Safety of Switching From Rituximab to Ocrelizumab in MS Patients
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a prospective between and within group observational study to determine differences
      in tolerability, immunogenicity and safety related outcomes for 100 multiple sclerosis (MS)
      patients who have been administered at least two infusions of rituximab, six months apart and
      are willing to be switched to ocrelizumab compared to a 100 patients who are continuing on
      rituximab as a comparison cohort from the clinic population treated as part of clinical care.
    

Detailed description: 
      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.
    

Intervention name(s): Ocrelizumab; Rituximab
Intervention type(s): Drug; Drug
Intervention description(s): A humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells; A chimeric monoclonal antibody against CD20.
Other intervention name(s): Ocrevus; Rituxan
Intervention MeSH terms: Rituximab; Ocrelizumab
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment