SKY-0515 Shows Promising 12-Month Results in Huntington’s Disease Study

Huntington’s disease is one of the most devastating neurological disorders. It gradually affects movement, thinking, and daily functioning, and currently there is no approved treatment that can slow or stop the disease from progressing.
That is why the latest clinical data from Skyhawk Therapeutics is attracting attention. The company recently announced 12-month interim results from its ongoing Phase 1/2 clinical trial evaluating SKY-0515, an investigational oral therapy for Huntington’s disease.
The results showed meaningful reductions in key disease-driving proteins, encouraging clinical outcomes, and a favorable safety profile, offering hope for patients and families affected by this rare condition.
Understanding Huntington’s Disease
Huntington’s disease is a rare inherited neurodegenerative disorder caused by a mutation in the huntingtin gene.
The disease leads to the production of a harmful mutant huntingtin (mHTT) protein that gradually damages nerve cells in the brain. Over time, patients experience worsening movement disorders, cognitive decline, and psychiatric symptoms.
More than 40,000 people in the United States are living with symptomatic Huntington’s disease, while hundreds of thousands of individuals worldwide are affected either directly or through family risk.
Despite decades of research, there is still no approved disease-modifying therapy capable of slowing disease progression.
What Is SKY-0515?
SKY-0515 is an investigational oral small-molecule therapy developed using Skyhawk Therapeutics’ proprietary SKYSTAR platform.
Unlike traditional approaches, SKY-0515 works by modifying RNA splicing. The therapy is designed to reduce two important disease-related targets:
• Mutant huntingtin (mHTT) protein, the primary driver of Huntington’s disease
• PMS1 protein, a key contributor to somatic expansion of CAG repeats, which is associated with disease progression
By targeting both mechanisms simultaneously, researchers believe SKY-0515 may provide a unique therapeutic approach for slowing disease progression.
Strong Biomarker Results After 12 Months
One of the most important findings from the study was the significant reduction in disease-related biomarkers.
Patients receiving SKY-0515 achieved:
• Up to 69% reduction in mutant huntingtin protein levels in the blood
• Up to 26% reduction in PMS1 protein mRNA levels
These reductions were dose-dependent, meaning higher doses generally produced greater effects.
The ability to reduce mutant huntingtin protein to this extent is particularly significant because the protein is widely recognized as the central cause of Huntington’s disease pathology.
Encouraging Clinical Outcomes
Beyond biomarker improvements, researchers also reported encouraging trends in patient functioning.
The study evaluated patients using the Huntington’s Disease Unified Composite Rating Scale (cUHDRS), a commonly used measure that combines assessments of motor function, cognition, and daily living abilities.
At three, six, nine, and twelve months, patients treated with SKY-0515 showed average improvements ranging from +0.31 to +0.38 points compared with their baseline scores.
This is especially notable because historical data from natural disease progression studies suggest patients would typically experience a decline of approximately -0.92 points over a twelve-month period.
Researchers also observed favorable trends across all major components of the cUHDRS assessment, including:
• Total motor score
• Total functional capacity
• Symbol Digit Modalities Test
• Stroop Word Reading Test
Together, these findings suggest that SKY-0515 may be helping patients maintain function and potentially slow disease progression.
Safety and Tolerability Remain Positive
Safety continues to be one of the most encouraging aspects of the program.
According to the company, SKY-0515 demonstrated excellent central nervous system exposure and was generally safe and well tolerated across all dose levels studied.
The favorable tolerability profile is important because Huntington’s disease patients often require long-term treatment, making safety a critical factor for future clinical use.
Expert Reactions to the Data
The new results have generated positive reactions from leading experts in the field.
Phillip Sharp, Nobel Prize winner and member of Skyhawk’s Scientific Advisory Board, highlighted the potential of RNA splicing technology and described the results as an example of how small-molecule therapies can deliver meaningful treatment options to patients worldwide.
Bill Haney, Co-Founder and CEO of Skyhawk Therapeutics, pointed to the growing separation between treated patients and expected disease progression over time. According to him, the durability of biomarker reductions and encouraging clinical findings strengthen confidence in SKY-0515’s therapeutic potential.
Neurology expert Professor Ed Wild from University College London also described the findings as highly encouraging. He noted that SKY-0515 continues to achieve substantial reductions in mutant huntingtin protein while maintaining a favorable safety profile.
According to Professor Wild, the combination of mHTT and PMS1 reduction could offer a powerful dual mechanism for addressing key disease processes involved in Huntington’s disease.
Why PMS1 Matters
While most Huntington’s disease therapies focus on lowering mutant huntingtin protein, SKY-0515 also targets PMS1.
PMS1 plays a role in somatic expansion, a process where disease-causing CAG repeats continue to expand during a patient’s lifetime.
This expansion is believed to accelerate disease progression.
By reducing PMS1 activity, SKY-0515 may potentially slow this process, offering an additional layer of disease modification beyond huntingtin reduction alone.
The Ongoing FALCON-HD Program
Building on these positive early results, Skyhawk is advancing SKY-0515 through its global Phase 2/3 FALCON-HD clinical program.
The program consists of two major studies:
FALCON-HD 004-ANZ
This study enrolled 144 patients with stage 2 and early stage 3 Huntington’s disease across Australia and New Zealand. Recruitment has already been completed.
FALCON-HD 004-WW
This global study plans to enroll approximately 400 participants across more than 40 sites worldwide. Recruitment is currently ongoing.
Participants receive daily oral doses of SKY-0515 at various dose levels or placebo to further evaluate efficacy, safety, and biomarker changes.
Across the Phase 1/2 study and FALCON-HD program combined, more than 175 patients have now been enrolled.
An Oral Treatment Could Change the Treatment Landscape
One aspect that makes SKY-0515 particularly attractive is its oral administration.
Most advanced neurological therapies often require injections, infusions, or specialized treatment centers. SKY-0515 is being developed as a daily oral pill that patients can potentially take at home.
This convenience could significantly improve treatment accessibility and long-term adherence if the therapy ultimately reaches the market.
Looking Ahead
Skyhawk Therapeutics plans to continue advancing SKY-0515 through the pivotal FALCON-HD program while also expanding its pipeline of RNA-targeting therapies for rare neurological diseases.
The company expects additional programs targeting serious neurological disorders to enter clinical development before the end of 2027.
For now, the latest 12-month results provide encouraging evidence that SKY-0515 may have the potential to address multiple drivers of Huntington’s disease while maintaining a favorable safety profile.
Final Thoughts
The new Phase 1/2 data represent an important milestone for SKY-0515 and the broader Huntington’s disease community.
With significant reductions in mutant huntingtin protein, meaningful effects on PMS1, encouraging clinical trends, and strong tolerability data, SKY-0515 is emerging as one of the more closely watched investigational therapies in Huntington’s disease research.
While larger studies will ultimately determine whether these findings translate into a disease-modifying treatment, the current results offer renewed optimism for patients and families who have long waited for therapies capable of slowing the progression of this devastating disease.

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