change in self-rated occupational performance after hand training.
3. Molecular and Genetic Biomarkers:
- CTG Repeat Length: While not a direct endpoint in clinical trials, CTG repeat length is often used as a stratification factor and to explore genotype-phenotype correlations.
- Splicing Biomarkers: Changes in alternative splicing are a key mechanism in DM1 pathogenesis. Some studies are exploring splicing biomarkers as potential outcome measures. One study showed that exercise improved mRNA alternative splicing in a DM1 mouse model.
- Toxic RNA Foci: The accumulation of toxic RNA foci is a hallmark of DM1. One study demonstrated that a CRISPR-Cas13a system could reduce toxic RNA load in patient-derived myoblasts.
4. Other Clinical Outcomes:
- Cardiac Function: Cardiac conduction abnormalities and arrhythmias are common in DM1. ECG, Holter monitoring, and echocardiography are used to assess cardiac function. One study found a high prevalence of myocardial fibrosis in DM1, not predicted by standard cardiac assessments.
- Respiratory Function: Respiratory muscle weakness can lead to respiratory failure in DM1. Pulmonary function tests, such as forced vital capacity (FVC), are used to monitor respiratory function. One study found slowly progressive impairment of lung function in DM1.
- Survival: Given the potential for premature death in DM1, survival is an important long-term endpoint. One study developed and validated a prognostic score to predict 10-year survival in DM1 patients.
5. Emerging Areas:
- Cognitive Function: Cognitive impairment is increasingly recognized in DM1. Neuropsychological testing is used to assess various cognitive domains. One study found that DM1 patients demonstrated worse performance than controls in all cognitive domains.
- Gastrointestinal (GI) Function: GI symptoms are common in DM1. Patient-reported data and medical records are used to assess GI manifestations. One study analyzed GI symptoms in DM1 and DM2, finding a high frequency of swallowing problems and constipation.
- Endocrine Function: Endocrine abnormalities are frequent in DM1. One study investigated endocrine and metabolic aspects of DM1, finding a high frequency of abnormalities and highlighting the importance of endocrine monitoring.
These endpoints reflect the ongoing efforts to develop effective therapies for DM1 and to capture the complex and multi-faceted impact of the disease on patients' lives.
Drug used in other indications
The provided text focuses on Myotonic Dystrophy type 1 (DM1) and mentions several potential therapies, including tideglusib, mexiletine, and metformin. However, there is no mention of DYNE-101 or any other trials it might be involved in. Therefore, I cannot answer your question about other indications or intervention models for DYNE-101.
The text does discuss various aspects of DM1, including its prevalence, symptoms, and current treatment approaches. It highlights the lack of disease-modifying therapies and the focus on symptomatic treatments and management of organ-specific complications. Several studies mentioned explore the cardiac, respiratory, and cognitive aspects of DM1, as well as the use of pacemakers and ICDs in affected individuals. Additionally, the text mentions research on metabolic disturbances associated with DM1, such as impaired glucose tolerance, liver dysfunction, and dyslipidemia.
While the provided information offers valuable insights into DM1 and its management, it does not contain any information about DYNE-101 or its clinical trials.