#ResearchSpeak: how does B-cell depletion therapy work in MS?

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Can old news be good news? Yes, people with PPMS now have hope. #ResearchNews #MSBlog


The ocrelizumab in PPMS and RRMS studies were published yesterday. Although the results are old news, having been presented on this blog many times, their publication is good news. Peer-review publications are still the academic gold-standard. 


The clock is ticking and I sincerely hope, and expect, both the FDA and EMA, to greenlight ocrelizumab for both relasping forms of MS and PPMS. The latter is really the important news. Having a postive trial in PPMS challenges so much dogma in the field of MS and gives people with progressive MS hope that their disease is modifiable. I personally don’t agree with classifying MS as three diseases (relapsing-remitting, secondary progressive and primary progressive disease), but as one disease. However, that is a story for another time. I think MS is one disease and we should be thinking about how we attempt to modify different stages of the disease. 


The important point to focus on is the question about how does B-cell depletion work as a treatment for MS? I have been convinced for sometime that it is via the depeletion of the EBV-infected memory pool of B-cells. We have some ideas about how to test this hypothesis. I also agree that as an anti-EBV therapy anti-CD20 antibodies are a sledgehammer and they still don’t quite do enough. The intrathecal plasma cells, which I think are pathogenic in MS, are left unscathed. 

How to crack a nut? Do we need a sledgehammer?

Montalban et al. Ocrelizumab versus Placebo in PrimaryProgressive Multiple Sclerosis. NEJM Dec 21. 


BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests
that depleting B cells could be useful for treatment. We studied ocrelizumab,
a humanized monoclonal antibody that selectively depletes CD20-expressing B cells,
in the primary progressive form of the disease. 



METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive
multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or
placebo every 24 weeks for at least 120 weeks and until a prespecified number of
confirmed disability progression events had occurred. The primary end point was
the percentage of patients with disability progression confirmed at 12 weeks in a
time-to-event analysis. 



RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9%
with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval
[CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed
disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard
ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed
25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo
(P=0.04); the total volume of brain lesions on T2
-weighted magnetic resonance
imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with
placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab
versus 1.09% with placebo (P=0.02). There was no significant difference
in the change in the Physical Component Summary score of the 36-Item Short-Form
Health Survey. Infusion-related reactions, upper respiratory tract infections, and
oral herpes infections were more frequent with ocrelizumab than with placebo.
Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of
patients who received placebo; there was no clinically significant difference between
groups in the rates of serious adverse events and serious infections. 



CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was
associated with lower rates of clinical and MRI progression than placebo. Extended
observation is required to determine the long-term safety and efficacy of
ocrelizumab. (Funded by F. Hoffmann–La Roche; ORATORIO ClinicalTrials.gov
number, NCT01194570.)



Hauser et al. Ocrelizumab versus Interferon Beta-1ain Relapsing Multiple Sclerosis. NEJM Dec 21. 


BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized
monoclonal antibody that selectively depletes CD20+ B cells. 



METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with
relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg
every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times
weekly for 96 weeks. The primary end point was the annualized relapse rate. 



RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a
in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16
vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of
patients with disability progression confirmed at 12 weeks was significantly lower
with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60;
95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients
with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60;
95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions
per T1
-weighted magnetic resonance scan was 0.02 with ocrelizumab versus
0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab,
P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions,
P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite
measure of walking speed, upper-limb movements, and cognition; for this
z score, negative values indicate worsening and positive values indicate improvement)
significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs.
0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions
occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred
in 1.3% of the patients treated with ocrelizumab and in 2.9% of those
treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients
treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. 



CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with
lower rates of disease activity and progression than interferon beta-1a over a period
of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required.
(Funded by F. Hoffmann–La Roche; OPERA I and II ClinicalTrials.gov numbers,
NCT01247324 and NCT01412333, respectively.)



CoI: multiple, I am also a co-author on both of these papers

About the author

Gavin

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

21 comments

  • I have PPMS. For a many years now, since my twenties – I'm circa 40 – I have not developed any respiratory symptoms to speak of with cold viruses. Only a sore throat at the worst, tiredness. I wonder whether it is my innate immune system which is doing all the work, going into overdrive and going insane.

  • "Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections."

    Clinically significant – is that the same as statistically significant? Are the observed "neoplasms" (had to look that word up!) therefore of no concern???

    • Though there is an apparent increased risk in this cohort, scary is hugely overstating the case. From the accompanying editoriall which puts things in context;
      "Although the dreaded complication of other drugs for multiple sclerosis, infection with JC virus causing progressive multifocal leukoencephalopathy, has not been seen with B-cell depletion in multiple sclerosis to date, there does appear to be a higher-than-normal risk of herpes reactivation and of neoplasms, especially breast cancer. These side effects will need to be studied in future trials and in phase 4 monitoring in the community to understand the extent of the risk. Clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early."

    • Anon 11.43 (I wish you guys would use a pseudonym) the no clinically significant difference comment relates to other adverse events or infections not to the apparent increased risk of neoplasia, which might not be observed in larger treatment groups going forward.

    • "scary is hugely overstating the case"

      But isn't this a little bit subjective? I mean, if I say, if I go to this hairdresser, I have a 1 in a 100 chance of ending up with a really bad barnet, but it's cheap, that might not seem so bad. But if I say, if I cross this busy road, I have a 1 in a 100 chance of ending up a statistic, that might not seem such a great idea.

      "which might not be observed"

      Hmm, that sounds like crossing an unfamiliar road in fog with earmuffs on.

      I don't mean to be argumentative, it's just that this b-cell blasting gives me the heebie-jeebies.

  • Now that ocrelizumab is closer ( and Swedish neurologists use anti-CD20 antibody rituximab in MS) , I would really appreciate if prof G could make an easy "compare and contrast" table for anti-CD20 and anti-CD52 therapies in MS( Like he did for natalizumab/ alemtuzumab earlier). Treatment choices are getting many and more and more complicated.

    • More treatment choice is to be celebrated and certainly a huge change from when I started working in the MS field but you're right that decision making on what to go for is certainly becoming more and more difficult. It'll be the luck of the draw on how up to date with the latest information your neurologist is.

    • In my mind they are the same except that CD52 has a sell by date because it comes with added side effects. The CD20 is obviously also an induction therapy but they will create increased risks by having a 6 monthly dosing scheme. This is overkill.

      Why do I say it is an induction therapy…simple look at the unpublished phase ii extension data. Why unpublished they don't want you to know it is an induction therapy.

      Look at the rituximab data also.

  • As you state: "plasma cells in the CNS are left unscathed" this anti-CD20 therapy does not address these plasma B-cells, does not cross the BBB and target follicular lymph tissue in the meninges that may be contributing to progressive disease. The poor decrease in disability progression in PPMSers bear this out. This strategy of targeting lymphocytes in the periphery, whether B or T-cells, with monoclonal therapeutics is not adequate for treating progression. When will we acknowledge this? Or do the drug companies dictate the direction of MS therapies irregardless of their efficacy?

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