Trial Outcomes & Findings for A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease (NCT NCT05111249)

NCT ID: NCT05111249

Last Updated: 2025-05-16

Results Overview

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.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 26 participants
• Primary outcome timeframe: Baseline, Week 17
• Results posted on: 2025-05-16

Participant Flow

Participants took part in 12 investigative sites in 5 countries.

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.

Participant milestones

Measure	Placebo Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Overall Study STARTED	5	21
Overall Study COMPLETED	4	13
Overall Study NOT COMPLETED	1	8

Reasons for withdrawal

Measure	Placebo Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Overall Study Lost to Follow-up	0	2
Overall Study Physician Decision	0	1
Overall Study Participant decision	1	5

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly	Total n=26 Participants Total of all reporting groups
Age, Continuous	52.8 years STANDARD_DEVIATION 15.30 • n=5 Participants	49.6 years STANDARD_DEVIATION 10.06 • n=7 Participants	50.2 years STANDARD_DEVIATION 10.96 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	10 Participants n=7 Participants	11 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	11 Participants n=7 Participants	15 Participants n=5 Participants
Race/Ethnicity, Customized White	5 Participants n=5 Participants	18 Participants n=7 Participants	23 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=4 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=9 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline to Week 17 in mHTT Protein in CSF	-1.38 % change in mHTT protein Standard Deviation 20.517	-26.61 % change in mHTT protein Standard Deviation 22.354

PRIMARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	2 Participants	18 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Study drug-related AEs	1 Participants	14 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	0 Participants	4 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Study drug-related SAEs	0 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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.

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.

Outcome measures

Measure	Placebo n=4 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=17 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Total Brain Volume Week 17	-0.20 % change in total brain volume Standard Deviation 0.332	-0.43 % change in total brain volume Standard Deviation 2.362
Percentage Change From Baseline in Total Brain Volume Week 33	-0.67 % change in total brain volume Standard Deviation 0.352	-0.88 % change in total brain volume Standard Deviation 0.681
Percentage Change From Baseline in Total Brain Volume Week 53	-0.25 % change in total brain volume	-1.34 % change in total brain volume Standard Deviation 0.848
Percentage Change From Baseline in Total Brain Volume Week 69	—	-1.63 % change in total brain volume Standard Deviation 0.877

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Placebo n=4 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=15 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma Week 17	-0.20 % change in total brain volume Standard Deviation 0.332	-1.09 % change in total brain volume Standard Deviation 0.599
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma Week 33	-0.67 % change in total brain volume Standard Deviation 0.352	-0.80 % change in total brain volume Standard Deviation 0.675
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma Week 53	-0.25 % change in total brain volume	-1.30 % change in total brain volume Standard Deviation 0.748
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma Week 69	—	-1.68 % change in total brain volume Standard Deviation 0.751

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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.

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.

Outcome measures

Measure	Placebo n=3 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=17 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Lateral Ventricles Volume Week 17	1.63 % change in lateral ventricles volume Standard Deviation 1.392	8.84 % change in lateral ventricles volume Standard Deviation 11.599
Percentage Change From Baseline in Lateral Ventricles Volume Week 33	5.51 % change in lateral ventricles volume Standard Deviation 1.772	11.73 % change in lateral ventricles volume Standard Deviation 9.799
Percentage Change From Baseline in Lateral Ventricles Volume Week 53	3.43 % change in lateral ventricles volume	15.77 % change in lateral ventricles volume Standard Deviation 10.842
Percentage Change From Baseline in Lateral Ventricles Volume Week 69	—	17.40 % change in lateral ventricles volume Standard Deviation 10.182

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Placebo n=3 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=15 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma Week 17	1.63 % change in lateral ventricles volume Standard Deviation 1.392	9.47 % change in lateral ventricles volume Standard Deviation 6.061
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma Week 33	5.51 % change in lateral ventricles volume Standard Deviation 1.772	9.43 % change in lateral ventricles volume Standard Deviation 5.673
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma Week 53	3.43 % change in lateral ventricles volume	12.38 % change in lateral ventricles volume Standard Deviation 6.193
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma Week 69	—	14.45 % change in lateral ventricles volume Standard Deviation 6.040

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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.

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.

Outcome measures

Measure	Placebo n=4 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=17 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Left Caudate Volume Week 17	-0.93 % change in left caudate volume Standard Deviation 3.782	-4.44 % change in left caudate volume Standard Deviation 3.005
Percentage Change From Baseline in Left Caudate Volume Week 33	-3.95 % change in left caudate volume Standard Deviation 2.147	-4.30 % change in left caudate volume Standard Deviation 3.331
Percentage Change From Baseline in Left Caudate Volume Week 53	-2.69 % change in left caudate volume	-6.33 % change in left caudate volume Standard Deviation 4.417
Percentage Change From Baseline in Left Caudate Volume Week 69	—	-5.44 % change in left caudate volume Standard Deviation 7.864

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Placebo n=4 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=15 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma Week 17	-0.93 % change in left caudate volume Standard Deviation 3.782	-4.14 % change in left caudate volume Standard Deviation 2.300
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma Week 33	-3.95 % change in left caudate volume Standard Deviation 2.147	-3.58 % change in left caudate volume Standard Deviation 2.692
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma Week 53	-2.69 % change in left caudate volume	-6.24 % change in left caudate volume Standard Deviation 4.788
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma Week 69	—	-4.81 % change in left caudate volume Standard Deviation 8.351

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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.

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.

Outcome measures

Measure	Placebo n=3 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=17 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Right Caudate Volume Week 17	-3.28 % change in right caudate volume Standard Deviation 3.496	-2.79 % change in right caudate volume Standard Deviation 4.604
Percentage Change From Baseline in Right Caudate Volume Week 33	-6.91 % change in right caudate volume Standard Deviation 1.895	-4.11 % change in right caudate volume Standard Deviation 4.146
Percentage Change From Baseline in Right Caudate Volume Week 53	-5.34 % change in right caudate volume	-6.81 % change in right caudate volume Standard Deviation 4.251
Percentage Change From Baseline in Right Caudate Volume Week 69	—	-6.34 % change in right caudate volume Standard Deviation 6.934

SECONDARY outcome

Timeframe: Baseline, Week 17, Week 33, Week 53, 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, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Placebo n=3 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=15 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma Week 17	-3.28 % change in right caudate volume Standard Deviation 3.496	-2.67 % change in right caudate volume Standard Deviation 4.850
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma Week 33	-6.91 % change in right caudate volume Standard Deviation 1.895	-3.23 % change in right caudate volume Standard Deviation 3.437
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma Week 53	-5.34 % change in right caudate volume	-6.57 % change in right caudate volume Standard Deviation 4.418
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma Week 69	—	-5.60 % change in right caudate volume Standard Deviation 7.249

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=19 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
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	-0.8 score on scale Standard Deviation 2.39
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	-1.3 score on scale Standard Deviation 2.31
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 outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=19 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
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	5.1 score on scale Standard Deviation 9.14
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	2.6 score on scale Standard Deviation 8.83
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 outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=19 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS) Week 17	-1.0 score on scale Standard Deviation 11.40	-1.8 score on scale Standard Deviation 9.16
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	-4.7 score on scale Standard Deviation 8.19
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 outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Concentrations of mHTT Protein and Total HTT in CSF mHTT - Baseline	86.14 fmol Standard Deviation 35.590	102.03 fmol Standard Deviation 48.533
Concentrations of mHTT Protein and Total HTT in CSF mHTT - Week 9	86.31 fmol Standard Deviation 43.265	74.68 fmol Standard Deviation 37.111
Concentrations of mHTT Protein and Total HTT in CSF mHTT - Week 17	77.68 fmol Standard Deviation 33.077	65.58 fmol Standard Deviation 41.152
Concentrations of mHTT Protein and Total HTT in CSF Total HTT - Baseline	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in CSF.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in CSF.
Concentrations of mHTT Protein and Total HTT in CSF Total HTT - Week 9	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in CSF.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in CSF.
Concentrations of mHTT Protein and Total HTT in CSF Total HTT - Week 17	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in CSF.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in CSF.

SECONDARY outcome

Timeframe: Baseline, Week 17

Population: Safety Analysis Set (SAF)

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.

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Concentrations of mHTT Protein and Total HTT in Plasma mHTT - Baseline	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of mHTT protein in plasma.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of mHTT protein in plasma.
Concentrations of mHTT Protein and Total HTT in Plasma mHTT - Week 17	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of mHTT protein in plasma.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of mHTT protein in plasma.
Concentrations of mHTT Protein and Total HTT in Plasma Total HTT - Baseline	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in plasma.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in plasma.
Concentrations of mHTT Protein and Total HTT in Plasma Total HTT - Week 17	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in plasma.	NA fmol Standard Deviation NA Assay issues did not allow a reliable quantification of total HTT in plasma.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=21 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112 Branaplam - Week 1	26.1 ng/mL Standard Deviation 7.99	—
Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112 Branaplam - Week 17	45.3 ng/mL Standard Deviation 7.96	—
Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112 UFB112 - Week 1	31.9 ng/mL Standard Deviation 12.6	—
Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112 UFB112 - Week 17	53.3 ng/mL Standard Deviation 20.4	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=21 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112 Branaplam - Week 1	7.00 hours Interval 3.77 to 23.0	—
Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112 Branaplam - Week 17	4.18 hours Interval 4.0 to 7.0	—
Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112 UFB112 - Week 1	7.00 hours Interval 4.0 to 72.0	—
Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112 UFB112 - Week 17	14.5 hours Interval 4.28 to 22.0	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=21 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
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	—
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	—
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	—
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 outcome

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

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.

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.

Outcome measures

Measure	Placebo n=21 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
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	—
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 outcome

Timeframe: pre-dose at Weeks 2, 3, 5, 9, 13 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.

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.

Outcome measures

Measure	Placebo n=20 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma UFB112 - Week 13	18.5 ng/mL Standard Deviation 8.71	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma Branaplam - Week 2	4.10 ng/mL Standard Deviation 1.29	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma Branaplam - Week 3	6.54 ng/mL Standard Deviation 1.78	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma Branaplam - Week 5	8.50 ng/mL Standard Deviation 3.20	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma Branaplam - Week 9	7.85 ng/mL Standard Deviation 2.12	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma Branaplam - Week 13	8.54 ng/mL Standard Deviation 2.27	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma Branaplam - Week 17	7.88 ng/mL Standard Deviation 2.11	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma UFB112 - Week 2	12.1 ng/mL Standard Deviation 6.22	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma UFB112 - Week 3	18.0 ng/mL Standard Deviation 8.25	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma UFB112 - Week 5	21.9 ng/mL Standard Deviation 11.5	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma UFB112 - Week 9	21.2 ng/mL Standard Deviation 11.5	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma UFB112 - Week 17	16.1 ng/mL Standard Deviation 5.33	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=12 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF Branaplam - Week 9	0.870 ng/mL Standard Deviation 0.311	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF Branaplam - Week 17	0.602 ng/mL Standard Deviation 0.355	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF UFB112 - Week 9	0.269 ng/mL Standard Deviation 0.184	—
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF UFB112 - Week 17	0.230 ng/mL Standard Deviation 0.154	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=11 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg Treatment Arm A: branaplam 56 mg oral solution once weekly
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112 Branaplam - Week 9	0.115 concentration ratio Standard Deviation NA In alignment with the secondary endpoints defined in the protocol, the statistical analysis plan (SAP) included only the calculation of the mean concentration ratio CSF/plasma. Therefore, no dispersion values were derived.	—
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112 Branaplam - Week 17	0.0864 concentration ratio Standard Deviation NA In alignment with the secondary endpoints defined in the protocol, the statistical analysis plan (SAP) included only the calculation of the mean concentration ratio CSF/plasma. Therefore, no dispersion values were derived.	—
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112 UFB112 - Week 9	0.0141 concentration ratio Standard Deviation NA In alignment with the secondary endpoints defined in the protocol, the statistical analysis plan (SAP) included only the calculation of the mean concentration ratio CSF/plasma. Therefore, no dispersion values were derived.	—
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112 UFB112 - Week 17	0.0161 concentration ratio Standard Deviation NA In alignment with the secondary endpoints defined in the protocol, the statistical analysis plan (SAP) included only the calculation of the mean concentration ratio CSF/plasma. Therefore, no dispersion values were derived.	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum)

Population: Safety Analysis Set including all participants who received at least one dose of study drug. sNfL recovery was assessed in participants meeting the criterion for sNfL increase.

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

Outcome measures

Measure	Placebo n=5 Participants Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 Participants Treatment Arm A: branaplam 56 mg oral solution once weekly
Number of Participants With NfL Increase and Recovery sNfL increase	0 Participants	16 Participants
Number of Participants With NfL Increase and Recovery sNfL recovery	0 Participants	14 Participants
Number of Participants With NfL Increase and Recovery CSF NfL increase	0 Participants	13 Participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Branaplam 56 mg

Serious events: 4 serious events

Other events: 15 other events

Deaths: 0 deaths

Overall

Serious events: 4 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=5 participants at risk Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 participants at risk Treatment Arm A: branaplam 56 mg oral solution once weekly	Overall n=26 participants at risk All participants
Infections and infestations Vestibular neuronitis	0.00% 0/5 • From first dose of study treatment up to Week 69	4.8% 1/21 • From first dose of study treatment up to Week 69	3.8% 1/26 • From first dose of study treatment up to Week 69
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Reproductive system and breast disorders Uterine polyp	0.00% 0/5 • From first dose of study treatment up to Week 69	4.8% 1/21 • From first dose of study treatment up to Week 69	3.8% 1/26 • From first dose of study treatment up to Week 69

Other adverse events

Measure	Placebo n=5 participants at risk Treatment Arm A: matching placebo oral solution once weekly	Branaplam 56 mg n=21 participants at risk Treatment Arm A: branaplam 56 mg oral solution once weekly	Overall n=26 participants at risk All participants
Blood and lymphatic system disorders Anaemia	20.0% 1/5 • From first dose of study treatment up to Week 69	19.0% 4/21 • From first dose of study treatment up to Week 69	19.2% 5/26 • From first dose of study treatment up to Week 69
Blood and lymphatic system disorders Thrombocytosis	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Gastrointestinal disorders Diarrhoea	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
General disorders Puncture site pain	0.00% 0/5 • From first dose of study treatment up to Week 69	14.3% 3/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Infections and infestations COVID-19	20.0% 1/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Infections and infestations Cystitis	0.00% 0/5 • From first dose of study treatment up to Week 69	14.3% 3/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Infections and infestations Urinary tract infection	0.00% 0/5 • From first dose of study treatment up to Week 69	14.3% 3/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Injury, poisoning and procedural complications Head injury	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Nervous system disorders Balance disorder	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Nervous system disorders Headache	20.0% 1/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Nervous system disorders Neuropathy peripheral	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Nervous system disorders Paraesthesia	20.0% 1/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Nervous system disorders Polyneuropathy	0.00% 0/5 • From first dose of study treatment up to Week 69	14.3% 3/21 • From first dose of study treatment up to Week 69	11.5% 3/26 • From first dose of study treatment up to Week 69
Psychiatric disorders Delusional disorder, persecutory type	20.0% 1/5 • From first dose of study treatment up to Week 69	0.00% 0/21 • From first dose of study treatment up to Week 69	3.8% 1/26 • From first dose of study treatment up to Week 69
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/5 • From first dose of study treatment up to Week 69	9.5% 2/21 • From first dose of study treatment up to Week 69	7.7% 2/26 • From first dose of study treatment up to Week 69
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	20.0% 1/5 • From first dose of study treatment up to Week 69	0.00% 0/21 • From first dose of study treatment up to Week 69	3.8% 1/26 • From first dose of study treatment up to Week 69

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: Novartis.email@novartis.com

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
• Publication restrictions are in place

Restriction type: OTHER