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#Post#: 1493--------------------------------------------------
(Abst.) Ocrelizumab vs. placebo, ocrelizumab vs. interferon beta
-1a (NEJM)
By: agate Date: December 21, 2016, 6:36 pm
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NEJM (December 22, 2016) contains two articles on ocrelizumab
in PPMS--one on ocrelizumab vs. placebo, the other on
ocrelizumab vs. interferon beta-1a:
[quote]Ocrelizumab versus Placebo in Primary Progressive
Multiple Sclerosis
Xavier Montalban, M.D., Stephen L. Hauser, M.D., Ludwig Kappos,
M.D., Douglas L. Arnold, M.D., Amit Bar-Or, M.D., Giancarlo
Comi, M.D., Jérôme de Seze, M.D., Gavin Giovannoni, M.D.,
Hans-Peter Hartung, M.D., Bernhard Hemmer, M.D., Fred Lublin,
M.D., Kottil W. Rammohan, M.D., Krzysztof Selmaj, M.D., Anthony
Traboulsee, M.D., Annette Sauter, Ph.D., Donna Masterman, M.D.,
Paulo Fontoura, M.D., Ph.D., Shibeshih Belachew, M.D., Ph.D.,
Hideki Garren, M.D., Ph.D., Nicole Mairon, M.D., Peter Chin,
M.D., and Jerry S. Wolinsky, M.D., for the ORATORIO Clinical
Investigators
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.
B cells contribute to the pathogenesis of multiple sclerosis,
including the primary progressive form.Although the mechanisms
of tissue injury in multiple sclerosis are uncertain, B cells
may influence pathogenesis through antigen presentation,6
autoantibody production,or cytokine secretion.6 B cells are
present in meningeal inflammation, which is characteristic of
chronic multiple sclerosis and may cause adjacent cortical
demyelinating and neurodegenerative pathologic features.CD20 is
a cell-surface antigen found on pre-B cells and mature and
memory B cells but not on the earliest B-cell precursors or on
plasma cells.Ocrelizumab is a humanized monoclonal antibody that
selectively depletes CD20-expressing B cells while preserving
the capacity for B-cell reconstitution and preexisting humoral
immunity.
A previous phase 2–3 trial of the chimeric monoclonal anti-CD20
antibody rituximab (OLYMPUS trial) in primary progressive
multiple sclerosis did not meet its primary efficacy end point,
but a subgroup analysis showed delayed progression of disability
in younger patients (<51 years of age) with evidence of
increased inflammatory disease activity.3 Those results provided
the rationale and in part informed the trial design for this
investigation of ocrelizumab in patients with primary
progressive multiple sclerosis. Here, we report results from a
phase 3, randomized, parallel-group, double-blind,
placebo-controlled trial (ORATORIO) that investigated the
efficacy and safety of ocrelizumab in patients with primary
progressive multiple sclerosis.
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.)[/quote]
For discussion, see
HTML http://www.nejm.org/doi/full/10.1056/NEJMoa1606468?query=TOC#t=articleDiscussion
HTML http://www.nejm.org/doi/full/10.1056/NEJMoa1606468?query=TOC#t=articleDiscussion.
The entire article can be seen here
HTML http://www.nejm.org/doi/full/10.1056/NEJMoa1606468?query=TOC#t=articleTop.
_________________________________________
[quote]Ocrelizumab versus Interferon Beta-1a in Relapsing
Multiple Sclerosis
Stephen L. Hauser, M.D., Amit Bar-Or, M.D., Giancarlo Comi,
M.D., Gavin Giovannoni, M.D., Hans-Peter Hartung, M.D., Bernhard
Hemmer, M.D., Fred Lublin, M.D., Xavier Montalban, M.D., Kottil
W. Rammohan, M.D., Krzysztof Selmaj, M.D., Anthony Traboulsee,
M.D., Jerry S. Wolinsky, M.D., Douglas L. Arnold, M.D., Gaelle
Klingelschmitt, Ph.D., Donna Masterman, M.D., Paulo Fontoura,
M.D., Ph.D., Shibeshih Belachew, M.D., Ph.D., Peter Chin, M.D.,
Nicole Mairon, M.D., Hideki Garren, M.D., Ph.D., and Ludwig
Kappos, M.D., for the OPERA I and OPERA II Clinical
Investigators
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.)[/quote]
The entire article can be seen here
HTML http://www.nejm.org/doi/full/10.1056/NEJMoa1601277#t=articleTop.
#Post#: 1494--------------------------------------------------
B-cell depletion: A frontier in monoclonal antibodies for MS
By: agate Date: December 21, 2016, 6:45 pm
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NEJM Editorial about these two articles (December 22, 2016) by
Peter Calabresi, MD that gives a coherent summary of their
results:
[quote]EDITORIAL
B-Cell Depletion — A Frontier in Monoclonal Antibodies for
Multiple Sclerosis
Peter A. Calabresi, M.D.
Multiple sclerosis is a disabling autoimmune disease in which
immune cells target central nervous system (CNS) antigens,
leading to demyelination, glial activation, and subsequent loss
of neurons and axons. There are three main subtypes of multiple
sclerosis: relapsing–remitting, in which patients recover partly
or fully from attacks but go on to have others; secondary
progressive, in which patients with relapsing–remitting disease
have progression of disability between attacks; and primary
progressive, in which patients have continual progression from
the time of onset of the disease.
Over the past two decades, a remarkable number of new therapies
have been developed that reduce the rate of relapses, reduce
accumulation of lesions seen on magnetic resonance imaging
(MRI), and modestly slow disability, but these are effective
almost exclusively in relapsing multiple sclerosis.
Most therapies for multiple sclerosis target T-cell activation,
the trafficking of these cells into the CNS, and effector
functions of the lymphocytes, but many have concomitant effects
on B cells. Because B cells also migrate from the peripheral
blood into the CNS in patients with multiple sclerosis and these
cells produce immunoglobulins, which are a characteristic
finding in the cerebrospinal fluid, several phase 1b and 2
studies have tested the efficacy of the B-cell–depleting
chimeric anti-CD20 monoclonal antibody rituximab. This therapy
has reduced relapses and MRI activity in patients with
relapsing–remitting multiple sclerosis but has not slowed the
progression of disability in patients with primary progressive
multiple sclerosis, except in a post hoc analysis of patients
younger than 51 years of age and with gadolinium-enhancing
lesions on MRI. Hauser et al. and Montalban et al. now report in
the Journal the results of phase 3 trials of a new and fully
humanized monoclonal anti-CD20 antibody, ocrelizumab, in two
clinical trials in relapsing multiple sclerosis and one trial in
primary progressive multiple sclerosis.
In the identical trials involving patients with relapsing
multiple sclerosis, called OPERA I and OPERA II, Hauser et al.
compared ocrelizumab at a dose of 600 mg every 24 weeks versus
interferon beta-1a at a dose of 44 μg three times a week
for 96 weeks. Both trials showed a significant effect of
ocrelizumab on the primary outcome of annualized relapse rate,
with ocrelizumab resulting in a 46% or 47% lower rate than with
interferon beta-1a. The percentage of patients with disability
progression and the number of lesions on MRI were also
significantly lower in the ocrelizumab group. Remarkably, in the
ORATORIO trial by Montalban et al. involving patients with
primary progressive multiple sclerosis, a previously untreatable
subtype of the disease, the relative risk of disability
progression was approximately 25% lower among patients who
received 600 mg of ocrelizumab every 24 weeks for at least 120
weeks than among those who received placebo. In addition, the
total volume of brain lesions on T2-weighted MRI decreased with
ocrelizumab and increased with placebo. This is the first drug
to show a significant effect in slowing disability progression
in a phase 3 trial in primary progressive multiple sclerosis,
and therefore the trial represents a landmark study in the
field.
The mechanism by which B-cell depletion achieves these effects
is not fully understood but may be multifunctional, because B
cells have important roles in antibody secretion, antigen
presentation, and the release of effector cytokines. Although
there are several other antigen-presenting cells, such as
dendritic cells and monocytes, B cells by virtue of their number
may be important antigen-presenting cells in multiple sclerosis.
Previous studies have shown that rituximab rapidly reduced
secretion of the inflammatory cytokines interferon-γ and
interleukin-17 from T cells in patients with multiple sclerosis,
findings that are consistent with the early reduction of active
gadolinium-enhancing lesions observed with anti-CD20 therapy.
In addition, the B cell is a reservoir for Epstein–Barr virus,
which has been implicated in the pathogenesis of multiple
sclerosis by virtue of its high sequence homology with myelin
basic protein, and it is interesting to speculate that B-cell
depletion may eliminate this reservoir, thereby decreasing
autoreactivity, although this has not been proven.
Primary progressive multiple sclerosis is characterized by
insidious progression of disability over years with no remission
and low MRI activity, and it is generally considered less
inflammatory and more neurodegenerative than relapsing multiple
sclerosis. These features are cited as explanations for the
failure of other immunosuppressive drugs to decrease disease
progression in primary progressive multiple sclerosis.
One possible explanation for the positive effects of ocrelizumab
in the ORATORIO trial is that the patient population included
younger patients (mean age, approximately 45 years) and those
with active MRI scans (>25% had gadolinium-enhancing lesions),
allowing for a measurable antiinflammatory effect of ocrelizumab
in patients who had some inflammation at an early, reversible
stage of the disease.
Another possible explanation is that B cells may mediate
pathologic processes by secretion of cytokines or by deposition
of immunoglobulins after they enter the CNS. B cells and plasma
cells secrete antibodies that may target CNS antigens such as
myelin, neurons, and glia, which could accelerate
neurodegeneration or inhibit myelin repair. The continued
separation of disability progression curves in the ORATORIO
trial beyond 52 weeks, when antiinflammatory effects have been
maximized, and success in the relatively noninflammatory
disorder of primary progressive multiple sclerosis suggest that
additional mechanisms of action may be operational, and further
study is warranted.
Although ocrelizumab offers promise for patients with primary
progressive multiple sclerosis, who are desperately in need of a
therapy, side effects must also be considered. Agents that
target the immune system often result in some degree of immune
suppression, potentially rendering the host susceptible to
infections and impaired immune surveillance of new cancer cells,
which could increase the risk of neoplasms.
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.[/quote]
#Post#: 1501--------------------------------------------------
Re: (Abst.) Ocrelizumab vs. placebo, ocrelizumab vs. interferon
beta-1a (NEJM)
By: agate Date: December 26, 2016, 6:47 pm
---------------------------------------------------------
This news has been selected as one of the 10 top neurology
stories of 2016 by MedPage Today:
[quote]MedPage Today asked specialists in neurology around the
country to tell us what they thought were the most important
clinical developments in 2016. These were the five most commonly
mentioned.
1. Ocrelizumab for Primary Progressive MS
Multiple sclerosis experts were hoping that a new drug that
could treat not only relapsing MS, but also progressive disease,
would be approved by the end of the year. That's not going to
happen, since Genentech announced the FDA has pushed back the
PDUFA date for ocrelizumab (Ocrevus) by 3 months as it reviews
additional data on the company's manufacturing process.
But hopes are high that the B-cell-targeting drug will be the
first to win approval for progressive MS. Although there are
several treatments for relapsing disease, no other drug has ever
been approved to treat the more aggressive form.
Updated findings from the OPERA and ORATORIO studies were
presented at various meetings throughout the year, and drugmaker
Genentech has continued to tout the 24% reduced relative risk of
disability progression in primary progressive MS, although some
have expressed concern that its effects in PPMS are not as
strong as in RRMS.
"The excitement around the first effective therapy in PPMS is
tempered by that benefit being predominantly in patients with
active inflammation at the start of the trial, with little
benefit seen among those without active inflammation at the
start of the trial," said Robert Fox, MD, of the Cleveland
Clinic. "To me, this trial suggests that patients with
progressive MS and active inflammation may benefit from an
anti-inflammatory therapy, but a treatment for the gradual,
insidious progression seen in the majority of progressive MS
patients remains elusive."
Jerry Wolinsky, MD, of UTHealth and Memorial Hermann in Houston,
said that even if ocrelizumab isn't approved for PPMS, "the
effects of the drug in relapsing forms of the disease are
impressive, and have refocused the field into considering B
cells as contributing more to the immunopathogenesis of the
disease than we have in the past."[/quote]
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