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Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients with Huntington’s Disease

Summary
EudraCT number	2016-005095-10
Trial protocol	GB DK FR DE
Global end of trial date	11 May 2021

Results information
Results version number	v1(current)
This version publication date	04 Feb 2022
First version publication date	04 Feb 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

WVE-HDSNP1-001

ISRCTN number

US NCT number

NCT03225833

WHO universal trial number (UTN)

Sponsor organisation name

Wave Life Sciences UK Limited

Sponsor organisation address

1 Chamberlain Square CS, Birmingham, United Kingdom, B3 3AX

Public contact

Chief Medical Officer, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com

Scientific contact

Chief Medical Officer, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 May 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 May 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the safety and tolerability of WVE-120101 in patients with early manifest Huntington’s disease (HD).

Protection of trial subjects

The study was conducted according to the study protocol and standard operating procedures that meet the guidelines provided by the International Conference on Harmonisation for Good Clinical Practice in clinical studies, and any other applicable local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Dec 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 17

Country: Number of subjects enrolled

Canada: 12

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Poland: 19

Country: Number of subjects enrolled

United Kingdom: 3

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This Phase 1b/2a placebo-controlled study was conducted in adult patients with early manifest HD who carry a targeted single nucleotide polymorphism rs362307. Following completion of this study, eligible patients were enrolled in an open-label extension study (WVE-HDSNP1-002).

Screening details

The study consists of prescreening period (at least 6 weeks), screening period (up to 4 weeks), single-dose period (1 day) followed by multiple-dose period (8 weeks), and follow-up period (14 weeks). A total of 61 patients received treatment in this study.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Pooled Placebo

Arm description

Placebo: 0.9% Sodium Chloride.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Placebo matching with WVE-120101 was administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

WVE-120101 (2 milligram [mg])

Arm description

WVE-120101: WVE-120101 is a stereopure antisense oligonucleotide (ASO).

Arm type

Experimental

Investigational medicinal product name

WVE-120101

Investigational medicinal product code

WVE-120101

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-120101 2 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

WVE-120101 (4 mg)

Arm description

WVE-120101: WVE-120101 is a stereopure ASO.

Arm type

Experimental

Investigational medicinal product name

WVE-120101

Investigational medicinal product code

WVE-120101

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-120101 4 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

WVE-120101 (8 mg)

Arm description

WVE-120101: WVE-120101 is a stereopure ASO.

Arm type

Experimental

Investigational medicinal product name

WVE-120101

Investigational medicinal product code

WVE-120101

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-120101 8 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

WVE-120101 (16 mg)

Arm description

WVE-120101: WVE-120101 is a stereopure ASO.

Arm type

Experimental

Investigational medicinal product name

WVE-120101

Investigational medicinal product code

WVE-120101

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-120101 16 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

WVE-120101 (32 mg)

Arm description

WVE-120101: WVE-120101 is a stereopure ASO.

Arm type

Experimental

Investigational medicinal product name

WVE-120101

Investigational medicinal product code

WVE-120101

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-120101 32 mg administered via intrathecal injection on Day 1 in single-dose phase followed by once every 4 weeks for a period of 8 weeks in multiple-dose phase.

Number of subjects in period 1	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Started	16	9	9	9	8	10
Single Dose Period Only	1 ^[1]	1 ^[2]	2 ^[3]	0 ^[4]	0 ^[5]	4
Multiple Dose Period Only	0 ^[6]	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	1
Single Dose and Multiple Dose Periods	15	8	7	9	8	5
Completed	11	8	7	9	7	0
Not completed	5	1	2	0	1	10
Consent withdrawn by subject	1	-	-	-	1	-
Adverse event, non-fatal	-	1	2	-	-	2
Sponsor Decision	-	-	-	-	-	1
Termination of Study by Sponsor	4	-	-	-	-	7

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.
[10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Patients treated in single dose period only, multiple dose period only and both single dose and multiple dose periods in each reporting group are presented in separate milestones.

Baseline characteristics

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Reporting group title

Pooled Placebo

Reporting group description

Placebo: 0.9% Sodium Chloride.

Reporting group title

WVE-120101 (2 milligram [mg])

Reporting group description

WVE-120101: WVE-120101 is a stereopure antisense oligonucleotide (ASO).

Reporting group title

WVE-120101 (4 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (8 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (16 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (32 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)	Total
Number of subjects	16	9	9	9	8	10	61
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	15	9	9	9	8	10	60
From 65-84 years	1	0	0	0	0	0	1
85 years and over	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	7	3	5	6	1	7	29
Male	9	6	4	3	7	3	32
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0	0
Not Hispanic or Latino	16	9	9	9	8	10	61
Unknown or Not Reported	0	0	0	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0
White	16	9	9	9	8	10	61
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0
Region of Enrollment
Units: Subjects
Australia	4	0	0	6	3	4	17
Canada	4	2	2	1	0	3	12
Denmark	0	0	0	1	1	0	2
France	1	0	0	0	1	2	4
Germany	2	0	0	0	1	1	4
Poland	4	7	5	1	2	0	19
United Kingdom	1	0	2	0	0	0	3
Diagnosis Stage
Units: Subjects
Stage 1	9	7	3	3	4	7	33
Stage 2	7	2	6	6	4	3	28
Time since initial diagnosis
Units: years
arithmetic mean (standard deviation)	7 ± 6.93	4.9 ± 4.28	3.4 ± 6.37	3.2 ± 3.03	6.6 ± 6.09	8.7 ± 7.26	-
Age at Disease Onset
Units: years
arithmetic mean (standard deviation)	40.75 ± 11.079	37.33 ± 7.826	42.89 ± 9.280	46.11 ± 6.254	44.88 ± 12.495	44.60 ± 10.865	-

End points

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Reporting group title

Pooled Placebo

Reporting group description

Placebo: 0.9% Sodium Chloride.

Reporting group title

WVE-120101 (2 milligram [mg])

Reporting group description

WVE-120101: WVE-120101 is a stereopure antisense oligonucleotide (ASO).

Reporting group title

WVE-120101 (4 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (8 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (16 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (32 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Primary: Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs)

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End point title

Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs) ^[1]

End point description

All TEAEs reported or observed during the study, including TEAEs resulting from concurrent illnesses, reactions to concurrent medications, or progression of disease states. Safety population included all patients who received at least 1 dose of WVE-120101 or placebo. A summary of serious and all other non-serious adverse events (AEs), regardless of causality, is located in the reported AEs module.

End point type

Primary

End point timeframe

Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analysis was performed for the primary end point.

End point values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	16	9	9	9	8	10
Units: patients	12	8	8	9	7	9

No statistical analyses for this end point

Primary: Safety: Number of Patients With Severe TEAEs

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End point title

Safety: Number of Patients With Severe TEAEs ^[2]

End point description

Severity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Safety population included all patients who received at least 1 dose of WVE-120101 or placebo. A summary of serious and all other non-serious AEs, regardless of causality, is located in the reported AEs module.

End point type

Primary

End point timeframe

Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analysis was performed for the primary end point.

End point values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	16	9	9	9	8	10
Units: patients	1	2	1	1	0	5

No statistical analyses for this end point

Primary: Safety: Number of Patients With Serious TEAEs

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End point title

Safety: Number of Patients With Serious TEAEs ^[3]

End point description

A serious TEAE is defined as any event that results in death, is immediately life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect not present at prescreening. Safety population included all patients who received at least 1 dose of WVE-120101 or placebo. A summary of serious and all other non-serious AEs, regardless of causality, is located in the reported AEs module.

End point type

Primary

End point timeframe

Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analysis was performed for the primary end point.

End point values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	16	9	9	9	8	10
Units: patients	0	2	1	0	0	4

No statistical analyses for this end point

Primary: Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs

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End point title

Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs ^[4]

End point description

Patients withdraw from the study when serious or intolerable AE that in the Investigator’s opinion was reported. Safety population included all patients who received at least 1 dose of WVE-120101 or placebo. A summary of serious and all other non-serious AEs, regardless of causality, is located in the reported AEs module.

End point type

Primary

End point timeframe

Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analysis was performed for the primary end point.

End point values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	16	9	9	9	8	10
Units: patients	0	1	2	0	0	2

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)

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End point title

Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) ^[5]

End point description

Cmax of WVE-120101 in plasma. The PK population included all treated patients in the safety population with at least 1 post-dose plasma or cerebrospinal fluid (CSF) WVE-120101 concentration measurement. Here, n= number of patients analyzed at specific timepoint and '99999'= not applicable as no patient was analyzed.

End point type

Secondary

End point timeframe

Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only reporting groups in which patients received WVE-120101 were evaluated for this PK end point.

End point values	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	9	9	9	8	10
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Day 1 (n= 9, 9, 9, 8, 10)	7.70 ± 7.901	23.54 ± 18.139	32.82 ± 22.964	184.48 ± 209.470	229.01 ± 168.330
Day 112 (n= 9, 4, 0, 0, 0)	13.296 ± 6.057	14.27 ± 12.574	99999 ± 99999	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Secondary: PK: Time of Occurrence of Cmax (Tmax)

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End point title

PK: Time of Occurrence of Cmax (Tmax) ^[6]

End point description

Tmax of WVE-120101 in plasma. The PK population included all treated patients in the safety population with at least 1 post-dose plasma or CSF WVE-120101 concentration measurement. Here, n= number of patients analyzed at specific timepoint and '99999'= not applicable as no patient was analyzed.

End point type

Secondary

End point timeframe

Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only reporting groups in which patients received WVE-120101 were evaluated for this PK end point.

End point values	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	9	9	9	8	10
Units: hour
arithmetic mean (standard deviation)
Day 1 (n= 9, 9, 9, 8, 10)	1.34 ± 1.103	1.58 ± 1.081	2.66 ± 1.391	2.71 ± 3.068	4.61 ± 7.054
Day 112 (n= 9, 4, 0, 0, 0)	1.99 ± 0.934	2.23 ± 1.175	99999 ± 99999	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Secondary: PK: Area Under the Plasma Concentration-time Curve (AUClast)

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End point title

PK: Area Under the Plasma Concentration-time Curve (AUClast) ^[7]

End point description

AUClast from time 0 to the last quantifiable concentration of WVE-120101 in plasma. The PK population included all treated patients in the safety population with at least 1 post-dose plasma or CSF WVE-120101 concentration measurement. Here, n= number of patients analyzed at specific timepoint and '99999'= not applicable as no patient was analyzed.

End point type

Secondary

End point timeframe

Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only reporting groups in which patients received WVE-120101 were evaluated for this PK end point.

End point values	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	9	9	9	8	10
Units: hour*ng/mL
arithmetic mean (standard deviation)
Day 1 (n= 5, 8, 8, 8, 9)	35.20 ± 16.037	90.77 ± 50.672	255.14 ± 98.342	1133.74 ± 551.997	1968.31 ± 1188.173
Day 112 (n= 8, 3, 0, 0, 0)	36.19 ± 20.135	49.54 ± 34.735	99999 ± 99999	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Secondary: PK: Terminal Elimination Rate Constant

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End point title

PK: Terminal Elimination Rate Constant ^[8]

End point description

Elimination rate of WVE-120101 from plasma (t1/2). The PK population included all treated patients in the safety population with at least 1 post-dose plasma or CSF WVE-120101 concentration measurement.

End point type

Secondary

End point timeframe

Day 1 up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only reporting groups in which patients received WVE-120101 were evaluated for this PK end point.

End point values	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	0 ^[9]	0 ^[10]	9	8	10
Units: hour
median (full range (min-max))	( to )	( to )	8.12 (7.1 to 40.0)	12.30 (6.9 to 25.5)	14.38 (5.5 to 46.9)

Notes
[9] - No patients were analyzed for this endpoint.
[10] - No patients were analyzed for this endpoint.

No statistical analyses for this end point

Secondary: Pharmacodymanics: Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

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End point title

Pharmacodymanics: Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

End point description

Percent change from baseline in concentration of mHTT protein in CSF was determined. Safety population included all patients who received at least 1 dose of WVE-120101 or placebo.

End point type

Secondary

End point timeframe

Baseline (Day 1) and last observation (up to Day 140 [32 mg cohort] or Day 196 [all other cohorts])

End point values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	16	9	9	9	8	10
Units: percent change
median (inter-quartile range (Q1-Q3))	-6.62 (-16.76 to 7.73)	-5.20 (-10.94 to 0.15)	-12.33 (-19.81 to 9.63)	-8.58 (-11.92 to -1.79)	-11.73 (-20.44 to 3.37)	-9.13 (-37.51 to 15.29)

No statistical analyses for this end point

Secondary: Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

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End point title

Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

End point description

Percent change from baseline in the TFC, administered as part of the Unified Huntington's Disease Rating Scale was determined. Safety population included all patients who received at least 1 dose of WVE-120101 or placebo.

End point type

Secondary

End point timeframe

Baseline (Day 1) and last observation (up to Day 140 [32 mg cohort] or Day 196 [all other cohorts])

End point values	Pooled Placebo	WVE-120101 (2 milligram [mg])	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Number of subjects analysed	16	9	9	9	8	10
Units: percent change
median (inter-quartile range (Q1-Q3))	0.00 (-9.09 to 0.00)	0.00 (-4.17 to 9.09)	0.00 (-7.69 to 11.11)	0.00 (-20.00 to 0.00)	4.17 (-3.85 to 10.42)	0.00 (0.00 to 0.00)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 to end of study (Day 182 [32 mg cohort in all regions except Canada] or Day 196 [32 mg cohort in Canada] or Day 210 [all other cohorts]).

Adverse event reporting additional description

Safety population included all patients who received at least 1 dose of WVE-120101 or placebo.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

8.2

Reporting group title

Pooled Placebo

Reporting group description

Placebo: 0.9% Sodium Chloride.

Reporting group title

WVE-120101 (2 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (4 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (8 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (16 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Reporting group title

WVE-120101 (32 mg)

Reporting group description

WVE-120101: WVE-120101 is a stereopure ASO.

Serious adverse events	Pooled Placebo	WVE-120101 (2 mg)	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 16 (0.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	4 / 10 (40.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull Fracture
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Agitation
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pooled Placebo	WVE-120101 (2 mg)	WVE-120101 (4 mg)	WVE-120101 (8 mg)	WVE-120101 (16 mg)	WVE-120101 (32 mg)
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 16 (75.00%)	8 / 9 (88.89%)	8 / 9 (88.89%)	9 / 9 (100.00%)	7 / 8 (87.50%)	9 / 10 (90.00%)
Vascular disorders
Flushing
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Hot flush
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Hypertension
subjects affected / exposed	1 / 16 (6.25%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0	0
Hypotension
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	1
General disorders and administration site conditions
Administration site bruise
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Administration site pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Asthenia
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Fatigue
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	4	0	0	0	0	2
Gait disturbance
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	0	3
Influenza like illness
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Injection site pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Puncture site haemorrhage
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Vessel puncture site bruise
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Vessel puncture site pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Rhinorrhea
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Psychiatric disorders
Affect lability
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Anxiety
subjects affected / exposed	2 / 16 (12.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	3	0	0	1	1	0
Bradyphrenia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Delirium
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Depression
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Depression suicidal
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Emotional disorder
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Insomnia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Irritability
subjects affected / exposed	1 / 16 (6.25%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	1	0
Restlessness
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Investigations
Blood bilirubin increased
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 8 (12.50%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1	1
CSF lymphocyte count increase
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
CSF protein increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
CSF white blood cell count increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Hepatic enzyme increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Neutrophil count increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Platelet count increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
White blood cell count increased
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 16 (6.25%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	1	0	0	0	0
Eye contusion
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Fall
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 8 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	2	2	1	2	1
Foot fracture
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Hand fracture
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Head injury
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Post lumbar puncture syndrome
subjects affected / exposed	2 / 16 (12.50%)	1 / 9 (11.11%)	2 / 9 (22.22%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	3	2	2	0	1	0
Post procedural contusion
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Post procedural discomfort
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Procedural headache
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Procedural nausea
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Procedural pain
subjects affected / exposed	3 / 16 (18.75%)	0 / 9 (0.00%)	2 / 9 (22.22%)	3 / 9 (33.33%)	1 / 8 (12.50%)	2 / 10 (20.00%)
occurrences all number	6	0	5	5	1	2
Procedural vomiting
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Thermal burn
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Wound
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Ataxia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Balance disorder
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	1
Chorea
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	2	0	0
Dizziness
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 8 (12.50%)	4 / 10 (40.00%)
occurrences all number	0	1	0	3	1	5
Dysarthria
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	0	2
Dysgeusia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Headache
subjects affected / exposed	5 / 16 (31.25%)	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	2 / 8 (25.00%)	4 / 10 (40.00%)
occurrences all number	7	0	1	4	7	4
Hyperreflexia
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0
Hypoaesthesia
subjects affected / exposed	1 / 16 (6.25%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0	0
Hyporeflexia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Lethargy
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Lumbosacral radiculopathy
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Migraine
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	1	0	0
Pleocytosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Post-traumatic headache
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Radicular pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Sensory disturbance
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Diarrhoea
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Nausea
subjects affected / exposed	1 / 16 (6.25%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	1	0	1	0	0
Vomiting
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Dermatitis contact
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0	0
Rash vesicular
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Urinary retention
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 16 (12.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	0	0	0	0	1
Back pain
subjects affected / exposed	3 / 16 (18.75%)	3 / 9 (33.33%)	1 / 9 (11.11%)	2 / 9 (22.22%)	3 / 8 (37.50%)	0 / 10 (0.00%)
occurrences all number	4	4	1	4	4	0
Limb discomfort
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	1	0
Muscle spasms
subjects affected / exposed	2 / 16 (12.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Neck pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Osteoarthritis
subjects affected / exposed	0 / 16 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0
Pain in extremity
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	1	0
Spinal pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Ear infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Influenza
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0
Respiratory tract infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 16 (6.25%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	1
Viral upper respiratory tract infection
subjects affected / exposed	1 / 16 (6.25%)	2 / 9 (22.22%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 8 (12.50%)	0 / 10 (0.00%)
occurrences all number	3	2	1	1	1	0
Metabolism and nutrition disorders
Increased appetite
subjects affected / exposed	1 / 16 (6.25%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

29 Aug 2018

• Implemented edits made in United Kingdom versions 0.1 and 0.2, and made minor clarifications and corrections. • Allowed patients to enter directly into the multiple-dose portion of the study. A separate schedule of assessments was added for these patients. • Added objective criteria for individual stopping criteria in the multiple-dose phase per Regulatory feedback. • Extended the washout required for other investigational agents to a minimum of 1 year.

21 Jan 2020

• Added the 32 mg cohort to the study. • For the 32 mg cohort, the washout period after a single dose was 4 weeks (instead of 8 weeks) based on available nonclinical and clinical data to date. A new schedule of assessments specific to the 32 mg cohort was added to account for this. • Change in the inclusion criterion for body mass index (ie, <=30 changed to <=32). • Addition of new urine sample PK assessments. • New electrocardiogram data collection timepoints.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Based on the efficacy findings in this study at the time of the interim analysis, the Sponsor decided to terminate the study, as the benefit-risk analysis did not warrant continued treatment or dose escalation.

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Clinical trials

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients with Huntington’s Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs)

Primary: Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs)

Primary: Safety: Number of Patients With Severe TEAEs

Primary: Safety: Number of Patients With Severe TEAEs

Primary: Safety: Number of Patients With Serious TEAEs

Primary: Safety: Number of Patients With Serious TEAEs

Primary: Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs

Primary: Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs

Secondary: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)

Secondary: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)

Secondary: PK: Time of Occurrence of Cmax (Tmax)

Secondary: PK: Time of Occurrence of Cmax (Tmax)

Secondary: PK: Area Under the Plasma Concentration-time Curve (AUClast)

Secondary: PK: Area Under the Plasma Concentration-time Curve (AUClast)

Secondary: PK: Terminal Elimination Rate Constant

Secondary: PK: Terminal Elimination Rate Constant

Secondary: Pharmacodymanics: Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

Secondary: Pharmacodymanics: Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

Secondary: Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

Secondary: Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients with Huntington’s Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs)

Primary: Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs)

Primary: Safety: Number of Patients With Severe TEAEs

Primary: Safety: Number of Patients With Severe TEAEs

Primary: Safety: Number of Patients With Serious TEAEs

Primary: Safety: Number of Patients With Serious TEAEs

Primary: Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs

Primary: Safety and Tolerability: Number of Patients Who Withdraw From the Study Due to TEAEs

Secondary: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)

Secondary: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)

Secondary: PK: Time of Occurrence of Cmax (Tmax)

Secondary: PK: Time of Occurrence of Cmax (Tmax)

Secondary: PK: Area Under the Plasma Concentration-time Curve (AUClast)

Secondary: PK: Area Under the Plasma Concentration-time Curve (AUClast)

Secondary: PK: Terminal Elimination Rate Constant

Secondary: PK: Terminal Elimination Rate Constant

Secondary: Pharmacodymanics: Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

Secondary: Pharmacodymanics: Percent Change From Baseline in the Concentration of Mutant Huntingtin (mHTT) Protein at the Last Measured Observation

Secondary: Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

Secondary: Clinical Effects: Percent Change From Baseline in the Total Functional Capacity (TFC) at the Last Measured Observation

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-120101 Administered Intrathecally in Patients with Huntington’s Disease