Skyhawk Reports 15-Month Phase 1/2 Results for SKY-0515 in Huntington’s Disease

SKY-0515 Shows Changes in Clinical Measures After 15 Months

Skyhawk Therapeutics has announced final 15-month results from its Phase 1/2 clinical trial of SKY-0515, an investigational oral treatment being developed for Huntington’s disease (HD).

The company reported that patients treated with SKY-0515 showed improvements in a clinical measure called the composite Unified Huntington’s Disease Rating Scale, or cUHDRS, when compared with an external group of untreated patients from the Enroll-HD natural history database.

At Month 15, the average cUHDRS score in patients receiving SKY-0515 improved by 0.94 points from baseline. The external comparison group declined by an average of 0.65 points.

This resulted in a difference of 1.59 points between the two groups, with a 95% confidence interval of 1.09 to 2.09 and a p-value below 0.001.

What Is Huntington’s Disease?

Huntington’s disease is a rare inherited disorder that gradually damages nerve cells in the brain.

The disease can affect movement, thinking, memory and a person's ability to carry out everyday activities.

HD is caused by a genetic mutation in the huntingtin gene. The disease is ultimately fatal, and there are currently no approved therapies shown to slow or stop the underlying progression of the disease.

More than 40,000 people in the United States have symptomatic Huntington’s disease, while hundreds of thousands of people worldwide are affected directly or through their families.

How Was the SKY-0515 Study Designed?

The Phase 1/2 study was a randomized, double-blind and placebo-controlled parallel-group clinical trial.

During the first 12 weeks, patients received either placebo or one of two doses of SKY-0515.

After this initial period, participants entered a 12-month blinded extension period. During the extension, all participants received active treatment at either a lower dose or higher dose.

The extension doses were 4 mg or 9 mg once daily, with most patients receiving the 9 mg dose.

The final analysis looked at patients after 15 months from the beginning of the study.

SKY-0515 Patients Showed a 1.59-Point Difference on cUHDRS

The main clinical measure reported at Month 15 was the cUHDRS.

The cUHDRS combines several different measurements of Huntington's disease. It looks at a person's daily function, movement and cognitive performance.

At Month 15, patients treated with SKY-0515 had an average improvement of 0.94 points from baseline.

The external control group, made up of untreated patients from natural history datasets, had an average decline of 0.65 points.

The resulting treatment difference was 1.59 points.

The difference was statistically significant, with a p-value below 0.001.

Improvements Were Seen Across All Four cUHDRS Measures

Skyhawk also reported results for the four individual measures that make up the cUHDRS.

The first measure was Total Functional Capacity, which looks at daily functioning. Patients treated with SKY-0515 had a treatment difference of 0.98 points compared with the external control group.

The second was Total Motor Score, which measures movement problems. The treatment difference was -9.38 points. For this measure, a lower score represents better performance.

The third measure was the Symbol Digit Modalities Test, which looks at processing speed. The treatment difference was 4.15 points.

The fourth was the Stroop Word Reading Test, which measures reading speed. The treatment difference was 4.18 points.

Skyhawk reported that all four differences were statistically significant at Month 15.

Clinical Differences Were Seen Throughout the Study

The company reported that the difference between SKY-0515-treated patients and the external comparison group was present at every scheduled assessment.

At Month 3, the difference was 0.66 points.

At Month 6, it was 0.78 points.

At Month 9, the difference increased to 1.04 points.

At Month 12, the difference was 0.79 points.

At Month 15, it reached 1.59 points.

The differences became statistically significant from Month 9 onward.

The average cUHDRS score for SKY-0515-treated patients remained at or above their baseline level at every assessment through Month 15.

The external comparison group's average score began declining from Month 6 onward.

The Study Used an External Control Group

The 15-month analysis compared patients receiving SKY-0515 with an external control group rather than a continuously placebo-treated group.

The external control data came from natural history datasets, including Enroll-HD, 2CARE and CREST-E.

Researchers used overlap-weighted propensity score methods to make the comparison between the treated patients and the external control population.

At Month 15, data from 15 SKY-0515-treated patients were included in the analysis, compared with 1,337 patients in the external control dataset.

The company noted that the number of treated patients decreased at later timepoints because of the study design.

SKY-0515 Targets Two Disease-Related Mechanisms

SKY-0515 is an oral small-molecule RNA splicing modifier.

The drug was developed using Skyhawk's proprietary SKYSTAR platform.

The treatment is designed to reduce mutant huntingtin, or mHTT, as well as PMS1.

Mutant huntingtin is the abnormal protein produced as a result of the genetic mutation that causes Huntington's disease.

PMS1 is involved in somatic CAG repeat expansion, a biological process that has been linked to Huntington's disease progression.

By targeting both pathways, SKY-0515 is being developed with the aim of affecting disease-related biology rather than only treating individual symptoms.

SKY-0515 Reduced Mutant Huntingtin and PMS1

Throughout the study, patients receiving the 9 mg dose showed average reductions of more than 60% in mutant huntingtin protein.

The same patients also showed an average reduction of approximately 25% in PMS1 mRNA.

These biological changes were observed consistently during the study.

The company said the results provide evidence that SKY-0515 is affecting both of its intended molecular targets.

The Drug Reached the Central Nervous System

Skyhawk also reported that SKY-0515 demonstrated strong central nervous system exposure.

This is important for Huntington's disease because the disease primarily affects the brain and other parts of the nervous system.

A treatment intended to modify disease-related processes therefore needs to reach the relevant tissues.

According to the company, SKY-0515 was generally well tolerated across the dose levels studied through 15 months.

No treatment-related serious adverse events were reported.

Experts Comment on the 15-Month Results

Dr. Samuel Frank, Director of the Huntington's Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center, said the Phase 1/2 results provide clinical data that warrant further study.

He highlighted the difference in cUHDRS between SKY-0515-treated patients and the weighted natural history control group at 15 months.

He also pointed to the changes seen across functional, motor and cognitive measures.

Dr. Frank noted that these findings need to be further evaluated in ongoing placebo-controlled studies.

Patient Advocates Highlight the Oral Treatment Approach

Katie Jackson, Chief Executive Officer of Help 4 HD International, also commented on the results.

She highlighted the reported changes in function, movement and cognition and the importance of developing treatments for families affected by Huntington's disease.

SKY-0515 is taken orally once a day at home.

This means the treatment does not require an infusion or administration at a specialized medical center.

The ongoing clinical program will provide more information about whether the benefits observed so far can be confirmed in larger controlled studies.

Skyhawk Is Advancing SKY-0515 Into Phase 2/3 Development

The worldwide Phase 2/3 FALCON-HD-004-WW pivotal study of SKY-0515 is now active.

The study is being conducted across more than 10 countries and 20 clinical sites.

Together, the Phase 1/2 and FALCON-HD pivotal studies have enrolled more than 200 patients, according to Skyhawk.

The Phase 2/3 study is intended to provide more extensive clinical data on the safety and effectiveness of SKY-0515 in people with Huntington's disease.

The FALCON-HD Study Will Provide Further Evidence

The results from the Phase 1/2 study are early-stage clinical findings.

The use of an external natural history control means the 15-month comparison is different from a conventional randomized placebo-controlled comparison at that timepoint.

The ongoing FALCON-HD pivotal program is therefore an important part of the development process because it is designed to provide additional controlled clinical evidence.

Future results will help researchers understand whether the changes reported in the Phase 1/2 study can be reproduced in a larger patient population.

Skyhawk Is Applying Its SKYSTAR Platform to Other Diseases

SKY-0515 was developed using Skyhawk's SKYSTAR platform, which is designed to create small-molecule medicines that modify RNA splicing.

The company is also applying the platform to other neurological diseases.

Skyhawk expects to advance additional therapies targeting rare neurological diseases with no approved disease-modifying treatments into clinical development by the end of 2027.

What Happens Next for SKY-0515?

Skyhawk will continue the global Phase 2/3 FALCON-HD-004-WW pivotal study of SKY-0515.

The company will use the ongoing program to further evaluate clinical outcomes, safety and the drug's effects on disease-related biology.

The 15-month Phase 1/2 results showed a 1.59-point difference in cUHDRS compared with the overlap-weighted external control group, along with reported differences across daily function, motor performance, processing speed and reading speed.

Further data from the pivotal program will determine how these findings translate into the larger clinical development of SKY-0515 for Huntington's disease.