The goal of this clinical trial is to test if the drug SKY-0515, an oral medication, can lower harmful proteins linked to Huntington's Disease (HD) and improve the symptoms of participants with HD. This study includes men and women aged 25 and older who have HD confirmed by genetic testing and meet certain requirements for physical ability and independence.
This study is a randomized, double-blind, placebo-controlled trial conducted across multiple sites. This clinical trial aims to evaluate the safety, pharmacodynamics, and efficacy of SKY-0515, a novel, orally administered small molecule. Huntington's Disease (HD) is a rare, inherited neurodegenerative condition caused by a mutation in the huntingtin (HTT) gene, resulting in excessive production of mutant huntingtin (mHTT) protein, which damages nerve cells and leads to progressive motor, cognitive, and psychiatric symptoms. SKY-0515 is designed to reduce mHTT protein levels, leading to a decrease in both wild-type and mutant forms of HTT protein. Additionally, the drug lowers postmeiotic segregation 1 (PMS1) protein, which plays a role in somatic CAG repeat expansion-a key driver of HD progression. Participants must be aged 25 or older, have genetically confirmed HD (CAG repeat length ≥ 40), and meet specific functional and motor criteria. They will be assigned randomly to one of four treatment arms (three doses of SKY-0515 and one placebo group). Safety and efficacy will be evaluated through blood tests, imaging (MRI), and clinical assessments, including the Unified Huntington's Disease Rating Scale (UHDRS).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
400
Type: Small molecule Dosage Level(s): Low, mid, high Route of Administration: Oral Dosage Frequency: Once daily Blinded Treatment Duration: 18 months Use: Experimental
Route of Administration: Oral Dosage Frequency: Once daily Blinded Treatment Duration: 18 months Use: Experimental
Change From Baseline in the Z-score from the Composite Unified Huntington's Disease Rating Scale (cUHDRS)
cUHDRS includes the Total Functional Capacity (range, 0-13; higher score means better functioning), Total Motor Score (range, 0-124; higher score means worse motor severity), Symbol Digit Modality Test (range, 0-110, correctly paired numbers-symbols in 90 seconds; higher score means better cognitive performance), and Stroop Color and Word Test (range, 0-no max value, correctly read color words in 45 seconds; higher score means better cognitive performance) scores. A z-score for each test is calculated, which alone can be used to describe relationship between an individual's test score and the mean score of a target population. A z-score of 0 is the mean, and ±1 is 1 standard deviation from the mean. For cUHDRS, z-scores of each test are summed, whereby a higher cUHDRS score is better (score of -3.06-no max value) and a change of ≥1.2 is a meaningful worsening, shown to track functional decline.
Time frame: 72 weeks
Change from Baseline in Total Motor Score (TMS)
The total motor score (TMS) assessed motor features of HD with standardized ratings of oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability. Some items (such as chorea and dystonia) required grading each extremity (face, bucco-oral-lingual, and trunk) separately. Eye movements require both horizontal and vertical grades. The total motor impairment score is the sum of all the individual 31 motor sub-items (each rated from 0 to 4), with higher scores indicating more severe motor impairment than lower scores. The range of TMS is 0-124.
Time frame: 72 weeks
Change from Baseline in Total Functional Capacity (TFC)
TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best).
Time frame: 72 weeks
Change from Baseline in Independence Scale Score (IS)
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CenExel Denver CO
Englewood, Colorado, United States
NOT_YET_RECRUITINGHospital El Cruce
Buenos Aires, Buenos Aires, Argentina
RECRUITINGBuenos Aires British Hospital
CABA, Buenos Aires, Argentina
RECRUITINGIADIN (Instituto Argentino de Investigación Neurológica)
CABA, Buenos Aires, Argentina
RECRUITINGCINME Centro de Investigaciones Metabólicas
CABA, Buenos Aires, Argentina
RECRUITINGSanatorio Mater Dei
CABA, Buenos Aires, Argentina
RECRUITINGFundación Scherbovsky
Mendoza, Mendoza Province, Argentina
RECRUITINGCentro de Pesquisas Clínicas do Hospital das Clínicas da Universidade Federal de Minas Gerais - Filial EBSERH
Belo Horizonte, Minas Gerais, Brazil
ENROLLING_BY_INVITATIONHospital Angelina Caron
Campina Grande do Sul, Paraná, Brazil
NOT_YET_RECRUITINGPUCPR - Centro de Pesquisa da Pontifícia Universidade Católica do Paraná
Curitiba, Paraná, Brazil
RECRUITING...and 14 more locations
The independence scale assesses independence on a 0 to 100 scale with higher scores indicating better functioning.
Time frame: 72 weeks
Change from Baseline in Symbol Digit Modalities Test (SDMT)
The SDMT assesses attention, visuoperceptual processing, working memory, and cognitive/psychomotor speed. The score is the number of correctly paired abstract symbols and specific numbers in 90 seconds with higher scores indicating better cognitive functioning.
Time frame: 72 weeks
Change from Baseline in the Stroop Color and Word Test (SCWT)
In the Stroop Color and Word Test (SCWT) the number of words and colors read correctly is counted, with a higher score indicating better cognitive performance scores. There is no upper limit for SWR as it is a time-based task. The lower limit (worst possible) however is 0; higher score is better meaning less severity.
Time frame: 72 weeks