Formulary monograph

SKY-0515

Every statement is a verbatim quote from the source cited beneath it. · 57 sources

Monograph section

Field	Value
Drug	SKY-0515
Indication reviewed	Huntington's disease
Therapeutic category	RNA splicing modulators
Manufacturer	Skyhawk Therapeutics
Regulatory status	Not approved in any country. Provisional approval application submitted to Australia's Therapeutic Goods Administration in March 2026
Data as of	September 21, 2026
Prepared by	To be completed by the reviewing plan
Review status	Draft for pharmacy and therapeutics committee review

Introduction

Disease background

Definition: progressive motor, cognitive, and psychiatric manifestations inherited in an autosomal dominant manner

“Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric manifestations.” (opens the source at this quote in a new tab)
“HD is inherited in an autosomal dominant manner. Offspring of an individual with a heterozygous CAG repeat expansion in HTT have a 50% chance of inheriting a CAG repeat expansion.” (opens the source at this quote in a new tab)

Etiology: expanded CAG trinucleotide repeat in HTT

“The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin.” (opens the source at this quote in a new tab)

United States prevalence: symptomatic population and claims-based estimates

“Today, there are approximately 41,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.” (opens the source at this quote in a new tab)

“In the Medicare population, 1,941 prevalent and 819 incident cases of HD were identified in 2017, corresponding to a prevalence proportion of 13.1 per 100,000 persons and incidence rate of 6.1 per 100,000 person-years. In the Medicaid population, 353 prevalent cases of HD were identified in 2014, corresponding to a prevalence proportion of 15.2 per 100,000 persons.” (opens the source at this quote in a new tab)

United States incidence: commercial insurance claims, 2003 to 2016

“Using an insurance database of over 67 million enrollees, we retrospectively identified a cohort of 3,707 individuals diagnosed with Huntington’s disease between 2003–2016.” (opens the source at this quote in a new tab)
“We estimated a cumulative age-adjusted HD frequency rate of 6.52 per 100,000 persons and a cumulative incidence rate of 1.22 per 100,000 person years.” (opens the source at this quote in a new tab)

Age at onset and prodromal phase

“The mean age of onset is approximately 45 years” (opens the source at this quote in a new tab)
“About two thirds of individuals first present with neurologic manifestations; others present with psychiatric changes.” (opens the source at this quote in a new tab)
“These subtle changes can occur as early as 15-20 years prior to the clinical onset of manifest HD.” (opens the source at this quote in a new tab)
“In approximately 25% of individuals with HD, the onset is delayed until after age 50 years, with some after age 70 years” (opens the source at this quote in a new tab)

Survival after onset and age at death

“In late stages of HD, motor disability becomes severe, and the individual is often totally dependent, mute, and incontinent. The median survival time after onset is 15 to 18 years (range: 5 to >25 years). The average age at death is 54 to 58 years” (opens the source at this quote in a new tab)

Motor symptoms: chorea early and hypokinetic features later

“Chorea, an involuntary movement disorder consisting of nonrepetitive, nonperiodic jerking of limbs, face, or trunk, is the major sign of HD. Chorea is present in most individuals and typically increases in severity during the first ten years.” (opens the source at this quote in a new tab)

“Early in the disease, they are primarily hyperkinetic with involuntary chorea. In later stages, however, hypokinesia with bradykinesia and dystonia may predominate.” (opens the source at this quote in a new tab)

Non-motor symptoms: functional impact, depression, and apathy

“Chorea and other aspects of the movement disorder are the most visible aspect of the disease. However, non-motor features have greatest affect on functional independence and quality of life, so require recognition and management.” (opens the source at this quote in a new tab)

“Depression is the most common psychiatric manifestation, affecting 40% of individuals with HD, followed by anxiety” (opens the source at this quote in a new tab)
“Apathy is a common and disabling symptom that is related to disease stage and worsens with progression” (opens the source at this quote in a new tab)

Burden: health-related quality of life and healthcare costs by disease stage

“Mean HRQoL values declined across disease phases for the 84 participants; early phase (n = 34): mean = 0.84 (SD = 0.13), middle phase (n = 19): mean = 0.74 (SD = 0.10) and advanced phase (n = 31): mean = 0.65 (SD = 0.5).” (opens the source at this quote in a new tab)

“We identified 3,688 matched pairs of beneficiaries with and without HD.” (opens the source at this quote in a new tab)
“Mean [SD] annual total healthcare costs were higher for HD beneficiaries than beneficiaries without HD ($41,631 [57,393] vs. $17,222 [31,218], p < .001) and were primarily driven by outpatient pharmacy costs ($19,182 [45,469] vs. $4,318 [11,553], p < .001).” (opens the source at this quote in a new tab)
“In the stratified analysis, total healthcare costs were highest among beneficiaries with late-stage HD (mean [SD] cost: $20,475 [$41,122] for early-stage vs. $29,733 [$44,977] for middle-stage vs. $56,657 [$64,185] for late-stage; p < .001).” (opens the source at this quote in a new tab)

Development and regulatory status

Investigational status: not approved in any country

“SKY-0515 is an investigational, once-daily oral medicine that is currently only available through clinical trials. It is not approved for use in any disease or in any country.” (opens the source at this quote in a new tab)

Current development phase: FALCON-HD pivotal program

“The FALCON-HD pivotal program (NCT06873334 and NCT07378644) is a randomized, double-blind, placebo-controlled, dose-ranging study evaluating the pharmacodynamics, safety and efficacy of SKY-0515.” (opens the source at this quote in a new tab)

Australia: TGA provisional approval pathway eligibility and application submission

“Australia's Therapeutic Goods Administration (TGA), responsible for approval of the safety, quality, and efficacy of therapeutic goods, has determined that Skyhawk's SKY-0515 orally-administered small molecule therapy for the treatment of Huntington's disease meets TGA eligibility criteria for registration via the provisional approval pathway.” (opens the source at this quote in a new tab)
“Skyhawk delivered its application for provisional approval to the TGA today.” (opens the source at this quote in a new tab)

Australia: date of the application submitted to the TGA

“BOSTON, March 3, 2026 /PRNewswire/” (opens the source at this quote in a new tab)
“Skyhawk delivered its application submission to the TGA for provisional approval today.” (opens the source at this quote in a new tab)

Australia: duration of provisional registration

“Provisional registration is time-limited: it’s granted initially up to two years, with the option to extend up to a maximum of six years.” (opens the source at this quote in a new tab)
“To be clear: this is not approval.” (opens the source at this quote in a new tab)

United States, Canada, and United Kingdom: clinical trial authorizations

“announces it has received additional regulatory approvals to open its Phase 2/3 FALCON-HD (004-ANZ and 004-WW) pivotal trial, with an IND acceptance in the United States and CTA acceptances in each Canada and the United Kingdom.” (opens the source at this quote in a new tab)

Anticipated launch as early as 2027

“Industry veteran brings more than 30 years of experience launching therapies for neurological diseases, including Huntington's disease, and will prepare Skyhawk for the launch of SKY-0515 as early as 2027.” (opens the source at this quote in a new tab)

FDA or EMA marketing application, orphan, fast track, breakthrough therapy, or PRIME designations

No evidence found.

Pharmacology and usage

Mechanism of action

Mechanistic classification

“SKY-0515 is an investigational, orally available, brain-penetrant small molecule RNA splicing modulator developed using Skyhawk’s novel RNA-splicing platform.” (opens the source at this quote in a new tab)

HTT lowering through splicing modulation

“SKY-0515 is designed to reduce mHTT protein levels by lowering of HTT messenger RNA (mRNA) through a splicing mechanism, leading to a decrease in both wild-type and mutant forms of HTT protein.” (opens the source at this quote in a new tab)
“Additionally, the drug lowers postmeiotic segregation 1 (PMS1) protein, which plays a role in somatic CAG repeat expansion-a key driver of HD progression.” (opens the source at this quote in a new tab)

Molecular mechanism: cryptic exon inclusion in HTT pre-mRNA

“Inducing the 5’ss of intron 49b to include poison exon 49b introducing a premature termination codon and destabilizing HTT mRNA” (opens the source at this quote in a new tab)

Rationale for PMS1 lowering

“PMS1 contributes to somatic instability of the CAG repeat expansion, particularly in striatal neurons. Continued expansion of the repeats leads to increased cellular toxicity and is a key driver in time to disease onset and progression.” (opens the source at this quote in a new tab)

Target selectivity: independent commentary

“SKY-0515, like PTC Therapeutics’ votoplam, isn’t specific for huntingtin.” (opens the source at this quote in a new tab)

“we currently have no direct evidence that the reductions in PMS1 reported by SKY-0515 are actually slowing somatic expansion in the brains of people with HD” (opens the source at this quote in a new tab)

Pharmacodynamics

Healthy volunteers: blood HTT mRNA reduction

“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)

Participants with HD: blood mHTT and total HTT protein through 12 months

“In Part Cii, increasing reductions in blood mHTT and total HTT (tHTT) proteins were observed at months 1, 2 and 3, reaching mean reductions of up to ~62% and ~65%, respectively, at the 9 mg dose at month 3.” (opens the source at this quote in a new tab)
“Over the following 9 months in Part Cii Extension, the reduction of mHTT and tHTT stabilized, with a maximum mean reduction at the 9mg dose of ~69% for both mHTT and tHTT, supporting the preservation of ~30% of WT HTT protein.” (opens the source at this quote in a new tab)

Participants with HD: biomarker reductions through 15 months

“SKY-0515 has shown consistent average reductions of more than 60% mutant huntingtin protein (mHTT) and 25% PMS1 mRNA in patients at the 9 mg dose throughout the study.” (opens the source at this quote in a new tab)

Neurofilament light chain

“Across all arms, NfL levels remained generally stable from baseline through Day 270 (Month 9), with no consistent dose-related increases observed.” (opens the source at this quote in a new tab)

“Plasma NfL (up to 12 months) and CSF NfL (up to 9 month) has been generally stable.” (opens the source at this quote in a new tab)

CSF markers of neuroinflammation and neuronal injury

“Ten CSF protein markers of neuroinflammation and neuronal injury were measured at Day 1 and Month 9 by NULISA” (opens the source at this quote in a new tab)
“All 10 markers remained stable, including: YKL-40/CHI3L1 (astrocyte activation; p=0.85), CSF NfL/NEFL (axonal injury; p=0.11), S100B (glial injury; p=0.39), MAPT (neurodegeneration; p=0.53), CCL2/MCP-1 (monocyte recruitment; p=0.17), and five pro-inflammatory cytokines (IL-6, IL-8, IL-1B, IL-17A, TNF; all p>0.23).” (opens the source at this quote in a new tab)

Pharmacokinetics

Healthy volunteers: systemic exposure

“The Safety Review Committee has determined that SKY-0515 has been generally well tolerated at all tested doses with a dose proportional increase in systemic exposure” (opens the source at this quote in a new tab)

Participants with HD: dose proportionality and steady state

“The pharmacokinetic properties of SKY-0515 in patients demonstrated a linear and dose proportional PK profile reaching steady state in 5-7 days, and favorable brain penetrance.” (opens the source at this quote in a new tab)
“SKY-0515 shows an approximate 3-fold increase in exposure between 3 mg and 9 mg doses and reaches a plateau by day 8, showing stable concentration at all subsequent time points.” (opens the source at this quote in a new tab)

Participants with HD: CSF penetration

Dose	Kp,uu
3 mg (N = 10)	“0.84”
9 mg (N = 7)	“0.73”

Elimination after discontinuation

“In HD patients, SKY-0515 reaches stable levels in about a week and is eliminated in ~1 week after discontinuing drug (data not shown).” (opens the source at this quote in a new tab)

Terminal half-life, food effect results, metabolism, and renal excretion

No evidence found.

Indications

Indication under regulatory review in Australia

“the Company's SKY-0515 orally-administered small molecule therapy for the treatment of Huntington's disease meets TGA eligibility criteria for registration via the provisional approval pathway.” (opens the source at this quote in a new tab)

Population studied in pivotal trials

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

Current availability limited to clinical trials

“SKY-0515 is an investigational, once-daily oral medicine that is currently only available through clinical trials.” (opens the source at this quote in a new tab)

Dosing and administration

Drug	Available formulations	Route	Frequency studied	Comments
SKY-0515	“9 mg tablets of SKY-0515”	“Oral”	“Once daily”	“Open label SKY-0515 will be self-administered daily (QD).”

SKY-0515-001 Part C: randomized period dosing

“A single dose of SKY-0515 or placebo will be administered orally once daily on Days 1 to 28 (Cycle 1), Days 29 to 56 (Cycle 2) and Days 57 to 84 (Cycle 3).” (opens the source at this quote in a new tab)

SKY-0515-001 Part C: extension dosing

“followed by a twelve-month blinded Extension period during which all participants receive active treatment at either a low or high dose (4mg or 9mg), with the majority of patients on the 9 mg dose.” (opens the source at this quote in a new tab)

FALCON-HD: dose levels

“Eligible patients receive once-daily oral SKY-0515 at one of three dose levels or placebo.” (opens the source at this quote in a new tab)

Dose strengths studied in participants with HD

“Part C (ii): Two dose levels (3mg and 9mg) of study drug SKY-0515-001 will be evaluated.” (opens the source at this quote in a new tab)
“Part C (ii) Extension: Two dose levels (9mg and 4 mg) of study drug SKY-0515-001 will be evaluated.” (opens the source at this quote in a new tab)

Proposed commercial dose, dose adjustment, and administration with food

No evidence found.

Clinical efficacy summary

SKY-0515-001 part C

Design and population

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)

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.”

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)

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)

Baseline characteristics by extension dose group, 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”

Endpoints

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)

Efficacy results

Month 15 change from baseline versus overlap-weighted external control

Endpoint	SKY-0515 LS mean (SE), Month 15 (n=15)	External control LS mean (SE), Month 15	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 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)

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)

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)

Limitations

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

Design and population

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)

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)

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)

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)

Endpoints

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)

Limitations

No evidence found.

FALCON-HD 004-ANZ

Design and population

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)

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 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”

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)

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)

Efficacy results

No evidence found.

Limitations

No evidence found.

FALCON-HD 004-WW

Design and population

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)

Registered site countries

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

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 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)

Planned enrollment: registry record

Enrollment type	Participants
Estimated	“400”

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)

Endpoints

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”

Efficacy results

No evidence found.

Limitations

No evidence found.

SKY-0515-008

Design and population

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)

Study dates and countries

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

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)

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)

Planned enrollment

Enrollment type	Participants
Estimated	“500”

Endpoints

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)

Efficacy results

No evidence found.

Limitations

No evidence found.

Clinical guidelines

Guidelines predate SKY-0515 and describe no therapy that halts or slows progression

“There is currently no cure or treatment which can halt, slow or reverse the progression of the disease.” (opens the source at this quote in a new tab)

“Despite the clear etiology of Huntington’s disease, there are currently no approved therapies to delay the onset or to slow the disease’s progression.” (opens the source at this quote in a new tab)

“Only pharmacological interventions were included and none proved to be effective as a disease-modifying therapy for HD.” (opens the source at this quote in a new tab)

European Huntington's Disease Network guideline (2019): chorea, psychiatric symptoms, and multidisciplinary care

“Drug treatment should be considered if chorea causes the patient distress or discomfort.” (opens the source at this quote in a new tab)
“Tetrabenazine is one of the first-line treatments for this symptom (Grade A)” (opens the source at this quote in a new tab)
“unless the patient suffers from not well-managed depression or suicidal thoughts.” (opens the source at this quote in a new tab)
“Deutetrabenazine may indeed be proposed as an alternative to tetrabenazine for the treatment of chorea in countries where the marketing authorization is already obtained, like in the USA.” (opens the source at this quote in a new tab)
“Second generation neuroleptics are the first line treatment for hallucinations and delusions (Grade C)” (opens the source at this quote in a new tab)
“An antidepressant may be suggested if depression occurs in HD (Grade B)” (opens the source at this quote in a new tab)
“Suicide risk should be assessed in HD irrespective of the stage, being particularly vigilant at the time of diagnosis and when the disease starts to impact on day-to-day life.” (opens the source at this quote in a new tab)
“Early referral to a physiotherapist is recommended in order to facilitate the development of a therapeutic relationship, promote sustainable exercise behaviors and ensure long-term functional independence.” (opens the source at this quote in a new tab)
“Good nutritional care is a fundamental element of the management of HD (Grade C)” (opens the source at this quote in a new tab)
“Based on present knowledge, no pharmacological treatment is recommended for the treatment of cognitive symptoms.” (opens the source at this quote in a new tab)
“In this work, based on therapeutic trials conducted between 1965 and 2015, only one grade A study was found among 376 studies analyzed, which is insufficient to eliminate or recommend enough products to meet the patients' needs.” (opens the source at this quote in a new tab)

American Academy of Neurology evidence-based guideline (2012), retired in 2022: chorea and neuroleptics

“If HD chorea requires treatment, clinicians should prescribe tetrabenazine (up to 100 mg/day), amantadine (300-400 mg/day), or riluzole (200 mg/day) (Level B) for varying degrees of expected benefit. Occurrence of adverse events should be discussed and monitored, particularly depression/suicidality and parkinsonism with tetrabenazine and elevated liver enzymes with riluzole.” (opens the source at this quote in a new tab)
“Data are insufficient to make recommendations regarding the use of neuroleptics or donepezil for HD chorea treatment (Level U).” (opens the source at this quote in a new tab)

“This guideline is retired.” (opens the source at this quote in a new tab)
“Retired on July 16, 2022.” (opens the source at this quote in a new tab)

German Neurological Society guideline (2023): tiapride, tetrabenazine, psychiatric symptoms, and psychosocial interventions

“The quality of data from RCTs is currently best for VMAT2 inhibitors” (opens the source at this quote in a new tab)
“Because of the favorable profile of side effects, in particular with regard to extrapyramidal (akathisia, Parkinsonism) and behavioral (depression) symptoms, the consensus in the Delphi group was that tiapride should be considered as first line treatment.” (opens the source at this quote in a new tab)
“The use of tetrabenazine (in combination or as monotherapy) is recommended if treatment with tiapride is either not tolerated or not efficacious.” (opens the source at this quote in a new tab)
“Comparative studies (comparing head-to-head compounds for their ability to suppress hyperkinesias short- and long-term) are unavailable.” (opens the source at this quote in a new tab)
“There is hardly any data from RCTs or controlled studies on treating mental health problems in HD. Recommendations are therefore based on expert opinion.” (opens the source at this quote in a new tab)
“Symptom-based psychosocial interventions such as psychological procedures, occupational therapy, and physical activity are recommended to stabilize and maintain everyday functions.” (opens the source at this quote in a new tab)

Movement Disorder Society evidence-based review (2022): interventions supported by eligible evidence

“These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea.” (opens the source at this quote in a new tab)
“Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms.” (opens the source at this quote in a new tab)
“There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality.” (opens the source at this quote in a new tab)
“Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments.” (opens the source at this quote in a new tab)

Huntington Study Group expert consensus (2026): medication classes used for chorea

“Despite the negative impact chorea can have on many aspects of day-to-day life, pharmacologic treatment remains underutilized in clinical practice.” (opens the source at this quote in a new tab)
“The two most common medication classes used to suppress chorea are vesicular monoamine transporter 2 (VMAT2) inhibitors and antipsychotics.” (opens the source at this quote in a new tab)

Huntington's Disease Society of America physician's guide (2011): when to treat chorea, off-label neuroleptics, and antidepressants

“Symptoms that indicate the need for possible pharmacologic management of chorea include muscle pain, frequent dropping of items, repetitive injuries, falls associated with chorea of the trunk and limbs, poor sleep, and weight loss.” (opens the source at this quote in a new tab)
“Individuals who do not tolerate tetrabenazine, or have other contraindications to its use, may benefit from off-label use of neuroleptics for reduction in chorea.” (opens the source at this quote in a new tab)
“Side effects of neuroleptics include apathy, sedation, akathisia, worsening of voluntary motor control, tardive dyskinesia and neuroleptic malignant syndrome.” (opens the source at this quote in a new tab)
“There is no single preferred antidepressant for treating depression in HD.” (opens the source at this quote in a new tab)

Diagnostic confirmation and staging criteria that define the treated population

“The diagnosis of HD is established in a proband with suggestive findings and a heterozygous CAG trinucleotide repeat expansion in HTT identified by molecular genetic testing (see Table 1).” (opens the source at this quote in a new tab)
“Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.” (opens the source at this quote in a new tab)

“The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments.” (opens the source at this quote in a new tab)

“If there are signs of neurodegeneration, evidenced by atrophy of the caudate or putamen, individuals are assigned to stage 1. If disease signs are measurable by the TMS or Symbol Digit Modalities Test (SDMT), they are classified as stage 2. Finally, if there is an impact on daily functioning as assessed by the Total Functional Capacity (TFC) or the Independence Scale, individuals are assigned to stage 3.” (opens the source at this quote in a new tab)
“Clinical motor diagnosis, or a Diagnostic Confidence Level (DCL) of 4, corresponds to the latter part of HD-ISS stage 2.” (opens the source at this quote in a new tab)

Safety summary

Contraindications

No approved labeling and therefore no labeled contraindications: SKY-0515 is not approved for use in any disease or in any country

“SKY-0515 is an investigational, once-daily oral medicine that is currently only available through clinical trials. It is not approved for use in any disease or in any country.” (opens the source at this quote in a new tab)

Phase 2/3 exclusion criterion: psychiatric history

“You have a history of suicidal thoughts, severe depression, or have attempted suicide in the past year.” (opens the source at this quote in a new tab)

Boxed warning

No approved labeling and therefore no boxed warning: SKY-0515 is not approved for use in any disease or in any country

“SKY-0515 is an investigational, once-daily oral medicine that is currently only available through clinical trials. It is not approved for use in any disease or in any country.” (opens the source at this quote in a new tab)

Warnings and precautions

No approved labeling and therefore no labeled warnings and precautions: SKY-0515 is not approved for use in any disease or in any country

“SKY-0515 is an investigational, once-daily oral medicine that is currently only available through clinical trials. It is not approved for use in any disease or in any country.” (opens the source at this quote in a new tab)

Peripheral neuropathy monitoring in participants with Huntington's disease

“There have been no TEAEs suggestive of peripheral neuropathy in participants with HD during the 9 months treatment period.” (opens the source at this quote in a new tab)

Class context: prior splice modulator branaplam

“Previously, another splice modulator called branaplam, developed by Novartis, had significant side effects in people with HD causing the trial to halt early” (opens the source at this quote in a new tab)

Common adverse reactions

Most common related treatment-emergent adverse events in participants with Huntington's disease

“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)

Adverse event severity and distribution across treatment arms 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)

Serious adverse events in the phase 1/2 trial

“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)

“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)

Adverse events in healthy participants in Parts A and B

“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)

Tolerability through fifteen months of treatment

“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.

Drug interactions

Protocol restriction: St. John’s Wort

“St. John’s Wort (hypericin) may not be taken within 30 days prior to first dose of study drug.” (opens the source at this quote in a new tab)

Clinical drug interaction studies

No evidence found.

Special populations

Age ranges studied in the phase 1, phase 1/2, and phase 2/3 trials

Study	Quoted criterion
Part C, participants with HD	“Males and females, aged between 25 and 70 years.”

“Healthy male or female, aged between 18 and 70 years, inclusive at screening.” (opens the source at this quote in a new tab)

“You must be 25 years or older.” (opens the source at this quote in a new tab)

Renal and hepatic impairment: phase 1 exclusion criteria

“Laboratory results at screening that indicate inadequate renal function (estimated creatinine clearance of lesser than 30 mL/min calculated by the Cockcroft and Gault formula).” (opens the source at this quote in a new tab)
“Liver function test results elevated more than 1.5-fold above the ULN for GGT, ALP, AST or ALT.” (opens the source at this quote in a new tab)

Pregnancy, lactation, and contraception: phase 2/3 criteria

“Women who can have children must have a negative pregnancy test before starting and use two types of birth control during the study and for 30 days after the last dose of the study drug.” (opens the source at this quote in a new tab)
“Men must agree to use birth control during the study and for 90 days after the last dose.” (opens the source at this quote in a new tab)
“You are pregnant, breastfeeding, or planning to become pregnant during the study.” (opens the source at this quote in a new tab)

Pediatric and juvenile-onset HD, pharmacokinetics in renal or hepatic impairment

No evidence found.

Comparators and place in therapy

Approved symptomatic therapies for chorea: labeled indication, boxed warnings, and labeled adverse reaction rates

“XENAZINE is indicated for the treatment of chorea associated with Huntington’s disease.” (opens the source at this quote in a new tab)
“XENAZINE can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of XENAZINE must balance the risks of depression and suicidality with the clinical need for control of chorea.” (opens the source at this quote in a new tab)
“In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease, 10 of 54 patients (19%) treated with XENAZINE were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients.” (opens the source at this quote in a new tab)
“Sedation is the most common dose-limiting adverse reaction of XENAZINE.” (opens the source at this quote in a new tab)

“AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease.” (opens the source at this quote in a new tab)

“VMAT2 inhibitors, including INGREZZA and INGREZZA SPRINKLE, can increase the risk of depression and suicidal thoughts and behavior in patients with Huntington’s disease.” (opens the source at this quote in a new tab)
“Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease.” (opens the source at this quote in a new tab)

Approved symptomatic therapies for chorea: treatment effects in placebo-controlled trials

“As shown in Figure 1, Total Chorea Scores for patients in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of patients receiving XENAZINE returned to baseline.” (opens the source at this quote in a new tab)
“In general, measures of functional capacity and cognition showed no difference between XENAZINE and placebo.” (opens the source at this quote in a new tab)

“Total Maximal Chorea Scores for patients receiving AUSTEDO improved by approximately 4.4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001).” (opens the source at this quote in a new tab)

“The mean change in Total Maximal Chorea scores for patients receiving INGREZZA improved by 4.6 units (LS mean) from baseline to the end of the treatment period (average of Week 10 and Week 12), compared to 1.4 units in the placebo group. The treatment effect of -3.2 units was statistically significant (p<0.0001)” (opens the source at this quote in a new tab)

Comparisons among approved and off-label antichoreic agents

“Compared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each).” (opens the source at this quote in a new tab)

“There is low-quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety.” (opens the source at this quote in a new tab)

“We conducted a pragmatic, randomized, open-label trial across 11 centers of the French-Speaking Huntington's Network, enrolling 179 patients with Huntington's disease.” (opens the source at this quote in a new tab)
“Tetrabenazine was most frequently associated with mood disorders and sedation, while olanzapine caused occasional weight gain and mild increases in LDL and total cholesterol.” (opens the source at this quote in a new tab)

Investigational disease-modifying candidates: differences in mechanism, route, and dosing

“Furthermore, the DMTs currently under development vary in mechanism of action (small molecule, ASO, gene therapy), route of administration (oral, intrathecal, intraparenchymal), and once vs recurrent therapy; these contingencies make it difficult at this time to assign a DMT price in our exploratory analysis.” (opens the source at this quote in a new tab)

“Unlike earlier approaches such as antisense oligonucleotides ( ASOs) given by spinal tap, or virus-based gene therapies delivered by brain surgery, SKY-0515 is a small-molecule compound which can be taken by mouth and can spread throughout the body. This is very similar to votoplam, another splice modulator in development for HD by Novartis and PTC Therapeutics.” (opens the source at this quote in a new tab)

AMT-130: administration, 36-month results versus external controls, and FDA position

“Treated patients receive a single administration through targeted, MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen).” (opens the source at this quote in a new tab)
“The BLA and MAA are supported by the previously announced three-year data analysis from the Phase I/II clinical study of ifezuntirgene inilparvovec, compared to a propensity score-matched external control derived from the Enroll-HD natural history database.” (opens the source at this quote in a new tab)

“The prespecified analysis included 29 treated participants (17 high-dose, 12 low-dose), with 12 patients per cohort reaching 36 months of follow-up. Outcomes were compared with propensity score-matched external controls from the Enroll-HD natural history dataset (n = 940 for high dose; n = 626 for low dose). At 36 months, high-dose AMT-130 met the primary endpoint, demonstrating a statistically significant 75% slowing of disease progression versus controls, as measured by the cUHDRS” (opens the source at this quote in a new tab)

“The FDA stated that it cannot agree that data from the Phase I/II studies, compared to an external control, are sufficient to provide the primary evidence of effectiveness required to support a marketing application for AMT-130. The FDA strongly recommended uniQure conduct a prospective, randomized, double-blind, sham surgery-controlled study.” (opens the source at this quote in a new tab)

“In addition, the FDA seeks to align on the confirmatory study design prior to the BLA submission, including consideration of concurrent control on standard-of-care therapy instead of a sham procedure.” (opens the source at this quote in a new tab)

“Astute HDBuzz readers will have noticed that this is a similar type of comparison that was made for the AMT-130 clinical trial data which was contentious among some HD researchers.” (opens the source at this quote in a new tab)

Tominersen: phase 3 GENERATION HD1 design, discontinuation, and week 69 results

“in which 791 participants with manifest Huntington’s disease were randomly assigned in a 1:1:1 ratio to receive intrathecal tominersen, at a dose of 120 mg every 8 weeks or every 16 weeks, or placebo” (opens the source at this quote in a new tab)
“The primary end point was the change from baseline in the score on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) or Total Functional Capacity (TFC) scale at week 101.” (opens the source at this quote in a new tab)
“Biomarker end points included levels of mutant HTT in CSF, levels of neurofilament light protein (NfL) in CSF, and ventricular volume.” (opens the source at this quote in a new tab)

“On the basis of an overall benefit–risk assessment by an independent data monitoring committee, treatment was stopped in March 2021; therefore, an ad hoc analysis of the results at week 69 was carried out” (opens the source at this quote in a new tab)
“In the every-8-week tominersen group, the mean change from baseline in the score on the cUHDRS at week 69 was significantly worse than that in the placebo group (−0.54 points, adjusted P=0.001), but the mean change from baseline in the score on the TFC scale did not differ significantly (−0.40 points, adjusted P=0.09).” (opens the source at this quote in a new tab)
“In the every-16-week tominersen group, the mean changes from baseline in the scores on the cUHDRS and the TFC scale did not differ significantly from those in the placebo group (−0.16 points, adjusted P=0.84; and −0.04, adjusted P=1.00, respectively)” (opens the source at this quote in a new tab)
“Nonetheless, these results must be interpreted with caution, given the ad hoc nature of the analysis.” (opens the source at this quote in a new tab)

“More adverse events occurred in the participants in the every-8-week tominersen group than in those in the placebo group and the every-16-week tominersen group” (opens the source at this quote in a new tab)

“GENERATION HD2 is a phase II, randomised, double-blind, placebo-controlled, dose-finding clinical trial comparing 60 mg tominersen, 100 mg tominersen and placebo.” (opens the source at this quote in a new tab)
“The clinical trial remains ongoing, and definitive conclusions regarding clinical benefit will only be possible once the data are unblinded and fully analysed. This is anticipated to be late 2026.” (opens the source at this quote in a new tab)

Votoplam: oral splicing modifier results and comparability with the SKY-0515 dataset

“PTC518 (also known as votoplam), an orally administered huntingtin mRNA splice modulator.” (opens the source at this quote in a new tab)
“The study met its primary endpoint, showing dose-dependent reductions in blood HTT protein levels at week 12, along with a favourable safety and tolerability profile across all dose levels and disease stages.” (opens the source at this quote in a new tab)

“In the interim analysis following 24 months of votoplam treatment, there was evidence of dose-dependent benefit in slowing progression on the Composite Unified Huntington's Disease Rating Scale (cUHDRS) relative to a propensity weighted natural history cohort in Stage 2 participants, with 52% and 28% slowing for 10 mg and 5 mg participants, respectively.” (opens the source at this quote in a new tab)
“Votoplam (formerly PTC518) is a small molecule splicing modifier that acts via a unique mechanism to promote the inclusion of a novel pseudoexon containing a premature termination codon, thus triggering Huntingtin (HTT) mRNA degradation and subsequent reduction in HTT protein levels.” (opens the source at this quote in a new tab)

“In PTC/Novartis’s data, for example, people taking votoplam seemed specifically to do better on thinking tests; in this study, people taking SKY-0515 seemed to do better on all of the tests.” (opens the source at this quote in a new tab)
“That’s a novel observation worth highlighting, but the studies are too different in length, size, and the way the data is presented to make a true comparison.” (opens the source at this quote in a new tab)

Pridopidine: phase 3 PROOF-HD primary endpoint and CHMP opinion

“The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population.” (opens the source at this quote in a new tab)

“Prilenia and Ferrer announced that the European Medicines Agency's Committee for Medicinal Products for Human Use had recommended refusal of marketing authorisation for pridopidine in HD.” (opens the source at this quote in a new tab)

Anticipated use and care setting for SKY-0515: studied population, oral administration, and specialist care

“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)
“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)

“Eligible patients will receive once-daily oral SKY-0515 at one of three dose levels or placebo.” (opens the source at this quote in a new tab)

“Treated patients received a single administration of AMT-130 through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen).” (opens the source at this quote in a new tab)

“HDSA Centers of Excellence provide a multidisciplinary team approach to Huntington’s disease care.” (opens the source at this quote in a new tab)
“There are currently 60 HDSA Centers of Excellence and 9 Partner Sites covering 37 States plus the District of Columbia.” (opens the source at this quote in a new tab)

Direct head-to-head clinical comparison with votoplam, AMT-130, tominersen, WVE-003, or another active therapy

No evidence found.

Conclusion

No approved therapy alters the course of the disease

“There is currently no cure or treatment which can halt, slow or reverse the progression of the disease.” (opens the source at this quote in a new tab)

“Despite the clear etiology of Huntington’s disease, there are currently no approved therapies to delay the onset or to slow the disease’s progression.” (opens the source at this quote in a new tab)

Strongest reported efficacy result: 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”

Constraint on that result: the comparison is against an external control, not a randomized placebo group

“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)

Safety statement carried by the program to date

“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)

Regulatory standing: eligibility for a provisional pathway is not an approval

“Provisional registration is time-limited: it’s granted initially up to two years, with the option to extend up to a maximum of six years.” (opens the source at this quote in a new tab)
“To be clear: this is not approval.” (opens the source at this quote in a new tab)

Current availability

“SKY-0515 is an investigational, once-daily oral medicine that is currently only available through clinical trials. It is not approved for use in any disease or in any country.” (opens the source at this quote in a new tab)

Monograph section

1Introduction

Definition: progressive motor, cognitive, and psychiatric manifestations inherited in an autosomal dominant manner

Etiology: expanded CAG trinucleotide repeat in HTT

United States prevalence: symptomatic population and claims-based estimates

United States incidence: commercial insurance claims, 2003 to 2016

Age at onset and prodromal phase

Survival after onset and age at death

Motor symptoms: chorea early and hypokinetic features later

Non-motor symptoms: functional impact, depression, and apathy

Burden: health-related quality of life and healthcare costs by disease stage

Investigational status: not approved in any country

Current development phase: FALCON-HD pivotal program

Australia: TGA provisional approval pathway eligibility and application submission

Australia: date of the application submitted to the TGA

Australia: duration of provisional registration

United States, Canada, and United Kingdom: clinical trial authorizations

Anticipated launch as early as 2027

FDA or EMA marketing application, orphan, fast track, breakthrough therapy, or PRIME designations

2Pharmacology and usage

Mechanistic classification

HTT lowering through splicing modulation

Molecular mechanism: cryptic exon inclusion in HTT pre-mRNA

Rationale for PMS1 lowering

Target selectivity: independent commentary

Healthy volunteers: blood HTT mRNA reduction

Participants with HD: blood mHTT and total HTT protein through 12 months

Participants with HD: biomarker reductions through 15 months

Neurofilament light chain

CSF markers of neuroinflammation and neuronal injury

Healthy volunteers: systemic exposure

Participants with HD: dose proportionality and steady state

Participants with HD: CSF penetration

Elimination after discontinuation

Terminal half-life, food effect results, metabolism, and renal excretion

3Indications

Indication under regulatory review in Australia

Population studied in pivotal trials

Current availability limited to clinical trials

4Dosing and administration

SKY-0515-001 Part C: randomized period dosing

SKY-0515-001 Part C: extension dosing

FALCON-HD: dose levels

Dose strengths studied in participants with HD

Proposed commercial dose, dose adjustment, and administration with food

5Clinical efficacy summary

Randomized placebo-controlled period followed by blinded active extension

Age and genetic diagnosis

HD-ISS stage criteria

Randomized period and extension regimens

Participants analyzed by timepoint and external control sizes

Baseline characteristics by extension dose group, mean ± SD

Registered primary safety endpoints

Secondary and exploratory endpoints

Externally controlled cUHDRS analysis: designated primary timepoint

Month 15 change from baseline versus overlap-weighted external control

cUHDRS change by timepoint versus overlap-weighted external control

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

Pharmacodynamic results at day 84 and month 12

Clinician and Patient Global Impression at 12 months

Interpretation of global impression data: independent commentary

External control limitation: independent commentary

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

Food-effect cohort

CSF sampling cohorts

Key inclusion criteria

Dose ranges

Planned sample sizes

Pharmacodynamic results: blood HTT mRNA

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

Study periods and safety oversight

Key inclusion criteria

Key exclusion criteria

Treatment arms

Completed enrollment

Registered primary outcomes

Primary goal as described at HDSA 2026

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

Registered site countries

Key inclusion criteria

Introduction

Pharmacology and usage

Indications

Dosing and administration

Clinical efficacy summary

Clinical guidelines

Safety summary