Investigational status

“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

“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 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: 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)

Company-projected approval and launch timing

“Skyhawk may receive accelerated approval for SKY-0515 in Australia within the next twelve months, and in other major markets during 2027” (opens the source at this quote in a new tab)
“will prepare Skyhawk for the launch of SKY-0515 as early as 2027.” (opens the source at this quote in a new tab)

Regulatory submission: TGA provisional approval application submitted March 2026

“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)

Launch: Anticipated as early as 2027, market not specified

“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)

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)

Global trial footprint

“The worldwide Phase 2/3 FALCON-HD-004-WW pivotal study is now active across more than ten countries and twenty clinical sites. SKY-0515's Phase 1/2 and FALCON-HD pivotal studies have now enrolled more than 200 patients.” (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.

Manufacturer: Skyhawk Therapeutics

“Skyhawk Therapeutics, Inc.” (opens the source at this quote in a new tab)

Product names

“Study Drug Name (INN): SKY-0515” (opens the source at this quote in a new tab)

Nonproprietary name and brand name

No evidence found.

Therapeutic class

“SKY-0515 is an orally administered investigational small molecule RNA splicing modifier developed using the company's proprietary SKYSTAR platform. SKY-0515 is designed to reduce both mHTT and PMS1 proteins.” (opens the source at this quote in a new tab)

Oral tablet: open-label extension study

“initiate open label treatment with 9 mg tablets of SKY-0515” (opens the source at this quote in a new tab)

Oral capsule: phase 1 placebo matching

“Capsules of matching appearance and formulation to the investigational product, however without the SKY-0515 active ingredient will be administered as placebo in this study.” (opens the source at this quote in a new tab)

Strengths studied: healthy volunteers

“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)

Strengths studied: 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)

Strengths studied: phase 2/3 FALCON-HD

“Dosage Level(s): Low, mid, high” (opens the source at this quote in a new tab)

Commercial formulation and strength

No evidence found.

Product price and anticipated annual cost per participant

Not applicable.

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)

AHFS classification

No evidence found.

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)

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)

Preclinical pharmacology: human cells and Hu97/18 mice

“In vitro pharmacology studies demonstrated that SKY-0515 promotes HTT mRNA and protein lowering in cultured human lymphocytes, with a limited number of off-target genes” (opens the source at this quote in a new tab)
“In Hu97/18 mice treated with SKY-0515 at 1, 3, 10 and 30 mg/kg once daily (QD) for 30 days, a concurrent and comparable dose-dependent decrease of mHTT protein compared to vehicle controls occurred in brain and peripheral blood” (opens the source at this quote in a new tab)

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 mRNA and mHTT protein at day 84

“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)

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)

Caudate volume and volumetric MRI results

No evidence found.

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.

FDA-approved prescribing information, contraindications, boxed warnings, and REMS

Not applicable.

Most common adverse events observed in clinical studies

“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)

Peripheral neuropathy monitoring

“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)

Age range studied

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)

Psychiatric history: phase 2/3 exclusion

“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)

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

No evidence found.

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.

Clinical drug interaction studies

No evidence found.

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)

Open-label extension: dose

“Dosage Level(s): 9mg Route of Administration: Oral Dosage Frequency: Once daily” (opens the source at this quote in a new tab)

Proposed commercial dose and dose adjustment

No evidence found.

Route and frequency

“Route of Administration: Oral Dosage Frequency: Once daily” (opens the source at this quote in a new tab)

Self-administration

“Open label SKY-0515 will be self-administered daily (QD).” (opens the source at this quote in a new tab)

Administration with food

No evidence found.

Current access through clinical trials only

“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)

Continued access for trial completers

“Treatment Duration: until drug becomes commercially available or until the development of SKY-0515 is terminated by the Sponsor.” (opens the source at this quote in a new tab)

Commercial preparation

“I'm thrilled to join the company to prepare for the launch of SKY-0515 and to help ensure the broadest number of patients can access this important therapy.” (opens the source at this quote in a new tab)

Expanded access program, specialty distribution, and REMS

No evidence found.

Part C: permitted background HD medications

“Medications used for management for HD may be permitted (at the discretion of the Investigator), if patient commenced medication at least 12 weeks prior to first drug administration and are on a dose regimen that is not anticipated to change during the study” (opens the source at this quote in a new tab)
“participants who have been on a stable dose of the aforementioned therapies for at least 12 weeks prior to screening and who are on a dose regimen that is not anticipated to change during the study may be included (at the discretion of the Investigator).” (opens the source at this quote in a new tab)

Part C: prior HTT-lowering therapy exclusion

“Concurrent enrolment or previous participation at any time in any Huntingtin lowering antisense oligonucleotide, small molecule, gene therapy study.” (opens the source at this quote in a new tab)

Part C: changes in background therapy as intercurrent events

“initiation of a medication that could confound assessment of treatment effect, or a change in background Huntington's disease therapeutic intervention.” (opens the source at this quote in a new tab)

FALCON-HD: prior gene therapy exclusion

“You have had any kind of gene therapy.” (opens the source at this quote in a new tab)

Baseline concomitant medication use in studied participants

No evidence found.

AAN movement disorders quality measurement sets: conditions covered

“Find measures to improve care for your patients diagnosed with a movement disorder.” (opens the source at this quote in a new tab)
“Parkinson's disease (2020)” (opens the source at this quote in a new tab)
“Essential tremor (2016)” (opens the source at this quote in a new tab)

SKY-0515-specific effect on quality measures

No evidence found.

Summary

No head-to-head clinical comparison of SKY-0515 with an approved symptomatic therapy or with another huntingtin-lowering agent has been reported. The investigational disease-modifying candidates differ in route: SKY-0515 and votoplam are oral small-molecule splicing modifiers, tominersen is an intrathecal antisense oligonucleotide, and AMT-130 is a one-time gene therapy delivered by stereotactic neurosurgery into the striatum. Efficacy claims for AMT-130, votoplam, and SKY-0515 beyond 12 months rest on comparisons with propensity-weighted, propensity score-matched, or overlap-weighted natural history cohorts rather than concurrent randomized controls. Sponsor announcements describe SKY-0515 mHTT lowering as the greatest demonstrated in patients; independent commentary noted that the SKY-0515 and votoplam studies differ too much in length, size, and data presentation for a true comparison. In the placebo-controlled phase 3 GENERATION HD1 trial of intrathecal tominersen (791 participants), treatment was stopped in March 2021; in an ad hoc week 69 analysis, the cUHDRS change with 120 mg every 8 weeks was significantly worse than with placebo (-0.54 points; adjusted P=0.001), neither cUHDRS nor TFC change with the every-16-week regimen differed significantly from placebo, and more adverse events occurred with the every-8-week regimen. Among approved symptomatic agents, no blinded head-to-head RCT of VMAT2 inhibitors exists; two indirect comparisons of the TETRA-HD and First-HD trials reached different overall conclusions on safety, and an open-label randomized trial of 179 participants compared tetrabenazine, tiapride, and olanzapine.

SKY-0515 in relation to huntingtin-only lowering: independent trials review

“SKY-0515 is designed to reduce both HTT and PMS1 proteins, the latter implicated in somatic CAG repeat expansion, a mechanistic process increasingly recognised as a key driver of neuronal loss in HD.” (opens the source at this quote in a new tab)
“This important phase II/III clinical trial of SKY-0515 will assess whether HTT and PMS1 lowering can offer greater therapeutic benefit than HTT reduction alone in early-stage HD.” (opens the source at this quote in a new tab)

Magnitude of HTT lowering relative to other agents: statements in sponsor announcements

“SKY-0515’s HTT reduction has the highest dynamic range I’ve seen from any therapeutic modality” (opens the source at this quote in a new tab)

“SKY-0515 continues to reduce mHTT protein to the greatest extent demonstrated by any therapeutic tested to date in patients” (opens the source at this quote in a new tab)

“SKY-0515 continues to reduce mHTT protein to the greatest extent demonstrated in patients, with clinical and biomarker data showing the drug is well tolerated at all doses tested.” (opens the source at this quote in a new tab)

HTT lowering targets in other trials: independent commentary

“Astute readers may notice that 70% lowering is a fair bit higher than the current target in other HTT lowering trials of around 50%. Currently, most companies have targeted the 30-50% range for HTT lowering drugs.” (opens the source at this quote in a new tab)

Route of administration compared with antisense oligonucleotides and gene therapy

“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)

Investigational disease-modifying candidates: differences in route and regimen

“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)

cUHDRS component pattern compared with votoplam

“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)

External natural-history comparisons across HTT-lowering trials

“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)

AMT-130 (ifezuntirgene inilparvovec): administration and regulatory submissions

“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)

AMT-130: 36-month topline results versus external controls

“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)

AMT-130: FDA position after the January 2026 Type A meeting

“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)

AMT-130: FDA position after the June 2026 Type B meeting

“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)

Tominersen: phase 3 GENERATION HD1 dosing discontinued

“The iDMC made its recommendation based on the investigational therapy’s potential benefit/risk profile for study participants.” (opens the source at this quote in a new tab)
“Study participants were randomised to either 120 mg every-2-months or 120 mg every-4-months intrathecal injections of tominersen, or placebo. The study has recruited 791 participants from 18 countries around the world.” (opens the source at this quote in a new tab)

Tominersen: GENERATION HD1 design and primary end points

“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)

Tominersen: GENERATION HD1 ad hoc week 69 clinical results

“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)

Tominersen: GENERATION HD1 biomarkers, adverse events, and post hoc subgroup analyses

“The changes in mutant HTT levels in CSF were consistent with dose regimen–dependent decreases and concomitant increases in ventricular volume” (opens the source at this quote in a new tab)
“The absence of whole-brain volume loss in the context of ventricular expansion and the absence of a correlation between the change in CSF NfL levels and change in ventricular volume suggest that increases in ventricular volume do not reflect increased atrophy” (opens the source at this quote in a new tab)
“A transient increase was seen in CSF NfL levels in the every-8-week tominersen group at week 21; although neuroaxonal damage may be implicated, increased levels of leukocytes and total protein in CSF in some participants suggest an inflammatory component” (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)
“The results of post hoc analyses support the hypothesis that younger participants (who have less disease burden) may benefit from tominersen therapy” (opens the source at this quote in a new tab)
“this hypothesis is currently being tested in a phase 2 dose-finding trial (GENERATION HD2; NCT05686551).” (opens the source at this quote in a new tab)

Tominersen: phase 2 GENERATION HD2

“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, 24-month extension versus natural history

“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)

Votoplam: route and 12-week PIVOT-HD primary endpoint

“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)

Pridopidine: phase 3 PROOF-HD and EMA 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)

Modeled comparison of investigational agents with standard of care: tominersen and AMT-130

“Compared with SoC, Tominersen increased costs by $2.11 million and QALYs by 0.93, resulting in an ICER of $2.28 million per QALY gained, whereas AMT-130 increased costs by $1.49 million and QALYs by 5.23, resulting in an ICER of $285,703 per QALY gained in the base case.” (opens the source at this quote in a new tab)

Approved VMAT2 inhibitors: indirect tolerability comparison of deutetrabenazine and tetrabenazine

“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)

Approved VMAT2 inhibitors: GRADE-based indirect comparison

“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)

Symptomatic antichoreic agents: open-label randomized comparison of tetrabenazine, tiapride, and olanzapine

“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)

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

No evidence found.

Definition: progressive motor, cognitive, and psychiatric disorder

“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 repeat in HTT encoding a polyglutamine tract

“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)

“Huntington's disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties.” (opens the source at this quote in a new tab)

CAG repeat length thresholds

Allele category	CAG repeat length
Normal alleles	“26 or fewer CAG repeats”
Intermediate alleles	“27 to 35 CAG repeats”
Reduced-penetrance HD-causing alleles	“36 to 39 CAG repeats”
Full-penetrance HD-causing alleles	“40 or more CAG repeats”

Reduced penetrance of 36 to 39 CAG repeat alleles

“Variable penetrance for alleles carrying 36-39 repeats has been noted, but the disease appears fully penetrant when the repeat numbers are >40.” (opens the source at this quote in a new tab)

“A total of 18 of 7,315 individuals had ≥36 CAG, revealing that approximately 1 in 400 individuals from the general population have an expanded CAG repeat associated with HD (0.246%).” (opens the source at this quote in a new tab)
“The infrequent diagnosis of HD at this CAG length is likely due to low penetrance.” (opens the source at this quote in a new tab)

CAG repeat length and age of onset

“A significant inverse correlation exists between the number of HTT CAG repeats and the age of onset of HD” (opens the source at this quote in a new tab)
“On average, CAG repeat length accounts for up to 70% of the variability in age of onset, with an estimated 10%-20% of the residual variability being accounted for by heritable factors” (opens the source at this quote in a new tab)

“For example, our model predicts a 91% chance that a 40-year-old individual with 42 repeats will have onset by the age of 65, with a 95% confidence interval from 90 to 93%.” (opens the source at this quote in a new tab)

Juvenile Huntington's disease and anticipation

“Juvenile HD is rare and historically defined as HD with an onset of symptoms before age 20 years” (opens the source at this quote in a new tab)
“The proportion of individuals with juvenile HD varies from 1% to 15% of individuals diagnosed with HD” (opens the source at this quote in a new tab)
“Large expansions (i.e., an increase in allele size of >7 CAG repeats) occur almost exclusively through paternal transmission.” (opens the source at this quote in a new tab)

“HTT CAG repeat length in individuals with juvenile HD is usually >55 CAG repeats and is often caused by anticipation, usually via paternal transmission” (opens the source at this quote in a new tab)

Global incidence: updated systematic review and meta-analysis, 2010 to 2022

“A total of 33 studies published between 2010 and 2022 were included. Pooled incidence was 0.48 cases per 100,000 person-years (95% CI, 0.33-0.63). Subgroup analysis by continent demonstrated a significantly higher incidence of HD in Europe and North America than in Asia.” (opens the source at this quote in a new tab)

Global incidence: systematic review and meta-analysis, 1985 to 2010

“Meta-analysis of data from four incidence studies revealed an incidence of 0.38 per 100,000 per year (95% confidence interval [CI]: 0.16, 0.94). Lower incidence was reported in the Asian studies (n = 2), compared to the studies performed in Europe, North America, and Australia (n = 6).” (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)

United States incidence: Medicare beneficiaries aged 65 years or older

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

United Kingdom incidence: primary care records

“The data showed that the incidence of HD has remained constant between 1990 and 2010 with an overall rate of 7.2 (95% CI 6.5 to 7.9) per million person-years. The systematic review identified 14 independent estimates of incidence with substantial heterogeneity and consistently lower rates reported in studies from East Asia compared with those from Australia, North America and some--though not all--those from Europe.” (opens the source at this quote in a new tab)

“There were 586 incident cases of HD from a total at‐risk population of 10,756,901 persons (corresponding to 80,048,926 PY) during the study period (Table 1). There was no evidence that incidence increased over time (β = 0.004, p = 0.4), with 16–44 newly diagnosed cases per year identified. In 2018, incidence of HD was 0.8 (0.5–1.19) per 100,000 PY.” (opens the source at this quote in a new tab)

Global prevalence: updated systematic review and meta-analysis

“Pooled prevalence was 4.88 per 100,000 (95% CI, 3.38-7.06). Subanalyses by continent demonstrated that the prevalence of HD was significantly higher in Europe and North America than in Africa.” (opens the source at this quote in a new tab)

Global prevalence: systematic review and meta-analysis, by region

“The worldwide service-based prevalence of HD, based on a meta-analysis (n = 13 studies), was 2.71 per 100,000 (95% CI: 1.55-4.72). Eleven studies were conducted in Europe, North American, and Australia, with an overall prevalence of 5.70 per 100,000 (95% CI: 4.42-7.35). Three studies were conducted in Asia, with an overall prevalence of 0.40 per 100,000 (95% CI: 0.26-0.61).” (opens the source at this quote in a new tab)

Geographic variation and prevalence trends

“The prevalence of HD varies more than tenfold between different geographical regions.” (opens the source at this quote in a new tab)
“There was evidence of an increasing prevalence of between 15 and 20% per decade in studies from Australia, North America and Western Europe.” (opens the source at this quote in a new tab)

“In populations of European ancestry, HD occurs at an average prevalence of 9.71:100,000 [Rawlins et al 2016], with up to 17:100,000 when multiple sources of ascertainment are accounted” (opens the source at this quote in a new tab)

United States: symptomatic and at-risk population

“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)

“as many as ~40,000 people may have manifest HD in the US.” (opens the source at this quote in a new tab)
“Sources frequently state that 30,000 individuals living in the US have HD, but the methodology used to derive this prevalence estimate is unclear.” (opens the source at this quote in a new tab)

United States: claims-based prevalence

“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)

“We estimated a cumulative age-adjusted HD frequency rate of 6.52 per 100,000 persons” (opens the source at this quote in a new tab)

United Kingdom: primary care prevalence

“The estimated prevalence (expressed per 100 000 population) rose from 5.4 (95% CI 3.8 to 7.5) in 1990 to 12.3 (95% CI 11.2 to 13.5) in 2010.” (opens the source at this quote in a new tab)

“Annual prevalence steadily increased throughout the study period, with prevalence estimates ranging from 4.3 cases (3.6–5.1) per 100,000 in 2000 to 9.2 cases (8.1–10.5) per 100,000 people in 2018 (β = 0.27, p < 0.001).” (opens the source at this quote in a new tab)

Juvenile and pediatric Huntington's disease: proportion in Enroll-HD

“50 compared with 7544 adult (0.66%) and 22 out of 16,124 family participants (0.14%) were pediatric.” (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)

Prodromal change detected before diagnosis: PREDICT-HD

“1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0-12·0). 225 (21%) of these participants received a motor diagnosis of Huntington's disease during the study.” (opens the source at this quote in a new tab)

“This work showed that measurable brain and behavioral changes can be detected up to 15 years before an HD diagnosis.” (opens the source at this quote in a new tab)

Disease stages: Huntington's Disease Integrated Staging System

“The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3).” (opens the source at this quote in a new tab)

Progression in premanifest and early disease: TRACK-HD

“In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months.” (opens the source at this quote in a new tab)

“For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease.” (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)

“For these fully ascertained subjects, the range, mean, SD, and median of duration values were 0–46, 15.4, 6.8, and 15 years, respectively.” (opens the source at this quote in a new tab)
“We found that, as with clinical onset, HD age at death is determined by expanded CAG-repeat length and has no contribution from the normal CAG allele. Surprisingly, disease duration is independent of the mutation's length.” (opens the source at this quote in a new tab)

Mortality relative to the general population: UK cohort

“The KM survival curve (Figure 1) shows a median survival time of 12.4 years (95% CI 10.6–15.2). Median age at death in individuals with HD and controls was 71 (IQR 59–79) and 81 (IQR 73–86) years, respectively. Individuals with HD were at 4.5 times greater risk of death than controls (hazard ratio 4.51, 95% CI 3.36–6.06, p < 0.001) after multivariable adjustment of baseline covariates (Figure S1).” (opens the source at this quote in a new tab)

Age at death and causes of death: Norwegian national registries

“Mean age at death for individuals with HD was found to be 63.9 years (NCDR) and 61.7 years (CRD), compared to a mean of 76.9 years in the general population (NCDR).” (opens the source at this quote in a new tab)
“In 73.5% of individuals with HD, the underlying cause of death was HD, followed by cardiovascular diseases, cancer and respiratory diseases. The most common immediate cause of death was respiratory diseases (44.2%). Suicide was a more common cause of death in the population with HD (2.3%) compared to the general population (1.3%).” (opens the source at this quote in a new tab)

Causes of death: aspiration pneumonia

“Two hundred twenty four charts of deceased HD patients were reviewed, of which 216 (111/104 male/female, one unknown) had records available, 147 listed a cause of death (Table 1), which was pneumonia in 81 (55%) cases.” (opens the source at this quote in a new tab)
“The conclusion is that the majority (86.8%) of our HD patients where the cause of death could be identified died from aspiration pneumonia.” (opens the source at this quote in a new tab)

Suicide and suicidal ideation

“Incidence of suicidal ideation, suicide attempt, and suicide are higher among those with HD relative to the non-HD population.” (opens the source at this quote in a new tab)

“At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation.” (opens the source at this quote in a new tab)
“The 4-year cumulative incidence of suicidal ideation was 9.9%.” (opens the source at this quote in a new tab)

“The critical periods for suicide risk are just prior to receiving a diagnosis and later, when affected individuals experience a loss of independence” (opens the source at this quote in a new tab)

Juvenile Huntington's disease: progression and survival

“Disease progression of JHD is faster compared to AOHD and the disease duration is shorter, particularly in case of higher CAG repeat lengths.” (opens the source at this quote in a new tab)

“Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002).” (opens the source at this quote in a new tab)

Mutant huntingtin: toxic gain of function

“In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confer toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death.” (opens the source at this quote in a new tab)

“The expanded polyQ tract confers a toxic gain of function, resulting in the dysregulation of vital cellular processes, which ultimately leads to protein aggregation and cell death” (opens the source at this quote in a new tab)

“At the cellular level mutant huntingtin results in neuronal dysfunction and death through a number of mechanisms, including disruption of proteostasis, transcription and mitochondrial function and direct toxicity of the mutant protein. Early macroscopic changes are seen in the striatum with involvement of the cortex as the disease progresses.” (opens the source at this quote in a new tab)

Striatal degeneration: neuropathological grading

“The earliest changes were seen in the medial paraventricular portions of the caudate nucleus (CN), in the tail of the CN, and in the dorsal part of the putamen. Counts of neurons in the CN reveal that 50% are lost in grade 1 and that 95% are lost in grade 4” (opens the source at this quote in a new tab)

Genetic modifiers of onset: DNA repair genes identified by GWAS

“Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD.” (opens the source at this quote in a new tab)

“The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion.” (opens the source at this quote in a new tab)
“Four genes at 3 loci were significant after Bonferroni correction: FAN1 (p = 1.9E-22), MSH3 (1.9E-8), PMS1 (6.1E-7), and ASNSD1 (5.3E-6) with later onset associated with increased FAN1, PMS1, and ASNSD1 expression and decreased MSH3 expression.” (opens the source at this quote in a new tab)

“Repeatedly implicated MMR genes include MSH3, MLH1, PMS1, PMS2, and LIG1” (opens the source at this quote in a new tab)

Genetic modifiers of progression: MSH3 and PMS1

“The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis” (opens the source at this quote in a new tab)
“encodes an aminoacid change (Pro67Ala) in MSH3” (opens the source at this quote in a new tab)
“Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation.” (opens the source at this quote in a new tab)

“Genome-wide association studies (GWASs) of Huntington disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage.” (opens the source at this quote in a new tab)
“In addition, we identified additional modifier effects at the PMS1 and PMS2 loci and implicated a potential second locus on chromosome 7.” (opens the source at this quote in a new tab)

Somatic CAG repeat expansion in striatal projection neurons

“We found that the HTT CAG repeat expands somatically from 40-45 to 100-500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150-500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost.” (opens the source at this quote in a new tab)
“We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene, and that HD pathogenesis is a DNA process for almost all of a neuron’s life.” (opens the source at this quote in a new tab)

“Somatic expansion within the striatum correlates strongly with earlier disease onset” (opens the source at this quote in a new tab)
“In this model, somatic instability acts as a catalyst for expansion, while a subsequent toxic gain-of-function mechanism drives cell death once the repeat length crosses a critical threshold.” (opens the source at this quote in a new tab)

PMS1 as a modifier of somatic CAG repeat expansion

“Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention.” (opens the source at this quote in a new tab)

Multiple pathogenic mechanisms

“Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course.” (opens the source at this quote in a new tab)

Establishing the diagnosis: clinical findings and molecular genetic testing

“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 diagnosis is usually confirmed through identification of an increased CAG repeat length in the huntingtin gene in a patient with clinical features of the condition. Though diagnosis is usually straightforward, unusual presentations can occur, and it can be difficult to know when someone has transitioned from being an asymptomatic carrier into the disease state.” (opens the source at this quote in a new tab)

Laboratory testing standards

“Assays used to diagnose Huntington disease must be optimized to ensure the accurate and unambiguous quantitation of CAG repeat length.” (opens the source at this quote in a new tab)

Clinical motor diagnosis: diagnostic confidence level

“Huntington's disease (HD) is currently diagnosed based on the presence of motor signs indicating 99% "diagnostic confidence" for HD. Recent advances in the understanding of HD natural history and neurobiology indicate that disease-related brain changes begin at least 12 to 15 years before the formal diagnosis based on motor onset.” (opens the source at this quote in a new tab)

“with the gene mutation for Huntington's disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntington's Disease Rating Scale)” (opens the source at this quote in a new tab)

Staging: Huntington's Disease Integrated Staging System

“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)

Predictive genetic testing in at-risk individuals

“Testing of asymptomatic adults at risk for HD is possible but requires careful deliberation, as there is currently no cure for the disorder” (opens the source at this quote in a new tab)
“Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed.” (opens the source at this quote in a new tab)

“Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not.” (opens the source at this quote in a new tab)

Biomarkers: plasma neurofilament light protein

“Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next.” (opens the source at this quote in a new tab)
“In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48-7·34, p=0·0036).” (opens the source at this quote in a new tab)

Neuroimaging

“Regional atrophy of the caudate and putamen is among the earliest pathologic changes in HD” (opens the source at this quote in a new tab)

Motor symptoms: chorea

“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)

Motor symptoms: dystonia, bradykinesia, rigidity, and oculomotor disturbance

“With advancing disease duration, chorea may decrease and other movement abnormalities such as bradykinesia, rigidity, and dystonia occur. Impairment in voluntary motor function is an early sign.” (opens the source at this quote in a new tab)
“Difficulty in initiating ocular saccades, slow and hypometric saccades, and problems in gaze fixation occur in up to 75% of symptomatic individuals” (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)

Motor symptoms: gait disturbance and falls

“Compared to controls, Huntington patients had a decreased gait velocity (1.15 m/s versus 1.45 m/s, P < 0.001) and a decreased stride length (1.29 m versus 1.52 m, P < 0.001).” (opens the source at this quote in a new tab)

Cognitive symptoms: executive dysfunction and progressive decline

“A global and progressive decline in cognitive capabilities occurs in all individuals with HD. Cognitive changes include forgetfulness, slowness of thought processes, impaired visuospatial abilities, and impaired ability to manipulate acquired knowledge” (opens the source at this quote in a new tab)
“These initial changes often involve loss of mental flexibility and impairment of executive functions such as mental planning and organization of sequential activities.” (opens the source at this quote in a new tab)

“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)

Psychiatric symptoms: depression, irritability, apathy, and anxiety

“Ninety eight per cent of the patients exhibited neuropsychiatric symptoms, the most prevalent being dysphoria, agitation, irritability, apathy, and anxiety.” (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)

“Apathy was already present in 32% of preHD-A increasing to 62% of early-HD patients.” (opens the source at this quote in a new tab)

Psychiatric symptoms: suicidality

“Eleven (20%) pre-motor and 20 (20%) motor symptomatic mutation carriers were considered suicidal compared to none of the non-carriers.” (opens the source at this quote in a new tab)

Other symptoms: weight loss

“Individuals with HD tend to experience substantial weight loss, reduced muscle mass, and lower body mass index compared to unaffected individuals.” (opens the source at this quote in a new tab)
“Individuals usually have very high calorie requirements to simply maintain their weight.” (opens the source at this quote in a new tab)

Other symptoms: dysarthria and dysphagia

“Speech impairment reflects a combination of dysarthria and word-finding difficulties, and in advanced disease some individuals may progress to complete anarthria. Swallowing difficulties arise from incoordination of oral and pharyngeal muscles, and can lead to choking episodes and aspiration pneumonia, a frequent cause of death in HD.” (opens the source at this quote in a new tab)

Other symptoms: sleep and circadian disturbance

“The most common sleep problems reported by HD patients include insomnia, difficulties in falling asleep, frequent nocturnal awakenings, and excessive daytime sleepiness.” (opens the source at this quote in a new tab)

Juvenile Huntington's disease: presentation

“In the first decade of life, individuals with juvenile HD present with common clinical manifestations of behavior disturbance and impairment of school performance, followed by dysarthria, seizures, rigidity, gait disturbances, bradykinesia, and dystonia” (opens the source at this quote in a new tab)

“Seizures occur in 30 percent to 50 percent of children with this condition.” (opens the source at this quote in a new tab)

Loss of functional independence

“Most individuals are forced to give up their employment and depend increasingly on others for help, although they are still able to maintain a considerable degree of personal independence.” (opens the source at this quote in a new tab)
“In late stages of HD, motor disability becomes severe, and the individual is often totally dependent, mute, and incontinent.” (opens the source at this quote in a new tab)

“They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits.” (opens the source at this quote in a new tab)
“People with advanced HD need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure or other complications.” (opens the source at this quote in a new tab)

Neuropsychiatric symptoms and functional capacity: systematic review

“Significant associations with decreased functional capacity were found most commonly with depression (N=7, median r=0.48) and apathy (N=5, median r=0.47).” (opens the source at this quote in a new tab)

Falls and injury

“Twenty-seven patients (60%) reported two or more falls in the previous year and were classified as fallers. During prospective follow-up 40% reported at least one fall. A high proportion of falls (72.5%) caused minor injuries.” (opens the source at this quote in a new tab)

“Three months before death, anxiety (11% vs. 5%, 2.11, 0.7–5.6, p = 0.15), depression (28% vs. 6%, 4.28, 1.72–8.67, p < 0.001), falls (25% vs. 8%, 2.5, 1.18–4.73, p < 0.05), insomnia (25% vs. 4%, 8.82, 3.62–20.19, p < 0.001) and fractures/breaks/sprains (20% vs. 10%, 1.83, 0.85–3.35, p = 0.09) were more prevalent in HD cases.” (opens the source at this quote in a new tab)

Pneumonia, weight loss, dementia, and other comorbidities after diagnosis

“Incidence rates of the following were statistically higher in individuals with HD than controls: psychotic disorders, psychosis, insomnia, dementia, depression, pneumonia, weight loss and falls.” (opens the source at this quote in a new tab)
“The most commonly mentioned causes of death (any mention) were HD (78.3%), bronchopneumonia (unspecified) (15.9%), pneumonitis due to food and vomiting (10.4%), unspecified dementia (6.6%) and sepsis (6.6%) (Table S8).” (opens the source at this quote in a new tab)

Aspiration pneumonia

“It is most likely that dysphagia is the causative factor for this aspiration pneumonia.” (opens the source at this quote in a new tab)

Institutionalization: skilled nursing facility placement

“Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents' average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%).” (opens the source at this quote in a new tab)
“In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement.” (opens the source at this quote in a new tab)

Juvenile Huntington's disease: long-term motor morbidity and seizures

“Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup.” (opens the source at this quote in a new tab)

HDBOI study: EQ-5D-5L, SF-6D, and H-QoL-I scores by disease stage

“A total of 2,094 PwHD were enrolled with completed eCRFs (100%) and PPIE-P forms (n = 482, 23%).” (opens the source at this quote in a new tab)
“The mean EQ-5D-5L (n = 336) utility score was 0.59 (SD, 0.27), with the highest mean utility scores [SD] in ES (0.72 [0.22]) followed by MS (0.62 [0.18]) and AS (0.37 [0.30]), p < 0.001.” (opens the source at this quote in a new tab)
“The mean SF-6D score (n = 482) was 0.57 (SD, 0.10), with mean values decreasing with advanced disease (ES, 0.61; MS, 0.56; AS, 0.50, p < 0.001).” (opens the source at this quote in a new tab)
“H-QoL-I mean scores (n = 482) also worsened with more advanced disease, from 0.58 for ES to 0.49 for MS and 0.37 for AS, p < 0.001.” (opens the source at this quote in a new tab)
“Overall proxy respondents reported on average worse outcomes than PwHD (self-reported) across all outcomes and disease stages suggesting a possible unawareness of deficits by PwHD.” (opens the source at this quote in a new tab)

Health state utility values: systematic literature review

“Of 383 articles screened, 16 articles reported utility values estimated in 11 distinct studies.” (opens the source at this quote in a new tab)
“The EQ-5D index range was 0.89 - 0.72 for mild/prodromal HD and 0.71 - 0.37 for severe/late-stage disease.” (opens the source at this quote in a new tab)
“This study uncovered high variability in published utility estimates, indicating substantial uncertainty in existing data.” (opens the source at this quote in a new tab)

Health state utility values: EHDN REGISTRY SF-6D analysis

“11,328 questionnaires were completed by 5560 respondents with HD in 12 European countries.” (opens the source at this quote in a new tab)
“Women generally had lower HSUVs than men, and HSUVs were consistently lower than population norms for those with HD in the UK, and dropped with increasing disease severity.” (opens the source at this quote in a new tab)
“with TFC score, Behavioural score, and male gender significant predictors of SF-6D values (p < 0.001).” (opens the source at this quote in a new tab)

Stage-specific utility values applied in a U.S. cost-effectiveness model

“Health utilities for SoC were derived from the Hawton et al. study” (opens the source at this quote in a new tab)
“that used SF-6D preference-based measures to estimate stage-specific utilities for HD.” (opens the source at this quote in a new tab)

Health state	Utility, base case	Range
Early	“0.73”	“0.7–0.9”
Middle	“0.63”	“0.5–0.7”
Late	“0.57”	“0.4–0.6”

Norway cross-sectional study: EQ-5D-3L values by disease phase

“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)

Spain: H-QoL-I and EQ-5D-3L

“Fifty-five patients and an equal number of caregivers participated.” (opens the source at this quote in a new tab)
“The usual activities and anxiety/depression were the most severely altered dimensions according to the EQ-5D-3L results.” (opens the source at this quote in a new tab)
“Increase of disease severity resulted in lower patient QoL.” (opens the source at this quote in a new tab)

Chorea health states: time trade-off utility values in the general population

“Mean ± SD TTO-derived utility values were 0.07 ± 0.52, 0.26 ± 0.50, 0.48 ± 0.47, and 0.64 ± 0.41 for severe, moderate/severe, moderate/mild, and mild chorea severity, respectively.” (opens the source at this quote in a new tab)
“Respondents were willing to give up 3.6, 5.2, 7.4, and 9.3 years during a 10-year life span to avoid living with mild, mild/moderate, moderate/severe, and severe chorea, respectively.” (opens the source at this quote in a new tab)

HDQLIFE: development of a disease-specific HRQoL measurement system

“Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD.” (opens the source at this quote in a new tab)
“HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.” (opens the source at this quote in a new tab)

HDQLIFE physical function measures: reliability and validity

“A total of 510 individuals with Huntington's disease completed 2 Quality of Life in Neurological Disorders (Lower Extremity Function and Upper Extremity Function) and 3 Huntington's Disease Health-Related Quality of Life (Chorea, Speech Difficulties, and Swallowing Difficulties) measures.” (opens the source at this quote in a new tab)
“Reliabilities for the new patient reported physical functioning measures were excellent (all Cronbach's α > .92).” (opens the source at this quote in a new tab)

Chorea and HRQoL: U.S. online survey using HDQLIFE

“A total of 115 participants (n = 35 caregivers; n = 80 individuals with HD) were included in this study.” (opens the source at this quote in a new tab)
“Among those experiencing chorea (n = 83, 74% of respondents), 66% indicated it was 'Very Important' to manage chorea; however, only 47% agreed that their current medication regimen helped manage their movements.” (opens the source at this quote in a new tab)
“significantly higher Anxiety (P = 0.0423) and stigma (P < 0.0001) scores were observed among respondents with high chorea than in those with low chorea.” (opens the source at this quote in a new tab)

Determinants of HRQoL: functional capacity and depressive mood

“Multiple regression analyses showed that functional capacity and depressive mood were significantly associated with HrQOL, in that greater impairments in HrQOL were associated with higher levels of depressive mood and lower functional capacity.” (opens the source at this quote in a new tab)
“Motor symptoms and cognitive function were not found to be as closely linked with HrQOL.” (opens the source at this quote in a new tab)

Psychiatric burden: suicidal ideation and sleep disturbance in the HDBOI study

“PwHD reported current (13%, n = 272) or previous (28%, n = 575) suicidal ideation, which was more common with advanced HD (ES, 11%; MS, 14%; AS, 15%; p < 0.05).” (opens the source at this quote in a new tab)
“Of 482 questionnaire respondents, 91% (n = 437) reported difficulty sleeping, which was more common with AS HD (p < 0.05; [p = 0.000]).” (opens the source at this quote in a new tab)

Psychiatric burden: suicidal ideation measured with HDQLIFE Concern with Death and Dying items

“We examined 496 participants with premanifest or manifest HD.” (opens the source at this quote in a new tab)
“Our sample had a significantly higher occurrence of suicidal ideation (19.76%) and suicidal plans (2.1%) than the general population (p < 0.0001).” (opens the source at this quote in a new tab)

U.S. survey: individuals with HD and care partners compared with Parkinson's disease and the general population

“IHD had greater comorbid anxiety (IHD = 51.2%, IPD = 28.8%, GP = 2.0%), and HD-CP had greater comorbid anxiety (HD-CP = 52.5%, PD-CP = 28.6%, GP-CP = 19.6%) and depression (HD-CP = 65.0%, PD-CP = 29.9%, GP-CP = 19.6%), relative to other cohorts (p < 0.05).” (opens the source at this quote in a new tab)
“Respective of their GP cohorts, IHD exhibited lower HRQoL (EQ-5D: 0.66 ± 0.21 vs. 0.81 ± 0.17) and greater depression (PHQ-9: 11.59 ± 7.20 vs. 5.85 ± 6.71), whereas HD-CP exhibited greater depression only (PHQ-9: 6.84 ± 6.38 vs. 4.15 ± 5.58) (p < 0.001).” (opens the source at this quote in a new tab)

Canada: HRQoL of individuals with HD and care partner strain

“A total of 62 adult individuals with HD (or their proxies) and 48 care partners met defined eligibility criteria.” (opens the source at this quote in a new tab)
“For individuals with HD, the greatest HRQoL burden (i.e., lowest score) was for the SF-36v1 Role -Physical scale (46.8 [42.9]).” (opens the source at this quote in a new tab)
“Among care partners, 55.3% experienced high strain, as indicated by the CSI.” (opens the source at this quote in a new tab)

Caregiver burden: prospective longitudinal study of patient and caregiver pairs

“105 caregiver/patient pairs were included in the analysis.” (opens the source at this quote in a new tab)
“Of the two clusters of patients with advanced disease, cluster A was characterized by high levels of irritability and obsessive-compulsive behaviors, with high and increasing burden (N = 30; 29%), cluster B, the more apathetic group, with low and decreasing burden (N = 22; 21%).” (opens the source at this quote in a new tab)

Caregiver burden: determinants in a U.S. clinic sample

“Total functional capacity and being sole caregiver were significantly associated with higher caregiver burden via MCSI.” (opens the source at this quote in a new tab)

Caregiver burden: South Korea prospective cohort

“Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study.” (opens the source at this quote in a new tab)
“A higher caregiver burden was associated with a more severe Shoulson-Fahn stage (p = 0.038) of the patients.” (opens the source at this quote in a new tab)

Caregiver burden: systematic review

“Twelve studies were included in the review involving 569 caregivers of patients with HD.” (opens the source at this quote in a new tab)
“Neuropsychiatric symptoms and the hereditary nature of the disease have been identified as important correlates of caregiver strain.” (opens the source at this quote in a new tab)

Patient and caregiver experience: ICER stakeholder input

“Caregiver impact increases as the disease progresses and individuals become more dependent on others, with 24/7 care eventually needed, particularly during the last five years of life.” (opens the source at this quote in a new tab)
“Motor symptoms are also a prominent feature of the disease and affect individuals’ ability to walk, talk, eat, and sleep.” (opens the source at this quote in a new tab)

Multigenerational burden: qualitative study across six European countries

“Cognitive and psychiatric symptoms were particularly burdensome, driving declines in quality of life (QoL) and emotional well-being.” (opens the source at this quote in a new tab)
“Caregivers reported extensive physical, financial, and psychological strain, with many assuming care responsibilities from a young age or eventually caring for multiple relatives.” (opens the source at this quote in a new tab)

U.S. commercial and Medicaid claims (2002 to 2009): direct medical costs by stage

“Among 1272 HD patients, the mean age was similar in commercial (752 patients) and Medicaid (520 patients) populations” (opens the source at this quote in a new tab)
“The mean total annualized cost per patient increased by stage (commercial: $4947 (SD = $6040)-$22,582 (SD = $39,028); Medicaid: $3257 (SD = $5670)-$37,495 (SD = $27,111).” (opens the source at this quote in a new tab)
“The vast majority (73.8%) of Medicaid Late stage patients received nursing home care and the majority (54.6%) of Medicaid Late stage costs were associated with nursing home care.” (opens the source at this quote in a new tab)
“Key limitations include the classification of patients into a single stage, as well as a lack of visibility into full long-term care/nursing home-related costs for commercial patients.” (opens the source at this quote in a new tab)

U.S. Medicare fee-for-service claims (2013 to 2017): costs versus matched beneficiaries and by stage

“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)

U.S. Medicaid Analytic eXtract (2010 to 2014): costs versus matched beneficiaries and by stage

“A total of 1,785 beneficiaries without HD were matched to 595 beneficiaries with HD (139 early-, 78 middle-, and 378 late-stage).” (opens the source at this quote in a new tab)
“The mean (SD) annual total costs were higher for beneficiaries with HD than beneficiaries without HD ($73,087 [$75,140] vs. $26,834 [$47,659], p <.001) and driven by inpatient costs ($45,190 [$48,185] vs. $13,808 [$39,596], p <.001).” (opens the source at this quote in a new tab)
“Total healthcare costs were highest among beneficiaries with late-stage HD (mean [SD] cost: $22,797 [$31,683] for early-stage HD vs. $55,294 [$129,290] for middle-stage HD vs. $95,251 [$60,197] for late-stage HD; p <.001).” (opens the source at this quote in a new tab)

U.S. MarketScan commercial, Medicaid, and Medicare Supplemental claims (2009 to 2018): HRU and costs per patient per month by stage

“A total of 2,669 individuals with HD were identified. Of these, 1,432 (53.7%), 689 (25.8%), and 548 (20.5%) had early-, middle-, and late-stage HD at baseline, respectively.” (opens the source at this quote in a new tab)
“Mean total all-cause healthcare cost PPPM for individuals with HD was $2,889, and it was significantly higher in middle-stage individuals, at $7,988, compared with early- and late-stage individuals, at $3,726 and $5,125, respectively; p <0.0001.” (opens the source at this quote in a new tab)
“Our evaluations didn't include the indirect costs of HD, which may be substantial as HD typically affects people at their peak earning potential.” (opens the source at this quote in a new tab)

U.S. MarketScan claims: costs versus propensity-matched controls without HD

“A total of 2,473 individuals with HD and 9,522 matched non-HD controls were identified.” (opens the source at this quote in a new tab)
“Mean total costs (2018 USD PPPM) for the HD cohort ($2,260 [SD = $4,682]) were twice the total costs in the non-HD cohort ($1,056 [SD = $3,078]) (P < 0.0001) and were highest across all disease stages.” (opens the source at this quote in a new tab)

U.S. MarketScan claims: late-onset versus adult-onset HD

“In total, 763 individuals with LoHD and 1,073 individuals with AoHD were matched with 3,762 non-HD controls.” (opens the source at this quote in a new tab)
“In the 12 months post-index, mean total costs for the LoHD cohort ($29,055) were significantly higher than for non-HD controls (≥60 years old: $17,286; 21-59 years old: $12,688; p <.001) and similar to total costs in the AoHD cohort ($31,701; p =.47).” (opens the source at this quote in a new tab)

U.S. MarketScan claims (2017 to 2021): HD-related costs by diagnosing provider type

“Three hundred and forty eligible patients had a mean age at diagnosis of 49 years.” (opens the source at this quote in a new tab)
“HD-related mean costs totaled $2,489 ($1,179 inpatient and $1,310 outpatient).” (opens the source at this quote in a new tab)
“Patients diagnosed by neurologists had significantly lower HD-related total non-medication costs vs. those diagnosed by PCPs (-$2,256; p < 0.05).” (opens the source at this quote in a new tab)

Systematic review of cost-of-illness studies: annual costs by stage and cost type (2023 U.S. dollars)

Cost type and study	“Early”	“Middle”	“Late”
Inpatient, Divino	“1150”	“5045”	“9216”
Inpatient, Exuzides	“1225”	“4250”	“22,228”
Inpatient, Patel	“791”	“3,070”	“65,465”
Outpatient, Divino	“2956”	“10,508”	“30,104”
Outpatient, Exuzides	“4736”	“10,361”	“13,665”
Outpatient, Patel	“5676”	“11639”	“6226”
Drug, Divino	“2483”	“4518”	“4838”
Drug, Exuzides	“15,663”	“16,790”	“23,944”
Drug, Patel	“6330”	“14149”	“13,108”
Caregiving, Jones	“6073”	“44,662”	“133,200”
Caregiving, Silva-Pardes	“6041”	“16,502”	“21,438”

Systematic review of cost-of-illness studies: synthesis

“Only five studies were included for extraction and synthesis including three from the USA, one from the United Kingdom (UK), and one from Peru.” (opens the source at this quote in a new tab)
“Outpatient costs were approximately 2.5 times greater than inpatient costs for early and middle stages of HD.” (opens the source at this quote in a new tab)
“Among all the costs associated with HD, annual caregiver cost emerges as the most significant costs in the economic burden of HD, ranging from a minimum of $6041 for early stage to a maximum of $133,200 for late-stage HD.” (opens the source at this quote in a new tab)

Global systematic review: annual costs by region (2024 U.S. dollars)

“Out of the initial 608 de-duplicated articles, 19 full-text articles were included.” (opens the source at this quote in a new tab)
“Annual costs in 2024 USD ranged significantly by region: Americas ($2542-$90,515), Europe ($40,000-$215,020), Asia ($1915-$7132), and Oceania ($3678-$8721).” (opens the source at this quote in a new tab)

HDBOI study (France, Germany, Italy, Spain, United Kingdom, United States): direct, nondirect, and indirect costs

“HDBOI cost estimates were €12,663 (n = 2094) for direct medical costs, €2984 (n = 359) for nondirect medical costs, and €47,576 (n = 436) for indirect costs.” (opens the source at this quote in a new tab)
“Costs are higher in patients who are at later stages of disease; for example, direct medical costs estimates were €9220 (n = 846), €11,885 (n = 701), and €18,985 (n = 547) for ES, MS, and AS, respectively.” (opens the source at this quote in a new tab)
“Costs show large variations between patients and countries.” (opens the source at this quote in a new tab)

HDBOI study: design, participants, and costing methods

“The HDBOI study is a noninterventional, retrospective, cross-sectional, international burden of illness study of people with diagnosed HD in France, Germany, Italy, Spain, the UK, and the USA.” (opens the source at this quote in a new tab)
“A total of 2094 PwHD were enrolled in the HDBOI study, 40% of whom (n = 846) were classified as ES, 34% as MS (n = 701), and 26% as AS (n = 547; Table 1).” (opens the source at this quote in a new tab)
“Information regarding HD-related health care resource use used to compute direct medical costs was available for all 2094 PwHD. Information on direct nonmedical costs was available for 359 PwHD and indirect costs for 436 PwHD.” (opens the source at this quote in a new tab)
“Costs are reported in 2020 euros for all outcomes” (opens the source at this quote in a new tab)
“To minimize underestimation of costs due to potentially reduced care interactions during the coronavirus disease 2019 (COVID-19) pandemic, health care resource use (used to compute direct medical costs) was extracted for a set time period before the pandemic (March 2019 through March 2020).” (opens the source at this quote in a new tab)
“For actively employed PwHD and caregivers, productivity loss was quantified as the number of days missed from work due to HD in the past 3 months multiplied by the country average salary per day.” (opens the source at this quote in a new tab)
“For those unable to work due to HD, an opportunity cost was assigned based on 1 year of average salary per country.” (opens the source at this quote in a new tab)

HDBOI study: mean annual costs by disease stage (2020 euros)

Cost category	Total, mean (SD)	Early stage, mean (SD)	Mid stage, mean (SD)	Advanced stage, mean (SD)
Direct medical costs	“€12,663 (€34,012)”	“€9220 (€31,855)”	“€11,885 (€31,827)”	“€18,985 (€38,811)”
Direct nonmedical costs	“€2984 (€3627)”	“€2275 (€3530)”	“€2956 (€3632)”	“€4180 (€3500)”
Indirect costs	“€47,576 (€47,985)”	“€35,859 (€44,874)”	“€51,996 (€45,549)”	“€56,947 (€51,723)”
Total costs	“€62,372 (€51,197)”	“€42,477 (€45,651)”	“€64,688 (€53,698)”	“€86,177 (€44,966)”

HDBOI study: cost drivers and mean annual cost components by stage (2020 euros)

“Inpatient hospitalizations and residential care were the primary drivers of direct medical costs” (opens the source at this quote in a new tab)
“Total costs (sum of direct medical, nonmedical, and indirect costs), available for a subsample of 307 PwHD (patients with a completed eCRF, PPIE-P, and PPIE-C), were driven primarily by indirect costs, which accounted for 84%, 80%, and 66% of ES, MS, and AS total costs, respectively (Appendix Table A2).” (opens the source at this quote in a new tab)

Cost component	Early stage, mean (SD) and n	Mid stage, mean (SD) and n	Advanced stage, mean (SD) and n
Consultations	“€727 (€1216) n = 829”	“€767 (€975) n = 693”	“€1051 (€1335) n = 545”
Hospital inpatient	“€35,803 (€102,653) n = 28”	“€30,698 (€39,581) n = 23”	“€12,658 (€42,550) n = 60”
Treatment	“€6333 (€25,525) n = 667”	“€6539 (€28,257) n = 571”	“€7922 (€26,248) n = 454”
Residential care	“€41,879 (€46,946) n = 16”	“€56,673 (€40,806) n = 26”	“€45,977 (€31,915) n = 98”
Professional caregiver	“€1286 (€4355) n = 204”	“€2308 (€9831) n = 164”	“€2582 (€8632) n = 114”
State support, patient	“€841 (€2123) n = 204”	“€1199 (€2497) n = 164”	“€2677 (€3437) n = 114”
Lost productivity, PwHD	“€23,216 (€16,848) n = 75”	“€31,824 (€13,934) n = 109”	“€34,343 (€10,295) n = 98”

HDBOI study: mean annual costs by country (2020 euros)

“Direct nonmedical costs were highest in Italy (€3977) and the UK, and indirect costs were highest in the USA (€74,228 [$90,187]), the UK, and Italy” (opens the source at this quote in a new tab)
“The HDBOI study reported direct medical costs of €27,743 in the USA and a substantial indirect cost burden of €74,228 from lost work productivity.” (opens the source at this quote in a new tab)

Country	Direct medical costs	Indirect costs
France	“4167”	“39471”
Germany	“11560”	“39451”
Italy	“6934”	“47048”
Spain	“5814”	“43547”
United Kingdom	“12606”	“52472”
United States	“27743”	“74228”

HDBOI study: stated limitations of the cost estimates

“Because recruitment was driven through clinician office visits, AS patients may have been underrepresented if they were admitted to long-term residential or nursing care homes.” (opens the source at this quote in a new tab)
“Cost estimates for AS PwHD may have been underestimated due to the small sample of patients with advanced disease and subsequent subgroup analyses.” (opens the source at this quote in a new tab)
“For Germany, direct medical costs may have been underestimated, as only copayments were publicly available, which do not reflect the true cost of the service delivered.” (opens the source at this quote in a new tab)

United Kingdom EHDN REGISTRY: annual societal costs by TFC stage (2013 pounds)

Category	“Stage I: TFC 11–13 (n = 43)”	“Stage II: TFC 7–10 (n = 37)”	“Stage III: TFC 3–6 (n = 38)”	“Stage IV: TFC 1–2 (n = 13)”	“All stages (n = 131)”
Informal care, mean	“£1073.86”	“£4941.41”	“£21 051.79”	“£62 784.00”	“£14 085.24”
Total, mean	“£2250.06”	“£11 867.76”	“£29 671.91”	“£89 759.62”	“£21 605.08”

United Kingdom EHDN REGISTRY: cost drivers

“The mean annual cost per person with HD was £21 605. The largest proportion of this cost (65%) was due to informal care (£14 085).” (opens the source at this quote in a new tab)
“This equates to £195 million per year in the UK.” (opens the source at this quote in a new tab)

Norway: six-month healthcare and societal costs

“Total six-month healthcare costs and total societal costs were € 18,538 and € 66,789 respectively.” (opens the source at this quote in a new tab)
“Main six-month cost components for the three disease phases were informal care costs (€ 30,605) accounting for approximately half the total societal costs, and costs due to production loss (€ 18,907) being slightly higher than the total healthcare costs.” (opens the source at this quote in a new tab)

Long-term care in advanced HD: North American systematic literature review

“Most patients with advanced HD receive LTC in a nursing home (35%) or at home (32%), with fewer patients receiving LTC from hospitals, hospices, and multi-setting facilities” (opens the source at this quote in a new tab)
“A long period of time is spent in both nursing home and hospice care, leading to sizeable annual costs for this care provision.” (opens the source at this quote in a new tab)

Hospice and palliative care utilization in the United States

“Of the 164,032 patients admitted to these hospices, 101 (0.06%) had a primary diagnosis of HD.” (opens the source at this quote in a new tab)
“Patients had a median length of stay in hospice of 42 days, which was significantly longer than that of other hospice patients in the sample (17 days), P < 0.001.” (opens the source at this quote in a new tab)

“8521 patients with HD were admitted to the hospital. Of those, 321 (3.8%) received specialty PC.” (opens the source at this quote in a new tab)

Predictors of health care utilization: Enroll-HD Northern America

“Visits from 1,631 participants in the Northern America region from the Enroll-HD study were included in this study.” (opens the source at this quote in a new tab)
“Clinical factors, such as psychiatric symptoms, functional ability, and comorbidities, were associated with use of multiple types of health care services.” (opens the source at this quote in a new tab)

Employment loss by disease stage: Enroll-HD

“At baseline visit, 47.5% of patients with TFC score 11–13 (n=2,512) were unemployed; 19.9% of them due to illness and 15.4% were on sick leave.” (opens the source at this quote in a new tab)
“89.8% of patients with TFC score 7–10 (n=2,794) were unemployed; 37.8% of them due to illness and 19.7% were on sick leave.” (opens the source at this quote in a new tab)
“By 4 years post-clinical diagnosis, <20% patients stayed employed.” (opens the source at this quote in a new tab)

Employment and work productivity: HDBOI participants

“Approximately 27% of the PPIE-P sample reported stopping work early (i.e., retiring) due to HD.” (opens the source at this quote in a new tab)
“Of those who reported being employed for pay overall work productivity loss increased with disease severity: 43% in ES, 55% in MS, and 57% in AS.” (opens the source at this quote in a new tab)

Employment: chorea and cognitive decline

“Patients with chorea were less likely to be employed full-time (16.7% vs 25.7%; P<0.04) and more likely to be on long-term sick leave (17.4% vs 5.0%; P<0.01).” (opens the source at this quote in a new tab)

“For every year delay in cognitive symptom onset, there was a 0.806 year increase in age at leaving work (SE = 0.030, p < 0.001, adj-R2 = 0.628).” (opens the source at this quote in a new tab)

“Twenty-three studies were identified and showed that while employment and working capacity in HD are negatively influenced by cognitive decline and motor impairments, apathy already plays a role in the prodromal stage.” (opens the source at this quote in a new tab)

Canada (Alberta): direct healthcare costs under a universal public system

“The mean total all-cause direct healthcare costs were $23,211 [$38,599] per person-year, with hospitalizations accounting for 57.8% of all-cause costs.” (opens the source at this quote in a new tab)
“Costs were higher among individuals with a long-term care stay, a proxy for disease severity.” (opens the source at this quote in a new tab)

Other countries: Israel, China, Peru, Brazil, and Germany

“Total healthcare and medication costs per patient (US dollars) were significantly higher for PwHD than controls ($7,343 vs. $3,625; P < 0.001).” (opens the source at this quote in a new tab)

“The average annual direct medical cost, direct non-medical cost, and indirect cost were 3,265.65, 805.82, and 801.97 Euros, respectively.” (opens the source at this quote in a new tab)

“The average annual cost of HD reached USD 8120 per patient in 2015.” (opens the source at this quote in a new tab)
“The mean cost of HD increased with the degree of patient dependency: from USD 6572 for Barthel 4 & 5 (slight dependency and total independency, respectively) to USD 23,251 for Barthel 1 (total dependency).” (opens the source at this quote in a new tab)

“Significant economic impacts were observed, with average annual direct medical costs of $4686.82 per HD patient.” (opens the source at this quote in a new tab)
“Thirty-three out of 34 HD patients were unemployed or retired, and 16 relied on government benefits, reflecting broader socioeconomic implications.” (opens the source at this quote in a new tab)

“Physical therapy was the most often used medical aid in HD patients (46.4%). Nursing services and speech therapy were used by 27.9 and 22.7% of HD patients, respectively, whereas use of psychotherapy was rare (3.2%).” (opens the source at this quote in a new tab)

U.S. indirect and out-of-pocket costs: HD-Charge survey

“The indirect and out-of-pocket costs of HD in the US have not been quantified.” (opens the source at this quote in a new tab)
“Quantify out-of-pocket expenses for HDGECs and companions” (opens the source at this quote in a new tab)

Informal care and caregiver productivity costs: HDBOI study (2020 euros)

“Indirect costs for informal care were calculated as the total number of hours per week of informal care multiplied by the number of weeks per year. Total number of hours per year was multiplied by the country average salary per hour.” (opens the source at this quote in a new tab)
“Caregiver state support accounted for 58%–75% of all direct nonmedical costs. Indirect costs were driven by lost productivity for PwHD (34%–42%) and costs of informal care requirements (40%–42%; Appendix Table A2).” (opens the source at this quote in a new tab)

Cost component	Early stage, mean (SD) and n	Mid stage, mean (SD) and n	Advanced stage, mean (SD) and n
Informal care	“€27,760 (€37,790) n = 121”	“€30,243 (€37,046) n = 120”	“€37,758 (€45,515) n = 83”
Lost productivity, caregiver	“€18,225 (€19,864) n = 33”	“€12,988 (€15,621) n = 46”	“€17,280 (€19,266) n = 49”
State support, caregiver	“€5134 (€5834) n = 22”	“€5897 (€5098) n = 36”	“€4778 (€3359) n = 43”

Informal caregiver time and objective burden: France

“We included 80 ICs (mean [SD] age 57 [12.9] years, 60% women) in charge of 80 individuals with early to advanced stage HD” (opens the source at this quote in a new tab)
“The mean hours of informal care time was high: 7.3 (7.9) h/day (range 0-24); the mean professional home care was 2.8 (2.8) h/day (range 0.1-12.3).” (opens the source at this quote in a new tab)
“The burden was partially related to the multiplex caregiving status (19%). Protective factors lowering the IC burden included the absence of financial hardship (57%), a strong social network (16%) and keeping active on the job market outside home (46%).” (opens the source at this quote in a new tab)

Caregiver employment and work productivity: HDBOI caregivers

“A total of 37 (7%) respondents had to stop working because of their caregiving duties and 206 (41%) reported that their duties have impacted their career.” (opens the source at this quote in a new tab)
“Of the 206, approximately 59% were prevented from working more hours, 54% prevented from career progression, and 19% were required to choose an alternative career (See Table 3).” (opens the source at this quote in a new tab)
“High levels of informal care were reported, with an average of 34 hours of informal care per week.” (opens the source at this quote in a new tab)
“Overall impairment in caregiver daily activities increased with participant’s disease severity: 42% in ES, 48% in MS, and 52% in AS.” (opens the source at this quote in a new tab)

Caregivers of people with advanced HD in North America: systematic literature review

Caregiver outcome	Quoted value
Mean time spent as primary carer (years)	“10.2 years”
Total hours of formal care per week	“43 hours”
Total hours of informal care per week	“41 hours”
Prevented career progression	“51%”
Prevented from working more hours	“70%”
Overall work productivity loss	“54%”

“Caregivers often give up their job, change careers, or reduce their hours to accommodate the long hours required to provide LTC.” (opens the source at this quote in a new tab)

Informal care as a share of societal cost: United Kingdom and Norway

“Informal care was the largest driver of costs across all stages of HD; thus there is a need to also consider the needs of carers when planning services for people with HD.” (opens the source at this quote in a new tab)

“Our results highlight the crucial role the informal caregivers play in the care provided to HD patients in all disease phases. Future research should focus on the estimation of productivity loss among informal caregivers.” (opens the source at this quote in a new tab)

Out-of-pocket financing by families: Peru

“Direct non-healthcare costs represented 78.3% of total cost, indirect costs 14.4% and direct healthcare costs the remaining 7.3%.” (opens the source at this quote in a new tab)
“Direct costs were primarily financed by patients and their families.” (opens the source at this quote in a new tab)

Juvenile-onset HD: costs to the NHS and to families (England and Wales, 2020 pounds)

“The overall mean JoHD cost to the NHS per year (2020) was £126,966 which varied according to disease severity, costing just under £11,000 in mild disease, £132,419 in moderate disease, and £221,797 in advanced JoHD.” (opens the source at this quote in a new tab)
“The proportion of indirect costs to families and carers was 64% for mild disease and 17% for advanced disease.” (opens the source at this quote in a new tab)

Severity	“No. accessing”	Costs to family, “Mean (SD)”
Mild	“9 (90%)”	“£19,269 (£17,995)”
Moderate	“7 (100%)”	“£33,118 (£45,657)”
Advanced	“14 (100%)”	“£48,696 (£55,825)”
All	“32 (97.0%)”	“£35,993 (£43,918)”

Family financial and care needs: ICER stakeholder input

“Many people with HD require care in a long-term care facility because of the heavy caregiving needs, and caregivers often need to change their career or work less to accommodate the needs of the individual with HD” (opens the source at this quote in a new tab)
“clinicians emphasized the importance of multidisciplinary care, including neurologists, psychiatrists, therapists, social workers, and geneticists, as families need assistance not only with medical issues but also with financial issues such as long-term care and life insurance, and testing for family members.” (opens the source at this quote in a new tab)

At-risk family members: genetic discrimination in insurance

“Discrimination was reported by 93 respondents (39.9%). Reported experiences occurred most often in insurance (29.2%), family (15.5%), and social (12.4%) settings.” (opens the source at this quote in a new tab)
“Family history of Huntington's disease, rather than the result of genetic testing, was the main reason given for experiences of genetic discrimination.” (opens the source at this quote in a new tab)

“Across all three countries, a total of 46.2% of respondents report genetic discrimination or stigma based on either their family history of HD or genetic testing for the HD gene mutation.” (opens the source at this quote in a new tab)
“We report on the overall incidence of discrimination and stigma in the domains of insurance (25.9%), employment (6.5%), relationships (32.9%), and other transactions (4.6%) in the United States, Canada, and Australia combined.” (opens the source at this quote in a new tab)

Cost of predictive genetic testing at HDSA Centers of Excellence in the United States

“As of 2019 there were 47 HDSA COE’s in the US, and in the preceding year, they performed HD predictive genetic testing on a total of 777 individuals.” (opens the source at this quote in a new tab)
“The average cost of these tests was $1,157.12, with a range of $275-3,640 (Figure 1).” (opens the source at this quote in a new tab)
“The average cost for the various components of the predictive testing process included: $199.80 for genetic counselling, $278.40 for psychology, $666.33 for neuropsychology, $317.50 for neurology, $52.83 for social work, $352.80 for gene testing, and $210.80 for miscellaneous fees (Figure 2).” (opens the source at this quote in a new tab)
“59.6% of COE’s covered the cost of some component of the testing process out of COE grant funds, and 57.5% offered other financial assistance to offset the cost of the testing process.” (opens the source at this quote in a new tab)

Predictive testing uptake among at-risk individuals

“9407 predictive tests were performed across 23 UK centres.” (opens the source at this quote in a new tab)
“Using a prevalence figure of 12.3 × 10−5, the cumulative uptake of predictive testing in the 50% at-risk UK population from 1994 to 2014 was estimated at 17.4% (95% CI: 16.9–18.0%).” (opens the source at this quote in a new tab)
“Future therapies in HD will likely target presymptomatic individuals; therefore, identifying the at-risk population whose gene status is unknown is of significant public health value.” (opens the source at this quote in a new tab)

“The uptake of predictive testing in the entire HD 50% at-risk population in 2001 was calculated by three methods giving a range of 12.3-14.6%. Uptake after 20 years was estimated to be 14.7%.” (opens the source at this quote in a new tab)

Fear of health insurance loss and out-of-pocket payment for testing: North America

“After enrollment, 83 individuals [8.3%] pursued genetic testing. Their greatest concern was losing health insurance, and 41.6% of them [vs. 6.7% of those who did not pursue testing; P < 0.001] reported paying out of pocket for testing or other medical services to conceal their genetic risk from their insurer/employer.” (opens the source at this quote in a new tab)
“Among individuals who were tested, more United States residents [46.1%] than Canadian residents [0.0%; P = 0.02] paid out of pocket for health services or genetic testing.” (opens the source at this quote in a new tab)

Insurance protections for genetic information in the United States

“GINA prohibits group health plans, individual and group health insurance companies, and Medicare issuers from:” (opens the source at this quote in a new tab)
“GINA only provides for protection under health insurance and Medicare. Issuers of other types of insurance, such as long term care insurance, disability insurance, and life insurance may still request genetic information to determine eligibility and other coverage terms.” (opens the source at this quote in a new tab)
“Under GINA, an individual’s genetic test result is protected; however, health plans are permitted to use information about an individual’s disease when the disease has manifested.” (opens the source at this quote in a new tab)

Access costs: travel, time away from work, and counseling

“Distance is a structural barrier, and relates to the time and travel required to access PT, the financial and other opportunity costs associated with taking time away from work and family to attend appointments and the stress of navigating urban centers.” (opens the source at this quote in a new tab)

“Genetic counseling is necessary for presymptomatic or symptomatic HD genetic testing, but the lack of access to counseling because of geography or expense is a critical gap for many patients.” (opens the source at this quote in a new tab)
“The main advantage of tele-GC was reduction in travel time for both in-person GC first (n = 16) and tele-GC first (n = 11) participants.” (opens the source at this quote in a new tab)

Testing decisions when genetic services are fully funded: Israel

“This pattern persists even when economic barriers are removed, demonstrating that psychological factors remain primary determinants of testing uptake.” (opens the source at this quote in a new tab)

Demand for predictive testing after therapeutic trial news

“the demand for predictive testing in at risk individuals significantly increased following the press release reporting the successful completion of the Ionis-HTTRx (RG 6042) trial.” (opens the source at this quote in a new tab)

Reproductive genetic testing: cost-effectiveness of preimplantation genetic testing

“Cost-effectiveness analysis in a theoretical cohort of 3,851 couples, where one individual is heterozygous for Huntington disease.” (opens the source at this quote in a new tab)
“In vitro fertilization preimplantation genetic testing was associated with 77 more QALYs and a cost savings of $46,394,268.” (opens the source at this quote in a new tab)
“Most notably, in our theoretical cohort of couples, IVF preimplantation genetic testing resulted in 1,079 fewer Huntington disease-affected offspring.” (opens the source at this quote in a new tab)

EHDN international guideline: first-line treatment of chorea

“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)

AAN evidence-based guideline on chorea (retired 2022): recommendation

“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)

AAN guideline status

“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: evidence for VMAT2 inhibitors and use of tetrabenazine

“The quality of data from RCTs is currently best for VMAT2 inhibitors” (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)

MDS evidence-based review of treatments for Huntington's disease

“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)

Cochrane review of symptomatic treatments

“22 trials (1254 participants) were included.” (opens the source at this quote in a new tab)
“Only tetrabenazine showed a clear efficacy for the control of chorea. The remaining pharmacological interventions revealed no clear effectiveness.” (opens the source at this quote in a new tab)

HSG expert consensus: classes used for chorea in North American practice

“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)

Tetrabenazine: FDA-approved indication and boxed warning

“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)

Tetrabenazine: label efficacy and functional outcomes in Study 1

“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)

Tetrabenazine: depression and sedation in the placebo-controlled trial

“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)

Tetrabenazine: TETRA-HD randomized trial

“The authors randomized 84 ambulatory patients with HD to receive TBZ (n = 54) or placebo (n = 30) for 12 weeks.” (opens the source at this quote in a new tab)
“There were five study withdrawals in the TBZ group and five serious adverse events (SAEs) in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer) compared with one withdrawal and no SAEs in the placebo group.” (opens the source at this quote in a new tab)

Deutetrabenazine: FDA boxed warning and label efficacy

“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)
“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)

Deutetrabenazine: First-HD randomized trial

“Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002).” (opens the source at this quote in a new tab)
“Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.” (opens the source at this quote in a new tab)

Valbenazine: FDA boxed warning and label efficacy

“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)
“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)

Valbenazine: parkinsonism in Huntington's disease

“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)

Valbenazine: KINECT-HD randomized trial

“Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo).” (opens the source at this quote in a new tab)
“No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine.” (opens the source at this quote in a new tab)

HDSA physician's guide: indications for pharmacologic treatment of chorea

“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)

EHDN international guideline: second-generation neuroleptics for chorea and psychiatric symptoms

“are first-line treatments for this symptom in particular when the patients have associated personality and/or behavioral or psychotic disorders. Monotherapy to treat chorea is preferred because combination therapy increases the risk of adverse effects and may complicate the management of non-motor symptoms.” (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)
“In patients with aggressive behavior, the recommended first-line treatment is a neuroleptic (Grade C)” (opens the source at this quote in a new tab)

German Neurological Society guideline: tiapride as first-line antichoreic treatment

“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)
“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)

AAN guideline (retired 2022): insufficient data for neuroleptics

“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)

HDSA physician's guide: off-label neuroleptics for chorea

“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)

International expert survey: first-choice antichoreic drug by region

“However, the experts did not agree on first choice of chorea drug, with the majority of experts in Europe favoring an antipsychotic drug (APD), and a near equal split in first choice between an APD and tetrabenazine (TBZ) among experts from North America and Australia.” (opens the source at this quote in a new tab)

Olanzapine: one-year randomized open-label trial

“Olanzapine improved chorea, behavior, and irritability, although with a slight increase in rigidity.” (opens the source at this quote in a new tab)

EHDN international guideline: depression, irritability, and anxiety

“An antidepressant may be suggested if depression occurs in HD (Grade B)” (opens the source at this quote in a new tab)
“It is recommended to use a selective SSRI or a serotonin noradrenaline reuptake inhibitor (SNRI), or alternatively Mianserin or Mirtazapine, in case of sleep disruption.” (opens the source at this quote in a new tab)
“Whilst SSRIs are first lines for irritability (Grade C)” (opens the source at this quote in a new tab)
“SSRI or SNRI are first line treatments of anxiety, especially when associated with depression.” (opens the source at this quote in a new tab)

EHDN international guideline: suicide risk assessment

“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)

HDSA physician's guide: pharmacotherapy for depression

“There is no single preferred antidepressant for treating depression in HD.” (opens the source at this quote in a new tab)

German Neurological Society guideline: psychiatric symptoms

“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)

Expert-based consensus guidelines on agitation, anxiety, apathy, psychosis, and sleep disorders

“An international committee of 11 multidisciplinary experts proposed a series of statements regarding the description and management of each symptom.” (opens the source at this quote in a new tab)
“High-level agreement (≥85% experts strongly agreed or agreed) was reached for 107 of the 110 statements that have been incorporated into the expert-based clinical recommendations presented herein.” (opens the source at this quote in a new tab)

Systematic review of pharmacological treatment of neuropsychiatric symptoms

“Fifteen articles qualified for critical evaluation: 10 randomized controlled trials (RCTs) (five placebo-controlled and five cross-over) and five open label studies.” (opens the source at this quote in a new tab)
“As a result, convincing evidence that could guide clinical practice is lacking.” (opens the source at this quote in a new tab)

MDS evidence-based review: psychiatric symptoms

“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)

EHDN international guideline: physiotherapy and exercise

“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)

EHDN international guideline: speech and language therapy and nutrition

“Early referral to Speech and Language Therapists is recommended (Grade C)” (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)
“Early assessment by a dietitian or nutritionist, and regular timely reviews of nutritional needs are recommended.” (opens the source at this quote in a new tab)

EHDN international guideline: cognitive symptoms

“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)

Physical therapy clinical recommendations

“We recommend the following specific physical therapy interventions for people with HD: aerobic exercise (grade A evidence), alone or in combination with resistance training to improve fitness and motor function, and supervised gait training (grade A evidence) to improve spatiotemporal features of gait.” (opens the source at this quote in a new tab)

German Neurological Society guideline: speech and occupational therapy

“Therefore, involving speech therapists in the multidisciplinary care of HD patients is essential.” (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)

MDS evidence-based review: nonpharmacologic interventions

“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)

Summary

Current therapies are symptomatic. No approved therapy delays onset or slows progression, and a Cochrane review of 8 trials involving 1,366 participants found no pharmacological intervention effective as a disease-modifying therapy. Only chorea has FDA-approved treatments. All three approved VMAT2 inhibitors carry boxed warnings for depression and suicidality: in the tetrabenazine placebo-controlled trial, depression or worsening depression was reported in 10 of 54 participants (19%) versus 0 of 30 receiving placebo, and tetrabenazine is contraindicated in untreated or inadequately treated depression, a common feature of the disease. Chorea benefit does not persist after discontinuation; scores returned to baseline 1 to 2 weeks after stopping tetrabenazine, deutetrabenazine, and valbenazine. The tetrabenazine label reports no difference from placebo on functional capacity and cognition, with a nominally significant decrement on one functional measure, and valbenazine labeling states that drug-induced parkinsonism can cause more functional disability than untreated chorea in some patients. Antipsychotics, antidepressants, and rehabilitation are used largely on the basis of expert consensus: the MDS review found no eligible evidence for treatments of depression, psychosis, irritability, apathy, or suicidality, or for physiotherapy, occupational therapy, exercise, or dietary interventions, and a systematic review identified 15 eligible studies of neuropsychiatric treatment. Guidelines differ on the first-line antichoreic agent (tetrabenazine in EHDN guidance; tiapride in DGN guidance), and no blinded head-to-head comparison is available. Investigational huntingtin-lowering therapies have not yet produced an approved product: tominersen phase 3 dosing was discontinued in 2021, and in an ad hoc week 69 analysis of the 791-participant GENERATION HD1 trial the cUHDRS change with the every-8-week regimen was significantly worse than with placebo (-0.54 points; adjusted P=0.001), with more adverse events than in the placebo and every-16-week groups; pridopidine missed its phase 3 primary endpoint and received a negative CHMP opinion in 2025, and after a January 2026 Type A meeting the FDA stated that AMT-130 phase I/II data compared with an external control were not sufficient as primary evidence of effectiveness before later agreeing to accept a BLA for accelerated approval.

Cochrane review of disease-modifying interventions

“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)

Absence of disease-modifying therapy

“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)

Tetrabenazine: contraindication in depression

“XENAZINE is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression” (opens the source at this quote in a new tab)

Limited trial evidence in a rare disease

“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)

Investigational HTT lowering: tominersen phase 3 treatment stopped, with worse cUHDRS change at the every-8-week regimen

“On the basis of an overall benefit–risk assessment by an independent data monitoring committee, treatment was stopped in March 2021” (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)” (opens the source at this quote in a new tab)
“The role of antisense oligonucleotide–related toxic effects (possibly inflammatory in nature), as compared with total HTT lowering, on the outcomes observed in GENERATION HD1 cannot be distinguished, given the close relationship between drug exposure and HTT lowering.” (opens the source at this quote in a new tab)

Summary

SKY-0515 is investigational and has no established place in therapy. Its studied use is as a once-daily oral therapy intended to slow disease progression, added to symptomatic care, in adults with symptomatic early disease: the phase 1/2 trial enrolled HD-ISS stage 1, stage 2, or mild stage 3 participants, and the FALCON-HD phase 2/3 trials enroll participants with stage 2 and early stage 3 disease, with registry eligibility thresholds of TFC 10 or higher and TMS 6 or higher. FALCON-HD 004-ANZ enrolled 144 participants in Australia and New Zealand; planned enrollment in FALCON-HD 004-WW was stated as up to an additional 400 participants in a July 2026 announcement and as approximately 600 participants in the September 2026 fifteen-month announcement. In HD-ISS terms, stage 2 denotes a measurable clinical phenotype and stage 3 denotes functional decline; clinical motor diagnosis corresponds to the latter part of stage 2. If approved, SKY-0515 would be used alongside, not in place of, symptomatic VMAT2 inhibitors, antipsychotics, antidepressants, and rehabilitation. Because administration is oral, SKY-0515 would not require the intrathecal injections used for tominersen or the MRI-guided neurosurgical procedure used for AMT-130. Specialist HD care in the United States is concentrated in the HDSA Centers of Excellence network (60 centers and 9 partner sites covering 37 states plus the District of Columbia), and the multidisciplinary care described in guidelines would continue regardless of disease-modifying treatment.

Studied population: FALCON-HD phase 2/3 trials

“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)

Studied population: phase 1/2 trial Part C

“Part C is a randomized, double-blind, placebo-controlled parallel-group study evaluating two dose levels of SKY-0515 in people living with Huntington's disease 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)

Anticipated administration: once-daily oral dosing

“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)

Target stages: HD Integrated Staging System

“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)
“These initial stages, which have only recently become a focus of study, are particularly promising as they may reveal the most effective targets for disease-modifying therapies.” (opens the source at this quote in a new tab)

HD-ISS as a framework for earlier intervention

“The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.” (opens the source at this quote in a new tab)

Comparator care setting: neurosurgical administration of AMT-130

“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)

Specialist care setting: HDSA Centers of Excellence

“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)

Pooled analyses across disease stage and dose

“This means we can’t yet see whether the drug could have different effects at different stages of HD, or if a higher dose has a stronger effect.” (opens the source at this quote in a new tab)

Baseline severity imbalance between extension dose groups

“Based on the CAP scores, the 9 mg cohort was represented by more severe participants compared to 4 mg cohort.” (opens the source at this quote in a new tab)

Dose-dependent biomarker response

“Participants switching from 3 mg to 4 mg showed incrementally an ~10% decrease, as expected.” (opens the source at this quote in a new tab)

Subgroup efficacy results by stage, CAG repeat length, or dose

No evidence found.

EHDN multidisciplinary position paper: managed care network and case manager

“The multidisciplinary team should be composed of different professionals who work closely together and interact within the group. It is also important to establish an individualised care and treatment plan for every single case of a patient and family. A case manager or coordinator may facilitate the work of the multidisciplinary team.” (opens the source at this quote in a new tab)
“This position paper reveals that there are key essential professional groups involved in the MDT who do not have an HD guideline available, like psychologists, social workers, nurses, case managers and general practitioners.” (opens the source at this quote in a new tab)

HDSA physician's guide: team care and Centers of Excellence

“No one doctor or one caregiver should attempt to manage all aspects of an HD case without assistance.” (opens the source at this quote in a new tab)
“Because there are no treatments which can slow, halt, or reverse the course of the disease, the goals of treatment are to reduce the burden of symptoms, maximize function, and optimize quality of life.” (opens the source at this quote in a new tab)

HDSA Centers of Excellence: team composition

“Patients benefit from expert neurologists, psychiatrists, social workers, therapists, counselors and other professionals who have extensive experience working with families affected by HD and who work collaboratively to help families plan the best HD care program throughout the course of the disease.” (opens the source at this quote in a new tab)

Advance care planning: EHDN guideline

“Advanced care planning is essential and alternative feeding methods (PEG, see swallowing disorders) should be anticipated and discussed with relatives and patients still able to understand the benefits and risks of the intervention.” (opens the source at this quote in a new tab)

Advance care planning and psychosocial support: German Neurological Society guideline

“Early in the disease process, it is recommended to document living wills and care directives” (opens the source at this quote in a new tab)
“Moreover, there should be support from a social worker to navigate the complex bureaucracy to apply for and obtain financial assistance and support for care needs.” (opens the source at this quote in a new tab)

Advance care planning: multicenter HDQLIFE study

“Most importantly, engaging in ACP does not cause untoward effects on HRQoL or STB for this rare neurodegenerative disease where the lifetime prevalence of STB approaches 30%.” (opens the source at this quote in a new tab)

Palliative care in advanced disease: scoping review

“Our search resulted in 333 articles, 38 of which were included.” (opens the source at this quote in a new tab)
“Most literature was underpinned by a low level of evidence, except for the topics on social care (Level III-V), advance care planning (Level II-V) and end-of-life needs assessments (Level II-III).” (opens the source at this quote in a new tab)

Palliative care across disease stages

“But for those with pain, anxiety, sleep disturbances, and difficulty coping with their diagnosis, referral to palliative care should be strongly considered.” (opens the source at this quote in a new tab)

Summary

For symptomatic therapy, the expected outcome is symptom control; guidelines state that treatment goals are to reduce symptom burden, maximize function, and optimize quality of life. For a disease-modifying therapy such as SKY-0515, the expected outcome is slower clinical progression, measured in current trials by change in the cUHDRS, a composite of TFC, TMS, SDMT, and Stroop Word Reading, and by its TFC component. An anchor-based analysis of registry data proposed a cUHDRS decline of 1.2 points as a clinically meaningful within-patient change. The sponsor of AMT-130 reported in 2025 that the FDA considered the cUHDRS an acceptable intermediate clinical endpoint for accelerated approval, and the phase 3 INVEST-HD trial of votoplam uses change in cUHDRS to month 36 as its primary endpoint. Other endpoints proposed for earlier-stage populations include time to HD-ISS stage 3 (functional decline); modeling of a 9-month or longer delay in that transition yielded feasible sample sizes. Decision modeling indicates that the health effects of a disease-modifying therapy depend on stage at treatment: a hypothetical therapy produced life-year and QALY gains in all modeled populations, and cost savings only in individuals treated before functional decline.

Composite clinical progression measure in early Huntington's disease

“Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.” (opens the source at this quote in a new tab)

Clinically meaningful change on the cUHDRS

“Analyses anchored against CGI-S and IS support that a decline on the cUHDRS of 1.2 points is clinically meaningful, and that the cUHDRS tracks function decline.” (opens the source at this quote in a new tab)
“Based on these values, a decline of 1.2 points is recommended as an estimate of meaningful within-patient decline for use in a responder analysis endpoint in clinical trials in patients with early manifest HD.” (opens the source at this quote in a new tab)

Regulatory acceptance of cUHDRS as an intermediate clinical endpoint: sponsor-reported FDA feedback

“The FDA continued to support its prior agreement that the composite Unified Huntington’s Disease Rating Scale (cUHDRS) may serve as an acceptable registrational, intermediate clinical endpoint for accelerated approval.” (opens the source at this quote in a new tab)

Phase 3 disease-modifying trial endpoint: votoplam INVEST-HD

“The primary endpoint will be the change from baseline up to month 36 in the cUHDRS.” (opens the source at this quote in a new tab)

SKY-0515 trial outcome measures

“Primary outcome measures are change from baseline to 12 months in blood mHTT protein levels, MRI-derived brain volumes and UHDRS scores.” (opens the source at this quote in a new tab)

Time to functional decline as an endpoint

“A delay of 9 months or more in the transition to Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in planning future trials.” (opens the source at this quote in a new tab)

Cognitive endpoints and regulatory meaningfulness

“Thus, improvements or declines in performance on the SDMT alone are not sufficient for demonstrating meaningful effects that could lead to regulatory approval of a treatment.” (opens the source at this quote in a new tab)

Aims of disease-modifying treatment and modeled long-term outcomes

“Potential disease-modifying treatments (DMTs) such as gene therapy (GTx), antisense oligonucleotides (ASOs), and small molecule–based therapeutic approaches aim to provide long-term health benefits for people with HD by slowing down, arresting, or even reverting disease progression.” (opens the source at this quote in a new tab)
“Although hypothetical DMTs led to cost savings in the PFD population by delaying the cost burdens of functional decline, they increased costs in SF1 and SF2 populations by prolonging time spent in expensive progressive HD states.” (opens the source at this quote in a new tab)

Expected outcomes of symptomatic chorea treatment

“By integrating pharmacologic therapy with multidisciplinary care and holistic, goal-oriented communication about the impact of chorea, clinicians can meaningfully improve safety, independence, and quality of life for individuals and families affected by HD.” (opens the source at this quote in a new tab)