Sunday, 29 April 2018

Another CD20 depleting agent shows efficacy

First there was rituximab (part mouse, part human), then there was ocrelizumab (largely human and a tiny bit mouse) and now there is ofatumumab (which is all human) as yet another B cell depleting antibody.



Ofatumumab was being developed as an infusion but this was put on hold and studies were generated using a formulation injected under the skin and it (lower dose) was dosed much more frequently than the 6 monthly infusions with agents usch as ocrelizumab.

When the results were rebased-lined after waiting for 4 weeks for the drug to work, then the agent was very effective at inhibiting gadolinium enhancing lesions.

Ocrelizumab flat-lines B cell levels but you don't need to do this as shown in this study, but we have shown this with cladribine too, but is a a B cell cell subset?  

More anti-CD20 to come!


Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, Derosier FJ, Lopez MC, Kavanagh ST, Miller AE, Sorensen PS. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018. pii: 10.1212/WNL.0000000000005516.

OBJECTIVE:

To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).

METHODS:

Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.

RESULTS:

The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.

CONCLUSION:

Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.


Oligoclonal bands are a hallmark of MS. In this study they look at antibodies in the cerebrospinal fluid and they find that when they look in clinically isolated syndrome that the production of IgM is a better indicator than if IgG is produced. IgM is typically the first type of antibody produced and when stimulated they typical convert to IgG. So what does this mean?

I don't know. Maybe that this has nothing to do with the specificity of the antibody, but maybe the antibody does something to glia and nerves that is not dependent on the antigen binding activity like activating the glia.

Huss A, Abdelhak A, Halbgebauer S, Mayer B, Senel M, Otto M, Tumani H.
Ann Neurol. 2018 Apr 17. doi: 10.1002/ana.25237. [Epub ahead of print]


Markers predicting the course of patients with clinically isolated syndrome (CIS) towards multiple sclerosis (MS) are urgently needed. We evaluated the predictive values of an intrathecal IgG and IgM production with different methods towards conversion to definite MS according to revised McDonald 2010 criteria in a cohort of 126 CIS patients. An intrathecal IgM production showed the highest likelihood ratio for the conversion of CIS patients to definite MS of 6.3, whereas it was 1.4 for oligoclonal IgG bands. We conclude that the determination of intrathecal IgM is a valuable tool to predict the disease course of patients with CIS.

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