OBIVAS

ObiVas is a randomised, phase II, double blind, controlled trial designed to evaluate the mechanistic effect of obinutuzumab versus rituximab in active AAV. Participants will be randomised to one of two treatment groups in a 1:1 ratio and receive obinutuzumab (2 x 1000 mg, two weeks apart) plus prednisolone or rituximab (2 x 1000 mg, two weeks apart) plus prednisolone. All participants will undergo nasal biopsies at baseline and Week 26. Follow up will last for 18 months following entry into the study.

26 participants will be randomised and dosed with obinutuzumab/rituximab. Primary endpoint analysis will be performed after all participants have completed the 26 week biopsy and assessment.

6              Rationale for Trial

6.1          Rationale for the use of obinutuzumab: B cell depletion

B cells and T cells are both important in the autoimmune response in AAV. The central role of B cells is highlighted by the presence of activated B cells in inflammatory lesions, the association of B cell activation status with disease activity and the efficacy of B cell depletion therapy with rituximab (Voswinkel et al., 2008)(Popa et al., 1999)(Stone et al., 2010). The role of B cells extends beyond their function as precursors for ANCA-producing plasma cells. B cells can secrete pro-inflammatory cytokines, present antigen to autoreactive T cells and provide the co-stimulatory signals required for T cell activation.

ANCAs are usually of the immunoglobulin G (IgG) isotype, suggesting that the B cells that produce them have undergone class switching, a process that usually requires a germinal centre response and cognate T cell help (Brouwer et al., 1991). AAV is associated with an increased number of circulating CD4+ effector memory T cells, as well as with a functional defect in circulating regulatory T cells that may contribute to a breakdown in immune tolerance and to the emergence of pathogenic ANCA (Abdulahad et al. 2006)(Morgan et al., 2010)(Abdulahad et al. 2007). Furthermore, a disease-associated CD4 T peripheral helper subset has recently been defined in AAV, which displays cytotoxic potential and upregulated chemokine receptors that aid their migration to sites of inflammation. (Gopaluni, unpublished data). 

B cell depletion therapy with rituximab, a type I mAb directed against the B cell surface molecule CD20, is an effective strategy to both induce and maintain remission in AAV (Stone et al., 2010)(Jones et al., 2015). The cytotoxic effect is achieved by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated cell lysis and apoptosis. Although effective at inducing remission in patients with AAV, rituximab induction therapy does not improve subsequent relapse rates. When a single induction course of rituximab is used to treat a relapse, 75% of patients will relapse again within 2 years. Therefore, further doses of rituximab are needed to maintain remission, commonly delivered as fixed-interval (every 6 months), repeat doses over a 2-year period. However, there are complications related to repeated dosing of rituximab such as hypogammaglobulinaemia and increased susceptibility to infections. Thus, there is an unmet need to develop a treatment regimen that induces prolonged remission without a need for maintenance therapy.

After a single dose of rituximab, depletion of circulating peripheral blood B cells lasts for a median of 12 months (range 6-24), before B cells re-emerge at low level. Relapses usually coincide with the return of peripheral B cells (Stone et al. 2010); however, relapses can occur without detectable peripheral B cells, possibly driven by B cells in the tissue that are resistant to rituximab. The resistance of tissue B cells to depletion may reflect the limitations of the effector mechanisms of rituximab, or the presence of local B cell survival factors; indeed, increased levels of the B cell survival cytokine BAFF (B cell activating factor of the tumour necrosis factor family) observed following systemic B cell depletion may even enhance B cell survival within the tissue niche (Zhao et al. 2012). Furthermore, CD20-rituximab-complex internalisation and removal of CD20-rituximab by the monocytes from the cell surface (a process known as trogocytosis) may also reduce the half-life of rituximab (Golay et al., 2013). Thus, localised resistance to B cell depletion by rituximab may account for the treatment failures and inability of single courses of rituximab to induce long-lasting remission in patients with AAV.

Obinutuzumab is a type-II glycoengineered mAb directed against CD20 epitopes found only on B cells. Its modified structure leads to higher affinity CD20 antigen binding and increased direct cell death (DCD) compared to rituximab. It also enhances antibody-dependent cellular cytotoxicity (ADCC) by nearly 100-fold due to increased Fc binding affinity for activating Fc gamma receptors (FcyRs) on immune effector cells. It is not associated with surface CD20-mAb internalisation by B cells and is not susceptible to trogocytosis, all of which contribute to its superior potency compared to rituximab.

As discussed above, the efficacy of obinutuzumab and superior B cell depletion in comparison to rituximab has been shown in animal studies as well as in clinical trials involving patients with CLL and follicular lymphoma. Furthermore, in primates, depletion of B cells in the spleen and lymph nodes was greater with obinutuzumab compared to rituximab (Mössner et al., 2010).

The primary hypothesis for this trial is that B cell depletion in inflamed tissues in AAV patients is greater following obinutuzumab compared to rituximab. Secondary hypotheses are that greater tissue B cell depletion reduces B cell differentiation into ANCA-producing plasma cells and reduces antigen presentation by B cells to auto-reactive T cells, translating into more prolonged peripheral blood B cell depletion, greater normalisation of T cell repertoire with obinutuzumab versus rituximab, supporting the potential for longer treatment-free remissions with obinutuzumab.