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BLU Amp at AAN 2014 (part II): Move Over T-Cell; Targeting B-Cells in MS

Read Part I here

Paradigm shift in MS: it’s not just about T-cells anymore

Auto-immune diseases, including multiple sclerosis and rheumatoid arthritis, are generally considered to be driven by T-cells. On the other hand, B-cell depletion shows compelling efficacy in the same auto-immune diseases as was first demonstration by rituximab, a chimeric anti-CD20 monoclonal antibody.

Rituximab (Roche/Genentech), which has been on the market since 1997 (B-cell lymphoma), was approved for rheumatoid arthritis in 2006.

In 2008, the New England Journal of Medicine published the results of a randomized phase II study of rituximab in RRMS [Hauser et al., NEJM, 2008]:

“A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks (…) The magnitude of this effect and the rapidity of its onset provide support for the theory of B-cell involvement in the immunopathologic process of multiple sclerosis”

Unfortunately, no further trials of rituximab in MS were initiated. While two second generation CD20 monoclonal antibodies have been evaluated in MS since the publication of this landmark paper, it’ll be at least two years before patients can potentially have access to this effective treatment option.

Roche/Genentech: favoring ocrelizumab over rituximab

Rituximab is a first generation, chimeric antibody, with a patent expiration date in 2015. In 2008, Roche/Genentech began clinical trials in relapsing MS with a second generation, humanized antibody, ocrelizumab [NCT00676715].Data from this trial, published in Lancet [Kappos et al., Lancet, 2011], where equally impressive as the original rituximab data.

So, in 2011, Roche/Genentech initiated a phase III program in MS. OPERA I [NCT01247324] and OPERA II [NCT01412333] are double-dummy, double-blind trials comparing ocrelizumab (IV, once every 24 weeks) to standard Rebif in relapsing MS. Both studies completed accrual in May 2013, suggesting topline data will be available 2H2015. Based on the phase II data, the efficacy outcomes of these trials are very likely to be positive – potentially good enough to overcome safety concerns related to opportunistic infections (e.g., one patient died in the phase II trial).

A third phase III trial, ORATIO [NCT01194570], randomizes PPMS patients to either ocrelizumab or methylprednisolone. The rationale to pursue a trial in PPMS is not as clear – a randomized phase II study of rituximab in PPMS (vs. placebo) did not show significant improvement in confirmed disease progression [Hawker et al., Ann Neurol. 2009].

  • AAN 2014: Roche/Genentech presented preclinical data confirming a role for B-cell depletion in MS. Exposure to an unspecified CD20 mAb reduced T-cell recruitment and demyelination in a rat model of MS. Microglial activation, a quantitative marker of lesion volume, was reduced to a similar extent by the CD20 mAb and fingolimod, an S1PR agonist which targets T-cells [Anthony et al., AAN 2014; P1-182]

GSK: ofatumumab in limbo?

Like ocrelizumab, ofatumumab is a second generation, humanized CD20 monoclonal antibody. Ofatumumab (Arzerra, GSK) was approved in 2009 for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Clinical development in MS initiated in 2008 and a, small, randomized phase II study showed impressive activity in RRMS [Sorensen et al., Neurology. 2014]. Next, GSK initiated a larger phase II study, MIRROR, to evaluate a subcutaneously delivered formulation of ofatumumab in RRMS [NCT01457924]. Topline results were announced in October 2013 [press release], and full data were presented at AAN 2014.

  • AAN 2014: The MIRROR study randomized RRMS patients to either placebo or four different ofatumumab dosing schedules. When dosed at 30-60mg, once every 12 weeks, reduction in cumulative T1 Gad-enhancing lesions exceeded 90% compared to placebo. A linear relationship between B cell-depletion and residual annualized disease activity was established: at a threshold of approximately 32 to 64 cells/μL was associated with a one or less new lesion per year (compared to 16 new lesions per year without treatment). [Bar-Or et al., AAN 2014; S23.006]

No other trials are ongoing in MS and no new trials have been announced so far. With ocrelizumab data just around the corner, any further development of ofatumumab in MS would seem too little, too late. Unless….the pending acquisition of the GSK oncology assets (which would include ofatumumab) by Novartis may allow for some creative trial designs, including combination therapies.