Clinical Trials Register

Summary
EudraCT Number:	2020-003675-18
Sponsor's Protocol Code Number:	ANX005-wAIHA-02
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:	2021-08-02
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

2020-003675-18

A.3

Full title of the trial

A Phase 2, Open-Label, Repeat Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Proof-of-Concept of Intravenous ANX005 in Subjects with Warm Autoimmune Hemolytic Anemia

Studio in aperto, di fase 2, a dosi ripetute per valutare la sicurezza, la tollerabilità, la farmacocinetica, la farmacodinamica e la prova di fattibilità di ANX005 mediante iniezione endovenosa in soggetti con anemia emolitica autoimmune calda

A.3.1

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

Study to Assess the Safety, Tolerability, Efficacy, PK, PD and POC of Intravenous ANX005 in Patients With wAIHA

Studio per valutare la sicurezza, la tollerabilità, l'efficacia, PK, PD e POC di ANX005 per via endovenosa in pazienti con wAIHA

A.3.2

Name or abbreviated title of the trial where available

Study with intravenous ANX005 in patients with wAIHA

Studio con ANX005 per via endovenosa in pazienti con wAIHA

A.4.1

Sponsor's protocol code number

ANX005-wAIHA-02

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	Annexon, Inc
B.1.3.4	Country	United States
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	Annexon, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Annexon, Inc.
B.5.2	Functional name of contact point	Clinical Trials Informations
B.5.3	Address:
B.5.3.1	Street Address	180 Kimbali Way
B.5.3.2	Town/ city	South San Francisco
B.5.3.3	Post code	CA94080
B.5.3.4	Country	United States
B.5.4	Telephone number	+16508225500
B.5.5	Fax number	+16506369773
B.5.6	E-mail	info@annexonbio.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	ANX005
D.3.2	Product code	[ANX005]
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ANX005
D.3.9.3	Other descriptive name	Recombinant humanized monoclonal antibody: IgG4 (heavy chain); kappa (light chain)
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

warm autoimmune hemolytic anemia

anemia emolitica autoimmune calda

E.1.1.1

Medical condition in easily understood language

warm autoimmune hemolytic anemia

anemia emolitica autoimmune calda

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10003825
E.1.2	Term	Autoimmune hemolytic anemia
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this repeat dose Phase 2 study is as follows:
• To evaluate the safety, tolerability, and proof of concept of two once-weekly intravenous infusions of 100 mg/kg ANX005 in subjects with wAIHA.

L'obiettivo principale di questo studio di Fase 2 è di valutare la sicurezza, tollerabilità e prova di fattibilità di due infusioni endovenose una volta alla settimana di 100 mg/kg di ANX005 in soggetti con anemia emolitica autoimmune calda (wAIHA)

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are as follows:
• To evaluate the pharmacokinetic (PK) profile of ANX005 in subjects with wAIHA
• To evaluate the effect of ANX005 on classical complement pathway inhibition as measured by complement system related biomarkers in subjects with wAIHA
• To assess the effect of 2 once-weekly doses of ANX005 on the following disease activity markers in subjects with wAIHA:
Hemoglobin,
Lactate dehydrogenase (LDH),
Total and Indirect bilirubin,
Haptoglobin,
Reticulocyte count, Platelet count,
CRP, Direct Antibody Test (DAT).

• Valutare il profilo farmacocinetico (PK) di ANX005 in soggetti con wAIHA;
• Valutare l'effetto di ANX005 sull'inibizione della via classica del complemento come misurato dai biomarker relativi al sistema del complemento in soggetti con wAIHA
• Valutare l'effetto di 2 dosi una volta a settimana di ANX005 sui seguenti marker di attività della malattia in soggetti con wAIHA:
o Emoglobina
o Lattato deidrogenasi (LDH)
o Bilirubina indiretta e totale
o Aptoglobina
o Conta dei reticolociti
o Conta delle piastrine
o CRP
o Test anticorpi diretti (DAT)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or non-pregnant, non-lactating female = 18 years of age on the day of signing informed consent
2. Diagnosis of wAIHA at least 3 months prior to screening
3. Hgb level > 10.0 g/dL (pre-transfusion) with no alternative explanation for anemia apart from wAIHA at screening
4. Positive direct antiglobulin test (DAT) = 1 + for C3d and IgG
5. Evidence of classical complement pathway activation by one of the
below:
a. Serum complement component 4 (C4) below the lower limit of normal
b. CH50 below the lower limit of normal
6. Evidence of active hemolysis based on at least one of the following:
a. LDH above the ULN
b. Indirect bilirubin above the ULN
c. Haptoglobin below the LLN
7. Vaccinations against encapsulated bacterial organisms (N. meningitidis, H. influenzae and S. pneumoniae) within 5 years prior to screening or subject must be willing
to complete vaccinations at least 2 weeks prior to dosing with ANX005.
Documentation of vaccinations must be received at the study site in advance of the scheduled screening visit

1. Maschio o femmina non gravida, non in allattamento di età = 18 anni il giorno della firma del consenso informato
2. Diagnosi di wAIHA almeno 3 mesi prima dello screening
3. Livello di Hgb> 10,0 g / dL (pre-trasfusione) senza alternative spiegazioni per l'anemia a parte wAIHA allo screening
4. Test dell'antiglobulina diretta positivo (DAT) = 1 + per C3d e IgG
5. Prova dell'attivazione della via classica del complemento da parte di uno dei sotto:
a. Componente del complemento sierico 4 (C4) al di sotto del limite inferiore della norma
b. CH50 al di sotto del limite inferiore del normale
6. Evidenza di emolisi attiva basata su almeno uno dei seguenti:
a. LDH sopra l'ULN
b. Bilirubina indiretta al di sopra dell'ULN
c. Aptoglobina al di sotto del LLN
7. Vaccinazioni contro organismi batterici incapsulati (N. meningitidis, H. influenzae e S.pneumoniae) entro 5 anni prima dello screening o il soggetto deve essere disponibile
completare le vaccinazioni almeno 2 settimane prima della somministrazione di ANX005.
La documentazione delle vaccinazioni deve essere ricevuta presso il sito dello studio in anticipo dalla visita di screening programmata

E.4

Principal exclusion criteria

1. History of or current lymphoma or lymphoproliferative disorder requiring therapy
2. Elevated aspartate aminotransferase or alanine aminotransferase levels > 2.5 times the upper limit of normal at screening
3. Platelet count < 30 x 109/L
4. History of cold agglutinin disease or IgM cold agglutinin titer > 1:64
5. History of solid organ, bone marrow, or stem cell transplantation
6. History of splenectomy within the 3 months prior to screening
7. Other wAIHA treatments:
- Received rituximab or other anti-CD20 monoclonal antibody < 3 months prior to screening
- Receiving steroids > 1 mg/kg of prednisone or equivalent daily at screening
8. Signs and symptoms of, or a diagnosis consistent with, a chronic autoimmune disorder not resulting from primary wAIHA and/or an ANA titer of = 1:160
9. Known genetic deficiencies of the complement cascade system

1. Anamnesi o attuale linfoma o disturbo linfoproliferativo che richiede terapia
2. Aspartato aminotransferasi o alanina aminotransferasi elevati livelli> 2,5 volte superiore il limite di normalità allo screening
3. Conta piastrinica <30 x 109 / L
4. Anamnesi di malattia da agglutinine fredde o titolo di agglutinine fredde IgM> 1:64
5. Storia di trapianto di organi solidi, midollo osseo o cellule staminali
6. Storia di splenectomia nei 3 mesi precedenti lo screening
7. Altri trattamenti wAIHA:
- Ricevuto rituximab o altro anticorpo monoclonale anti-CD20 <3 mesi prima dello screening
- Ricezione dose giornaliera di steroidi> 1 mg / kg di prednisone o equivalente allo screening
8. Segni e sintomi di, o una diagnosi coerente con, un cronico disturbo autoimmune non derivante da wAIHA primario e / o un titolo ANA di = 1: 160
9. Carenze genetiche note del sistema a cascata del complemento

E.5 End points

E.5.1

Primary end point(s)

Adverse events, infusion related reactions, safety laboratory assessments (serum chemistry, hematology, urine analysis), and vital signs.

Eventi avversi, reazioni correlate all'infusione, laboratorio di sicurezza valutazioni (chimica del siero, ematologia, analisi delle urine) e segni vitali.

E.5.1.1

Timepoint(s) of evaluation of this end point

10 weeks

10 settimane

E.5.2

Secondary end point(s)

Pharmacokinetic (PK) endpoints are:
-Maximum observed serum concentration (Cmax)
-Observed time to Cmax (Tmax)
-Area under the ANX005 serum concentration-time curve to the last
sample (AUC0-t) and
extrapolated through infinity
-Accumulation ratio
-Terminal half-life (t1/2)
-Terminal elimination rate constant
-Clearance (CL)
-Volume of distribution (Vss)
Pharmacodynamics (PD) Endpoints:
-Hemoglobin
-Lactate dehydrogenase (LDH)
-Total and Indirect bilirubin
-Haptoglobin
-Reticulocyte count
-Platelet count
-Direct Antibody Test (DAT)

Gli endpoint farmacocinetici (PK) sono:
-Massima concentrazione sierica osservata (Cmax)
-Tempo osservato a Cmax (Tmax)
-Area sotto la curva concentrazione sierica-tempo fino all'ultimo ANX005
campione (AUC0-t) e
estrapolato all'infinito
-Rapporto di accumulo
-Emivita terminale (t1 / 2)
-Velocità di eliminazione del terminale costante
-Cancellazione (CL)
-Volume di distribuzione (Vss)
Endpoint farmacodinamici (PD):
-Emoglobina
-Lattato deidrogenasi (LDH)
-Bilirubina totale e indiretta
-Haptoglobin
-Conteggio dei reticolociti
-Conteggio piastrine
-Test diretto degli anticorpi (DAT)

E.5.2.1

Timepoint(s) of evaluation of this end point

10 weeks

10 settimane

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

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability, Proof-of-Concept of Intravenous ANX005 in Subjects with Warm Autoimmune Hemolytic Anemia

Tollerabilità, prova di fattibilità di ANX005 endovena in soggetti con anemia emolitica autoimmune calda

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Studio a dosi ripetute in aperto

Open repeat dose study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

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

Austria

France

Germany

Hungary

Italy

Netherlands

Norway

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

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

LVLS

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)

Yes

F.1.3.1

Number of subjects for this age range:

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)

Once study participation is completed, the subject can discuss with their personal physician about treatment options.

Una volta completata la partecipazione allo studio, il soggetto potrà discutere con il proprio medico personale sulle opzioni di trattamento.

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

2020-12-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-03-31

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