Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells. Two phase III trials, OPERA I and OPERA II, compared ocrelizumab to interferon beta-1a in patients with relapsing-remitting multiple sclerosis. The studies found that ocrelizumab significantly reduced annualized relapse rates, disability progression, and MRI activity compared to interferon beta-1a over 96 weeks with an acceptable safety profile. Ocrelizumab was generally well-tolerated with a higher rate of infusion-related reactions but lower rates of serious adverse events and infections compared to interferon beta-1a. The trials provide support for the role of B

1. Moderator Speaker
Dr. L.P.Meena Dr. Chandan Kumar

2. Introduction:
 A progressive chronic inflammatory demyelinating
disorder of the CNS of autoimmune etiology
associated with destruction of myelin sheaths and
axons.
 Due to demyelination there is conduction block
which may be variable to complete.

3. • Women : Men 3 : 1

4. Mechanism of action of Injury by B-cells:

5. Symptoms

6.  Relapsing remitting MS (85%)
 Primary progressive MS (15%)
 Secondary progressive MS
 Progressive relapsing MS (5%)

7.  Treatments have been approved by FDA:
1.Interferon beta-1a (Avonex (i.m.)
2.Interferon beta-1a (Rebif)
3.Interferon beta-1b (Betaseron & Extavia )
4.Glatiramer acetate (Copaxone) a non-steroidalimmunomodulator.
5.Mitoxantrone is an immunosuppressant
6.Natalizumab (Tysabri)
7.Fingolimod (Gilenya 0.5mg OD)
8.Terifluonomide
9.Dimethyle fumarate
10.Alemtuzumab
Management:
Alemtuzumab approved by FDA(Nov.2014).Due to risk for severe autoimmune
adverse effects, it is reserved for use in patients who have an inadequate response
to 2 or more other drugs for MS. Is CD52 recomb.monoclonal ab hence promotes
antibody-dependent cell lysis.

8. Interferon β:
 Available drugs: IFN ß 1a and IFN ß 1b
 Mechanism:
 Downregulate the expression of MHC to APC
 Reducing proinflammatory and increasing regulatory
cytokine levels
 Inhibiting T cell proliferation
 limiting the trafficking of inflammatory cells in the
CNS
 Dose: Avonex 30 μg i.m. weekly,
Rebif 44 μg s.c. thrice wkly,
Betaseron 250 µ s.c.

10. Ocrelizumab:
 It is humunised monoclonal Anti CD20 antibody.
 Mechanism of action:
Its mechanism is through immuno-modulating action
through B-Cells.
Ocrelizumab binds to the large extracellular loop of
CD20 with high affinity, selectively depleting CD20-
expressing B cells while preserving the capacity for B-
cell reconstitution and preexisting humoral immunity
Dose: 600 mg i.v. 24th weekly

12.  Multicentre, randomised, parallel, double-blind,
placebo-controlled study done in 79 centres in 20
countries.
 Patients aged 18–55 years with RRMS were randomly
assigned (1:1:1:1) receive either placebo, low-dose
(600 mg) or high-dose (2000 mg) ocrelizumab in two
doses on days 1 &15, or IFN ß-1a (30 μg) i.m. once a
week.

13. Interpretation:
Pronounced effects of B-cell depletion with both
ocrelizumab doses on MRI and relapse-related
outcomes support a role for B-cells in disease
pathogenesis
 At 24 weeks, the number of GEL was 89% lower in the
600 mg ocrelizumab group than in the placebo group,
and 96% lower in the 2000 mg group
 serious adverse events in 2/54 (4%)patients in the
placebo group, 1/55 (2%) in the 600 mg ocrelizumab
group, 3/55 (5%)in the 2000 mg group, and 2/54(4%)in
the IFN ß-1a group.

14. Rituximab:
 In a phase 2, double-blind, 48-week trial involving
104 patients with RRMS
 69 patients to receive 1000 mg of i.v. rituximab and
35 patients to receive placebo on days 1 and 15
 As compared with the placebo group, in rituximab
group patients, relapses was significantly reduced
at week 24 (14.5% vs. 34.3%) and week 48 (20.3%
vs. 40.0%)

15. Despite the availability of several disease-modifying
treatments for relapsing forms of multiple sclerosis,
patients often continue to have clinical and subclinical
disease activity, and neurologic disability continues to
occure.Thus, there is a need for more effective
treatments with acceptable safety profiles.

17.  Phase III, multicenter, randomized, double-blind,
double-dummy, active-controlled, parallel-group
trials (OPERA I and OPERA II) to investigate the
efficacy and safety of Ocrelizumab, as compared
with subcutaneous interferon beta-1a, in patients
with relapsing multiple sclerosis.

18.  Age 18-55 years
 Diagnosis of multiple sclerosis (according to the
2010 revised McDonald criteria )
 EDSS score of 0 to 5.5 at screening
 At least two documented clinical relapses within
the previous 2 years or one clinical relapse within
the year before screening
 MRI brain showing abnormalities consistent with
multiple sclerosis
 No neurologic worsening for at least 30 days before
both screening and baseline (day 1 trial visit)

19. Expanded disability status score
•Pyramidal (ability to walk)
•Cerebellar (coordination)
•Brain stem (speech and swallowing)
•Sensory (touch and pain)
•Bowel and bladder functions
•Visual
•Mental
•Other (any other neurological findings)
Normal
Neurological
Exam
0.0
Death due to MS10.0
1.0
4.5
5.0
9.5
Fully ambulatory
Ambulation
impairment
 EDSS is a method of quantifying disability
in multiple sclerosis based on eight
Functional Systems (FS) developed by John
Kurtzke in 1983
The EDSS scale ranges from 0 to 10 in 0.5 unit increments that
represent higher levels of disability
EDSS steps 5.0 to 9.5 are defined by the impairment to walking

20.  Diagnosis of primary progressive multiple sclerosis
 Previous treatment with any B-cell–targeted
therapy or other immunosuppressive medication
 Disease duration of more than 10 years in
combination with an EDSS score of 2.0 or less at
screening

21. Trial design
 In the OPERA I trial, patients from 141 trial sites
across 32 countries underwent randomization
between Aug 31,2011, to Feb14, 2013.
 In the OPERA II trial, patients from 166 trial sites
across 24 countries underwent randomization
between Sept 20, 2011, to Mar 28, 2013.
 Patients were randomly assigned, in a 1:1 ratio.

22. OPERA I Trial

23. OPERA II Trial

24.  Ocrelizumab at a dose of 600 mg i.v. 24 weekly
administered as two 300-mg on days 1 and 15 for
the 1st dose and single 600-mg infusion thereafter.
 IFN ß -1a at a dose of 44 μg (Rebif), administered
s.c. thrice weekly throughout the 96-week period
 Patients in each group received a matching s.c. or
i.v. placebo, as appropriate.

26.  The neurologic assessments, including the Multiple
Sclerosis Functional Composite (a composite
quantitative measure, expressed as a z score, of
walking speed, upper-limb coordinated
movements, and cognition; for this z score, negative
values indicate worsening and positive values
indicate improvement) and the EDSS.
Analysis:

27. Results
Efficacy Safety
1. Relapses
2. Disability
3. MRI related secondary
end point
1. Adverse events
2. Infections
3. Infusion related
reactions
4. Laboratory assesments
5. Neoplasm

28. Relapse rate:
 The primary end point, the annualized relapse rate at
96 weeks, in the OPERA I & OPERA II trial was 0.16 in
the ocrelizumab group, as compared with 0.29 in the
interferon beta-1a group i.e; annualized relapse rate at
96 weeks –
 46% lower in OPERA I trial
 47% lower in OPERA II trial

29. Disablity:
 Percentage of patients with disability progression
Over the 96-week trial was 9.1% in ocrelizumab
group, and in IFN ß-1a group was 13.6% at 12
weeks
 at 24 weeks 6.9% in the ocrelizumab group, as
compared with 10.5% in the IFN ß -1a group
i.e; Overall 40% lower risk of disability progression in case of
ocrelizumab as compared with IFN ß -1a

30. Pooled Analysis of the Proportion of Patients Who Achieved
Disability Improvement Confirmed After at Least 12 Weeks.

31. MRI-Related Secondary End Points
 The total mean number of gadolinium-enhancing lesions per
T1 -weighted MRI scan in the OPERA I trial was 94% and in
OPERA II trial was 95% lower in Ocrelizumab group as
compared to IFN ß-1a group .

32. OPERA I OPERA II
Total number of new T1 Hypointense lesions

33. Adverse Events:
Serious adverse events reported in 6.9% ocrelizumab
and in 7.8% with IFN ß-1a group in OPERA I trial and
7.0% treated with ocrelizumab and in 9.6% of those
treated with IFN ß-1a in OPERA II trial
Infections:
In OPERA I trial 56.9% in ocrelizumab and 54.5% in IFN
ß -1a group and in OPERA II 62.5% and 52.5% in
ocrelizumab & IFN ß-1a group respectively.
Herpes infection was 5.9% in ocerlizimab and 3.4% in
IFN ß-1a group across the two trial

35. Infusion-Related Reactions:
In the OPERA I trial, at least one infusion related
reaction occurred in 30.9% patients in ocrelizumab
group and in 7.3% of those treated with IFN ß-1a
group; the corresponding values in the OPERA II trial
were 37.6% and 12.0%
One patient of ocrelizumab group in OPERA I trial
developed severe bronchospasm with 1st dose.

36. Proportion of Patients With Infusion-Related Reactions by Dose in the
Safety Population (Pooled OPERA I and OPERA II)

38. Laboratory Assessments
 The level of CD19+ cells decreased to negligible levels
with ocrelizumab treatment by week 2.
 CD19+ cells represent a measure of B-cell counts in
anti-CD20–treated patients.
OPERA I OPERA IIMedian CD 19 levels

39.  Antidrug-binding antibodies developed in 3 of 825
patients (0.4%) who received ocrelizumab across the
two trials, with neutralizing antibodies developing in 1
patient in the OPERA II trial. Across the two trials,
neutralizing anti–interferon beta-1a antibodies were
detected in 21.3% of the patients.

40. Neoplasms:
Across the two 96-week trials
 Ocrelizumab group:
4 neoplasm i.e; 0.5% patients
1. 2 Invasive ductal breast carcinoma
2. 1 Renal-cell carcinoma
3. 1 Malignant melanoma
 IFN ß-1a group:
2 neoplasm i.e; 0.2%
1. 1 Mantle-cell lymphoma
2. 1 Squamous-cell carcinoma in the chest

41.  The overall incidence rate of first neoplasm among
patients treated with ocrelizumab across all studies
involving patients with multiple sclerosis was 0.40%
patient-years of exposure as compared with 0.20%
patient-years of exposure in groups receiving
interferon beta-1a or placebo

42.  In the OPERA I and OPERA II trials, ocrelizumab was
associated with significantly lower annualized
relapse rates (primary end point) than IFN ß-1a,
during the 96-week treatment period.
 Ocrelizumab was associated with a lower rate of
disability progression confirmed at 12 weeks and at
24 weeks than IFN ß-1a
 Significantly greater suppression of development of
new areas of inflammation and new or newly
enlarged plaque formation (lesions on T2–weighted
MRI)

43.  Ocrelizumab also associated with a higher rate of
disability improvement confirmed at 12 weeks than
IFN ß-1a in the pooled analysis
 Infusion-related reactions were more common with
ocrelizumab than with IFN ß-1a and included one
life-threatening (grade 4) bronchospasm.

44.  The traditional view of the pathophysiology of
multiple sclerosis is that it is predominantly a T-
cell–mediated disease. The findings in two trials are
consistent with evidence that B cells play a role in
the pathogenesis of multiple sclerosis.
 The trafficking of activated oligoclonal populations
of B cells between the CNS and peripheral
circulation has been observed in persons with
relapsing multiple sclerosis and the disruption of
this network may explain the effects of ocrelizumab
in trials.

45.  The use of current therapies in patients with
relapsing multiple sclerosis has been associated
with an improved overall prognosis, as compared
with the pretreatment era.

48. Mc donald criteria 2010
Clinical presentation Additional criteria
• ≥2 attacks(relapse)
• ≥2 objective clinical lesion
None
• ≥2 attacks(relapse)
• ≥1 objective clinical lesion
Dissemination in space, demonstrated by MRI
or
Positive CSF and ≥2 MRI lesions consistent with MS
or
Further clinical attack involving different site
• ≥1 attacks(relapse)
• ≥2 objective clinical lesion
Dissemination in time demonstrated by
MRI or Second clinical attack
• ≥1 attacks(relapse)
• ≥1 objective clinical lesion
(monosymptomatic)
Dissemination in space demonstrated by MRI or positive
CSF and ≥2 MRI lesions consistent with MS
and Dissemination in time demonstrated by:
MRI or second clinical attack
• Insiduous neurological
progression S/O MS
(PPMS)
• One year of disease progression (retrospectively or
prospectively determined) and
• 2 of the following:
a. Positive brain MRI (9 T2 lesions or ≥4 T2 lesions with
positive VEP)
b. Positive spinal cord MRI (two focal T2 lesions)
c. Positive CSF