Relapsing Multiple Sclerosis

Primary: To demonstrate superior efficacy with evobrutinib compared to teriflunomide in terms of Annualized Relapse Rate (ARR) Secondary: 1. To demonstrate the efficacy of evobrutinib relative to that of teriflunomide on disability progression 2. To demonstrate the efficacy of evobrutinib relative to that of teriflunomide on patient reported symptoms and functional status 3. To demonstrate the efficacy of evobrutinib relative to that of teriflunomide on magnetic resonance imaging (MRI) lesion parameters 4. To characterize the safety and tolerability of evobrutinib

Evobrutinib

Evobrutinib

Film-coated Tablet

45

Primary:
ARR based on qualified relapses at Week 96 in participants with RMS
Secondary:
1.  Time to first occurrence of 12-week
confirmed disability progression (CDP) as
measured by the Expanded Disability Status
Scale (EDSS) over 96 weeks
 Time to first occurrence of 24-week CDP as
measured by the EDSS over 96 weeks
2.  Change from Baseline (CFB) in Patient
Reported Outcomes Measurement
Information System (PROMIS) physical
function (PF) score at 96 weeks
 CFB in PROMIS Fatigue score at 96 weeks
3.  Total number of T1 Gd+ lesions based on
assessments at Week 24, Week 48, and
Week 96
 Total number of new or enlarging T2 lesions
based on assessments at Week 24, Week 48,
and Week 96
4. Safety as assessed by the nature, severity, and
occurrence of adverse events (AEs) and adverse
events of special interest (AESIs); vital signs;
electrocardiograms (ECGs); absolute
concentrations and change from Baseline in
immunoglobulin (Ig) levels; and clinical
laboratory safety parameters up to Week 108

Age
1. Are 18 to 55 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Are diagnosed with RMS (relapsing-remitting multiple sclerosis [RRMS] or SPMS with
relapses) in accordance with 2017 Revised McDonald criteria (Thompson 2018).
3. One or more documented relapses within the 2 years before Screening with either:
a. one relapse which occurred within the last year prior to randomization, OR
b. the presence of at least 1 Gd+ T1 lesion within 6 months prior to randomization.
4. Have an EDSS score of 0 to 5.5 at Screening and Baseline (Day 1)
a. Participants with an EDSS score ≤ 2 at Screening and Baseline (Day 1) are only
eligible for participation if their disease duration (time since onset of symptoms) is
no more than 10 years.
5. Are neurologically stable for ≥ 30 days prior to both Screening and Baseline.
Sex
6. Are female or male
a. Male Participants:
Agree to the following during the study intervention period and for at least 2 years
after study intervention due to the long elimination period for teriflunomide of 2 years,
unless the participant undergoes an accelerated elimination procedure (see
Appendix 8) with a confirmed teriflunomide level of < 0.02 mg/L after the last dose
of study intervention:
Refrain from donating sperm
PLUS, either:
Abstain from intercourse with a Woman of Childbearing Potential (WOCBP).
OR
 Use a male condom:
o When having sexual intercourse with a WOCBP, who is not currently
pregnant, and advise her to use a highly effective contraceptive method
with a failure rate of < 1% per year, as described in Appendix 3, since
a condom may break or leak.
b. Female participants
 Are not pregnant or breastfeeding, and at least one of the following conditions
applies:
o Not a WOCBP.
OR
o If a WOCBP, use a highly effective contraceptive method (i.e., with a
failure rate of < 1% per year), preferably with low user dependency, as
described in Appendix 3 for the following time periods:
 Before the first dose of the study intervention(s), if using
hormonal contraception:
 Has completed at least one 4-week cycle of an oral
contraception pill and either had or has begun her menses
OR
 Has used a depot contraceptive or extended-cycle oral
contraceptive for at least 28 days and has a documented
negative pregnancy test using a highly sensitive assay.
AND
o A barrier method, as described in Appendix 3
 Have a negative serum or highly sensitive urine pregnancy test,
as required by local regulations, within 4 to 8 weeks and a highly
sensitive urine pregnancy test at Baseline before the first dose of
study intervention. If a urine test cannot be confirmed as negative
(e.g., an ambiguous result), a serum pregnancy test is required.
 During the Intervention Period
For at least 2 years after study intervention due to the long
elimination period for teriflunomide of (up to) 2 years, unless the
participant undergoes an accelerated elimination procedure (see
Appendix 8) with a confirmed teriflunomide level of < 0.02 mg/L
after the last dose of study intervention and agree not to donate
eggs (ova, oocytes) for reproduction during this period (see
Appendix 9). The Investigator evaluates the effectiveness of the
contraceptive method in relationship to the first dose of study
intervention.
 Additional requirements for pregnancy testing during and after study intervention are
in Sections 8.2.4 and 8.2.5.
 The Investigator reviews the medical history, menstrual history, and recent sexual
activity to decrease the risk for inclusion of a female with an early undetected
pregnancy.
Informed Consent
7. Capable of giving signed informed consent, as indicated in Appendix 2, which includes
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and this protocol.
8. Participants must be contactable by email or telephone throughout the study.

Medical Conditions
1. Participants diagnosed with progressive MS, in accordance with the 2017 Revised
McDonald criteria, as follows:
a. Participants with primary progressive MS.
b. Participants with SPMS without evidence of relapse.
2. Disease duration > 10 years in participants with an EDSS ≤ 2.0 at Screening and Baseline
(Day 1).
3. Immunologic disorder other than MS or any other condition requiring oral, intravenous
(IV), intramuscular, or intra-articular corticosteroid therapy, with the exception of
well-controlled Type 2 diabetes mellitus or well controlled thyroid disease.
4. History or current diagnosis of other neurological disorders that may mimic MS, including
but not limited to: neuromyelitis optica, transverse myelitis, bilateral optic neuritis of
simultaneous onset, Lyme disease, HTLV-1-associated myelopathy, untreated vitamin
B12 deficiency, neurosarcoidosis, cerebrovascular disorders, documented peripheral
neuropathy (including polyneuropathy or mononeuropathy).
5. History or current diagnosis of PML. If a brain MRI has findings suggestive of PML,
cerebrospinal fluid JC virus polymerase chain reaction (CSF JCV PCR) should be
performed to rule out PML (see Appendix 7).
6. Active, clinically significant viral, bacterial, or fungal infection, or any major episode of
infection requiring hospitalization or treatment with parenteral anti-infectives within
4 weeks of Screening, or completion of oral anti-infectives within 2 weeks before or
during Screening, or a history of recurrent infections (i.e., 3 or more of the same type of
infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital
or oral herpes simplex virus considered by the Investigator to be sufficiently controlled
would not be exclusionary.
7. The participant:
 Has a history of or current diagnosis of active tuberculosis (TB)
OR
 Is currently undergoing treatment for latent TB infection (LTBI)
OR
 Has an untreated LTBI as determined by documented results within 3 months of the
Screening Visit of a positive TB skin test with purified protein derivative (PPD) with
induration ≥ 5 mm.
OR
 Has current household contacts with active TB, unless prophylaxis treatment has
been completed and documented evidence that household contacts have completed
treatment.
OR
 Has a positive QuantiFERON-TB test at Screening, unless the participant has
completed chemoprophylaxis for LTBI (as per applicable local guidelines) prior to
the Screening Visit. Study participants in high TB burden settings (> 100 cases / 100,000 individuals
[World Health Organization, 2019], based on World Health Organization [WHO] TB
database [WHO TB Burden Estimates]) must repeat QuantiFERON testing at least
annually at the visits indicated (see SoA Sections 1.3.1 and 1.3.2), using the assay
that was negative at Screening (see Exclusion Criterion 8).
In addition, participants can be tested for TB at any time during the study, at the
discretion of the Investigator.
Participants with documented completed appropriate LTBI treatment would not be
excluded and are not required to be tested.
Note: TB skin test with PPD will not be performed at Screening. Reference to TB
skin test results above is in reference to a potential participant’s past results.
8. If the QuantiFERON-TB test results are indeterminate, then the individuals will be
evaluated with T-SPOT.TB at the request of the Investigator. In this case, if the
T-SPOT.TB is negative, the individual may be enrolled (see Section 8 for exceptions to
tests analyzed by a central laboratory). If T-SPOT.TB is not available, the individual is
excluded from participation in the study.
9. Individuals with a diagnosis of hemochromatosis, Wilson’s disease, alpha-1-antitrypsin
deficiency, or any other chronic liver disease including Gilbert’s disease will be excluded
from the study.
10. Individuals with elevated transferrin saturation (> 50% transferrin saturation in males; and
> 40% transferrin saturation in females) and/or with elevated ferritin levels > 500 μg/L
will be excluded.
11. Individuals with sickle cell anemia, thalassemia and/or any chronic blood disorder
requiring blood transfusions will be excluded from the study.
12. History of splenectomy at any time, or any major surgery within 2 months prior
to Screening.
13. History of myocardial infarction or cerebrovascular event within 6 months prior to
Screening, or current active angina pectoris, history of or current congestive heart failure
New York Heart Association (NYHA) Class III or Class IV, uncontrolled seizures (remote
infantile febrile seizures are not exclusionary), prolonged untreated hypertension (systolic
≥ 160 mm Hg and/or diastolic ≥ 100 mm Hg), active gastrointestinal bleeding, or any
other significant active medical condition in the Investigator’s opinion or
Sponsor’s/designee’s opinion.
14. A history of attempted suicide within 6 months prior to Screening or a positive response
to items 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening.
15. An episode of major depression within the last 6 months prior to Screening (clinically
stable minor depression is not exclusionary).
16. History of cancer with the following exceptions:
 A confirmed history of nonmelanoma skin cancer Stage 0 (in situ) or Stage 1,
considered cured > 5 years is not exclusionary.
 A history of in situ cervical cancer, considered cured > 5 years, is not exclusionary.
 A history of Stage I prostate cancer with normal Prostate-Specific Antigen (PSA),
considered cured for > 5 years, is not exclusionary.
Any history of cancer not meeting these exceptions is exclusionary.
17. On Screening electrocardiogram (ECG), any abnormality (e.g., uncontrolled second or
third degree atrioventricular conduction block, ventricular tachyarrhythmias) that in the
Investigator’s opinion may impact participation in the study.
18. Any other clinically significant abnormality per Investigator opinion.
Prior/Concomitant Therapy
19. Contraindication to teriflunomide or leflunomide or incompatibility with teriflunomide or
leflunomide use, including;
a. Hypersensitivity to teriflunomide, or to any excipients.
b. Hypersensitivity to leflunomide, or to any excipients.
c. Cessation of teriflunomide therapy due to poor tolerability or safety concerns,
or suboptimal response.
20. Injectable (e.g., IV, intramuscular, intra-articular) or oral glucocorticoids, or ACTH (e.g.,
Acthar gel) within 4 weeks prior to randomization (inhaled and topical corticosteroids are
allowed) (see Section 8).
21. Treatment with monthly IV methylprednisolone (see Section 6.5.1).
22. Treatment with beta-interferons or glatiramer acetate within 4 weeks prior to
randomization.
23. Treatment with dimethyl fumarate, diroximel fumarate, or other approved fumaric acid
esters within 4 weeks prior to randomization provided lymphocyte count is
> 1,000 cells/μL prior to randomization.
24. Treatment with teriflunomide within 4 weeks with an accelerated elimination procedure
or 14 weeks without the completion of an accelerated elimination procedure prior to
randomization (see Appendix 8 for accelerated elimination procedure).
25. Use of lymphocyte trafficking blockers (e.g., natalizumab, fingolimod, or siponimod)
within 48 weeks prior to randomization.
26. Use of IV immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to
randomization.
27. Treatment with rituximab and/or ocrelizumab. Participants who have received 1 dose of
rituximab or ocrelizumab, and reason for treatment discontinuation was not treatment
failure, will be eligible to enter the study if the last dose of rituximab or ocrelizumab was
at least 48 weeks prior to randomization.
28. Treatment with any other B cell depleting therapy, BTK inhibitors (including
evobrutinib), mitoxantrone, or lymphocyte-depleting therapies (e.g., alemtuzumab,
antiCD4, cladribine, cyclophosphamide, azathioprine, total body irradiation, bone marrow
transplantation).
29. Concomitant treatment with medications commonly used for symptom management of
MS patients will be exclusionary as follows:
a. Participants taking dantrolene are to be excluded. Participants on other
antispasticity agents can be included if they have been on a stable dose over
the 3 months prior to randomization.
b. Participants on dalfampridine (Ampyra) or fampridine can be included only if
they have been on a stable dose 3 months prior to randomization.
c. Medications known to lower the seizure threshold are not permitted unless
reviewed and the eligibility of the participant is confirmed by the Medical
Monitor.
30. Treatment with medical marijuana for MS symptoms, unless it is consistent with local MS
treatment guidelines and local regulations. Dosage, formulation, and route of
administration should be recorded as a concomitant medication.
31. On anticoagulation, or antiplatelet therapy other than daily aspirin for cardioprotection.
Fish oil supplements must be stopped 4 weeks prior to randomization.
32. Participants currently receiving (or unable to stop using prior to receiving the first dose of
study intervention) potent (strong to moderate) inducers of CYP3A (must stop at least
3 weeks prior), medications or herbal supplements known to be potent (strong to
moderate) inhibitors of CYP3A (must stop at least 1 week prior), or drugs mainly
metabolized by CYP3A with a narrow therapeutic index (must be stopped at least 1 day
prior; see Section 6.5). Diabetes medications such as tolbutamide, and pioglitazone,
repaglinide and rosiglitazone or other CYP2C8 substrates are also exclusionary.
Prior/Concurrent Clinical Study Experience
33. Participation in any investigational drug study within 6 months or 5 half-lives of the
investigational drug, whichever is longest, prior to Screening.
Diagnostic Assessments
34. Any of the following:
a. History of or positive for human immunodeficiency virus (HIV) at Screening.
b. History of or positive for hepatitis C virus (HCV) antibody and/or HCV RNA
by PCR at Screening. However, if a participant has a history of HCV infection
and has completed and documented appropriate treatment at least 1 year prior
to Screening AND is negative for HCV RNA by PCR at Screening,
participants will not be excluded from the study.
Note: All participants found to be positive for anti-HCV antibody at Screening
will have reflex testing performed for HCV RNA by PCR to assess study
eligibility.
c. Positive for hepatitis B surface antigen (HBsAg) at Screening.
d. For participants who are negative for HBsAg at Screening but are anti-hepatitis
B surface antibody positive without history of vaccination for Hepatitis B
and/or anti-hepatitis B core antibody positive with or without history of
vaccination for Hepatitis B at Screening, reflex testing for hepatitis B virus
DNA (HBV DNA) by PCR will be performed:
i. Hepatitis B antibody positive participants who have detectable HBV
DNA are excluded.
ii. Hepatitis B antibody positive participants who are HBV DNA negative
are not excluded from the study. However, these participants will have
HBV DNA monitoring by PCR at visits noted in the Schedule of
Activities (SoA) (see Section 1.3).
35. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
as calculated by the
4-variable Modification of Diet in Renal-Disease equation by the central laboratory or any
renal condition that would preclude the administration of gadolinium (e.g., acute kidney
injury).
36. ALT, AST, amylase, or lipase > 2 × ULN of laboratory reference range, total bilirubin
> 1.5 × ULN, or any other clinically significant laboratory abnormality.
37. Significant cytopenia, including neutrophil count < 1,500 / mm3
, platelet count
< 75,000 / mm3
, absolute lymphocyte count < 1,000 / mm3
, or a white blood cell count
< 3,500 / mm3.
Other Exclusions
38. Any allergy, contraindication, or inability to tolerate teriflunomide or evobrutinib or any
of their excipients, including lactose, which is an excipient in the oral Study Intervention
(e.g., evobrutinib tablets, placebo tablets).
Note: Individuals with acquired lactose intolerance are not excluded but should be aware
that the oral study intervention contains lactose and should be monitored for
gastrointestinal symptoms related to the increased consumption of lactose in the study
intervention, and made aware of the risks.
39. Inability to comply with MRI scanning, including contraindications to MRI such as known
allergy or other contraindications to gadolinium contrast media, claustrophobia, presence
of a pacemaker, cochlear implants, ferromagnetic devices or clips, intracranial vascular
clips, insulin pumps, nerve stimulators.
40. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening.
41. Regular alcohol consumption within 6 months prior to the study defined as: an average
weekly intake of > 14 units for males or > 7 units for females. One unit is equivalent to
8 g of alcohol: a half pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL)
measure of spirits.