Breakthrough Clinical Results
ITF Therapeutics announced the publication of positive long-term safety and efficacy data for givinostat in treating Duchenne muscular dystrophy (DMD). Data from open-label extensions of Phase 2 and 3 trials (EPIDYS), published in Annals of Clinical and Translational Neurology, showed that long-term givinostat treatment, combined with corticosteroids, delayed disease progression in ambulant DMD patients aged six and older. The study demonstrated a delay in the loss of key mobility functions, such as rising from the floor, climbing stairs, and walking. Givinostat was well-tolerated, with no new safety signals observed during long-term treatment. The drug, marketed as Duvyzat, has received marketing authorization in the U.S., E.U., and U.K.
Key Highlights
- Long-term givinostat treatment delayed disease progression in DMD patients.
- Significant delays were observed in loss of key mobility functions.
- Givinostat remained well-tolerated with no new safety signals.
- Duvyzat (givinostat) is approved in the U.S., E.U., and U.K.
Incidence and Prevalence
Global Epidemiology of Duchenne Muscular Dystrophy: Latest Estimates
Prevalence Estimates
The global prevalence of Duchenne muscular dystrophy (DMD) varies across different studies and regions. According to a 2015 systematic review examining 38 articles from 19 countries, DMD has a prevalence of 1.7-4.2 per 100,000 individuals. A more recent meta-analysis from the same year provided a pooled prevalence of 4.78 per 100,000 males (95% CI 1.94-11.81).
More recent country-specific data shows: - A 2024 Danish study reports DMD prevalence at 1 per 3,600-6,000 male births - A 2024 Italian nationwide survey estimated DMD prevalence at 1.65 per 100,000 in the general population (3.4 per 100,000 males) - The 2009 CDC report indicated state-specific prevalences of Duchenne/Becker muscular dystrophy of 1.3-1.8 per 10,000 males aged 5-24 years across four participating US states
In the context of other muscular dystrophies, DMD remains one of the most common types alongside myotonic dystrophy (0.5-18.1 per 100,000) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000).
Incidence Rates
The incidence of DMD has been reported in several studies: - A 2015 meta-analysis found incidence ranging from 10.71 to 27.78 per 100,000 - A Dutch study from 1992 estimated the prevalence rate at birth at 23.7 × 10^(-5) (1:4215 male live births) - In North-West Tuscany (Italy), cumulative incidence decreased from 23.12 × 10^(-5) during 1965-1976 to 10.71 × 10^(-5) male live births during 1977-1994 - The birth prevalence has been estimated at 1 in 3,500 (2.9 per 10,000) male births according to 2009 data
Regional Variations
There are notable geographic variations in DMD prevalence: - In South Africa, a markedly low DMD prevalence in the indigenous black population (1/250,000) contributed to an overall low prevalence of 1/100,000 compared with the UK (1/40,000) - In Germany, muscular dystrophies collectively affect approximately 26,000 to 40,000 people based on a prevalence of 1:2000 to 1:3000 (2008 data) - A 2021 Italian nationwide study found that among 1902 patients with dystrophinopathies, 61% (n=1162) had DMD
Genetic Profile and Mortality
The genetic profile of DMD varies by region: - In the Italian cohort, genetic testing revealed deletions in 57%, duplications in 11%, and small mutations in 32% of DMD patients - A 2022 Chinese study of 1163 DMD patients found large deletions in 68.79%, large duplications in 7.14%, and small mutations in 24.07% of cases
A 2024 Canadian population-based study of 198 DMD patients observed mortality in 14% of the cohort, with Kaplan-Meier curves estimating 15% mortality by age 20 years and 20% by age 25 years.
Researchers emphasize the need for greater consistency in neuroepidemiological studies to enable better comparisons between studies, countries, and over time.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Duchenne Muscular Dystrophy Treatment
Gene Therapy Approaches
Recent advances in Duchenne muscular dystrophy (DMD) treatment include promising gene therapy approaches. Delandistrogene moxeparvovec, a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene transfer therapy, has shown encouraging results in the EMBARK trial, demonstrating decreased fat accumulation and improved T2 versus placebo, suggesting stabilization of muscle pathology. Additionally, microutrophin (µUtrn) gene therapy delivered via rAAV9 has emerged as a promising approach with less immunogenicity compared to microdystrophin, showing robust transgene expression and functional improvement in muscle performance.
Antisense Oligonucleotide Therapy
Antisense oligonucleotide therapy continues to advance with treatments like Viltolarsen for patients amenable to exon 53 skipping. This approach has demonstrated significant drug-induced dystrophin production (5.7-5.9% of normal) and improvements in timed function tests. Four phosphorodiamidate morpholino oligomer (PMO)-based antisense oligonucleotides are now FDA-approved, including Exondys51. Notably, combined exon-skipping therapy targeting both dystrophin and myostatin pre-mRNAs has shown superior results compared to dystrophin-only approaches.
Anti-inflammatory Approaches
The role of inflammation in DMD pathology has led to novel therapeutic targets. The NLRP3 inflammasome complex has been identified as crucial in DMD progression. MCC950, a specific inhibitor of NLRP3, has demonstrated significant benefits in mdx mice, including reduction of inflammation (-20 to -65%), less myonecrosis (-54%), reduced fibrosis (-75%), and enhanced muscle force (+20 to 60%). These effects occur through inhibition of active caspase-1 and cleaved gasdermin D (N-GSDMD), reducing pyroptosis.
Mitochondrial Targeting
Addressing mitochondrial dysfunction has emerged as a promising therapeutic approach. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission occurs in DMD models. Treatment with Mdivi-1, a selective Drp1 inhibitor, has effectively improved skeletal muscle strength and reduced serum creatine kinase in D2-mdx mice by inhibiting mitochondrial fission regulatory proteins and reducing damaged mitochondria content.
Cell-Based Therapies
Novel cell-based therapies include DT-DEC01, a Dystrophin Expressing Chimeric (DEC) cell therapy created by fusion of myoblasts from DMD patients and normal donors. This approach has demonstrated safety and preliminary efficacy with functional improvements in multiple assessments, including the 6-Minute Walk Test and North Star Ambulatory Assessment. Importantly, this therapy works regardless of mutation type and requires no immunosuppression.
Drug Repurposing
Drug repurposing offers additional treatment avenues. Dimethyl fumarate (DMF), an FDA-approved multiple sclerosis drug, has shown comparable efficacy to prednisone in reducing inflammation with additional anti-fibrotic and anti-lipogenic effects. Similarly, idebenone has demonstrated cardioprotective effects and improved exercise performance in mdx mice.
These emerging mechanisms represent promising approaches for DMD treatment, targeting the disease through genetic correction, inflammation reduction, mitochondrial function improvement, and novel cellular therapies.
Drug used in other indications
Clinical Indications for Givinostat Beyond Duchenne Muscular Dystrophy
Based on the available information, there are no other clinical indications beyond Duchenne muscular dystrophy (DMD) for which the histone deacetylase inhibitor givinostat is currently under investigation in Phase 1, Phase 2, or Phase 3 clinical trials.
The existing data only references givinostat in relation to DMD, where it functions as a histone deacetylase (HDAC) inhibitor. Research from 2018 demonstrated that givinostat significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. Clinical studies have focused on ambulant DMD boys aged 7 to under 11 years who were on stable corticosteroid treatment.
More recently, in 2024, the FDA approved Duvyzat (givinostat) specifically for Duchenne muscular dystrophy treatment. However, no information is available regarding givinostat being investigated for any other medical conditions in any phase of clinical trials.
Since there are no other indications currently being studied, there is consequently no information available about intervention models for trials beyond those conducted for DMD.
The current clinical development of givinostat appears to be exclusively focused on its application in Duchenne muscular dystrophy, with no evidence of active exploration in other therapeutic areas at this time.