Clinical Trials Register

Summary
EudraCT Number:	2020-004556-15
Sponsor's Protocol Code Number:	WVE-003-001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-23
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

Spain - AEMPS

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

Estudio de fase 1b/2a, multicéntrico, aleatorizado, doble ciego y controlado con placebo de WVE- 003 administrado por vía intratecal en pacientes con enfermedad de 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

Estudio de fase 1b/2a, multicéntrico, aleatorizado, doble ciego y controlado con placebo de WVE- 003 administrado por vía intratecal en pacientes con enfermedad de Huntington

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	+34900834223
B.5.6	E-mail	RegistroEspanolDeEstudiosClinicos@druginfo.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
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.3.10	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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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
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

Enfermedad de Huntington

E.1.1.1

Medical condition in easily understood language

Huntington's Disease

Enfermedad de Huntington

E.1.1.2

Therapeutic area

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

MedDRA Classification

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).

Evaluar la seguridad y la tolerabilidad de WVE-003 en pacientes con enfermedad de Huntington (EH).

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).

•Determinar la farmacocinética (FC) de WVE-003 en el plasma.
•Determinar la concentración de WVE-003 en el líquido cefalorraquídeo (LCR).

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.Capacidad documentada para comprender el o los DCI y el consentimiento del estudio por escrito y haber otorgado el consentimiento informado por escrito firmado antes de realizar ningún procedimiento del estudio.
2.Varones o mujeres ambulatorios.
3.Edad entre ≥25 y ≤60 años.
4.Índice de masa corporal (IMC) ≤32 kg/m2.
5.Repetición del codón CAG documentada ≥36 en el gen HTT.
6.Heterocigosis documentada en el SNP3.
7.Presencia documentada de la variante A del SNP3 en el mismo alelo que la expansión del codón CAG patogénico.
8.Diagnóstico clínico de las características motoras de la EH, definidas con una puntuación de confianza diagnóstica de la UHDRS = 4.
9.Puntuación de capacidad funcional total (TFC, Total Functional Capacity) de la UHDRS ≥9 y ≤13
10.En opinión del investigador, el paciente es capaz de tolerar todos los procedimientos del estudio y está dispuesto a cumplir todos los demás requisitos del protocolo.
11.Disposición a utilizar métodos anticonceptivos muy eficaces durante todo el estudio si los pacientes o sus parejas están en edad fértil. El protocolo define la ausencia de capacidad reproductiva y los métodos anticonceptivos muy eficaces.

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.Neoplasia maligna o tratamiento por una neoplasia maligna, excepto carcinoma basocelular o carcinoma epidermoide tratado, en los 5 años previos.
2.Positivo para el virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC).
3.Infección conocida por el virus de la inmunodeficiencia humana (VIH).
4.Hallazgo médico clínicamente significativo en la exploración física, aparte de la EH, que, en opinión del investigador, haga que el paciente no sea apto para participar en los procedimientos del estudio o que sea incapaz de completarlos.
5.Tratamiento previo con tominersén.
6.Tratamiento previo con terapia génica viral o celular.
7.Haber recibido otro fármaco de estudio, como un oligonucleótido en investigación, en el último año o 5 semividas del fármaco, lo que suponga más tiempo.
8.Dispositivo implantable del sistema nervioso central que pueda interferir en la capacidad de administrar el fármaco del estudio mediante punción lumbar o de someterse a una RM.
9.Antecedentes de trastorno por abuso de sustancias (excepto nicotina) en los 6 meses previos a la visita de selección.
10.Resultado positivo en opioides (no prescritos), cocaína, anfetaminas, metadona, barbitúricos, metanfetamina o fenciclidina en la visita de selección.
11.Inicio o modificación de la dosis de medicamentos concomitantes para el tratamiento de los síntomas de la EH o trastornos psiquiátricos en los 30 días previos a la visita de selección (se permiten los medicamentos concomitantes que se hayan administrado en una pauta estable durante ≥30 días).
12.Embarazo (determinado mediante una prueba de embarazo en suero) o lactancia materna en la visita de selección o previsión de quedarse embarazada durante el estudio.
13.Anormalidad en la analítica clínicamente significativa en la selección.
14.Anomalía clínicamente significativa en el electrocardiograma (ECG) en la fase de selección, como un intervalo QT corregido por la frecuencia cardíaca (QTc) ≥450 ms confirmado en los varones o ≥470 ms en las mujeres.
15.Enfermedad clínicamente significativa cardiovascular, endocrina, hepática, renal, pulmonar, digestiva, neurológica, maligna, metabólica, psiquiátrica o de otro tipo que, en opinión del investigador, impida la participación segura del paciente en el estudio o pueda interferir en las evaluaciones del estudio. El estado mental, los antecedentes médicos psiquiátricos y la elegibilidad para el estudio deberán documentarse en el cuestionario de selección.
16.Trastorno óseo, vertebral, hemorrágico o de otro tipo que exponga al paciente al riesgo de lesión o punción lumbar infructuosa.
17.Imposibilidad de someterse a una RM cerebral (con o sin sedación).
18.Riesgo significativo de comportamiento suicida según alguno de los criterios siguientes:
a.Opinión del investigador.
b.Respuesta afirmativa a los intentos de suicidio o comportamientos suicidas en la sección de comportamientos suicidas de la Escala de valoración de la gravedad del comportamiento suicida de Columbia (C-SSRS) con referencia a un período de 2 años antes de la visita de selección.
c.Respuesta afirmativa en cualquiera de los apartados de la sección de ideas suicidas de la C SSRS con referencia a un período de 6 meses antes de la visita de selección.
d.Respuesta afirmativa en cualquiera de los apartados de la sección de ideas suicidas de la C SSRS en la visita basal desde la última visita (visita de selección).
19.Interviene directa o indirectamente en la realización y administración de este estudio en calidad de investigador, subinvestigador, coordinador del estudio u otro miembro del personal del estudio, o el paciente es un familiar de primer grado, otro allegado o un familiar que reside con alguna de las personas mencionadas anteriormente involucradas directa o indirecta en el estudio.

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.

Seguridad:
Acontecimientos adversos, medicamentos concomitantes, exploraciones físicas con exploración neurológica detallada, constantes vitales, peso, ECG de 12 derivaciones, evaluaciones analíticas (bioquímica clínica, hematología y análisis de orina), evaluaciones de la seguridad en el LCR, RM cerebral y C-SSRS.
Farmacocinética:
•Parámetros farmacocinéticos de WVE-003 en plasma.
•Concentración de WVE-003 en el LCR.

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.

Los criterios de valoración primarios de seguridad y farmacocinética se evaluarán como el cambio con respecto a los valores basales en UHDRS, cUHDRS, SDMT, PBA-s y RM después que todos los pacientes de la cohorte del Período 1 recibieron el fármaco del estudio y completaron 4 semanas del seguimiento después de la dosis

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

Farmacodinámica:
•Variación con respecto al valor basal de proteína mHTT en el LCR.
•Variación con respecto al valor basal de proteína wtHTT en el LCR.
•Variación con respecto al valor basal de proteína tHTT en el LCR.
•Variación con respecto al valor basal de NfL en el LCR.

Efectos clínicos:
•Variación con respecto al valor basal de la TFC de la UHDRS.
•Variación con respecto al valor basal en la puntuación total motora de la UHDRS.
•Variación con respecto al valor basal de la escala de independencia de la UHDRS.
•Variación con respecto al valor basal del test de símbolos y dígitos.
•Variación con respecto al valor basal del test de lectura rápida de Stroop
•Variación con respecto al valor basal de la UHDRS combinada
•Variación con respecto al valor basal de la PBA-s.
•Variaciones con respecto al momento basal de la RM cerebral.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Desde los valores basales hasta la última medida de tiempo

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

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 fecha en la que el último paciente complete la última visita (incluye visitas de seguimiento).

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

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.

El Promotor planea iniciar un estudio de extensión abierto que proporcione tratamiento hasta 2 años para pacientes que completan la Fase 1b / 2a estudio. El estudio de extensión abierto se enviará con fecha posterior, cuando los datos toxicológicos requeridos estén disponibles.

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

2021-08-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-27

P. End of Trial
P.	End of Trial Status	Ongoing

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