Conditions: Multiple Sclerosis
Keywords: Relapsing Forms of Multiple Sclerosis GNbAC1 Human Endogenous Retrovirus Type W HERV-W Temelimab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
Randomized, double-blind, placebo-controlled Phase IIa clinical study, assessing safety, tolerability, pharmacodynamic effects and pharmacokinetics of temelimab, administered at three different dose levels (18 mg/kg or 36 mg/kg or 54 mg/kg).

In this study temelimab is administered subsequently to rituximab therapy, i.e. no co-administration of rituximab and temelimab is done in this study.

Detailed description:

Arms:
arm 1: Monthly IV repeated dose arm 2: Monthly IV repeated dose arm 3: Monthly IV repeated dose arm 4: Monthly IV repeated dose

Interventions: intervention 1: temelimab 18 mg/kg intervention 2: temelimab 36 mg/kg intervention 3: temelimab 54 mg/kg intervention 4: Placebo
Intervention descriptions: intervention 1: temelimab 18 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). intervention 2: temelimab 36 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). intervention 3: temelimab 54 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). intervention 4: Placebo will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total).

Protocol document:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo Controlled Trial, Examining 
the Safety, Tolerability, Pharmacodynamic Effects and 
Pharmacokinetics of Temelimab Following Rituximab Treatment in 
Patients with Relapsing Forms of Multiple Sclerosis (RMS) 
- ProTEct-MS 
 
 
Study code: 
 
 
GNC-401 
EudraCT number:  
2019-004822-15 
Version number:  
3.0 
Date:  
2020-05-01 
Sponsor:  
GeNeuro Innovation SAS 
60 avenue Rockefeller 
69008 Lyon 
France 
 
Principal Investigator: 
Fredrik Piehl, MD PhD, Prof. of Neurology 
Center for Neurology, 
 
Academic Specialist Center 
Solnavägen 1E 
Stockholm 113 65 
Sweden 
 
 
This document contains confidential information of GeNeuro Innovation SAS. Do not copy or distribute 
without written permission from the Sponsor. 
 
 


Study Code: 
 
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Contact information 
Role 
 
Sponsor 
 
 
 
Contact Person 
GeNeuro Innovation SAS 
60 avenue Rockefeller 
69008 Lyon 
France 
David Leppert, MD 
Chief Medical Officer 
Phone: +41793625621  
Email: dl@geneuro.com 
Sponsor 
 
 
 
Contact Person 
GeNeuro Innovation SAS 
60 avenue Rockefeller 
69008 Lyon 
France 
Thomas Rückle PhD 
Chief Development Officer 
Phone: +41 79 6214063 
Email: tr@geneuro.com 
Principal Investigator 
Fredrik Piehl 
Center for Neurology, 
Academic Specialist Center 
Solnavägen 1E 
Stockholm 113 65 
Sweden 
Phone: +46 73 671 81 01 
E-mail: Fredrik.piehl@sll.se 
Clinical monitoring organization 
 
 
Contact Person 
KTA Support 
Sabbatsbergssjukhus 
Olivecronasväg15 
113 61 Stockholm 
Sweden 
Sofia Henriksson 
Phone: +46 72-599 10 
E-mail: sofia.j.henriksson@sll.se 


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Role 
 
Contract Research Organization for data 
management, IWRS/eCRF and statistical 
analyses: 
eXYSTAT SAS 
4 Rue Ernest Renan 
92240 Malakoff 
France 
Phone : +33 9 81 15 18 30 
E-mail : contact@exystat.com 
Pharmacovigilance 
 
 
Contact Person 
Worldwide Clinical Trials – Pharmacovigilance  
1st Floor, Waterfront House 
Beeston Business Park, Beeston 
Nottingham, NG9 1LA  
UK 
Chandni Daudia 
Phone : +44 (0)115 922 0960 
E-mail : Chandni.Daudia@worldwide.com 
Manufacture, IMP and placebo, labeling and 
shipment 
Polymun Scientific 
Donaustr. 99 
3400 Klosterneuburg 
Austria 
Phone : +43 2243 25060 300 
Central laboratory for PK 
BioAgilytix Europe GmbH 
Lademannbogen 10 
22339 Hamburg 
Germany 
Phone : +49 40 526779 3 
Safety Laboratory 
KS Laboratory  
Karolinska Universitetssjukhuset  
Solna 
171 76 Stockholm 
Sweden 
E-mail: universitetslaboratoriet.karolinska@sll.se 
MRI Analysis 
MRI Acquisition & Reading Center 
Karolinska University Hospital 
Department of Neuroradiology 
141 86 Stockholm 
Sweden 
Phone: +46 8 585 808 48 
E-Mail: tobias.granberg@ki.se 
MRI Analysis 
MRI Reading Center  
Basel University Hospital, Department of Neurology 
E-mail: cristina.granziera@usb.ch 


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Role 
 
NfL Analysis 
Departments of Medicine 
Biomedicine and Clinical Research 
University Hospital Basel 
University Basel 
Phone: +41 613287191 
E-mail: Jens.Kuhle@usb.ch 
 
 
 


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List of used acronyms and abbreviations 
Ab 
ADA 
Antibody 
Anti drug antibody 
AE 
AESI 
Adverse event 
Adverse event of special interest  
ALT 
ARR 
Alanine aminotransferase  
Annual relapse rate 
AST 
CA 
CC 
Aspartate aminotransferase 
Competent Authorities 
Cerebral Cortex 
CNS 
Central nervous system 
CRO 
Contract research organization 
CSF 
CSP 
CRF 
Cerebrospinal fluid 
Clinical study protocol 
Case report form 
DBP 
DMT 
Diastolic blood pressure 
Disease modifying therapies 
DSMB 
Data Monitoring Safety Board 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDSS 
EMA 
Env 
EQ-5D 
FLAIR 
Expanded disability status scale 
European Medicines Agency 
Envelope protein 
EuroQol five dimension scale 
Fluid-attenuated inversion recovery 
FPCBP 
Female patient of childbearing potential 
GCP 
GDPR 
Good Clinical Practice 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
HBc / HBs 
Hepatitis B virus core / surface 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HERV 
Human endogenous retrovirus 
pHERV-W Env 
Pathogenic Human endogenous retrovirus W envelope protein 


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HIV 
Human immunodeficiency virus 
hsCRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IRS 
ISF 
Interactive response system 
Investigator site file 
IV 
LOCF 
Intravenous 
last observation carried forward 
LP 
Lumbar puncture 
mAb 
Monoclonal antibody 
MedDRA 
MPA 
Medical dictionary for regulatory activities 
Medical Products Agency 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MS 
Multiple sclerosis 
MSRV 
MTR 
Multiple sclerosis-associated endogenous retrovirus  
Magnetization transfer 
NAWM 
NBGLM 
Normal-appearing white matter  
Negative binomial generalized linear model 
NfL 
ODRS 
OPC 
PCBP 
Neurofilament light chain 
Overall Disability Response Score 
Oligodendrocyte precursor cell 
Partners of childbearing potential 
pHERV 
Pathogenic human endogenous retrovirus 
PK 
PT 
PMP 
Pharmacokinetics 
Preferred Term 
Procreative male patient 
PMS 
Progressive multiple sclerosis 
PPMS 
REMyDI 
QoL 
Primary progressive multiple sclerosis 
Rapid estimation of myelin for diagnostic imaging 
Quality of life 
RMS 
Relapsing multiple sclerosis 
RRMS 
Relapsing remitting multiple sclerosis 
SAE 
Serious adverse event 


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SAP 
SDMT 
SERA 
Statistical analysis plan 
Symbol Digit Modalities Test 
Swedish Ethical Review Authority 
SOC 
System Organ Class 
SPMS 
Secondary progressive multiple sclerosis 
SUSAR 
TEAE 
Suspected unexpected serious adverse reaction 
Treatment emergent adverse events 
TNF 
T25FW 
ULN 
WHO 
9-HPT 
Tumor necrosis factor 
Timed 25-foot walk 
Upper limit of normal range 
World Health Organization 
9-Hole Peg Test 
 
 
 
 
 
 


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1. Synopsis 
EudraCT number: 
2019-004822-15 
Title: 
A Randomized, Double-Blind, Placebo Controlled Trial, Examining the Safety, 
Tolerability, Pharmacodynamic Effects and Pharmacokinetics of Temelimab 
Following Rituximab Treatment in Patients with Relapsing Forms of Multiple 
Sclerosis (RMS) 
 
Study code:  
GNC-401 
Development 
Phase: 
IIa 
Short Rationale: 
Temelimab, a humanised, IgG4-κ monoclonal antibody represents a novel 
therapeutic approach for degenerative features of Multiple Sclerosis (MS).  
Preclinical studies have shown that the envelope protein of the pathogenic human 
endogenous retrovirus type W (pHERV-W Env) activates microglia into pro-
inflammatory phenotype. Furthermore, in the presence of pHERV-W Env, 
oligodendrocyte precursor cells (OPCs) will not mature into functional 
oligodendrocytes, thereby preventing optimal remyelination. Temelimab inhibits 
these effects in preclinical models, both in vitro and in vivo.  
The postulated mode of action of temelimab is to neutralise pHERV-W Env and 
hence to prevent the pHERV-W Env induced pro-inflammatory activation of 
microglia, and to preserve OPC maturation. Both these cell types are key cellular 
targets in neurodegeneration of MS that eventually manifests as disease 
progression/disability worsening independent of relapse activity and lesion 
formation. Therefore, temelimab, is expected to address an unmet medical need 
for patients suffering from MS. 
In neuropathological studies, pHERV-W Env was found in chronic active MS lesions, 
which are considered a main driver of progression in MS and may persist despite 
current standard disease modifying therapies. 
Temelimab has been studied in Phase 2b clinical studies in two-hundred-seventy 
(270) relapsing-remitting MS (RRMS) patients for up to 96 weeks. In these studies, 
temelimab showed neuroprotective effects, as documented by:  
• 
reduction in volume loss in whole brain, cerebral cortex and thalamus, 
• 
reduction in T1 hypointense (T1 Black Hole) lesion number and volume,   
• 
stabilization of magnetization transfer ratio (a magnetic resonance 
imaging (MRI) measure of myelin integrity) in both normal-appearing 
white matter and cerebral cortex, over 96 Weeks.  
However, no clinically-relevant effects were observed with temelimab as 
monotherapy on MRI measures of neuroinflammation in RRMS patients.  
Phase 2 clinical trial data with rituximab in RRMS patients demonstrated highly 
significant effects on neuroinflammation, which is seen even years after cessation 
of treatment. In contrast, rituximab failed to demonstrate a statistically significant 
effect on disease progression in Primary progressive multiple sclerosis (PPMS). 


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Although rituximab is not approved by the European Medicines Agency (EMA) for 
any form of MS, rituximab has become the most frequent disease modulatory 
treatment in Sweden for MS, based on positive results obtained in several real 
world cohorts.  
Therefore, the introduction of temelimab treatment, in relapsing MS (RMS) 
patients who have been treated with rituximab, and hence experience sustained 
reduction of relapse activity and lesion formation is postulated to have a 
significant additional beneficial effect on disease progression.  
In all preclinical as well as clinical studies to date, temelimab has shown to be well 
tolerated with no apparent safety signal either at repeated doses over two years 
in RRMS, or at single doses in healthy human volunteers as high as 110 mg/kg. 
In addition, no drug-drug interactions are expected with the staggered 
administration of temelimab after rituximab, based on data from human ex vivo 
models. 
This proposed clinical Phase 2a study will be performed in patients with RMS who 
have been receiving rituximab off-label, as per local clinical practice guidelines for 
at least 12 months. In this study temelimab is administered subsequently to 
rituximab therapy, i.e. no co-administration of rituximab and temelimab is done in 
this study. 
 
 
Primary 
objective: 
Secondary 
objective: 
 
Exploratory 
objectives: 
• 
To assess the safety and tolerability of temelimab following intravenous 
(IV) administration of 18 mg/kg, 36 mg/kg or 54 mg/kg, in patients with 
RMS who have been treated with rituximab for at least 1 year. 
 
• 
To determine the pharmacodynamic effects of temelimab on 
neuroprotection and remyelination based on neuroimaging. 
 
• 
To assess the clinical and cognitive effects of temelimab (including physical 
disability) 
• 
To assess the effect of temelimab on quality of life 
• 
To assess the effects of temelimab on exploratory neuroimaging 
endpoints associated with neuroprotection and remyelination. 
• 
To assess the effects of temelimab on fluid biomarkers associated to 
myelin integrity, target and immune function 
• 
To determine the PK characteristics of temelimab following repeated IV 
administration (including CSF distribution) and immunogenicity 
 
Study design: 
This is a randomized, double-blind, placebo-controlled Phase IIa clinical study, 
assessing safety, tolerability, pharmacodynamic effects and pharmacokinetics of 
temelimab, administered at three different dose levels (18 mg/kg or 36 mg/kg or 
54 mg/kg). 
The study will consist of a Screening period of a maximum duration of up to 3 
weeks (Days -21 to -1) and a treatment period of 48 weeks. On Day 1 all patients 
who meet eligibility criteria may be randomized (randomization ratio 1:1:1:1) into: 
• 
the placebo group 
• 
the 18 mg/kg group 


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• 
the 36 mg/kg group  
• 
the 54 mg/kg group 
When the first eight (8), patients randomized into either placebo, 18, 36 or 54 
mg/kg group respectively, have achieved ≥2 months (8 weeks) of exposure to IMP, 
formal review by an independent Data Safety Monitoring Board (DSMB) of all of 
the available safety data from the study will be performed. 
The independent DSMB will meet thereafter every 4 months and review all of the 
available safety data. 
 
All patients will receive double-blind IV infusions of study drug (temelimab 18 
mg/kg, 36 mg/kg, 54 mg/kg or matching placebo), via monthly IV infusions for up 
to Week 44. All patients will be observed for 6 hours following completion of the 
first administration of IMP infusion and at least 2 hours following completion of 
the subsequent IMP infusions (second to twelfth). Intra-patient dose escalation of 
temelimab is not permitted.  
Study population: Patients with RMS who have been treated with rituximab for at least 1 year and 
who meet inclusion/exclusion criteria. 
Number of 
subjects: 
40 patients with RMS will be randomized and enrolled (30 temelimab at three 
dose levels (18, 36 or 54 mg/kg) and 10 placebo)  
Inclusion criteria: 
1. The subject has given written informed consent to participate in the 
study 
2. Current diagnosis of RMS, based on the McDonald 2017 criteria1 
3. Having received treatment with rituximab, as per local clinical routine for 
at least 12 months prior to the Screening Visit 
4. Having received their last dose of rituximab not more than 8 weeks and 
not less than 4 weeks before Randomization (Study Day 1) 
5. Having B-cell count < Lower limit of detection (LLOD) (<0.01*10-9 CD19+ 
cells/ L) 
6. Having expanded disability status scale (EDSS) 2.5 – 5.5 inclusive at 
Screening 
7. Present clinical worsening in one or more neurological domains as 
assessed by EDSS, ambulatory function as assessed by 6MWT or T25FW, 
cognitive functioning as assessed by SDMT or increased need of walking 
aids or pharmacological/procedures for bowel and bladder functions  over 
the last year.  
8. Brain Magnetic resonance imaging (MRI), lesion burden with >9 T2 
cerebral lesions (assessed within the last 24 months) 
9. Stable clinical presentation of MS for 30 days prior to Screening e.g. no 
relapse, no acute neurological exacerbation. 
10. Age range from 18 to 55 years (both inclusive) 
11. Body weight between 40 – 100 kg (both ranges are inclusive) 
12. No disease modifying therapies (DMTs) other than rituximab, within 12 
months of Screening 


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13. No contraindication to Biomarker assessments: brain Magnetic resonance 
imaging (MRI), blood/serum collection and cerebrospinal fluid (CSF) 
collection 
14. Agreeing to undergo two lumbar puncture 
15. Be willing and able to follow all study procedures and assessments 
according to the study protocol 
16. Female patients of childbearing potential (FPCBP) or procreative male 
patients (PMP), willing to use highly effective contraceptive methods 
throughout the study duration and at least until 5 months after the last 
study treatment. The investigators must inform the participant about the 
risks not to use an effective method of birth control during the course of 
the study and they should discuss with the participant the most 
appropriate method. 
o FPCBP means female patients who are neither menopausal (for a 
minimum of at least 2 years), nor underwent irreversible surgical 
procedures leading to permanent infertility like bilateral tubal 
occlusion or hysterectomy; 
o PMP means male patients who have a female partner of 
childbearing potential and who are not vasectomized (vasectomy 
to have been a minimum of 10 weeks ago) or underwent other 
surgical procedures leading to permanent infertility; 
o Partners of childbearing potential (PCBP) means female partners 
of a PMP who are neither menopausal (for a minimum of at least 
2 years), nor underwent irreversible surgical procedures leading 
to permanent infertility like tubal ligation or hysterectomy; 
o FPCBP and PMP, as well as non-pregnant PCBP, must use an 
effective method of birth control, as described below, (additional 
local requirements may apply) throughout the study and for at 
least 5 months after the last dose of study treatment: 
▪ 
For FPCBP or PCBP, highly effective methods of birth 
control refer to those which result in a low failure rate (i.e. 
less than 1% per year), when used consistently and 
correctly, such as combined hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, 
transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, 
implantable), some intra uterine devices (IUDs), 
intrauterine hormone-releasing system (IUS), true sexual 
abstinence (when this is in line with the preferred and 
usual lifestyle of the participant), or male partner 
sterilization (vasectomy to have been a minimum of 10 
weeks ago);  
▪ 
For PMP, the barrier method of contraception, condom is 
considered as acceptable 
 
 


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Exclusion criteria: 1. Current diagnosis of primary progressive MS (PPMS) 
2. Any disease other than MS (e.g. myelitis and /or bilateral optic neuritis) that 
could better explain the patient’s signs and symptoms 
3. Usage of any of the following medications prior to the Screening visit: 
a) Any usage of interferon beta, glatiramer acetate, IV immunoglobulin 
(IVIG), dimethyl fumarate or teriflunomide within 12 months prior to 
Screening, 
b) Any history of exposure to mitoxantrone, cladribine, alemtuzumab, 
cyclophosphamide, systemic cytotoxic therapy, total lymphoid irradiation, 
and/or bone marrow transplantation at any time, 
c) Any usage of natalizumab within 24 months prior to Screening, 
d) Any usage of highly potent immune modulating therapy, such as: 
ocrelizumab, ofatumumab, fingolimod, siponimod, ozanimod or anti-
cytokine therapy, plasmapheresis or azathioprine within 12 months prior 
to Screening, 
e) Any usage of any experimental treatment if not washed out for ≥ 5 half-
lives or ≥ 12 months (whichever is longer), except rituximab which is 
allowed before the study. 
4. CTCAE Grade 2 or greater lymphopenia 
5. Any major medical or psychiatric disorder that would affect the capacity of the 
patient to fulfill the requirements of the study, including: 
a) Diagnosis or history of schizophrenia 
b) Current diagnosis of moderate to severe bipolar disorder, major 
depressive disorder, major depressive episode, history of suicide attempt, 
or current suicidal ideation 
c) Current or past (within the last 2 years) alcohol or drug abuse 
6. History or presence of serious or acute heart disease such as uncontrolled 
cardiac 
dysrhythmia 
or 
arrhythmia, 
uncontrolled 
angina 
pectoris, 
cardiomyopathy, or uncontrolled congestive heart failure (NYHA class 3 or 4) 
7. Known inability to undergo an MRI scan 
8. Contraindications to the use of glucose 5% infusion  
9. Inability to follow study instructions, or complete study assessments, as 
defined by the protocol 
10. Any history of cancer with the exceptions of basal cell carcinoma and/or 
carcinoma in situ of the cervix, and only if successfully treated by complete 
surgical resection, with documented clean margins and any medically unstable 
condition as determined by the investigator  
11. Legal incapacity or limited legal capacity 
12. Pregnant or breastfeeding women 


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13. History of, or positive serology for viral hepatitis B not explained by vaccination 
(see table) 
Serological Hepatitis B status 
HBsAg 
Anti-HBc AbAnti-HBs Ab
eligible 
• 
No history 
- 
- 
- 
yes 
• 
Vaccination 
- 
- 
+ 
yes 
• 
Past (resolved) infection 
- 
+ 
+ 
no 
• 
Acute infection / chronic 
carrier 
+ 
+/- 
- 
no 
• 
Doubtful case 
- 
+ 
- 
no 
14. History of, or positive serology for viral hepatitis C or human 
immunodeficiency virus (HIV) at any time 
15. Abnormal liver function tests: AST or ALT > 2 times upper limit of normal range 
(ULN), or conjugated bilirubin > 2 times ULN, or AP or GGT > 3 times ULN 
16. Positive pregnancy test at any time  
A FPCBP cannot be included in the study if any of the following occurs: 
• 
The urine dipstick pregnancy test indicates a positive result 
and the pregnancy has not yet been ruled out by the 
subsequent blood test 
• 
No urine dipstick pregnancy test has been performed 
• 
The urine dipstick pregnancy test indicates a negative 
result, but an early pregnancy (≤ 2 weeks from conception) 
is suspected by the investigator based on anamnestic or 
clinical elements and cannot be ruled out by further 
investigations 
 
Investigational 
product(s), 
dosage, 
administration: 
Temelimab 18 mg/kg, 36 mg/kg, 54 mg/kg or matching placebo will be given as 
monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations 
in total). 
 
Study endpoints: 
Primary endpoints:  
• 
Overall Summary of Adverse Events  
• 
AEs by Primary SOC and PT 
• 
SAE by Primary SOC and PT 
• 
Physical Examination: Shift from Baseline to worst post-dose result by 
Body System 
• 
ECG Interpretation: Change from Baseline to Week 48 and Summary 
Statistics for change from Baseline to Week 48 
• 
Vital Signs: Summary Statistics For Change From Baseline By Follow-Up 
Visit 


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• 
Concomitant Medications by WHO ATC Level Class 1 and WHO ATC 
Level Class 2 
• 
Hematology: Normal Range Shifts from Baseline by Follow-Up visit 
• 
Clinical Chemistry (including C-reactive protein): Normal Range Shifts 
from Baseline by Follow-Up Visit -Safety Set 
• 
Coagulation: Normal Range Shifts from Baseline by Follow-Up Visit -
Safety Set 
• 
Urinalysis: Normal Range Shifts from Baseline by Follow-Up Visit 
 
 
Secondary endpoints:  
• 
Change in magnetization transfer (MTR) in periventricular normal-
appearing white matter (NAWM) at week 48 compared to baseline 
• 
Change in magnetization transfer (MTR) in cerebral cortex at week 48 
compared to baseline   
• 
Change in T1 lesion volume at week 48 compared to baseline 
• 
Change in T2 lesion volume at week 48 compared to baseline 
• 
Change in brain parenchymal volume fraction at week 48 compared to 
baseline 
• 
Change in thalamic volume fraction at week 48 compared to baseline 
 
Exploratory endpoints   
• 
An “Overall Disability Response Score” (ODRS) which takes into 
consideration EDSS, T25FW, dominant and non-dominant 9-HPT, 
accounting 
for 
Worsening 
and 
Improvement 
on 
Respective 
Components from Baseline to Week 48 
• 
Event of relapse, as measured by time to relapse and annual relapse rate 
(ARR) 
• 
Change in Symbol Digit Modalities Test (SDMT) Score at Week 48 
compared to Baseline  
• 
Change in Quality of Life (EQ-5D) at Week 48 compared to Baseline. 
• 
Number of new T2 lesions at Week 48 
• 
Change in cortical thickness at week 48 compared to baseline 
• 
Change in REMyDI myelin fraction in lesions at week 48 compared to 
baseline 
• 
Change in REMyDI myelin fraction in NAWM at week 48 compared to 
baseline 
• 
Change in intra-lesional axonal density at week 48 compared to baseline 
as measured with multi-shell diffusion 
• 
Change in NAWM axonal density at week 48 compared to baseline as 
measured with multi-shell diffusion 
• 
Change in axonal density, MTR, REMyDI myelin fraction in rim lesions 
(as part of slowly expanding lesions) vs non-rim lesions at week 48 
compared to baseline 


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• 
Change in levels of neurofilament-light chain protein (NfL) in serum at 
Week 48 compared to baseline (Day 1) 
• 
Change in levels of neurofilament-light chain protein in CSF at Week 48 
compared to baseline (Day 1) 
• 
Change in levels of proteins or gene expression related to MS or the 
target of temelimab (pHERV-W ENV), in blood at Week 48 compared to 
Baseline and in CSF at Week 46 compared to Baseline  
• 
Change in levels of immunoglobulin (Ig) levels in blood (including Total 
Ig, IgG, IgM, and IgA isotypes) at Week 48 compared to baseline (Day 1) 
• 
Pharmacokinetics (PK) in serum of repeated doses of temelimab at 
Weeks 4, 24, 46 and 48 
• 
Levels of temelimab in CSF at D15 post last study drug administration 
(Week 46) 
• 
Antidrug antibodies (ADA) in serum of repeated doses of temelimab at 
pre dose Day 1, Weeks 4, 24, 46 and 48 (or, in case of early termination, at 
the study discontinuation visit) 
 
 
Study period: 
Q2 2020 (First Patient First Visit)– Q4 2021 (Last Patient Last Visit) 
 
 
2. Statistics 
 Statistical analysis will be performed by eXYSTAT SAS. A Statistical Analysis Plan (SAP), and 
associated templates for Tables, Listings and Figures, will be written and signed before the database 
lock and study unblinding. These specifications will detail the implementation of all the planned 
statistical analyses in accordance with the main characteristics stated in this protocol. 
2.1. Analysis population 
Randomized Set (RS): All patients to whom a therapeutic treatment was randomly assigned using 
IRS. Patients will be analyzed in their randomization group whatever the treatment they received 
Safety Set (SS): All patients having taken at least one dose of IMP. Patients will be affected to the 
group of treatment they received. 
 
 
2.2. Statistical methods 
2.2.1. 
General considerations 
The following descriptive statistics will be provided depending on the nature of considered data: 
- Qualitative data: number of observed values, number and percentage of patients per class; 
- Quantitative data: number of observed values, mean and standard deviation, median, first and 


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third quartiles, minimum and maximum; 
- Survival data (time to event occurrence or to censoring): total number of patients, total 
number and percentage of patients having an event, number of patients at risk, number of 
patients with censored data, number of patients with event of interest. 
 
The type I error will be set at α = 5% two-sided. 
The treatment effect (temelimab versus placebo) will be estimated as well as its precision: 
estimate of the difference, standard error (SE) of the estimate and two-sided 95% confidence 
interval (CI) of the estimate. 
In case of formal comparison between treatment groups, the two-sided p-value associated with 
the treatment effect will also be provided. 
All inferential analyses are considered as exploratory in order to have a first estimation of 
treatment effect. Consequently, no method to handle with multiplicity issues is needed. 
 
 
2.2.2. 
 Study patients:  
Demographic data and other baseline characteristics will be described by treatment group, to 
assess their comparability, and overall in the RS population. The main patients’ characteristics will 
also be described for SS population. 
Disposition of patients, including reasons for withdrawal, protocol deviations, extent of exposure 
and treatment compliance, as well as concomitant treatments will be described in the RS 
population. 
 
2.2.3. 
Safety analysis 
Safety and tolerability of temelimab and placebo will be assessed in each treatment group in the 
safety population. 
AE summaries will include all AEs starting on or after study day 1 (i.e. on the day of or following the 
day of first study treatment administration) and starting before the end of study visit, i.e. 4 weeks 
after the date of last study treatment administration. 
A Summary of AEs (number and % of patients, number of AEs) and summarized by System Organ 
Class (SOC) and Preferred Term (PT) will be tabulated by treatment group and overall for patients 
with: 
- 
at least one treatment-emergent adverse event (TEAE), 
- 
at least one related treatment-emergent adverse event (TEAE), 
- 
at least one severe treatment-emergent adverse event (TEAE), 
- 
at least one severe related treatment-emergent adverse event (TEAE), 
- 
at least one serious TEAE, 
- 
at least one serious TEAE related to the study treatment, 
- 
a TEAE leading to treatment discontinuation, 
- 
a related TEAE leading to treatment discontinuation, 
- 
a TEAE leading to death. 
 


Study Code: 
 
GNC-401 
Version No: 
 
3.0  
Version Date:  
2020-05-01 
 
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AEs will be summarized by presenting the number and percentage of patients having at least one AE 
and by number of AEs, overall and by treatment group. Data will be presented by SOC and PT using 
the latest version of MedDRA. A patient with multiple occurrences of the same PT will be counted 
only once in the AE category. 
Separate AE summaries will be presented by SOC, PT, and severity. In the summaries presented by 
severity, all AEs will be pooled. Specific tables will summarize related AEs to temelimab. 
Written narratives will be produced for all SAEs. 
Adverse events/SAEs occurring after signing the Inform Consent Form (ICF) but before starting study 
treatment, including those observed in patients included but never treated with the IMP, will be 
listed separately from those occurring after treatment start.  
Adverse events/SAEs occurring after 4 weeks after the date of last study treatment administration 
will be also listed separately. 
Laboratory data analysis: 
The summaries will include all laboratory assessments collected during the study.  
All laboratory values will be converted into SI units and will have a severity grade calculated using 
appropriate common terminology criteria for AEs (NCI CTCAE, version 4.03). A listing of laboratory 
values will be provided by laboratory parameter and by patient. A separate listing will display notable 
laboratory abnormalities (i.e. newly occurring CTCAE Grade 3 or 4 laboratory toxicities). The 
frequency of these notable laboratory abnormalities will be displayed by parameter.  
Shift tables using CTCAE grades to compare baseline to the worst post-baseline value will be 
produced for all relevant safety measures as described in the statistical analysis plan. Note that for 
parameters with two directions abnormalities (hypo/hyper), two tables will be presented. 
The shift tables using Normal Range Shifts from Baseline will be also produced for all safety measures 
as described in the section 4.3. 
Vital signs and physical examination 
Vital signs and physical examination will be described, in terms of value at baseline, value at each 
post-baseline visit; as well as in terms of change from baseline to each post baseline visit. For 
physical Examination: Shift from Baseline to Worst Post dose Result by Body System will be 
provided.  
Other safety data 
Other safety data (e.g. 12-lead electrocardiogram, concomitant medication use) will be listed, 
notable values will be flagged, and any other information collected will be listed as appropriate. Any 
statistical procedures performed in order to explore the data will be used only to highlight any 
comparisons that may warrant further consideration. Change from Baseline by Follow-Up Visit and 
Summary Statistics for Change from Baseline By Follow-Up Visit will be provided. 
 
10.2.4 Efficacy analyses  
Each secondary endpoint will be described by treatment group in the RS population. 


Study Code: 
 
GNC-401 
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For exploratory analyses, Frequentist and Bayesian methodologies will be used. 
For the frequentist approach change from baseline at Week 48 will be analyzed using a non-
parametric ANCOVA including baseline and treatment as factors.  
For all analyses, estimate of treatment effect (temelimab versus placebo), its SE and 95% CI, as well 
as the associated p-value will be provided. 
In addition, exploratory Bayesian analysis will be done using a non-informative prior on mean and 
standard error. The Posterior probability that the change from baseline at Week 48 is <0 will be 
provided for each dose and for placebo with its 95% credible interval (measure of Bayesian 
precision).  
An alternative Bayesian version of the T-test: Bayesian Estimation Supersedes the t-test (BEST) 
developed by (Kruschke, 2012) will also be used74. The difference of the change in lesion volume 
between each dose and placebo and the posterior probability that Delta versus placebo is >0  will be 
provided . If these posterior probabilities are > 80%, temelimab could be considered as interesting 
for future development. 
Those probabilities will also be provided for the other measurements of change. 
For sensitivity analyses, the same analyses will be performed comparing pooled dose with placebo. 
10.2.5 Exploratory analyses  
10.2.5.1 
PK interpretation 
Standard PK parameters such as minimum serum concentrations (Cmin) and, accumulation factor, 
will be derived. The PK parameters will be described by treatment groups to make an initial 
assessment of dose linearity/proportionality. 
Descriptive statistics (mean, standard deviation, median, min, max, variation coefficient) will be 
performed on CSF and serum concentrations of temelimab and PK parameters. Data will be 
evaluated by standard summary statistics and additional descriptive methods including individual 
data listings and plots of individual and group data. Further population PK analysis is envisaged based 
on the collected data. 
10.2.5.2 
Exploratory analyses 
Each exploratory endpoint will be described by treatment group in the RS population. 
Same Frequentist and Bayesian methodologies will be used. 
For frequentist approach change from baseline at Week 48 will be analyzed using a non-parametric 
ANCOVA including baseline and treatment as factors.  
Time to first relapse will be analyzed by Kaplan-Meier method and the associated log-rank test.   
For the number of new T2 lesions, each dose will be compared to placebo using a Negative Binomial 
Generalized Linear Model (NBGLM) studying treatment effect and adjusted for baseline and 
treatment.  
 


Study Code: 
 
GNC-401 
Version No: 
 
3.0  
Version Date:  
2020-05-01 
 
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2.3. Determination of sample size 
The total sample size (N=40) is not based on a formal statistical assessment. This number of subjects 
is considered sufficient to achieve the primary safety objective of the study which will be based on a 
descriptive evaluation of safety data, in addition the difference dosage and placebo will allow to 
assess any variations in terms of severity or frequency or adverse events between the doses. 
For the secondary endpoints the sample size was assessed as follows: 
 
Results from MTR% (peri-ventricular bands) in the GNC-004 study are:  
• 0.84%±4.84 in the 18 mg/kg dose (n=23) 
• -3.17%±2.05 for placebo (n=26) 
 
 
Simulation on SAS© Version 9.4 and on R software have been performed in order to explore the 
capability of the study to detect a signal of efficacy.  
 
The table below gives the power according to several hypotheses for the 40 patients. 
 
Table 3. Power and posterior probabilities simulations with alpha 5% two-sided 
Temelimab 
(n=10) 
Placebo (n=10) 
Delta 
Temelimab 
Placebo 
Power for 
at least 
one dose 
superior 
to placebo 
Power 
for 
pooled 
doses 
versus 
placebo 
Posterior P(at 
least one 
dose with 
delta>0)>95% 
Posterior 
P(pooled 
doses with 
delta>0)>95% 
Mean 
Std 
Mean 
Std 
Mean 
Std 
Non parametric Sign 
test 
MCMC simulations 
-0.84 
4.84 
-3.17 
2.05 
2.33 
5.26 
52% 
63% 
78% 
90% 
-0.5 
4 
-3 
2 
2.5 
4.47 
67% 
83% 
88% 
95% 
0 
4 
-3 
2 
3 
4.47 
80% 
94% 
96% 
>95% 
1 
4 
-3 
2 
4 
4.47 
95% 
>95% 
>95% 
>95% 
 
With 10 patients per group, -3%±2 for placebo and 0%±4 for temelimab, the study has 80% power to 
show a statistically significant (5% two-sided) difference for at least one dose. The power is higher 
than 80% for the comparison of pooled dose (n=30) versus placebo.