A PHASE IIIb MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF OCRELIZUMAB IN ADULTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease
of the CNS that affects approximately 2.3 million people worldwide (MSIF
2013). While MS is a global disease, its prevalence is highest in North
America and Europe (140 and 108 per 100,000 people, respectively) (MSIF 2013).
MS is commonly diagnosed during reproductive age, between 20 and 40 years
(Tullman 2013). Overall, MS is approximately twice as prevalent in women as in
men, except in individuals with the primary progressive form of the disease,
where there is no gender prevalence difference (MSIF 2013; Tullman 2013).
Reasons for these observed differences are unclear. However, progression, once
it begins, continues at similar rates in women and men (Leray et al. 2010).
In approximately 85% of patients, MS begins as a relapsing, episodic disorder
with gradual complete or incomplete recovery (referred to as relapsing
remitting MS [RRMS]). If left untreated, the majority of these patients will
transition to a progressive form characterized by worsening neurologic
disability, either with or without occasional super imposed relapses (relapsing
or non relapsing secondary progressive MS). Patients accumulate disability as
a result of incomplete recovery from acute relapses and/or gradual disease
progression (Tullman 2013). Primary progressive MS (PPMS) is a less common
form of MS, accounting for approximately 10% of all cases (approximately 40,000
individuals in the United States). PPMS is characterized by a progressive
course from disease onset, with infrequent superimposed discrete clinical
attacks or relapses (Lublin et al. 2014). Unlike RRMS, the typical age of
onset for PPMS is older at approximately 40 years, and men are affected nearly
as often as women (Cottrell et al. 1999). The absence of relapses imposes
special challenges for diagnosis, requiring clinical evidence that the disease
has advanced for at least 1 year from symptom onset independent of clinical
relapse (Thompson et al. 2018).
Ocrelizumab is a recombinant humanized, glycosylated, monoclonal IgG1 antibody
that selectively targets and depletes CD20 expressing B cells, while preserving
the capacity of B cell reconstitution and preexisting humoral immunity. CD20
is a B cell surface molecule that is restricted in expression to pre*B cells
and mature B cells but is not expressed earlier in the development of B cells
(Banchereau and Rousset 1992). Based on the results of ocrelizumab Phase III
studies in patient populations with relapsing MS (RMS) and PPMS, ocrelizumab
was approved by the US Food and Drug Administration (FDA) on 28 March 2017 for
the treatment of adult patients with RMS and PPMS and by the European Medicines
Agency (EMA) on 12 January 2018 for patients with active relapsing forms of MS
defined by clinical or imaging features and for patients with early PPMS in
terms of disease duration and level of disability, and with imaging features
characteristic of inflammatory activity.
Two identical randomized, active controlled studies (OPERA I [Study WA21092]
and OPERA II [Study WA21093]) have demonstrated superior efficacy outcomes
versus interferon * 1a in patients with RMS (Hauser et al. 2017); one
randomized placebo controlled study (ORATORIO [Study WA25046]) has demonstrated
superior efficacy in PPMS versus placebo (Montalban et al. 2017). Results of
these studies show that depletion of CD20+ B cells leads to a significant
impact on a broad range of clinical measures of disease, including disability
progression, in addition to an impact on magnetic resonance imaging (MRI)
outcomes related to disease progression and reflective of neural tissue loss,
thus further supporting the hypothesis that B cells are central to the
pathogenesis of both RMS and PPMS. Ocrelizumab has demonstrated a favorable
safety profile in patients with RMS and PPMS (Hauser et al. 2017; Montalban et
al. 2017). The proportion of patients with adverse events was similar in
patients treated with ocrelizumab compared with interferon * 1a (both 83.3%) or
placebo (95.1% vs. 90.0%). The proportion of patients experiencing a serious
adverse event was similar between ocrelizumab and the comparator groups (in
RMS: 6.9% [ocrelizumab] and 8.7% [interferon * 1a]; in PPMS: 20.4%
[ocrelizumab] and 22.2% [placebo]).
The pivotal Phase III Study WA25046 (ORATORIO) was a global, multicenter,
randomized, parallel group, double blind, placebo controlled trial evaluating
the efficacy and safety of ocrelizumab in adults with PPMS. Therefore, given
the encouraging results from Study WA25046, the primary objective of this study
is to evaluate the efficacy of ocrelizumab compared with placebo on the
preservation of upper limb function in a population that also includes patients
with more advanced PPMS who acquired significant lower extremity impairment.

This study will evaluate the efficacy and safety of ocrelizumab (Ocrevus®)
compared with placebo in patients with PPMS, including patients later in their
disease course.

Study WA40404 is a Phase IIIb, randomized, double blind, placebo controlled,
parallel group, multicenter study to evaluate efficacy on upper limb function
and safety of ocrelizumab administered at 600 mg IV infusions every 24 weeks in
patients with PPMS, including patients later in their disease course. This
study will consist of the following phases: screening, double blind treatment,
follow up 1 (FU1), an optional open label extension (OLE), follow up 2 (FU2),
and B cell monitoring (BCM).
The screening phase will last up to 24 weeks. Two brain MRI scans performed at
least 6 weeks apart or one brain MRI that can be compared with a brain MRI
performed in the previous 1 year will be performed to verify the brain MRI
activity status of the patient. For patients who fail the initial screening, a
maximum of two re screenings will be allowed.
Eligible patients will be randomized (1:1) in a blinded fashion to either
placebo or ocrelizumab. The expected sample size will be approximately 1000
patients, with at least 350 patients in the MRI active subgroup. The MRI
active subgroup will consist of patients with T1 Gd * lesion(s) and/or new
and/or enlarging T2 lesion(s) as detected by MRI scan during screening.
Patients will be treated for a minimum of 120 weeks (minimum of 5 study drug
doses, with each dose 24 weeks apart) and until approximately 362 events of
12-week confirmed upper limb disability progression (9 HPT events) have
occurred in the study and until 131 events of 12 week confirmed upper limb
disability progression (9 HPT events) have occurred in the MRI active
subgroup. The primary efficacy analysis will be performed after the
above-mentioned number of events has been reached (in accordance to the
definition of events for the primary analysis).
Patients who experience a double-progression event (DPE; defined as a confirmed
20% increase in 9 HPT time sustained for 24 weeks and a CDP sustained for 12
weeks) during the double blind treatment phase will be given the option to
switch to post*double progression ocrelizumab (PDP OCR) after completing at
least 120 weeks of the double-blind treatment phase.
All patients who prematurely discontinue from the double blind treatment phase
will enter the FU1 phase, including patients who receive PDP OCR treatment,
other immunomodulatory or immunosuppressive treatment(s) for MS, commercial
ocrelizumab, or no treatment. The FU1 phase will run in parallel with the
double blind treatment phase until the primary analysis is performed.
Scheduled visits will be performed every 12 weeks. In the FU1 phase, patients
will remain blinded to their original (randomized) treatment assignment.
Patients who withdraw from treatment should be encouraged to remain in the
study for the full duration of the FU1. All patients who are ongoing in the
FU1 and not on PDP OCR treatment at the time of the primary analysis will
continue in the FU2.
If the primary analysis is positive, an optional OLE phase is planned for
eligible patients who either have remained in the double-blind treatment phase
or are on PDP OCR treatment at the time of the primary analysis and, in the
opinion of the investigator, could benefit from ocrelizumab treatment.
Patients who are ongoing in the FU1 and not on PDP OCR treatment at the time of
the primary analysis will not participate in the OLE.
The OLE will be carried out for approximately 2 years (4 doses of
ocrelizumab). The 2 year duration of the OLE phase serves to further evaluate
long term safety and efficacy of ocrelizumab treatment in patients with PPMS.
The FU2 phase will begin after the primary analysis is performed. The
following patients will move into the FU2 phase: are ongoing in the FU1 and
not on PDP OCR treatment at the time of the primary analysis, are ongoing in
the double blind treatment phase or receiving PDP OCR at the time of the
primary analysis and do not enter the OLE phase, or complete or withdraw from
the OLE phase.
Laboratory and safety assessments for FU2 will be performed during the clinic
visits that occur every 24 weeks. All patients will continue in the FU2 until
the end of the phase. The end of FU2 is defined as 48 weeks after the last
patient to enter the OLE has had his or her last OLE visit.
At the end of the FU2, all patients will move into BCM phase until the end of
the study. This study will end when all patients who are not being treated
with an alternative B cell depleting therapy have repleted his or her B cells.
A patient*s B-cells will be considered to be repleted once B cell levels have
returned to baseline value or the lower limit of normal (whichever is lower).
An independent Data Monitoring Committee will be employed to monitor and
evaluate patient safety throughout the study, until the primary analysis is
performed.

End of Study
The end of the study will occur when all patients who are not being treated
with an alternative B cell depleting therapy have repleted his or her B-cells
(i.e., B cell level of the patient has returned to the baseline value or the
lower limit of normal, whichever is lower).
Length of Study
The total length of the study, from screening of the first patient to the end
of the study, is expected to be approximately 8.5 years (assuming that the last
patient randomized after 3 years from the study start receives blinded
treatment over 120 weeks, followed by 96 weeks of OLE, 48 weeks of FU2 and
[variable] BCM phase).

The dose level of ocrelizumab administered in this study is 600 mg every 24
weeks.
Ocrelizumab will be administered intravenously as dual infusions (300 mg on
Days 1 [Dose 1 Infusion 1] and 15 [Dose 1 Infusion 2]) for the first dose and
subsequently as a single IV infusion (600 mg) every 24 weeks in 500 mL 0.9%
sodium chloride. This dosing regimen is consistent with the dosing regimen
used in ocrelizumab Phase III/IV studies, as well as with the summary of
product characteristics (SmPC) and the U.S.
prescribing information (USPI). In the double-blind treatment phase, study drug
for patients randomized to the placebo
group will be administered analogously to those receiving ocrelizumab.

Rationale for Control Group
Given that no standard therapy exists in the European Union and some other
parts of the world for the treatment of patients with PPMS later in their
disease course/without imaging features characteristic of inflammatory
activity, a placebo controlled trial is acceptable provided that appropriate
patient consent and safeguards are instituted to minimize the risk of serious
or irreversible harm resulting from exposure to placebo. In this study,
patients randomized to placebo who experience a DPE during the double blind
treatment phase will be given the option to switch to ocrelizumab (see Section
3.1.1.2).
The Sponsor recognizes that a treatment period lasting 2.5*5.5 years poses
risks to patients randomized to placebo. For this reason, several study
elements will be employed to protect the well being of study participants:
The Informed Consent Form clearly defines the duration of the study including
the double blind treatment phase, OLE phase, and follow up phases. The
probabilities of assignment to placebo and ocrelizumab are indicated in easily
understood terms in multiple sections of the Informed Consent Form.
Patients who experience a DPE during the double-blind treatment phase will be
given the option to switch to PDP OCR after they have completed at least 120
weeks of double-blind treatment (see Section 3.1.1.2 for definition of DPE).
Patients will have to provide their informed consent prior to switching to PDP
OCR.
A thorough medical monitoring plan will be implemented by the study Sponsor to
ensure the safety of all study participants. Moreover, an iDMC will be
instituted to further protect the wellbeing of patients in the study.
Upon withdrawal from study treatment for any reason, patients will be
recommended to stay in the study for follow up but may be eligible for
treatment with some alternative therapies at the discretion of and in
consultation with their Treating Investigator.

Rationale for the Use of Premedications (Methylprednisolone and Antihistamines)
To reduce the frequency and severity of infusion-related reactions (IRRs),
patients will be premedicated with 100 mg methylprednisolone IV and an
antihistamine approximately 30 minutes prior to administration of ocrelizumab
(see Section 4.3.2.2). An integrated analysis of patients with MS who were
treated with ocrelizumab revealed that the addition of antihistamines to the
pretreatment with methylprednisolone decreased the incidence of IRRs by 2 fold
(OCREVUS® U.S. Package Insert). Administered infrequently at a low dose,
methylprednisolone is not anticipated to affect the efficacy or safety outcomes
of the study. Methylprednisolone (or an alternative steroid in patients where
methylprednisolone is contraindicated) will be administered to patients in both
treatment groups during the treatment period to maintain the treatment blind.

Rationale for Biomarker Assessments
A blood protein biomarker sample (plasma and serum) will be taken. Assessment
of the sample may include, but will not be limited to, neurofilament light
chain (NfL), a marker of neuronal injury and/or other
neurodegeneration/inflammatory markers. If the patient requires a CSF sample
to screen for IgG index or the presence of oligoclonal bands at screening, the
leftover CSF will be stored and the assessment of the sample may include, but
will not be limited to, NfL. Patients for whom screening CSF was collected
will have the option to participate in a collection of CSF at Week 48; this
sample will be used for exploratory biomarker determination that may include,
but may not be limited to, NfL. NfL, in addition to other possible markers,
may be used to assess the patient*s disease activity, and/or as a
pharmacodynamic, prognostic, or predictive biomarker(s) for disease progression
and/or to assess drug activity, efficacy, safety, or MS pathogenesis.

Side effects and discomforts caused by the the study drug and procedures can be
found in the study documents in this dossier (ICF, IB).

The sponsor feels that the side effects and the burden associated with
participation are in proportion considering the
positive effects that participation in the study might have on the patient's
quality of life.