NCT03225846: PRECISION-HD2

Safety and Tolerability of WVE-120102 in Patients With Huntington's Disease

Terminated Phase 1, PHASE2 Results posted Last updated 25 April 2022

What this trial tests

Phase 1, PHASE2 trial testing WVE-120102 in Huntington's Disease in 88 participants. Terminated before completion.

Timeline

17 July 2017

Primary endpoint
10 May 2021

10 May 2021

Quick facts

Lead sponsor	Wave Life Sciences Ltd.
Phase	Phase 1, PHASE2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	sequential
Masking	double
Primary purpose	treatment
Enrollment	88
Start date	17 July 2017
Primary completion	10 May 2021
Estimated completion	10 May 2021
Sites	26 locations across Denmark, France, United Kingdom, Germany, Poland, Canada, Australia, United States

Drugs / interventions tested

• WVE-120102 — full drug profile →
• Placebo

Conditions studied

• Huntington's Disease — all drugs for Huntington's Disease →

Sponsor

Wave Life Sciences Ltd. — full company profile →

Who can join

Adults 25 to 65, any sex, with Huntington's Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Safety: Number of Patients With Treatment-emergent Adverse Events (TEAEs) Primary · Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

All TEAEs reported or observed during the study, including TEAEs resulting from concurrent illnesses, reactions to concurrent medications, or progression of disease states

Group	Value	95% CI
Pooled Placebo	20
WVE-120102 (2 mg)	8
WVE-120102 (4 mg)	9
WVE-120102 (8 mg)	13
WVE-120102 (12 mg)	4
WVE-120102 (16 mg)	8
WVE-120102 (32 mg )	13

Safety: Number of Patients Who Experienced Severe TEAEs Primary · Time Frame: Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Number of patients who experienced a severe treatment-emergent adverse event. Severity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Group	Value	95% CI
Pooled Placebo	2
WVE-120102 (2 mg)	1
WVE-120102 (4 mg)	1
WVE-120102 (8 mg)	2
WVE-120102 (12 mg)	0
WVE-120102 (16 mg)	2
WVE-120102 (32 mg )	9

Safety: Number of Patients With Serious TEAEs Primary · Time Frame: Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

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.

Group	Value	95% CI
Pooled Placebo	0
WVE-120102 (2 mg)	1
WVE-120102 (4 mg)	2
WVE-120102 (8 mg)	2
WVE-120102 (12 mg)	0
WVE-120102 (16 mg)	0
WVE-120102 (32 mg )	9

Safety and Tolerability: Number of Patients Who Withdraw Due to TEAEs Primary · Time Frame: Day 1 to end of study (up to Day 182 [32 mg cohort]/ Day 210 [all other cohorts])

Group	Value	95% CI
Pooled Placebo	0
WVE-120102 (2 mg)	0
WVE-120102 (4 mg)	0
WVE-120102 (8 mg)	0
WVE-120102 (12 mg)	0
WVE-120102 (16 mg)	0
WVE-120102 (32 mg )	6

Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) Secondary · Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.

Cmax of WVE-120102 in plasma

Day 1

Group	Value	95% CI
WVE-120102 (2 mg)	1.35	± 2.714
WVE-120102 (4 mg)	8.54	± 6.073
WVE-120102 (8 mg)	29.87	± 31.891
WVE-120102 (16 mg)	31.49	± 15.801
WVE-120102 (32 mg )	96.21	± 57.394

Day 112

Group	Value	95% CI
WVE-120102 (2 mg)	7.46	± 15.411
WVE-120102 (4 mg)	15.55	± 14.587
WVE-120102 (8 mg)	36.16	± 30.012
WVE-120102 (16 mg)	59.49	± 35.718

PK: Time of Occurrence of Cmax (Tmax) Secondary · Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.

tmax of WVE-120102 in plasma

Day 1

Group	Value	95% CI
WVE-120102 (2 mg)	3.33	± 7.742
WVE-120102 (4 mg)	1.26	± 1.044
WVE-120102 (8 mg)	1.77	± 1.101
WVE-120102 (16 mg)	1.77	± 1.345
WVE-120102 (32 mg )	3.09	± 3.752

Day 112

Group	Value	95% CI
WVE-120102 (2 mg)	1.22	± 0.314
WVE-120102 (4 mg)	1.86	± 0.874
WVE-120102 (8 mg)	2.06	± 1.206
WVE-120102 (16 mg)	1.98	± 0.828

PK: Area Under the Plasma Concentration-time Curve (AUC 0-t) Secondary · Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.

AUC 0-t from time zero to the last quantifiable concentration of WVE-120102 in plasma

Day 1

Group	Value	95% CI
WVE-120102 (2 mg)	24.65	± 9.108
WVE-120102 (4 mg)	62.05	± 67.358
WVE-120102 (8 mg)	132.44	± 91.913
WVE-120102 (16 mg)	804.92	± 1456.786
WVE-120102 (32 mg )	919.14	± 271.997

Day 112

Group	Value	95% CI
WVE-120102 (2 mg)	23.83	± 23.187
WVE-120102 (4 mg)	35.47	± 22.280
WVE-120102 (8 mg)	107.83	± 70.198
WVE-120102 (16 mg)	133.22	± 67.683

PK: Terminal Elimination Half-life Secondary · Patients participating in Period 1 (SAD) had PK samples collected on Day 1 predose through 24-48 hours postdose. Patients participating in Period 2 (MAD) had PK samples collected predose on Day 112 and through 4 hours postdose.

Terminal elimination half life of WVE-120102 in plasma (t1/2)

Group	Value	95% CI
WVE-120102 (4 mg)	33.42	± 30.983
WVE-120102 (8 mg)	6.23	± NA
WVE-120102 (16 mg)	13.45	± 4.604
WVE-120102 (32 mg )	18.17	± 20.969

Pharmacodynamics (PD): Percentage Change From Baseline in Mutant Huntingtin Protein Secondary · Day 1 to last observation - up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Percentage change from baseline to last observation in mutant huntingtin protein

Group	Value	95% CI
Pooled Placebo	-2.64	-14.89 – 11.71
WVE-120102 (2 mg)	3.46	-7.67 – 7.80
WVE-120102 (4 mg)	-3.53	-4.20 – 2.41
WVE-120102 (8 mg)	-3.45	-6.46 – 7.35
WVE-120102 (16 mg)	-5.82	-12.09 – 6.44
WVE-120102 (32 mg )	-2.06	-28.72 – 7.84

Clinical Effects: Total Functional Capacity (TFC) Secondary · Day 1 Day 1 to last observation - up to Day 140 (32 mg cohort) or Day 196 (all other cohorts)

Percentage change from baseline to the last measured time point in the Total Functional Capacity score, administered as part of the Unified Huntington's Disease Rating Scale (UHDRS). Total Functional Capacity is scored 13 (normal) to 0 (severe disability)

Group	Value	95% CI
Pooled Placebo	0.0	0.00 – 0.00
WVE-120102 (2 mg)	0.0	-2.00 – 0.00
WVE-120102 (4 mg)	0.0	0.00 – 0.00
WVE-120102 (8 mg)	-4.17	-13.89 – 0.00
WVE-120102 (16 mg)	-8.33	-16.67 – 0.00
WVE-120102 (32 mg )	0.00	0.00 – 0.00

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 to end of study (Day 196 [32 mg cohort] or Day 210 [all other cohorts]). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Pooled Placebo

Serious: 0/22 (0%)

Deaths: 0/22

WVE-120102 (2 mg)

Serious: 1/9 (11%)

Deaths: 1/9

WVE-120102 (4 mg)

Serious: 2/12 (17%)

Deaths: 0/12

WVE-120102 (8 mg)

Serious: 2/15 (13%)

Deaths: 1/15

WVE-120102 (12 mg)

Serious: 0/8 (0%)

Deaths: 0/8

WVE-120102 (16 mg)

Serious: 0/9 (0%)

Deaths: 0/9

WVE-120102 (32 mg )

Serious: 9/13 (69%)

Deaths: 0/13

Serious adverse events (18 terms)

Reaction	System	Pooled Placebo	WVE-120102 (2 mg)	WVE-120102 (4 mg)	WVE-120102 (8 mg)	WVE-120102 (12 mg)	WVE-120102 (16 mg)	WVE-120102 (32 mg )
Amnesia	Nervous system disorders	—	—	—	—	—	—	—
Delirium	Psychiatric disorders	—	—	—	—	—	—	—
Cerebellar ataxia	Nervous system disorders	—	—	—	—	—	—	—
Dysarthria	Nervous system disorders	—	—	—	—	—	—	—
Disorientation	Psychiatric disorders	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—
Meningitis	Infections and infestations	—	—	—	—	—	—	—
Accident at work	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Subdural hematoma	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Ataxia	Nervous system disorders	—	—	—	—	—	—	—
Cerebrovascular accident	Nervous system disorders	—	—	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—	—	—
Vertigo CNS origin	Nervous system disorders	—	—	—	—	—	—	—
Aggression	Psychiatric disorders	—	—	—	—	—	—	—
Completed suicide	Psychiatric disorders	—	—	—	—	—	—	—
Confusional State	Psychiatric disorders	—	—	—	—	—	—	—
Conversion disorder	Psychiatric disorders	—	—	—	—	—	—	—
Psychotic Disorder	Psychiatric disorders	—	—	—	—	—	—	—

Other adverse events (114 terms — click to expand)

Reaction	System	Pooled Placebo	WVE-120102 (2 mg)	WVE-120102 (4 mg)	WVE-120102 (8 mg)	WVE-120102 (12 mg)	WVE-120102 (16 mg)	WVE-120102 (32 mg )
Headace	Nervous system disorders	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Skin abrasion	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—	—	—	—
Gait disturbance	General disorders	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—
Respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Procedural Pain	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Post lumbar puncture syndrome	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Post procedural discomfort	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—
Hyporeflexia	Nervous system disorders	—	—	—	—	—	—	—
Visual acuity reduced	Eye disorders	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Soft tissue injury	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
C-reactive protein increased	Investigations	—	—	—	—	—	—	—
Blood creatinine phosphokinase increased	Investigations	—	—	—	—	—	—	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Amnesia	Nervous system disorders	—	—	—	—	—	—	—
Hypoaesthesia	Nervous system disorders	—	—	—	—	—	—	—
Paraesthesia	Nervous system disorders	—	—	—	—	—	—	—
Presyncope	Nervous system disorders	—	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—	—
Disorientation	Psychiatric disorders	—	—	—	—	—	—	—
Irritability	Psychiatric disorders	—	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—	—
Hyperacusis	Ear and labyrinth disorders	—	—	—	—	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—	—	—	—	—
Dry eye	Eye disorders	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—
Abdominal hernia	Gastrointestinal disorders	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—	—	—
Irritable bowel syndrome	Gastrointestinal disorders	—	—	—	—	—	—	—
Paraesthesia oral	Gastrointestinal disorders	—	—	—	—	—	—	—

Most-reported serious reactions: Amnesia, Delirium, Cerebellar ataxia, Dysarthria, Disorientation, Pyrexia, Meningitis, Accident at work.

Data from ClinicalTrials.gov NCT03225846 adverse events section.

Sponsor's own description

PRECISION-HD2 is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of WVE-120102 in adult patients with early manifest Huntington's disease (HD) who carry a targeted single nucleotide polymorphism (SNP) rs362331 (SNP2).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Noncoding RNA therapeutics - challenges and potential solutions.
   Winkle M, El-Daly SM, Fabbri M, Calin GA. · · 2021 · cited 1123× · PMID 34145432 · DOI 10.1038/s41573-021-00219-z
2. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.
   Gao C, Jiang J, Tan Y, Chen S. · · 2023 · cited 998× · PMID 37735487 · DOI 10.1038/s41392-023-01588-0
3. Antisense Oligonucleotide Therapies for Neurodegenerative Diseases.
   Bennett CF, Krainer AR, Cleveland DW. · · 2019 · cited 263× · PMID 31283897 · DOI 10.1146/annurev-neuro-070918-050501
4. Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities.
   Tabrizi SJ, Estevez-Fraga C, van Roon-Mom WMC, Flower MD, et al · · 2022 · cited 245× · PMID 35716694 · DOI 10.1016/s1474-4422(22)00121-1
5. Antisense technology: A review.
   Crooke ST, Liang XH, Baker BF, Crooke RM. · · 2021 · cited 237× · PMID 33600796 · DOI 10.1016/j.jbc.2021.100416
6. New Avenues for the Treatment of Huntington's Disease.
   Kim A, Lalonde K, Truesdell A, Gomes Welter P, et al · · 2021 · cited 130× · PMID 34445070 · DOI 10.3390/ijms22168363
7. Gene-based therapies for neurodegenerative diseases.
   Sun J, Roy S. · · 2021 · cited 126× · PMID 33526943 · DOI 10.1038/s41593-020-00778-1
8. Gene therapy for neurodegenerative disorders: advances, insights and prospects.
   Chen W, Hu Y, Ju D. · · 2020 · cited 114× · PMID 32963936 · DOI 10.1016/j.apsb.2020.01.015