Clinical Trials Register

Summary
EudraCT Number:	2020-004556-15
Sponsor's Protocol Code Number:	WVE-003-001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-10-06
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-004556-15

A.3

Full title of the trial

A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-003 Administered Intrathecally in Patients With Huntington’s Disease

Studio di Fase 1b/2a multicentrico, randomizzato, in doppio cieco, controllato con placebo su WVE-003 somministrato per via intratecale a pazienti affetti da malattia di Huntington

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-003 Administered Intrathecally in Patients With Huntington’s Disease

Studio di Fase 1b/2a multicentrico, randomizzato, in doppio cieco, controllato con placebo su WVE-003 somministrato per via intratecale a pazienti affetti da malattia di Huntington

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

WVE-003-001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Wave Life Sciences UK Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Wave Life Sciences UK Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PPD
B.5.2	Functional name of contact point	Adrian Haines
B.5.3	Address:
B.5.3.1	Street Address	1-2 Crown Walk, Jewry Street
B.5.3.2	Town/ city	Winchester, Hampshire
B.5.3.3	Post code	SO23 8BB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441223771251
B.5.5	Fax number	0000000
B.5.6	E-mail	Adrian.Haines@ppd.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	WVE-003
D.3.2	Product code	[WVE-003]
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intrathecal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	WVE-003
D.3.9.2	Current sponsor code	WVE-003
D.3.9.4	EV Substance Code	SUB222412
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intrathecal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Huntington's Disease

Malattia di Huntington

E.1.1.1

Medical condition in easily understood language

Huntington's Disease

Malattia di Huntington

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10070668
E.1.2	Term	Huntington's disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety and tolerability of WVE-003 in patients with Huntington’s disease (HD).

Valutare la sicurezza e la tollerabilità di WVE-003 in pazienti con malattia di Huntington (HD).

E.2.2

Secondary objectives of the trial

• To characterize the pharmacokinetics (PK) of WVE-003 in plasma.
• To characterize the concentration of WVE-003 in cerebrospinal fluid (CSF).

¿ Caratterizzare la farmacocinetica (PK) di WVE-003 nel plasma.
¿ Caratterizzare la concentrazione di WVE-003 nel liquido cerebrospinale (CSF).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Documented ability to understand the written study ICF(s) and consent, and has provided signed written informed consent prior to any study procedures.
2. Ambulatory male or female
3. Age =25 to =60 years old
4. Body mass index (BMI) =32 kg/m2
5. Documented CAG triplet repeats =36 in the HTT gene
6. Documented heterozygosity at SNP3
7. Documented presence of the A variant of SNP3 on the same allele as the pathogenic CAG triplet expansion
8. Clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4
9. UHDRS Total Functional Capacity (TFC) scores =9 and =13
10. In the opinion of the Investigator, the patient is able to tolerate all study procedures, and is willing to comply with all other protocol requirements.
11. Willingness to practice highly effective contraception for the duration of the study if patients or their partners are of childbearing potential. Non-childbearing potential and highly effective methods of contraception are defined in the protocol.

1. Capacità documentata di comprendere il consenso e gli ICF scritti dello studio e rilascio del consenso informato scritto firmato prima di qualsiasi procedura dello studio.
2. Paziente deambulante maschio o femmina
3.Età compresa tra =25 e =60 anni
4. Indice di massa corporea (BMI) =32 kg/m2.
5. Ripetizioni documentate della tripletta CAG =36 nel gene HTT
6. Eterozigosi documentata per l'SNP3
7. Presenza documentata della variante A dell'SNP3 sullo stesso allele dell'espansione patogena della tripletta CAG
8. Caratteristiche motorie diagnostiche cliniche di HD, definite come punteggio di confidenza diagnostica della UHDRS = 4
9. Punteggi di capacità funzionale totale (TFC) della UHDRS =9 e =13
10. Secondo il giudizio dello Sperimentatore, il paziente è in grado di tollerare tutte le procedure dello studio ed è disposto a rispettare tutti gli altri requisiti del protocollo.
11. Volontà di praticare una contraccezione altamente efficace per tutta la durata dello studio in caso di pazienti o partner dei pazienti in età fertile. La non fertilità e i metodi di contraccezione altamente efficaci sono definiti nel protocollo.

E.4

Principal exclusion criteria

1. Malignancy or received treatment for malignancy, other than treated basal cell or squamous cell carcinoma of the skin, within the previous 5 years.
2. Positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
3. Known to be positive for human immunodeficiency virus (HIV).
4. Clinically significant medical finding on the physical examination other than HD that, in the judgment of the Investigator, will make the patient unsuitable for participation in and/or completion of the study procedures.
5. Previously received tominersen.
6. Received prior treatment with viral or cellular-based gene therapy.
7. Received any other study drug, including an investigational oligonucleotide, within the past 1 year or 5 half-lives of the drug, whichever is longer
8. Implantable central nervous system device that may interfere with ability to administer study drug via lumbar puncture or undergo MRI scan.
9. History of substance abuse disorder (except nicotine) within 6 months prior to the Screening Visit.
10. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, methamphetamine, or phencyclidine at the Screening Visit.
11. Started or changed dose for concomitant medication for the treatment of HD symptoms or psychiatric disorders within 30 days prior to the Screening Visit (concomitant medications that have been administered on a stable regimen for =30 days are permitted).
12. Pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening Visit, or plans to become pregnant during the course of the study.
13. Clinically significant laboratory abnormality at Screening.
14. Clinically significant abnormality at Screening electrocardiogram (ECG), including but not necessarily limited to a confirmed QT interval corrected for heart rate (QTc) =450 msec for males or =470 msec for females.
15. Clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the opinion of the Investigator, precludes the patient’s safe participation in the study or would interfere with the study assessments. Mental status, psychiatric medical history, and eligibility for the study must be documented in the screening questionnaire.
16. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture.
17. Inability to undergo brain MRI (with or without sedation).
18. Deemed to be at significant risk for suicidal behavior based on any of the following criteria:
a. The opinion of the Investigator; or
b. Answers “yes” to Actual Suicide Attempts or Suicidal Behaviors in the Suicidal Behaviors section of the Columbia-Suicide Severity Rating Scale (C-SSRS) with reference to a 2 year period prior to the Screening Visit; or
c. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS with reference to a 6-month period prior to the Screening Visit; or
d. Answers “yes” on any items in the Suicidal Ideation section of the C-SSRS at the Baseline Visit since the last visit (Screening Visit).
19. Involved directly or indirectly in the conduct and administration of this study as an Investigator, sub-investigator, study coordinator, or other study staff member, or the patient is a first-degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the study.

1. Tumore maligno o trattamento per tumore maligno, fatta eccezione per carcinoma della pelle a cellule squamose o basali trattato, nei 5 anni precedenti.
2. Positività al virus dell'epatite B (HBV) o al virus dell'epatite C (HCV).
3. Nota positività al virus dell'immunodeficienza umana (HIV).
4. Risultato medico clinicamente significativo all’esame obiettivo, diverso dalla HD, che a giudizio dello sperimentatore renderà il paziente inadatto per la partecipazione e/o per il completamento delle procedure dello studio.
5. Precedente trattamento con tominersen.
6. Precedente trattamento con terapia genica basata su virus o cellule.
7. Trattamento con qualsiasi altro farmaco in studio, compreso un oligonucleotide sperimentale, nel corso degli ultimi 12 mesi o 5 emivite del farmaco, a seconda di quale sia il periodo più lungo
8. Dispositivo impiantabile a livello del sistema nervoso centrale che potrebbe interferire con la capacità di somministrare il farmaco in studio attraverso una puntura lombare o di sottoporsi a una RMI.
9. Anamnesi di disturbo da abuso di sostanze (eccetto la nicotina) nei 6 mesi precedenti la Visita di screening.
10. Positività a oppioidi (senza prescrizione), cocaina, amfetamine, metadone, barbiturici, metamfetamina o fenciclidina alla Visita di screening.
11. Inizio di terapia con o variazione della dose di farmaci concomitanti per il trattamento dei sintomi di HD o di disturbi psichiatrici nei 30 giorni precedenti la Visita di screening (sono consentiti farmaci concomitanti che sono stati somministrati con un regime stabile per =30 giorni).
12. Gravidanza (come stabilito da un test di gravidanza su siero) o allattamento alla Visita di screening o pianificazione di una gravidanza nel corso dello studio.
13. Anomalia di laboratorio clinicamente significativa allo Screening.
14. Anomalia clinicamente significativa nell'elettrocardiogramma (ECG) allo Screening, incluso a titolo di esempio un intervallo QT corretto per la frequenza cardiaca (QTc) confermato =450 msec per i maschi o =470 msec per le femmine.
15. Condizione cardiovascolare, endocrina, epatica, renale, polmonare, gastrointestinale, neurologica, maligna, metabolica, psichiatrica o altra condizione che, secondo il giudizio dello Sperimentatore, precluda la partecipazione sicura del paziente allo studio o interferisca con le valutazioni dello studio. Lo stato mentale, l'anamnesi medica psichiatrica e l'eleggibilità allo studio devono essere documentati nel questionario di screening.
16. Disturbo delle ossa, della colonna vertebrale, emorragico o altro disturbo che espone il paziente al rischio di lesioni o di insuccesso della puntura lombare.
17. Incapacità di sottoporsi alla RMI del cervello (con o senza sedazione).
18. Valutazione di rischio significativo di comportamento suicidario in base a uno di dei seguenti criteri:
a. Giudizio dello sperimentatore; o
b. Risposta affermativa alla domanda sui comportamenti suicidari o sui tentativi di suicidio concreti nella sezione relativa ai comportamenti suicidari della Scala della Columbia University per la valutazione della gravità del rischio di suicidio (C-SSRS) con riferimento a un periodo di 2 anni prima della Visita di screening;
c. Risposta affermativa ad una qualsiasi voce nella sezione relativa all'ideazione suicidaria della scala C-SSRS in relazione a un periodo di 6 mesi prima della Visita di screening; o
d. Risposta affermativa a qualsiasi voce della sezione relativa all'ideazione suicidaria della C-SSRS alla Visita basale dall'ultima visita (Visita di screening).
19.Direttamente o indirettamente coinvolto nella conduzione e gestione del presente studio in qualità di sperimentatore, assistente sperimentatore, coordinatore dello studio o altro membro dello staff di ricerca oppure il paziente è un parente di primo grado, partner, o parente residente presso una delle suddette persone coinvolte direttamente o indirettamente nello studio.

E.5 End points

E.5.1

Primary end point(s)

Safety:
Adverse events, concomitant medications, physical examinations including detailed neurological examination, vital signs, weight, 12-lead ECGs, clinical laboratory evaluations (including clinical chemistry, hematology, and urinalysis), CSF safety evaluations, MRI of the brain, and C-SSRS.

Pharmacokinetics:
•Pharmacokinetic parameters of WVE-003 in plasma.
•Concentration of WVE-003 in CSF.

Sicurezza:
Eventi avversi, farmaci concomitanti, esami obiettivi compreso l'esame neurologico dettagliato, funzioni vitali, peso, ECG a 12 derivazioni, valutazioni cliniche di laboratorio (tra cui chimica clinica, ematologia e analisi delle urine), valutazioni di sicurezza del CSF, RMI del cervello e C-SSRS.

Farmacocinetica:
•Parametri farmacocinetici di WVE-003 nel plasma.
•Concentrazione di WVE-003 nel CSF.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary safety and PK endpoints will be assessed as the change from baseline parameters in UHDRS, cUHDRS, SDMT, PBA-s and MRIs after all patients in Period 1 cohort received study drug and completed 4 weeks of post-dose follow up.

Gli endpoint primari di sicurezza e PK saranno valutati come il cambiamento dai parametri basali in UHDRS, cUHDRS, SDMT, PBA-s e MRIs dopo che tutti i pazienti della coorte del Periodo 1 hanno ricevuto il farmaco in studio e completato 4 settimane di follow up post-dose.

E.5.2

Secondary end point(s)

Pharmacodynamics
•Change from baseline in the level of mHTT protein in CSF
•Change from baseline in the level of wtHTT protein in CSF
•Change from baseline in the level of tHTT protein in CSF
•Change from baseline in the level of NfL in CSF

Clinical Effects:
• Change from baseline in the UHDRS TFC
• Change from baseline in UHDRS total motor score
• Change from baseline in the UHDRS independence scale
• Change from baseline in Symbol Digit Modalities Test
• Change from baseline in Stroop word reading test
• Change from baseline in the composite UHDRS
• Change from baseline in the PBA-s
• Changes from baseline in MRI of the brain

Farmacodinamica
• Variazione dalla baseline nel livello di proteina mHTT nel CSF
• Variazione dalla baseline nel livello di proteina wtHTT nel CSF
• Variazione dalla baseline nel livello di proteina tHTT nel CSF
• Variazione dalla baseline nel livello di NfL nel CSF

Effetti clinici:
• Variazione dalla baseline nel punteggio TFC della UHDRS
• Variazione dalla baseline nel punteggio motorio totale della UHDRS
• Variazione dalla baseline nella scala di indipendenza della UHDRS
• Variazione dalla baseline nel Symbol Digit Modalities Test
• Variazione dalla baseline nel test di lettura delle parole di Stroop
• Variazione dalla baseline nella scala composita UHDRS
• Variazione dalla baseline nella PBA-s
• Variazione dalla baseline nella RMI del cervello

E.5.2.1

Timepoint(s) of evaluation of this end point

At study time points from baseline value to last measured time point

Ai momenti definiti dello studio dalla baseline all'ultimo momento definito misurato

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

Denmark

France

Germany

Italy

Poland

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The date on which the last patient completes the last visit (includes follow-up visit).

La data in cui l'ultimo paziente completa l'ultima visita (compresa la visita di follow-up).

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The Sponsor plans to initiate an open-label extension study providing treatment for up to 2 years for patients who complete the Phase 1b/2a study. The open-label extension study will be submitted as a separate CTA at a later date, when the required toxicology data are available.

Lo sponsor programma di iniziare uno studio di estensione in aperto che prevede un trattamento fino a 2 anni per i pazienti che completano lo studio di fase 1b/2a. Lo studio di estensione in aperto sarà sottomesso come una CTA separata in un secondo momento, quando saranno disponibili i dati tossicologici richiesti.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-12-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-05-24

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