Section 4 of 6

Clinical evidence

92 evidence topics · 22 sources

Study summaries

FALCON-HD 004-ANZ

Objective

Registered study goal

“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.” (opens the source at this quote in a new tab)

Location and study date

Study dates

Milestone	Registry record
Study start (actual)	“2025-05-27”
Primary completion (estimated)	“2027-05”
Study completion (estimated)	“2027-12”

Countries and first dosing site

“FALCON-HD 004-ANZ enrolled 144 participants with Stage 2 and early Stage 3 HD across sites in Australia and New Zealand, and enrollment is complete.” (opens the source at this quote in a new tab)

“The initial dosing took place at Flinders Medical Centre in Adelaide, Australia.” (opens the source at this quote in a new tab)

Study design

Phase 2/3 randomized, double-blind, placebo-controlled, dose-ranging design

“A Phase 2/3 Randomized, Double Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Pharmacodynamics, Safety and Efficacy of SKY-0515 in Participants With Huntington's Disease” (opens the source at this quote in a new tab)
“They will be assigned randomly to one of four treatment arms (three doses of SKY-0515 and one placebo group) in a 1:1:1:1 ratio.” (opens the source at this quote in a new tab)

Study periods and safety oversight

“Screening Period (up to 4 weeks): Participants will undergo eligibility assessments.” (opens the source at this quote in a new tab)
“Double-Blind Treatment Period (12 months): Participants will take SKY-0515 or a placebo once daily and undergo regular clinic visits for monitoring.” (opens the source at this quote in a new tab)
“Follow-Up Period (4 weeks): After completing treatment, participants will be monitored for any remaining effects.” (opens the source at this quote in a new tab)
“An independent Data Safety Monitoring Board (DSMB) will oversee the trial to ensure participant safety.” (opens the source at this quote in a new tab)

Eligibility criteria

Key inclusion criteria

Criterion	Quoted registry text
Age	“You must be 25 years or older.”
Genetic diagnosis	“You must have Huntington's Disease confirmed through genetic testing, with a specific gene change (CAG repeat of 40 or more).”
Function	“Total Functional Capacity (TFC) score of 10 or more).”
Motor signs	“Total Motor Score (TMS) of 6 or more).”
Independence	“Independence Score (IS) of 70 or more).”

Key exclusion criteria

“You have a condition that interferes with protocol-specified assessments, like an implanted medical device or difficulty getting an MRI.” (opens the source at this quote in a new tab)
“You have had any kind of gene therapy.” (opens the source at this quote in a new tab)
“Your liver function tests show significant abnormalities.” (opens the source at this quote in a new tab)

Treatment

Treatment arms

Arm	Quoted registry description
1 (Active)	“Dosage Level(s): Low dose once daily oral”
2 (Active)	“Dosage Level(s): Mid dose once daily oral”
3 (Active)	“Dosage Level(s): High dose once daily oral”
4 (Control)	“Matching placebo once daily oral”

Blinded treatment duration

“Blinded Treatment Duration: 12 months” (opens the source at this quote in a new tab)

Numeric dose levels

No evidence found.

Study outcomes

Rationale for using blood mHTT protein, MRI brain volume, and UHDRS change as the primary endpoints

Registered primary outcomes

Primary outcome	Time frame
“Changes in blood mHTT protein levels”	“12 months”
“Changes in brain volume measured through MRI”	“12 months”
“Changes in UHDRS”	“12 months”

Primary goal as described at HDSA 2026

“The main goal of both FALCON-HD portions is to assess changes in the cUHDRS score after 72 weeks, or nearly 1.5 years.” (opens the source at this quote in a new tab)

Rationale for endpoint selection

No evidence found.

Statistical analysis description

Number of participants (Planned and analyzed)

Planned enrollment: registry record

Enrollment type	Participants
Estimated	“120”

Planned enrollment: independent trials review

“This multi-centre clinical trial will enrol 120 adults (≥25 years) with genetically confirmed HD (CAG repeat length ≥40)” (opens the source at this quote in a new tab)

Completed enrollment

“The Company also announces that the Australia and New Zealand (004-ANZ) portion of its Phase 2/3 FALCON-HD pivotal study completed enrollment six months ahead of schedule with 144 patients enrolled” (opens the source at this quote in a new tab)

Analyzed population

No evidence found.

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

No evidence found.

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

No evidence found.

Study limitations

Summary

No results have been reported. The registry lists three primary outcomes at 12 months (blood mHTT, MRI brain volume, and UHDRS change) and an estimated enrollment of 120 participants, while 144 participants were enrolled and conference coverage describes cUHDRS change at 72 weeks as the main goal; the numeric dose levels, final analysis plan, and multiplicity handling are not public. Eligibility requires TFC of 10 or more and TMS of 6 or more, so results will apply to stage 2 and early stage 3 HD in adults aged 25 years or older.

FALCON-HD 004-WW

Objective

Registered study goal

“This clinical trial aims to evaluate the safety, pharmacodynamics, and efficacy of SKY-0515, a novel, orally administered small molecule.” (opens the source at this quote in a new tab)

Location and study date

Study dates

Milestone	Registry record
Study start (actual)	“2026-01-06”
Primary completion (estimated)	“2028-12”
Study completion (estimated)	“2029-08”

Registered site countries

Country
“Argentina”
“Brazil”
“Canada”
“Chile”
“Colombia”
“Georgia”
“United States”

Expansion to the United Kingdom

“We are excited to now begin enrolling patients in our pivotal trial for Huntington's in the United States, the United Kingdom and Canada” (opens the source at this quote in a new tab)

Study design

Phase 2/3 randomized, double-blind, placebo-controlled, dose-ranging design

“A Phase 2/3 Randomized, Double Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Pharmacodynamics, Safety and Efficacy of SKY-0515 in Participants With Huntington's Disease” (opens the source at this quote in a new tab)
“They will be assigned randomly to one of four treatment arms (three doses of SKY-0515 and one placebo group).” (opens the source at this quote in a new tab)

Eligibility criteria

Key inclusion criteria

Criterion	Quoted registry text
Age	“25 years or older.”
Genetic diagnosis	“Huntington's Disease confirmed through genetic testing, with a specific change in exon 1 of the HTT gene (CAG repeat of 40 or more).”
Function	“Total Functional Capacity (TFC) score of 10 or more).”
Motor signs	“Total Motor Score (TMS) of 6 or more).”
Independence	“Independence Score (IS) of 70 or more).”

Treatment

Treatment arms and duration

“Type: Small molecule Dosage Level(s): Low, mid, high Route of Administration: Oral Dosage Frequency: Once daily Blinded Treatment Duration: 18 months Use: Experimental” (opens the source at this quote in a new tab)

Numeric dose levels

No evidence found.

Study outcomes

Rationale for using cUHDRS change as the primary endpoint

Primary outcome definition

“Change From Baseline in the Z-score from the Composite Unified Huntington's Disease Rating Scale (cUHDRS)” (opens the source at this quote in a new tab)
“72 weeks” (opens the source at this quote in a new tab)

Rationale for cUHDRS: registry description

“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.” (opens the source at this quote in a new tab)

Secondary outcomes

Secondary outcome	Time frame
“Change from Baseline in Total Motor Score (TMS)”	“72 weeks”
“Change from Baseline in Total Functional Capacity (TFC)”	“72 weeks”
“Change from Baseline in Independence Scale Score (IS)”	“72 weeks”
“Change from Baseline in Symbol Digit Modalities Test (SDMT)”	“72 weeks”
“Change from Baseline in the Stroop Color and Word Test (SCWT)”	“72 weeks”

Statistical analysis description

Number of participants (Planned and analyzed)

Planned enrollment: registry record

Enrollment type	Participants
Estimated	“400”

Planned enrollment: company statement of up to an additional 400 participants

“FALCON-HD 004-WW plans to enroll up to an additional 400 participants with Stage 2 and early Stage 3 HD across more than 40 sites worldwide and is actively treating patients at a number of these sites presently.” (opens the source at this quote in a new tab)

Planned enrollment: company statement of approximately 600 participants

“FALCON-HD 004-WW plans to enroll approximately 600 participants with Stage 2 and Stage 3 HD across more than 40 sites worldwide and is actively recruiting.” (opens the source at this quote in a new tab)

Analyzed population

No evidence found.

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

No evidence found.

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

No evidence found.

Study limitations

Summary

The trial is recruiting and has reported no results; the estimated primary completion is December 2028. Planned enrollment is 400 participants in the registry record and "up to an additional 400" in the July 2026 expansion announcement, whereas the September 2026 fifteen-month announcement states approximately 600. The 72-week primary endpoint is cUHDRS change, with TMS, TFC, IS, SDMT, and Stroop as secondary outcomes; numeric dose levels, the statistical hierarchy, and whether results will be pooled with the 004-ANZ trial have not been disclosed.

SKY-0515-008

Objective

Long-term safety, tolerability, and efficacy

“This is an OLE study to investigate the long-term safety, tolerability, and efficacy of SKY-0515 administered orally in participants with HD.” (opens the source at this quote in a new tab)

Location and study date

Study dates and countries

Item	Registry record
Study start (actual)	“2026-04-10”
Primary completion (estimated)	“2029-12”
Countries	“Australia”· “New Zealand”

Study design

Open-label extension design

“An Open Label Extension of SKY-0515 in Participants With Huntington's Disease Who Completed a Prior SKY-0515 Treatment Study” (opens the source at this quote in a new tab)

Eligibility criteria

Completion of a prior SKY-0515 study

“Must have completed treatment in a prior SKY-0515 treatment study and, in the opinion of the Investigator, have been compliant with the prior SKY-0515 treatment protocol study procedures.” (opens the source at this quote in a new tab)

Treatment

Open-label 9 mg once daily

“participants will be consented to enter the OLE study and initiate open label treatment with 9 mg tablets of SKY-0515. Open label SKY-0515 will be self-administered daily (QD).” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using long-term safety and tolerability as the primary endpoint

Primary outcome definition

“To investigate the long-term safety and tolerability of SKY-0515 through the Incidence, severity, and relationship of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) (including withdrawals due to TEAEs)” (opens the source at this quote in a new tab)

Secondary efficacy assessments schedule

“Every 3 months for the first year, beginning with enrollment, then every six months for approximately 36 months.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Planned enrollment

Enrollment type	Participants
Estimated	“500”

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

No evidence found.

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

No evidence found.

Study limitations

Summary

This single-group, open-label extension has no concurrent control and has reported no results. All participants receive 9 mg once daily regardless of prior assignment, so longer-term efficacy outcomes will be difficult to separate from natural history and expectation effects; its primary contribution will be long-term safety data over approximately 36 months in up to an estimated 500 participants.

SKY-0515-001 part C

Objective

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)

Location and study date

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)

Study design

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)

Eligibility criteria

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)

Treatment

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)

Study outcomes

Rationale for using safety and tolerability as the primary endpoint

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.

Statistical analysis description

Number of participants (Planned and analyzed)

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)

Description of analysis sets

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)

Results

Participant disposition

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.

Baseline characteristics

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”

Efficacy results

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.

Health-related quality of life and patient-reported outcomes

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.

Safety results

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.

Study limitations

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)

SKY-0515-001 parts A and B

Objective

Primary objectives

“To investigate the safety and tolerability of a single oral dose administration of SKY-0515 in healthy adult participants” (opens the source at this quote in a new tab)
“To investigate the safety and tolerability of multiple oral dose administrations of SKY-0515 in healthy adult participants.” (opens the source at this quote in a new tab)

Location and study date

Site and enrollment start

Item	Registry record
Recruitment hospital	“CMAX Clinical Research Pty Ltd - Adelaide”
Date of first participant enrolment (actual)	“20/11/2023”

Study design

Randomized, double-blind, placebo-controlled SAD and MAD

“This is a randomised, double-blind, placebo-controlled, single ascending dose (SAD), multiple ascending dose (MAD) multi-cohort study.” (opens the source at this quote in a new tab)

Food-effect cohort

“Cohort 6 (food effect) a fed or fasted, 2-period, open label, crossover design, 8 healthy adult participants will be randomised to one of 2 treatment sequences (AB/BA)” (opens the source at this quote in a new tab)

CSF sampling cohorts

“Cerebrospinal Fluid samples will also be taken from participants enrolled in Cohorts 9 and 10.” (opens the source at this quote in a new tab)

Eligibility criteria

Key inclusion criteria

“Healthy male or female, aged between 18 and 70 years, inclusive at screening.” (opens the source at this quote in a new tab)
“Body mass index (BMI) of 18 to 35 kg/m2, inclusive, with body weight greater than or equal to 50.0 kg and < 130.0 kg.” (opens the source at this quote in a new tab)

Treatment

Dose ranges

“In Part A, five cohorts of participants were dosed with escalating single doses of SKY-0515 ranging from 1mg to 16mg or placebo.” (opens the source at this quote in a new tab)
“In Part B, three cohorts of participants were randomized to receive multiple ascending doses of SKY-0515 ranging from 1mg to 9mg or placebo administered daily from days 1 to 14 (inclusive).” (opens the source at this quote in a new tab)

Placebo

“Placebo drug product is microcrystalline cellulose capsule, packaged and encapsulated to look identical in appearance to SKY-0515.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using safety and tolerability as the primary endpoint

Not applicable.

Statistical analysis description

Number of participants (Planned and analyzed)

Planned sample sizes

“The sample sizes of 40 participants (30 receiving SKY-0515 and 10 placebo) in Part A (Cohorts 1 to 5), 8 participants (all receiving SKY-0515) in Part A (Cohort 6), 32 participants (24 receiving SKY-0515 and 8 placebo) in Part B are considered adequate to meet the objectives of the study.” (opens the source at this quote in a new tab)

Enrolled and analyzed participants

No evidence found.

Description of analysis sets

Sample size justification

“This is a FIH study for SKY-0515. As such, no formal sample size calculations have been performed.” (opens the source at this quote in a new tab)

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

Pharmacodynamic results: blood HTT mRNA

“SKY-0515 demonstrated an average HTT mRNA reduction of 72% at a daily oral dose of 9mg and was generally well tolerated at all doses tested.” (opens the source at this quote in a new tab)

“SKY-0515 produced dose-dependent reductions in HTT mRNA, with maximum decreases of 67% after a single 16 mg dose and 72% after 14 days of 9 mg daily dosing.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

Not applicable.

Safety results

Severe and serious adverse events and TEAE severity

“In healthy participants (SKY-0515-001 Parts A and B), no severe or serious adverse events were observed at single doses up to 16 mg and multiple doses up to 9 mg/day over 14 days; all treatment-emergent adverse events were mild or moderate, the most common being headache.” (opens the source at this quote in a new tab)

Adverse event incidence by cohort

No evidence found.

Study limitations

Summary

Parts A and B were designed for up to 80 healthy adults (40 in single ascending dose cohorts, 8 in a food-effect cohort, and 32 in multiple ascending dose cohorts) with no formal sample size calculation. Multiple dosing lasted 14 days. Only topline HTT mRNA reductions and a summary safety statement have been disclosed; enrolled numbers, adverse event incidence, half-life, food-effect, and CSF results from this part have not been published.