A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease

A Randomized, Double-Blind, Placebo-Controlled Dose Range Finding Study With Open-Label Extension to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of LMI070/Branaplam Administered as Weekly Oral Doses in Participants With Early Manifest Huntington's Disease

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05111249

Acronym

VIBRANT-HD

Enrollment

Registered

2021-11-08

Start date

2021-12-08

Completion date

2023-10-27

Last updated

2025-05-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Early Manifest Huntington Disease

Keywords

Early Manifest, Huntington Disease, Branaplam, LMI070, Dose Range Finding, Safety, HD, mHTT, Pharmacokinetics, oral, Adult

Brief summary

This is the first study of branaplam in adults with Huntington's Disease (HD) to determine the correct dose required to lower mutant huntingtin protein (mHTT) levels in the cerebrospinal fluid (CSF) to a degree expected to be efficacious over longer periods of time.

Detailed description

This study was a randomized, double-blind, placebo-controlled study with a variable duration (between approximately 17 weeks to approximately 53 weeks) for the core period and a one-year open label extension (OLE) in early-stage manifest Huntington's disease (HD) participants. After screening period and baseline assessments, the following two Treatment Periods were planned: • The core period consisted of a 17-week double-blind, placebo-controlled, Dose Range Finding (DRF) portion of the study, followed by a blinded extension (BE) of variable duration (up to approximately 53 weeks). The DRF Period was to evaluate the safety, tolerability, pharmacokinetivs (PK) and pharmacodynamics (PD) of branaplam, as well as determine the optimal dose(s) to explore in further clinical evaluations. The core period was planned to consist of 3 treatment arms: * Cohort 1: Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly * Cohort 2: Treatment Arm B: branaplam 112 mg oral solution or matching placebo, once weekly * Cohort 3: Treatment Arm C: branaplam 154 mg oral solution or matching placebo, once weekly or Treatment Arm X: branaplam 84 mg oral solution or matching placebo, once weekly or Treatment Arm Y: branaplam 28 mg oral solution or matching placebo, once weekly • The OLE was a one-year open-label extension to assess both long-term safety and tolerability, as well as the efficacy of the recommended optimal dose(s) for branaplam. Due to safety concerns an urgent safety measure (USM) follow-up notification dated 06-Dec-2022 was issued to permanently discontinue the study treatment in all participants. At that point, only cohort 1 was enrolled. Therefore, only cohort 1 data is available for analysis (Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly). Participants who received active treatment (branaplam) were to remain in the study for follow-up for approximately one year following initial treatment discontinuation. The OLE part was not opened.

Interventions

DRUGBranaplam

messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly.

DRUGPlacebo

Matching placebo oral solution once weekly

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

This was a randomized double blind study. Participants were planned to be randomized in an equal randomization rate among the open treatment arms, and then in a 4:1 ratio for active vs. placebo within each arm.

Intervention model description

The study design used a staggered cohort approach, allowing safety and tolerability of lower doses to be assessed before randomizing subjects to higher doses. At the time of the Cohort Gating Assessments (CGAs), all available data was reviewed from a safety and dose finding perspective by an independent Sponsor team to support the decision to open the next cohort. The independent Data Monitoring Committee (DMC) reviewed the data separately. The decision to open a new cohort was planned to be made by the Sponsor in consultation with the DMC.

Eligibility

Sex/Gender

ALL

Age

25 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Signed informed consent must be obtained prior to participation in the study. * Clinically diagnosed Stage 1 or 2 Huntington's disease with a diagnostic confidence level (DCL) = 4 and a United Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) \>8 at screening. * Genetically confirmed Huntington's disease, with presence of ≥40 cytosine-adenineguanine (CAG) repeats in the huntingtin gene. * Male and female participants between 25 to 75 years of age, inclusive, on the day of Informed Consent signature.

Exclusion criteria

* Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless participant received only placebo). * Participants taking medications prohibited by the protocol. * Any medical history, lumbar surgery or condition that would interfere with the ability to complete the protocol specified assessments. * Participant has other severe, acute or chronic medical conditions including unstable psychiatric conditions, or laboratory abnormalities that in the opinion of the Investigator may increase the risk associated with study participation, or that may interfere with the interpretation of the study results. * Any surgical or medical condition which might put the participant at risk in case of participation in the study. The Investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence at the Screening visit.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From first dose of study treatment up to Week 69	Incidence of AEs (any AEs regardless of seriousness) and SAEs, including changes in vital signs, neurological examination, electrocardiograms (ECGs) and laboratory parameters qualifying and reported as AEs. Participants received study treatment up to maximum Week 20 (placebo) and Week 22 (branaplam).
Percentage Change From Baseline to Week 17 in mHTT Protein in CSF	Baseline, Week 17	Mutant Huntingtin (mHTT) protein was measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. The percentage change from baseline to Week 17 in mHTT protein in CSF was calculated with the following formula: (mHTTweek17 - mHTTbaseline)/ mHTTbaseline \* 100. Baseline value for mHTT is the last evaluable measurements prior to the first administration of study drug.

Secondary

Measure	Time frame	Description
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Percentage Change From Baseline in Lateral Ventricles Volume	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Percentage Change From Baseline in Left Caudate Volume	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Percentage Change From Baseline in Right Caudate Volume	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Baseline, Week 17, Week 33 and Week 69	The TFC focuses on the investigator's assessment of the participant's capacity to perform a range of activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. TFC score range from 0 to 13, with higher scores representing better functioning.
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Baseline, Week 17, Week 33 and Week 69	The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. TMS score range from 0 to 124 with higher scores representing more significant impairment.
Concentrations of mHTT Protein and Total HTT in CSF	Baseline, Week 9, Week 17	Mutant Huntingtin (mHTT) protein and total HTT measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. Baseline value is the last evaluable measurement prior to the first administration of study drug.
Concentrations of mHTT Protein and Total HTT in Plasma	Baseline, Week 17	Mutant Huntingtin (mHTT) protein and total HTT measured in plasma. Baseline value is the last evaluable measurement prior to the first administration of study drug.
Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112	pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17	Pharmacokinetic (PK) parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112	pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17	PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.
Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112	pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17	PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-168h calculation.
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Branaplam and Its Metabolite UFB112	pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1	PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method and the regression analysis of the terminal elimination phase were used for AUCinf calculation.
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma	pre-dose at Weeks 2, 3, 5, 9, 13 and 17	Branaplam and its metabolite UFB112 concentrations were determined in plasma. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF	pre-dose at Weeks 9 and 17	Branaplam and its metabolite UFB112 concentrations were determined in cerebrospinal fluid (CSF) obtained via lumbar puncture. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	pre-dose at Weeks 9 and 17	Branaplam and its metabolite UFB112 concentrations were determined plasma and in cerebrospinal fluid (CSF) obtained via lumbar puncture. Concentration ratios CSF/plasma were calculated for subjects for whom CSF and plasma concentrations were available at the respective time point.
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Baseline, Week 17, Week 33 and Week 69	The IS represents the investigator's assessment of the participant's level of independence, including topics of employment, finances, self-care and feeding. The scale has 19 discrete scores, from 10 (tube fed, total bed care) to 100 (no special care needed) with 5-point increments in between.
Percentage Change From Baseline in Total Brain Volume	Baseline, Week 17, Week 33, Week 53, Week 69	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.

Other

Measure	Time frame	Description
Number of Participants With NfL Increase and Recovery	From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum)	Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and serum in case of axonal damage in a variety of neurological disorders. The levels of NfL were determined in serum and CSF and the following 3 categories were defined: * Serum NfL (sNfL) increase: \> 100 pg/mL or \> 2 x baseline (BL) sNfL * sNfL recovery: Worsening criteria are no longer met (sNfL \<= 100 pg/mL or sNfL \<= 2 x BL sNfL) for visits after last visit with increase * CSF NfL increase: \> 10000 pg/mL or \> 2 x BL CSF NfL or \> 2 x CSF NfL of the previous assessment

Countries

Canada, France, Germany, Hungary, Spain

Participant flow

Recruitment details

Participants took part in 12 investigative sites in 5 countries.

Pre-assignment details

The Screening period had a duration of up to 6 weeks. For eligible participants, the baseline measurements were performed within 6 days prior to the first dose of study treatment. At the Week 1 visit in the Core period participants were randomized (4:1) to receive either branaplam or placebo. The last study visit was performed at Week 69. The open label extension (OLE) period was not opened.

Participants by arm

Arm	Count
Placebo Treatment Arm A: matching placebo oral solution once weekly	5
Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly	21
Total	26

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	0	2
Overall Study	Participant decision	1	5
Overall Study	Physician Decision	0	1

Baseline characteristics

Characteristic	Placebo	Branaplam 56 mg	Total
Age, Continuous	52.8 years STANDARD_DEVIATION 15.3	49.6 years STANDARD_DEVIATION 10.06	50.2 years STANDARD_DEVIATION 10.96
Race/Ethnicity, Customized Unknown	0 Participants	3 Participants	3 Participants
Race/Ethnicity, Customized White	5 Participants	18 Participants	23 Participants
Sex: Female, Male Female	1 Participants	10 Participants	11 Participants
Sex: Female, Male Male	4 Participants	11 Participants	15 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 5	0 / 21	0 / 26
other Total, other adverse events	2 / 5	15 / 21	17 / 26
serious Total, serious adverse events	0 / 5	4 / 21	4 / 26

Outcome results

Primary

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Incidence of AEs (any AEs regardless of seriousness) and SAEs, including changes in vital signs, neurological examination, electrocardiograms (ECGs) and laboratory parameters qualifying and reported as AEs. Participants received study treatment up to maximum Week 20 (placebo) and Week 22 (branaplam).

Time frame: From first dose of study treatment up to Week 69

Population: Safety Analysis Set including all participants who received at least one dose of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	AEs	2 Participants
Placebo	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Study drug-related AEs	1 Participants
Placebo	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
Placebo	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Study drug-related SAEs	0 Participants
Branaplam 56 mg	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Study drug-related SAEs	3 Participants
Branaplam 56 mg	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	AEs	18 Participants
Branaplam 56 mg	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	SAEs	4 Participants
Branaplam 56 mg	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Study drug-related AEs	14 Participants

Primary

Percentage Change From Baseline to Week 17 in mHTT Protein in CSF

Mutant Huntingtin (mHTT) protein was measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. The percentage change from baseline to Week 17 in mHTT protein in CSF was calculated with the following formula: (mHTTweek17 - mHTTbaseline)/ mHTTbaseline \* 100. Baseline value for mHTT is the last evaluable measurements prior to the first administration of study drug.

Time frame: Baseline, Week 17

Population: Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and Week 17. SAF included all participants who received at least one dose of study drug.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Percentage Change From Baseline to Week 17 in mHTT Protein in CSF	-1.38 % change in mHTT protein	Standard Deviation 20.517
Branaplam 56 mg	Percentage Change From Baseline to Week 17 in mHTT Protein in CSF	-26.61 % change in mHTT protein	Standard Deviation 22.354

Secondary

Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112

PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-168h calculation.

Time frame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17

Population: Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and includes all participants with at least one evaluable concentration data sample.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112	Branaplam - Week 1	1880 hr*ng/mL	Standard Deviation 368
Placebo	Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112	Branaplam - Week 17	3190 hr*ng/mL	Standard Deviation 455
Placebo	Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112	UFB112 - Week 1	3670 hr*ng/mL	Standard Deviation 1560
Placebo	Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112	UFB112 - Week 17	5640 hr*ng/mL	Standard Deviation 2750

Secondary

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Branaplam and Its Metabolite UFB112

PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method and the regression analysis of the terminal elimination phase were used for AUCinf calculation.

Time frame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Branaplam and Its Metabolite UFB112	Branaplam - Week 1	2270 hr*ng/mL	Standard Deviation 467
Placebo	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Branaplam and Its Metabolite UFB112	UFB112 - Week 1	3530 hr*ng/mL	—

Secondary

Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)

The IS represents the investigator's assessment of the participant's level of independence, including topics of employment, finances, self-care and feeding. The scale has 19 discrete scores, from 10 (tube fed, total bed care) to 100 (no special care needed) with 5-point increments in between.

Time frame: Baseline, Week 17, Week 33 and Week 69

Population: Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Week 17	-1.0 score on scale	Standard Deviation 11.4
Placebo	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Week 33	1.3 score on scale	Standard Deviation 16.52
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Week 17	-1.8 score on scale	Standard Deviation 9.16
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Week 33	-4.7 score on scale	Standard Deviation 8.19
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Week 69	-6.5 score on scale	Standard Deviation 13.29

Secondary

Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)

The TFC focuses on the investigator's assessment of the participant's capacity to perform a range of activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. TFC score range from 0 to 13, with higher scores representing better functioning.

Time frame: Baseline, Week 17, Week 33 and Week 69

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Week 17	-1.0 score on scale	Standard Deviation 2.35
Placebo	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Week 33	-0.5 score on scale	Standard Deviation 2.52
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Week 17	-0.8 score on scale	Standard Deviation 2.39
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Week 33	-1.3 score on scale	Standard Deviation 2.31
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Week 69	-1.2 score on scale	Standard Deviation 2.94

Secondary

Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)

The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. TMS score range from 0 to 124 with higher scores representing more significant impairment.

Time frame: Baseline, Week 17, Week 33 and Week 69

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Week 17	6.0 score on scale	Standard Deviation 11.29
Placebo	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Week 33	2.5 score on scale	Standard Deviation 10.34
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Week 17	5.1 score on scale	Standard Deviation 9.14
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Week 33	2.6 score on scale	Standard Deviation 8.83
Branaplam 56 mg	Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Week 69	3.6 score on scale	Standard Deviation 8.99

Secondary

Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112

Branaplam and its metabolite UFB112 concentrations were determined plasma and in cerebrospinal fluid (CSF) obtained via lumbar puncture. Concentration ratios CSF/plasma were calculated for subjects for whom CSF and plasma concentrations were available at the respective time point.

Time frame: pre-dose at Weeks 9 and 17

Population: Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and included all participants with at least one evaluable concentration data sample.

Arm	Measure	Group	Value (MEAN)
Placebo	Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	UFB112 - Week 9	0.0141 concentration ratio
Placebo	Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	Branaplam - Week 9	0.115 concentration ratio
Placebo	Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	Branaplam - Week 17	0.0864 concentration ratio
Placebo	Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	UFB112 - Week 17	0.0161 concentration ratio

Secondary

Concentrations of mHTT Protein and Total HTT in CSF

Mutant Huntingtin (mHTT) protein and total HTT measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. Baseline value is the last evaluable measurement prior to the first administration of study drug.

Time frame: Baseline, Week 9, Week 17

Population: Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at the corresponding study visit. SAF included all participants who received at least one dose of study drug.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Concentrations of mHTT Protein and Total HTT in CSF	mHTT - Week 9	86.31 fmol	Standard Deviation 43.265
Placebo	Concentrations of mHTT Protein and Total HTT in CSF	Total HTT - Baseline	NA fmol	—
Placebo	Concentrations of mHTT Protein and Total HTT in CSF	mHTT - Baseline	86.14 fmol	Standard Deviation 35.59
Placebo	Concentrations of mHTT Protein and Total HTT in CSF	Total HTT - Week 9	NA fmol	—
Placebo	Concentrations of mHTT Protein and Total HTT in CSF	mHTT - Week 17	77.68 fmol	Standard Deviation 33.077
Placebo	Concentrations of mHTT Protein and Total HTT in CSF	Total HTT - Week 17	NA fmol	—
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in CSF	Total HTT - Week 17	NA fmol	—
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in CSF	mHTT - Baseline	102.03 fmol	Standard Deviation 48.533
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in CSF	mHTT - Week 9	74.68 fmol	Standard Deviation 37.111
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in CSF	mHTT - Week 17	65.58 fmol	Standard Deviation 41.152
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in CSF	Total HTT - Baseline	NA fmol	—
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in CSF	Total HTT - Week 9	NA fmol	—

Secondary

Concentrations of mHTT Protein and Total HTT in Plasma

Mutant Huntingtin (mHTT) protein and total HTT measured in plasma. Baseline value is the last evaluable measurement prior to the first administration of study drug.

Time frame: Baseline, Week 17

Population: Safety Analysis Set (SAF)

Arm	Measure	Group	Value (MEAN)
Placebo	Concentrations of mHTT Protein and Total HTT in Plasma	mHTT - Baseline	NA fmol
Placebo	Concentrations of mHTT Protein and Total HTT in Plasma	mHTT - Week 17	NA fmol
Placebo	Concentrations of mHTT Protein and Total HTT in Plasma	Total HTT - Baseline	NA fmol
Placebo	Concentrations of mHTT Protein and Total HTT in Plasma	Total HTT - Week 17	NA fmol
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in Plasma	Total HTT - Week 17	NA fmol
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in Plasma	mHTT - Baseline	NA fmol
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in Plasma	Total HTT - Baseline	NA fmol
Branaplam 56 mg	Concentrations of mHTT Protein and Total HTT in Plasma	mHTT - Week 17	NA fmol

Secondary

Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112

Pharmacokinetic (PK) parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.

Time frame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112	Branaplam - Week 1	26.1 ng/mL	Standard Deviation 7.99
Placebo	Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112	Branaplam - Week 17	45.3 ng/mL	Standard Deviation 7.96
Placebo	Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112	UFB112 - Week 1	31.9 ng/mL	Standard Deviation 12.6
Placebo	Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112	UFB112 - Week 17	53.3 ng/mL	Standard Deviation 20.4

Secondary

Percentage Change From Baseline in Lateral Ventricles Volume

Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.