Relapsing Multiple Sclerosis

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

Evobrutinib

Evobrutinib

Film-coated Tabelt

10, 25

Primary:
ARR based on qualified relapses at Week 96 in participants with RMS
Secondary:
1.  Time to first occurrence of 12-week confirmed Expanded
Disability Status Scale (EDSS) progression over 96 weeks
 Time to first occurrence of 24-week confirmed EDSS
progression 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 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 secondary
progressive multiple sclerosis [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 Baseline
a. Participants with an EDSS score ≤ 2 at Screening 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. Female participants
 Are not pregnant or breastfeeding, and at least one of the following conditions
applies:
o Not a Woman of Child Bearing Potential
OR
o If a Woman of Child Bearing Potential, 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:
o Has completed at least one 4-week cycle of an oral
contraception pill and either had or has begun her menses
OR
o 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
 During the Intervention Period
 After the study Intervention Period (i.e., after the last dose of study
intervention is administered) for at least 90 days, plus 30 days (a
menstrual cycle) after the last dose of study intervention and agree not
to donate eggs (ova, oocytes) for reproduction during this period.
The Investigator evaluates the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.
 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.
 Additional requirements for pregnancy testing during and after study intervention
are in Section 8.2.4.
 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 Secondary Progressive MS without evidence of relapse.
2. Disease duration > 10 years in participants with an EDSS ≤ 2.0 at Screening.
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, and cerebrovascular disorders.
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
tested to rule out PML (see Appendix 8).
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.
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. Indeterminate QuantiFERON-TB test results may be repeated once and will be
considered positive if retest results are positive. However, if results continue to be
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 after approval by the Medical Monitor (see Section 8 for exceptions to tests
analyzed by a central laboratory). If T-SPOT.TB is not available, then for the next
steps the Medical Monitor should be contacted.
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 GI
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 non-melanoma 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 ECG, any abnormality (e.g., uncontrolled second or third degree AV
conduction block, ventricular tachyarrhythmias) that in the Investigator’s opinion
may impact participation in the study.
18. An active infective process or any other clinically significant abnormality on
Screening Chest X-ray (CXR) taken within 4 weeks of the first dose, per Investigator
opinion. If a CXR has been taken within the previous 3 months and results are
available and normal, the CXR does not need to be repeated.
Prior/Concomitant Therapy
19. Contraindication to Avonex or incompatibility with Avonex use, including;
a. Hypersensitivity to natural or recombinant interferon-beta, or to any excipients.
b. Cessation of interferon therapy due to poor tolerability or safety concerns, or
suboptimal response.
20. IV or oral glucocorticoids within 4 weeks prior to randomization (inhaled
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 within 4 weeks prior to randomization provided
lymphocyte count is > 1000 cells/μL prior to randomization.
24. Treatment with teriflunomide within 12 weeks or after the accelerated elimination
procedure 12 days prior to randomization.
25. Use of lymphocyte trafficking blockers (natalizumab or fingolimod) within 48 weeks
prior to randomization.
26. Use of IV 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, 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.
31. On anticoagulation, or antiplatelet therapy other than daily aspirin for
cardioprotection. Use of fish oil supplements within 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 cytochrome P450
3A (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).
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 polymerase chain reaction (PCR) at Screening. However, if a participant
has a history of HCV infection and has completed, documented and
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)
(Section 1.3).
35. Estimated glomerular filtration rate (eGFR) by the 4-variable Modification of Diet in
Renal Disease equation of < 60 mL/min/1.73 m2
or any renal condition that would
preclude the administration of gadolinium (e.g., acute kidney injury).
36. ALT, AST, amylase, or lipase > 2 × upper limit of normal (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
< 3500/mm3
.
Other Exclusions
38. Any allergy, contraindication, or inability to tolerate Avonex 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
IMP, 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.