Registered objectives

“Part C (ii) only: To investigate the safety and tolerability of SKY-0515 in Huntington's Disease (HD) patients” (opens the source at this quote in a new tab)
“Part C (ii) Extension: To investigate the long-term safety and tolerability of SKY-0515 in HD patients” (opens the source at this quote in a new tab)

Company-stated objectives

“The objectives of the study are to evaluate safety, pharmacokinetic, and pharmacodynamic parameters including mutant HTT protein and PMS1 mRNA.” (opens the source at this quote in a new tab)

Recruitment dates

Milestone	Registry record
Date of first participant enrolment (actual)	“12/07/2024”
Date of last participant enrolment (actual)	“31/03/2025”

Recruitment hospitals

Site
“Westmead Hospital - Westmead”
“Flinders Medical Centre - Bedford Park”
“Royal Melbourne Hospital - City campus - Parkville”
“Calvary Health Care Bethlehem Ltd - Caulfield”

First dosing

“The first patients were dosed in SKY-0515's Part C in January 2025.” (opens the source at this quote in a new tab)

Randomized placebo-controlled period followed by blinded active extension

“Part C is a randomized, double-blind, placebo-controlled parallel-group study evaluating two dose levels of SKY-0515 in patients with early-stage HD (HD-ISS Stage 1, Stage 2, or mild Stage 3) over 84 days, followed by a twelve-month blinded Extension period during which all participants receive active treatment at either a low or high dose.” (opens the source at this quote in a new tab)

Observational run-in and randomization ratio

“Part C (i): Participants will be required to attend 2 clinic visits over a period of 28 days.” (opens the source at this quote in a new tab)
“Enrolled HD patients will be randomised to 3 parallel treatment arms at 2:3:3 ratio:” (opens the source at this quote in a new tab)

Extension treatment reassignment

“HD patients who were assigned to 9 mg SKY-0515, 3 mg SKY-0515 and placebo in Part C (ii) will be assigned to below treatment arms (blinded) respectively.” (opens the source at this quote in a new tab)
“-Arm 1: 9 mg SKY-0515” (opens the source at this quote in a new tab)
“-Arm 2: 9 mg SKY-0515 or 4 mg SKY-0515 in 1:1 ratio” (opens the source at this quote in a new tab)
“-Arm 3: 9 mg SKY-0515 or 4 mg SKY-0515 in 1:1 ratio” (opens the source at this quote in a new tab)

Treatment duration extension and volumetric MRI endpoint

“HREC also agreed to the inclusion of Volumetric MRI (vMRI) measurements as an early exploratory endpoint in the trial.” (opens the source at this quote in a new tab)

Age and genetic diagnosis

“Males and females, aged between 25 and 70 years.” (opens the source at this quote in a new tab)
“Genetically confirmed HD diagnosis by direct DNA testing. CAG repeat length greater than or equal to 40, and” (opens the source at this quote in a new tab)

HD-ISS stage criteria

Stage	Quoted registry criterion
Stage 2	“HD-ISS Stage 2: CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom. Total Motor Score (TMS) greater than 6; Independence Score (IS) equal to 100 and Total Functional Capacity (TFC) equal to 13, or”
Stage 3 (mild)	“HD-ISS Stage 3 (Mild): CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom & functional change. TMS greater than 6, IS greater than or equal to 70, and TFC greater than or equal to 8.”

Cognitive exclusion

“Have marked cognitive impairment defined as with a Montreal Cognitive Assessment (MoCA) score lesser than or equal to 18 and at the discretion of the investigator.” (opens the source at this quote in a new tab)

Functional eligibility threshold: TFC of 8 or more

“Key enrollment criteria include genetic diagnosis of HD (CAG≥40), age 25-70 years and clinical baseline of TFC≥8, IS≥70, and TMS≥6, reflecting an HD-ISS disease stage 2 or mild stage 3.” (opens the source at this quote in a new tab)

Functional eligibility threshold: TFC of 10 or more

“Key enrollment criteria include genetic diagnosis of HD (CAG≥40) and clinical baseline of TFC≥10, IS≥70, and TMS≥6, reflecting an HD-ISS disease stage 2 or mild stage 3.” (opens the source at this quote in a new tab)

Randomized period and extension regimens

“Patients were randomized to 3 mg (N=10), 9 mg (N=10) or placebo (N=6) for 84 days, after which patients rolled over onto active drug, receiving either 4 mg or 9 mg (blinded) for an additional 12 months.” (opens the source at this quote in a new tab)

Extension self-administration

“A single dose of SKY-0515 will be self-administered orally once daily for 12 months.” (opens the source at this quote in a new tab)

Registered primary safety endpoints

“Incidence, severity and relationship of adverse events (AEs) and serious adverse events (SAEs)” (opens the source at this quote in a new tab)
“Mental Health: Columbia-Suicide Severity Scale (C-SSRS)” (opens the source at this quote in a new tab)

Secondary and exploratory endpoints

“PK in blood and CSF” (opens the source at this quote in a new tab)
“HTT mRNA lowering in blood” (opens the source at this quote in a new tab)
“% caudate atrophy from baseline (main)” (opens the source at this quote in a new tab)

Externally controlled cUHDRS analysis: designated primary timepoint

“At Month 15, the primary timepoint, patients treated with SKY-0515 improved on the cUHDRS by an average of 0.94 points from where they started, while a comparison group of untreated patients from the Enroll-HD natural history database declined by an average of 0.65 points.” (opens the source at this quote in a new tab)

Rationale for endpoint selection

No evidence found.

Registry sample size, Parts C (i) and C (ii)

Item	Registry record
Target	“50”
Final	“42”

Randomized participants

“Patients were randomized to 3 mg (N=10), 9 mg (N=10) or placebo (N=6) for 84 days” (opens the source at this quote in a new tab)

Participants analyzed by timepoint and external control sizes

“Nominal timepoints are anchored to a participant's first dose of SKY-0515 (Day 1 to Month 3: n=24, Month 6: n=20, Month 9: n=20, Month 12: n=18, Month 15: n=15). Overlap-weighted propensity score weighting was performed using Enroll-HD, 2CARE and CREST-E datasets (Month 3: n=21, Month 6: n=180, Month 9: n=588, Month 12: n=3569, Month 15: n=1337).” (opens the source at this quote in a new tab)

15-month analysis: statistical model

“Phase 1/2 cUHDRS LS mean change from baseline versus external control at 3, 6, 9, 12 and 15 months, and cUHDRS subcomponents LS mean change from baseline versus external control at 15 months, were estimated via overlap-weighted ANCOVA for patients receiving SKY-0515 once daily.” (opens the source at this quote in a new tab)

15-month analysis: included participants and exclusions

“The primary analysis includes all eligible participants with an available Month 15 cUHDRS assessment. Per the study's statistical analysis plan, a small number of participant-timepoints were excluded following a qualifying intercurrent event” (opens the source at this quote in a new tab)

Interim analyses: exclusions and pooled doses

“One patient was excluded due to significant intercurrent events affecting her HUHDRS assessments.” (opens the source at this quote in a new tab)

“Two participants with significant non-HD-related comorbidities and/or receipt of prohibited medications were excluded based on investigator assessment.” (opens the source at this quote in a new tab)

Decline in analyzed participants over time

“The Month 15 decline in participants partly reflects study design, as the 12-month Extension period caps SKY-0515 exposure at 12 months for participants who initially received 3 months of placebo.” (opens the source at this quote in a new tab)

Discontinuations and reasons

No evidence found.

Extension dose groups, mean ± SD

Characteristic	SKY-0515 4 mg (n=7)	SKY-0515 9 mg (n=16)
Sex, % M/F	“57/43”	“38/62”
Age	“52.3 ± 8.8”	“57.8 ± 6.4”
CAG repeats	“42.4 ± 1.7”	“42.6 ± 2.1”
CAP score	“453.5 ± 64.4”	“510.2 ± 88.1”
cUHDRS	“12.1 ± 3.1”	“11.8 ± 2.3”
TFC	“11.4 ± 1.8”	“11.8 ± 1.7”

Month 15 change from baseline versus overlap-weighted external control

Endpoint	Treated LS mean (SE), M15 (n=15)	External control LS mean (SE), M15	Treatment difference	95% CI	p-value
cUHDRS (composite)	“+0.94 (0.42)”	“-0.65 (0.27)”	“+1.59”	“1.09, 2.09”	“<0.001”
TFC	“+0.38 (0.43)”	“-0.60 (0.26)”	“+0.98”	“0.34, 1.61”	“0.003”
TMS	“-6.85 (1.02)”	“+2.53 (0.59)”	“-9.38”	“-11.58, -7.19”	“<0.001”
SDMT	“+4.63 (1.60)”	“+0.48 (0.98)”	“+4.15”	“1.04, 7.25”	“0.009”
SWRT	“+3.55 (1.62)”	“-0.63 (0.98)”	“+4.18”	“0.55, 7.80”	“0.024”

cUHDRS change by timepoint versus overlap-weighted external control

Timepoint	Treated LS mean (SE)	Treated participants	External control LS mean (SE)	Treatment difference	95% CI	p-value
Month 3	“+0.70 (0.30)”	“n=24”	“+0.05 (0.47)”	“+0.66”	“-0.33, 1.64”	“0.191”
Month 6	“+0.47 (0.39)”	“n=20”	“-0.31 (0.21)”	“+0.78”	“0.00, 1.56”	“0.051”
Month 9	“+0.70 (0.38)”	“n=20”	“-0.34 (0.23)”	“+1.04”	“0.39, 1.70”	“0.002”
Month 12	“+0.29 (0.44)”	“n=18”	“-0.50 (0.26)”	“+0.79”	“0.11, 1.48”	“0.023”
Month 15	“+0.94 (0.42)”	“n=15”	“-0.65 (0.27)”	“+1.59”	“1.09, 2.09”	“<0.001”

Month 12 interim cUHDRS subcomponents versus propensity score-weighted natural history

“At twelve months, participants receiving SKY-0515 demonstrated favorable mean change from baseline” (opens the source at this quote in a new tab)

Component	SKY-0515 mean change	Expected change, natural history
TFC	“+0.07”	“-0.87”
TMS	“-2.00”	“2.21”
SDMT	“-0.19”	“-1.78”
SWRT	“+3.44”	“-3.13”

Month 12 interim cUHDRS versus propensity score-weighted natural history: June 2026 poster

“SKY-0515-001-treated participants maintained cUHDRS scores over 12 months, diverging from the decline predicted by matched natural history controls at every assessed timepoint.” (opens the source at this quote in a new tab)
“reaching a Δ=+1.25 at the primary 12-month endpoint” (opens the source at this quote in a new tab)
“The cUHDRS subcategories Total Motor Score (TMS), Total Functional Capacity (TFC), and Stroop Word Reading Test (SWRT) individually showed disease stabilization relative to baseline across all timepoints, with statistically significant separation from estimated natural history at various timepoints up to Month 12.” (opens the source at this quote in a new tab)
“Data show change from baseline (mean ± 95% CI) for pooled 4 mg and 9 mg treatment groups and includes additional participants who received placebo for three months prior to switching to active treatment (Day 1 to Month 9: n=21, Month 12: n=15).” (opens the source at this quote in a new tab)
“Months 3 and 9 estimates for propensity score (PS) methods are extrapolated. Month 6 used the CREST-E and CARE2 clinical trials to construct the external control arm (ECA) for the PS methods. Month 12 used ENROLL-HD natural history study to construct the ECA for the PS methods.” (opens the source at this quote in a new tab)

Month 9 interim cUHDRS

“At nine months, in a pooled analysis, this improvement is +0.64 points compared to expected worsening at nine months of cUHDRS in symptomatic patients of -0.73 points, based on propensity score weighting using Enroll-HD and TRACK-HD.” (opens the source at this quote in a new tab)

Pharmacodynamic results at day 84 and month 12

“HTT and PMS1 mRNAs in blood were lowered by 62% and 26%, respectively, at the high treatment dose (9mg). Similarly, levels of mHTT protein in blood were lowered by 62% in patients receiving the 9mg dose, and 29% in patients receiving the 3mg dose.” (opens the source at this quote in a new tab)

“Treatment with SKY-0515 resulted in dose-dependent reductions in mutant huntingtin (mHTT) protein in blood of up to 69% as well as reductions in PMS1 mRNA of up to 26%.” (opens the source at this quote in a new tab)

Placebo-controlled comparison of clinical outcomes at day 84

No evidence found.

Volumetric MRI and caudate atrophy results

No evidence found.

Clinician and Patient Global Impression at 12 months

“For HD participants for whom Huntington's disease is expected to cause considerable disease worsening of over twelve months, no clinicians or participants assessed any worsening at twelve months and 65% of participants and 50% of clinicians assessed that there had been improvement.” (opens the source at this quote in a new tab)

Interpretation of global impression data: independent commentary

“But they’re inherently subjective, shaped by expectation and perception, and they are not as influential towards showing that a drug is helpful as objective clinical measures like the cUHDRS itself.” (opens the source at this quote in a new tab)

Health-related quality-of-life instrument results

No evidence found.

Adverse event severity and laboratory findings through month 9

“In Part Cii and Part Cii Extension, the majority of TEAEs were Grade 1 (mild) or Grade 2 (moderate) in intensity and the incidence rate was similarly distributed across all arms. There have been no clinically significant changes in labs, ECG, vitals.” (opens the source at this quote in a new tab)

Severe or serious adverse events: February 2026 poster

“Severe/Serious adverse events included a prolonged headache (possibly drug related), an episode of psychosis (unlikely related to drug), a case of pneumonia and pleural effusion (unrelated to drug), and a case of abdominal pain and tooth infection (unrelated to drug). All events were resolved.” (opens the source at this quote in a new tab)

Serious adverse events and most common related TEAEs: June 2026 poster

“In SKY-0515-001 Part Cii and its Extension, the most common related treatment-emergent adverse events in HD participants (reported by two or more participants) were headache, diarrhea, and nausea, with the majority of events mild or moderate in severity.” (opens the source at this quote in a new tab)
“No serious adverse events were assessed as related to SKY-0515. In SKY-0515-001 Part Cii and its Extension, three participants experienced at least one serious adverse event (Grade 3 mania; Grade 3 tooth infection; and Grade 3 pneumonia and pleural effusion in one participant), none considered related to study drug” (opens the source at this quote in a new tab)

Safety through 15 months

“SKY-0515 has demonstrated excellent central nervous system exposure and has been generally well tolerated across all dose levels studied through fifteen months of treatment, with no treatment-related SAEs.” (opens the source at this quote in a new tab)

Adverse event incidence by treatment arm and discontinuations due to adverse events

No evidence found.

Summary

The placebo-controlled period lasted 84 days in 26 randomized participants (6 on placebo), and no placebo comparison of clinical outcomes has been reported. All clinical efficacy estimates (cUHDRS and components at months 3 to 15) compare treated participants with overlap-weighted external natural-history controls from Enroll-HD, 2CARE, and CREST-E, which cannot account for unmeasured confounding or for expectation effects after all participants were known to be receiving active drug. The month 15 analysis included 15 participants, pooled the 4 mg and 9 mg groups and HD-ISS stages, and excluded some participant-timepoints after intercurrent events; the 9 mg group had higher baseline CAP scores. The posters report differing TFC eligibility thresholds and differing attributions of a serious headache event. Data are available only in company press releases and posters, not in a peer-reviewed publication.

External control limitation: independent commentary

“Statistical methods were used to make these groups as comparable as possible, but an external control can never perfectly recreate a randomised placebo group. Differences between the groups that researchers haven’t measured or accounted for could contribute to the apparent treatment effect.” (opens the source at this quote in a new tab)