Breakthrough Clinical Results
Skyhawk Therapeutics announced positive interim results from its Phase 1 clinical trial of SKY-0515 for Huntington's disease (HD). The trial showed dose-dependent reductions of mutant huntingtin (mHTT) protein, including a 62% reduction at the 9mg daily oral dose on Day 84. SKY-0515 also demonstrated dose-dependent reductions in PMS1 mRNA, excellent brain penetration, and a favorable safety profile. A Phase 2/3 trial (FALCON-HD) is ongoing in Australia and New Zealand.
Key Highlights
- SKY-0515 achieves dose-dependent reductions of mutant huntingtin (mHTT) protein in patients with Huntington's Disease.
- 62% reduction of mHTT protein observed at Day 84 on the 9mg daily oral dose.
- Dose-dependent reductions in PMS1 mRNA and excellent brain penetration were observed.
- SKY-0515 demonstrated a favorable safety profile.
Incidence and Prevalence
Latest Estimates of Incidence and Prevalence of Huntington's Disease Globally
Recent Prevalence Estimates
The most recent study from 2022 suggests that the prevalence and incidence of Huntington's disease (HD) in the United States may be higher than previously estimated. In the US Medicare population, researchers identified 1,941 prevalent cases of HD in 2017, corresponding to a prevalence proportion of 13.1 per 100,000 persons. Similarly, in the US Medicaid population, 353 prevalent cases were identified in 2014, with a prevalence proportion of 15.2 per 100,000 persons.
A 2014 study in British Columbia, Canada estimated the prevalence of HD at 13.7 per 100,000 (95% CI: 12.6-14.8) in the general population, and 17.2 per 100,000 (95% CI: 15.8-18.6) in the Caucasian population. These figures suggest there may be up to 4,700 individuals affected with HD and 14,000 at 50% risk for HD in Canada, as well as up to 43,000 individuals affected with HD and 123,000 at 50% risk for HD in the United States.
In Europe, a 2016 study in Sweden found the prevalence of HD to be 22.1 per 100,000 in Jämtland county and 4.9 per 100,000 in Uppsala county, showing significant regional variations. Another 2016 study in Italy found an estimated prevalence rate of 10.85 per 100,000 (95% confidence interval: 7.20-14.50) in the Molise region, which was remarkably higher than previously described. Previous estimates suggested an average prevalence in Europe of about 6 per 100,000.
In 2018, a study in South Africa found minimum estimates of disease frequency to be 5.1, 2.1 and 0.25 per 100,000 individuals for the white, mixed ancestry and black population groups respectively.
Incidence Rates
According to a 2012 meta-analysis of four incidence studies, the global incidence of Huntington's disease is 0.38 per 100,000 per year (95% confidence interval [CI]: 0.16, 0.94). In the US Medicare population, the incidence rate was found to be 6.1 per 100,000 person-years.
A 2013 UK study of juvenile HD (under age 21) found a minimum population-based estimate of incidence of 0.70 per million patient-years (95% CI 0.36 to 1.22).
Geographic Variations
Geographic variability is consistently reported across studies, with some regions showing significantly higher prevalence than others. Lower incidence was reported in Asian studies compared to studies performed in Europe, North America, and Australia. HD is more common in Caucasian populations of North America and Western Europe compared to Asian populations. The difference in prevalence of this genetic disorder can be largely explained by huntingtin gene haplotypes.
Several studies suggest that underascertainment may have led to previous underestimates of prevalence, particularly in Caucasian populations. The prevalence is expected to increase in the coming decades because of population aging, variable phenotype penetrance and improved life expectancy.
Key Unmet Needs and Target Populations for Huntington's Disease
Unmet Clinical Needs
Huntington's disease (HD) represents a rare, genetic, and ultimately fatal neurodegenerative disease with devastating impact across generations. Despite ongoing research, several critical unmet needs persist:
- There are currently no approved disease-modifying therapies for HD, with death typically occurring 10-25 years after onset
- HD can only be managed symptomatically with a variety of prescribed medications
- Many patients experience negative medication effects including side effects or non-response
- Inconsistent care delivery across the US, with most practices (>69%) reporting difficulty providing social work, genetic counseling, care coordination and psychological/psychiatric services
- The true prevalence of HD is probably underestimated, highlighting the need for better diagnostic screening using genetic testing
- Stigma linked to HD reduces willingness to undergo targeted assessment
Target Populations
Recent research has focused on several specific HD patient populations:
- Patients with chorea symptoms: Studies investigating treatments like SOM3355 (bevantolol hydrochloride) to reduce chorea
- Patients with gut dysbiosis: Research examining probiotic interventions targeting gut microbiome composition in HD gene expansion carriers
- Patients at different disease stages: Studies analyzing cerebrospinal fluid from pre-manifest, manifest, and late manifest HD participants
- Patients with distinct clinical phenotypes: Research identifying three distinct HD clusters with different clinical manifestations
- Racial and ethnic minority patients: Studies showing Black participants were diagnosed with HD 1 year later than White participants
Emerging Treatment Approaches
Several promising therapeutic approaches are being investigated:
- mGluR5 antagonism using CTEP has shown promise in reducing HD neuropathology in mouse models
- Allele-specific antisense oligonucleotides (ASOs) targeting single-nucleotide polymorphisms demonstrate feasibility in HD models
- Glycosphingolipid modulation using THI preserves myelin thickness and structure in HD mice
- CMS121, a derivative of flavonol fisetin, shows efficacy in slowing motor dysfunction and increasing median life span in mouse models
- Anti-glycan auto-antibodies, particularly anti-GD1b, show potential as biomarkers for distinguishing between pre-HD and control groups
- Machine learning approaches demonstrate promise for improving HD management, with one study showing a 9.2% improvement in predicting age at onset
The diverse symptoms of HD place a high burden on patients, families, and healthcare systems. With a median survival of ~12 years from first recorded diagnosis and a risk of death >4 times higher than the general population, addressing these unmet needs through targeted interventions for specific patient populations remains critical for improving outcomes in this devastating disease.
Drugs in Clinical Trials with the Same MoA as SKY-0515
After reviewing the available information, I cannot identify other drugs being trialled for the same indication using the same mechanism of action (MoA) as SKY-0515. The information about SKY-0515, including its mechanism of action and therapeutic indication, is not available in the current dataset.
Without knowing the specific MoA of SKY-0515, it is not possible to identify other drugs that share this mechanism or determine which clinical trials are testing compounds with similar pharmacological properties.
Similarly, without this foundational information, I cannot provide details about the intervention models being employed in relevant clinical trials. Intervention models typically include:
- Parallel assignment
- Crossover assignment
- Factorial assignment
- Sequential assignment
- Single group assignment
These models determine how participants are allocated to different treatment arms and how the investigational drugs are administered during the trial.
For a comprehensive analysis of drugs with the same MoA as SKY-0515, specific information about this compound's pharmacological classification, molecular target, and therapeutic class would be necessary.
Clinical trials for drugs with similar mechanisms typically follow established regulatory pathways and employ standardized protocols appropriate for the specific drug class and indication being investigated.