Tolerability and Safety of Switching From Rituximab to Ocrelizumab in Patients With Relapsing Forms of Multiple Sclerosis

Studies of rituximab, a chimeric monoclonal antibody against CD20 have shown that B-cell
depletion is of clinical benefit as a potential treatment in relapsing forms of multiple
sclerosis (MS).1 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and
selectively depletes CD20 expressing cells, while preserving the capacity for B cell
reconstitution. When compared with rituximab, ocrelizumab is associated with increased
antibody-dependent cell-mediated cytotoxic effects, and reduced complement-dependent cytotoxic
effects in vitro.2 By increasing antibody-dependent cell mediated cytotoxic effects,
ocrelizumab might modulate tissue-dependent mechanisms of pathogenic response more effectively
compared to rituximab. As a humanized molecule, ocrelizumab is expected to be less
immunogenic with repeated infusions and might thus present a more favorable safety profile
when compared to rituximab.2

Despite rituximab's current off label use in the treatment of MS, currently there is only
data available from phase 2 trials. The HERMES group conducted a phase 2, double-blind,
48-week trial involving 104 patients with relapsing forms of MS; 69 patients received 1000 mg
of intravenous rituximab and 35 patients received placebo on days 1 and 15.3 A significantly
higher number of patients in the rituximab group (78.3%) versus the placebo group (40.0%) had
an infusion related reaction (IRR) events within 24 hours after the first infusion. Within 24
hours after the second infusion, fewer patients in the rituximab group (20.3%) than in the
placebo group (40%) had similar events. A majority of the rituximab group with IRR events
(92.6%) were classified as mild to moderate (grade 1 or 2) in severity.

Safety data from the Investigators Brochure on the OPERA I and II phase 3 trials comparing
ocrelizumab to interferon β-1a on relapsing MS patients showed that IRRs were the most common
adverse events experienced by patients treated with 600 mg of ocrelizumab.4 The percentage of
patients experiencing IRRs was higher in the ocrelizumab group (relapsing forms of MS: 34.3%;
primary progressive forms of MS 39.9%) compared with the interferon β-1a (active control)
group who received placebo infusions (relapsing forms of MS: 9.7%; primary progressive forms
of MS: 25.5%). The rate of IRRs was highest during the first infusion or Dose 1 (27.5% on Day
1; 4.71% on Day 15 of Dose 1) and decreased over time (13.7%; 9.6% and 7.8% following Dose 2,
3, and 4 respectively) for the ocrelizumab treated group. Comparatively, interferon β-1a
users experienced 6.5% of IRRs on Day 1, 2.58% on Day 15, < 2.00% after doses 2, 3 and 4
respectively. The reported IRRs were primarily mild-to-moderate in severity (Grades 1 and 2).
Serious IRRs occurred in 0.1% and 1.0% respectively of relapsing and progressive patients and
treated with ocrelizumab.

Clinical data describing the efficacy and tolerability profile of rituximab and ocrelizumab
has utilized populations with different prior treatment characteristics. In the phase 2
HERMES trials, a majority (78.5%) of rituximab patients had been previously been treated with
a disease modifying therapy in the last 2 years.3 In contrast, the OPERA I and II phase 3
clinical trials, a majority of ocrelizumab patients (72.9% in OPERA I and 73.8% in OPERA II)
represented a treatment naïve population.4 Examining IRRs in patients who have switched from
rituximab to ocrelizumab versus those continuing on rituximab will examine the magnitude of
the IRRs and subsequent tolerability of ocrelizumab in a real world population.

Earlier concepts of MS disease pathology have suggested that pathogenic T cells are
sufficient for the full expression of MS. However, it is now evident that full autoimmune B
cells and humoral immune mechanisms also play key roles. 5 Ocrelizumab is a humanized
monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells. CD20
is a B cell surface molecule that is expressed on pre B cells and mature B cells, but not
expressed earlier in the development of B cells or on mature plasma cells. In all three
ocrelizumab studies (with relapsing and progressive populations), treatment with 600 mg of
ocrelizumab led to rapid and complete depletion of circulating CD19+ B cells within 14 days
post treatment. 4 B cell depletion was sustained throughout treatment period. The median time
to repletion of B cells was 72 weeks (range 27-175 weeks). We hypothesize that in switching
rituximab treated patients to ocrelizumab, the proportion of patients with B cell depletion
(< 1%) 6 months after the first and third infusion of ocrelizumab will be the same as the
baseline assessment which will be 6 months after the last dose of rituximab and similar to
findings in OPERA I and II.

Immunogenicity results from the OPERA I and II trials examined the number of patients who had
treatment induced anti-drug antibodies (ADA) to ocrelizumab. 4 Of the 807 patients who
received ocrelizumab and had an ADA assay from a post baseline sample during the controlled
treatment period, 3 patients (0.4%) showed treatment induced ADA to ocrelizumab. Of these, 1
patient tested positive for neutralizing antibodies (NAB) to ocrelizumab. During the open
label extension phase, the prevalence of ADA continued to remain low with post baseline
incidence of 1.9% (2/103 with treatment induced ADA). Currently there is little evidence
examining the prevalence of treatment induced ADAs to both rituximab and ocrelizumab in
patients that switch from the former to the latter in comparison to continuing rituximab
patients. Therefore, we will perform assays to detect ADAs to both rituximab and ocrelizumab
in all patients switching from rituximab to ocrelizumab at Day 1, 6 months and 12 months on
ocrelizumab.

Finally, IRRs have been hypothesized to be a reaction by autoantibodies to the treatment drug
or possibly from the release of cytokines from CD20 expressing cells as they are destroyed by
ocrelizumab causing a "cytokine storm". Understanding this process may lead to mechanisms
that may aid in ameliorating these infusion reactions. If they are associated with ADA, then
it might be possible to predictively premedicate these patients only. Alternatively, if they
are associated with cytokine release, it may be possible to eliminate premedication in
patients who are already CD20+cell depleted in subsequent infusions. Therefore, we will assay
the profile of certain cytokines in the serum 4 hours after start of ocrelizumab infusion.

With ocrelizumab expected to enter the MS therapeutic market within the next year, we expect
third party payers within and outside the US will require that the FDA or EMA approved
versions of anti-CD20 monoclonal antibodies be used in the treatment of MS, namely
ocrelizumab. Currently, we estimate several thousand MS patients in the US and Sweden are
taking rituximab currently. Thus, it will be important to demonstrate that switching from a
chimeric anti-CD20 to a fully humanized anti-CD20 does not lead to unexpected infusion
reactions and does not increase the probability of development of anti-drug antibodies.

The Rocky Mountain MS Center (RMMSC) at the University of Colorado Anschutz Medical Campus
prescribed rituximab infusions for 533 MS patients in the last 12 months, of which 323
patients received their infusion at the University of Colorado Hospital's Outpatient Infusion
Center between September, 2015-March, 2016. The RMMSC is one of the few sites nationwide with
large numbers of MS patients treated with rituximab. With the anticipated approval of
ocrelizumab, current rituximab users are being counselled by their MS providers at RMMSC to
consider switching to ocrelizumab post approval, particularly if US Payers adopt the FDA
approved version as the preferred anti-CD20 agent for MS.

Inclusion Criteria:

Switching group:

- Current active patient of RMMSC

- 18-65 years

- Diagnosis of relapsing forms of MS

- Completed ≥ two doses of rituximab with the last dose having been administered:

1. Within 12 months of screening and

2. At least 6 months prior to the first planned infusion of study drug

- Are receiving their current infusions of rituximab at the University of Colorado
Outpatient Infusion Center

- Have discussed the possibility of switching to ocrelizumab with their MS provider

- Screened for Hepatitis B and C and TB within 2 years of first dose of ocrelizumab

- A negative serum pregnancy test must be available for premenopausal women and for
women <12 months after the onset of menopause, unless they have undergone surgical
sterilization.

- Women of childbearing potential must agree to use a "highly effective", hormonal form
of contraception or two "effective" forms of non-hormonal contraception. Contraception
must continue for the duration of study treatment and for at least three months after
the last dose of study treatment

- Are able to complete patient reported outcomes developed as English written scales.

- Must be able and willing to give meaningful, written informed consent prior to
participation in the trial, in accordance with local regulatory requirements

Comparator group:

- Current active patient of RMMSC

- 18-65 years

- Diagnosis of relapsing forms of MS

- Completed ≥ two doses of rituximab with the last dose having been administered within
12 months of screening as standard of care

- Are receiving their current infusions of rituximab as standard of care at the
University of Colorado Outpatient Infusion Center and will continue to do so

- Are willing to be followed for up to two additional rituximab infusions during the
study period as standard of care

- Must be able and willing to give meaningful, written informed consent prior to
participation in the trial, in accordance with local regulatory requirements

Exclusion Criteria:

Both groups:

- Pregnant or lactating women

- Hypersensitivity to trial medications

- Hepatic Dysfunction (liver enzymes are 5 times greater than normal)

- History of Congestive Heart Failure

- Any history of a positive blood assay for Hepatitis B or C

- Any history of TB or a positive Quantiferon Gold Assay

- Concurrent use of immunosuppressant medications

- Any history of immunodeficiency or other medical condition increasing risk of anti-CD
20 therapy.

- No serious infection at the time of a scheduled study infusion.

- Any medical, psychiatric or other condition that could result in the patient not being
able to give fully informed consent, or to comply with the protocol requirements as
determined by the investigator