Clinical Trials Register

Summary
EudraCT Number:	2022-001796-14
Sponsor's Protocol Code Number:	CYTB323G12101
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-10-20
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

Germany - PEI

A.2

EudraCT number

2022-001796-14

A.3

Full title of the trial

An open-label, multi-center, phase 1/2 study to assess safety, efficacy and cellular kinetics of YTB323 in participants with severe, refractory systemic lupus erythematosus (srSLE).

A.3.1

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

An open-label study to assess safety, efficacy and cellular kinetics of YTB323 in severe, refractory systemic lupus erythematosus (srSLE).

A.4.1

Sponsor's protocol code number

CYTB323G12101

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	Novartis Pharma AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 911 273-12100
B.5.5	Fax number	+49 911 27312160
B.5.6	E-mail	infoservice.novartis@novartis.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.3.2	Product code	YTB323
D.3.4	Pharmaceutical form	Dispersion for 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.3.8	INN - Proposed INN	Not estabilished
D.3.9.3	Other descriptive name	YTB323
D.3.9.4	EV Substance Code	SUB221189
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	5000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
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

Systemic Lupus Erythematosus
Lupus Nephritis

E.1.1.1

Medical condition in easily understood language

Systemic Lupus Erythematosus
Lupus Nephritis

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10042945
E.1.2	Term	Systemic lupus erythematosus
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess safety of YTB323 in participants with srSLE.

E.2.2

Secondary objectives of the trial

•To characterize the in vivo cellular kinetics (pharmacokinetics, PK) of YTB323 in peripheral blood by quantitative polymerase chain reaction (qPCR)
•To characterize the incidence and prevalence of pre-existing and treatment induced immunogenicity (cellular and humoral) of YTB323
•To evaluate feasibility of the manufacturing process in srSLE
•Part A: To assess the effect of YTB323 on the following SLE disease activity scores
•Part A: To evaluate effect of YTB323 for srSLE participants who also have active lupus nephritis

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Signed informed consent.
- Adequate renal, hepatic, cardiac, hematological and pulmonary function.
- Men and women with SLE, aged ≥18 years and ≤65 years at acreening, fulfilling the 2019 European League Against Rheumatism EULAR/ACR classification criteria for SLE.
- Patient must be positive for at least one of the following autoantibodies at screening: antinuclear antibodies (ANA) at a titer of ≥1:80, or anti dsDNA (above the ULN); or anti-Sm (above the ULN).
- Active (severe) disease as defined by SLEDAI-2K ≥8 (not including the SLEDAI-2K domains of lupus headache, cerebrovascular accident, organic brain syndrome*) AND at least one of the following significant SLE related organ involvements that can result in debilitating and permanent damage or may represent a life-threatening condition as judged by the investigator and defined by:
- Renal**: histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV ("A" or "A/C") within 18 months of screening, AND at least one of the following at Screening (which must be fulfilled despite nephroprotective treatment, unless contraindicated and as per local standart of care):
- First morning void UPCR: 0.7 to 4mg/mg (79.1 to 452 mg/mmol) or
- Urine sediment consistent with active proliferative lupus nephritis such as presence of red blood cells, dysmorphic red blood cells, white blood cells, casts
- At least moderate or severe peri/myocarditis
- At least moderate or severe pleuritis or other lung involvement
- Vasculitis
- Failure to respond (i.e. having high disease activitiy as defined in criterion above despite the following therapy) to two or more standard immunosuppressive therapies (including one of mycophenolate or cyclophosphamide), unless contraindicated or having experienced documented adverse events or intolerance related to such immunosuppresive drugs not allowing their further use, in combination with glucocorticoids and failure to respond to at least on biological agent (unless contraindicated, the patient deemed ineligible by the Investigator or not available in a country). When country specific guidelines are in place pertaining to specific medications, these are to be followed by investigators unless otherwise clinically justified.

E.4

Principal exclusion criteria

- Clinically signficant active, opportunistic, chronic or recurrent infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, such as COVID-19 etc.) one month prior to or during screening. Patients who have had at least one severe infection that required prolonged hospitalization in the intensive care setting within 5 years prior to screening and/or at least one severe infection that required prolonged hospitalization within one year prior to screening.
- Uncontrolled diabetes mellitus, lung diseases or any other illness that are not related to SLE that in the opinion of the Investigator would jeopardize the ability of the patient to tolerate lymphodepletion and CD19 CAR T cell therapy.
- Prior history of malignancy except for localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured for at least 5 years by local surgica therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis.
- Any patients requiring medications probited by the protocol.
- Any psychiatric condition or disability compliance with treatment or informed consent impossible.
- Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy).
- History o bone marrow/hematopoietic stem cell or solid organ transplantation.
- Female participants who are pregnant or breastfeeding or intending to conceive during the course of the study.
- Women of childbearing potential, defined as all womoen physiologically capable of becoming pregnant, unless they are using a highly effective method of contraception starting from the time of enrollment to at least 12 months after the YTB323 administration and until CAR-T cells are no longer present by qPCR on two consecutive tests.
- Sexually active males unwilling to use a condom during intercourse from the time enrollment for at least 12 months after YTB323 administration and until CAR-T cells ar eno longer present by qPCR on two consecutive tests.
- Any acute, severe lupus related flare during screening that needs immediate treatment and/or makes the immunosuppressive washout impossible; thus, makes the patient ineligibile for CD19 CAR-T therapy as judged by the Investigator, such as acute central nervous system (CNS) lupus (e.g. psychosis, epilespy) or catastrophic antiphospholipid syndrome.
- Significant, likely irreversible organ damage related to SLE, including, end stage renal disease defined as glomerular filtration rate
<15mL/min/body surface or need for hemodialysis, ii) heart disease
defined as in Exclusion Criterion 11, severe valve insufficiency, or
ejection fraction <20%; iii) end.stage liver disease defined as Child-
Pugg class C; iv) severe lung disease defined as respiratory insufficiency requiring at least 1 l/min supplemental oxygen or as severe fibrotic changes at lung CT scan; v) any other severe condition that in the opinion of the Investigator renders CD19 CAR-T cell therapy as unlikely to benefit the patient.

E.5 End points

E.5.1

Primary end point(s)

•Safety parameters include vital signs, adverse events, laboratory parameters and ECG evaluation

E.5.1.1

Timepoint(s) of evaluation of this end point

720 days

E.5.2

Secondary end point(s)

•YTB323 transgene concentration by qPCR over time in peripheral blood;
cellular kinetics parameters (Cmax, AUC, Tmax, T1/2, Clast, Tlast)
•Pre-existing and treatment induced immunogenecity (cellular, humoral) of YTB323.
•Manufacture success (defined as meeting release specification and at or abiove the planned target dose)
•At various timepoints:
•SLEDAI-2K
•Physician's global assessment
•LLDAS
•Remission (DORIS)
•UPCR at various timepoints
•Complete Renal Response (CRR) at various timepoints

E.5.2.1

Timepoint(s) of evaluation of this end point

720 days

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

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

New indication/patient population

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

Yes

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

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

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

United States

France

Germany

Spain

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

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)

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)

All participants who either complete or prematurely discontinue from the study will be asked to participate in a long term follow-up (LTFU, see Section 4.1 of Protocol) either within this study or a dedicated LTFU study. In the LTFU semiannual and/or annual evaluations will be performed up to 15 years from the date of infusion as recommended by health authority guidance for participants treated with gene therapies.

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

2023-03-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-12-23

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

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