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
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
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
-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