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#Post#: 964--------------------------------------------------
(ECTRIMS abst.) Efficacy and safety of ocrelizumab in PPMS...
By: agate Date: October 10, 2015, 6:35 pm
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Presented at the ECTRIMS conference in Barcelona, October 10,
2015:
[quote]
Efficacy and safety of ocrelizumab in primary progressive
multiple sclerosis - results of the placebo-controlled,
double-blind, Phase III ORATORIO study
X. Montalban1, B. Hemmer2,3, K. Rammohan4, G. Giovannoni5, J. de
Seze6, A. Bar-Or7, D.L. Arnold7,8, A. Sauter9, A. Kakarieka9, D.
Masterman10, P. Chin10, H. Garren9, J. Wolinsky11, on behalf of
the ORATORIO Clinical Investigators
1Hospital Vall d'Hebron University, Barcelona, Spain,
2Technische Universität München, 3Munich Cluster for Systems
Neurology (SyNergy) (B.H.), Munich, Germany, 4University of
Miami, Miami, FL, United States, 5Queen Mary University of
London, London, United Kingdom, 6University Hospital of
Strasbourg, Strasbourg, France, 7McGill University, 8NeuroRx
Research, Montreal, QC, Canada, 9F. Hoffmann-La Roche Ltd.,
Basel, Switzerland, 10Genentech Inc., San Francisco, CA,
11University of Texas Health Science Center at Houston, Houston,
TX, United States
Background:
Primary progressive multiple sclerosis (PPMS) accounts for
10-15% of the MS population. There is currently no approved
disease-modifying treatment for PPMS.
B cells are believed to contribute to the pathogenesis of MS,
including PPMS. Ocrelizumab (OCR) is a recombinant humanised
monoclonal antibody that selectively targets CD20+ B cells.
Objectives:
ORATORIO is a Phase III, multicentre, randomised, double-blind,
placebo-controlled study aiming to assess the efficacy and
safety of OCR in patients with PPMS (NCT01194570).
Methods:
Patients were randomised (2:1) to receive OCR 600 mg (given as
two 300 mg intravenous infusions 14 days apart) or matching
placebo every 24 weeks for at least 120 weeks or until
approximately 253 three-month confirmed disability progression
events occurred.
Eligibility criteria included an age of 18-55 years, a
diagnosis of PPMS (2005 revised McDonald criteria); Expanded
Disability Status Scale (EDSS) score of 3.0-6.5 at screening;
disease duration (since MS symptoms) of < 15 years in patients
with an EDSS score of > 5.0 at screening and < 10 years in
patients with an EDSS score of ≤ 5.0 at screening; and
documented evidence of elevated immunoglobulin index and/or
presence of oligoclonal bands within the CSF. The primary
endpoint is time to onset of confirmed disability progression,
defined as a ≥ 12-week sustained increase in EDSS score.
Results:
Overall, 732 patients were randomised at 183 sites. Mean age at
baseline was 44.6 years; 49.3% of patients were female and 94.1%
were white. Mean (standard deviation, SD) baseline EDSS score
was 4.70 (1.17); mean (SD) duration since MS symptom onset was
6.48 (3.89) years; and mean (SD) duration since PPMS diagnosis
was 2.82 (3.22) years. The number of patients untreated with any
MS medication in the prior 2 years was 656 (89.6%).
At baseline, 26.4% of patients had gadolinium-enhancing (Gd+) T1
lesions; mean (SD) number of Gd+ T1 lesions was 1.0 (4.31);
median (min-max) volume of T2 lesions was 6.96 (0-90.3) cm3; and
mean (SD) normalised brain volume was 1464.99 (85.96) cm3 on
brain magnetic resonance imaging.
Conclusions:
The ORATORIO baseline characteristics are consistent with
disease characteristics of a PPMS population. As the primary
endpoint is an event-driven analysis, the treatment period will
be extended until approximately 253 three-month confirmed
disability progression events have occurred. The results from
this study will be presented after this target is reached.
_________
Disclosure:
Research funded by F. Hoffmann-La Roche Ltd., Basel,
Switzerland.
Xavier Montalban has received speaking honoraria and travel
expenses for scientific meetings, has been a steering committee
member of clinical trials or participated in advisory boards of
clinical trials in the past years with Bayer Schering Pharma,
Biogen Idec, Merck Serono, Genentech Inc., Genzyme, Novartis,
Sanofi-Aventis, Teva Pharmaceuticals, GSK, F. Hoffmann-La Roche
Ltd., Almirall, NMSS and MSIF; he is also Editor for Clinical
Cases for MSJ.
Bernhard Hemmer has served on scientific advisory boards for F.
Hoffmann-La Roche Ltd., Novartis, Bayer Schering, Merck Serono,
Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech
Inc. and Genzyme Corporation; serves on the international
advisory board of Archives of Neurology and Experimental
Neurology; has received speaker honoraria from Bayer Schering,
Novartis, Biogen Idec, Merck Serono, F. Hoffmann-La Roche Ltd.
and Teva Pharmaceutical Industries Ltd.; has received research
support from Biogen Idec, Bayer Schering, Merck Serono, Five
Prime Therapeutics Inc., Metanomics, Chugai Pharmaceuticals and
Novartis; and has filed a patent for the detection of antibodies
and T cells against KIR4.1 in a subpopulation of MS patients and
genetic determinants of neutralising antibodies to
interferon-beta.
Kottil Rammohan has received honoraria for participating in
advisory boards and consulting for Acorda, Biogen Idec, EMD
Serono, Genentech/F. Hoffmann-La Roche Ltd., Genzyme and Teva;
he has also received grants from Accera, NIH and NMSS.
Gavin Giovannoni has received honoraria from Abbvie, Bayer
HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline,
GW Pharma, Merck Serono, Novartis, Protein Discovery
Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and
Vertex; research grant support from Biogen, Ironwood, Merck
Serono, Merz, and Novartis; and compensation from Elsevier as
co−Chief Editor of MS and Related Disorders.
Jerome de Seze has nothing to declare.
Amit Bar-Or has received personal compensation for consulting,
serving on scientific advisory boards and/or speaking activities
from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS,
Diogenix, Eli Lilly, Genentech Inc., GSK, Guthy-Jackson/GGF,
Merck Serono, Novartis, Ono Pharmacia, F. Hoffmann-La Roche
Ltd., Sanofi-Aventis, Teva Neuroscience and Wyeth.
Douglas Arnold reports equity interest in NeuroRx Research,
which performed the MRI analysis for the trial, and consultation
fees from Acorda, Biogen Idec, Genzyme, F. Hoffmann-La Roche
Ltd., Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma,
Novartis, Receptos, Sanofi-Aventis and Teva.
Annette Sauter is an employee and/or shareholder of F.
Hoffmann-La Roche Ltd.
Algirdas Kakarieka is an employee and/or shareholder of F.
Hoffmann-La Roche Ltd.
Donna Masterman is an employee of Genentech Inc., a member of
the Roche Group.
Peter Chin is an employee of Genentech Inc., a member of the
Roche Group.
Hideki Garren is an employee and/or shareholder of F.
Hoffmann-La Roche Ltd.
Jerry Wolinsky has received compensation for service on steering
committees or data monitoring boards for Novartis, F.
Hoffmann-La Roche Ltd., Genzyme and Teva Pharmaceuticals;
consultant fees from AbbVie, Actelion, Alkermes, Athersys Inc.,
EMD Serono, Forward Pharma, Genentech Inc., Genzyme (Sanofi),
Novartis, F. Hoffmann-La Roche Ltd., Teva and XenoPort; and
research support from Genzyme, Sanofi, the NIH and the NMSS
through the University of Texas Health Science Center at Houston
(UTHSCH) and royalties for monoclonal antibodies out-licensed to
Chemicon International through UTHSCH.[/quote]
#Post#: 965--------------------------------------------------
Re: (ECTRIMS abst.) Efficacy and safety of ocrelizumab in PPMS..
.
By: agate Date: October 10, 2015, 6:42 pm
---------------------------------------------------------
Much of the material presented at the ECTRIMS and AAN
conferences seems to be drug-company hype, but the ocrelizumab
report has given rise to an article in MedPage Today, October
10, 2015:
[quote]2nd-Generation B-Cell Therapy Slows Progression in PPMS
Novel monoclonal antibody may work in relapsing remitting
disease as well
by Kristina Fiore
Staff Writer, MedPage Today
BARCELONA -- Ocrelizumab, an investigational monoclonal antibody
targeting B-cells, may slow disease progression in primary
progressive multiple sclerosis, a condition for which there are
currently no standard drug therapies, researchers reported here.
The anti-CD20+ drug reduced sustained 6-month disability
progression as measured by EDSS scores and reduced 120-week
development of new brain lesions and atrophy compared with
placebo in the ORATORIO study, according to a company press
release.
The drug also reduced annualized relapse rates and disease
progression over 2 years in two trials of patients with
relapsing-remitting MS, known as the OPERA I & II studies, the
company said.
Drugmaker Roche and its Genentech unit announced the results in
a press release ahead of scheduled presentations here at the
ECTRIMS meeting.
"While the field is concentrating on T cells ... we also know
that B cells are somehow involved in the disease," Jerry
Wolinsky, MD, of the University of Texas, who was on the
steering committee for the trials, told MedPage Today. "We've
generally gone after the T cell thinking that it was
simplistically the orchestra leader, but maybe there are two or
three other people leading this orchestra."
Several experts interviewed by MedPage Today said the
ocrelizumab data were the most exciting results presented at the
meeting, and that having a drug to treat progressive MS would be
a major advance.
Claire Riley, MD, director of the MS Center at Columbia
University Medical Center, said ocrelizumab was "the most
exciting thing that has happened in some time" in multiple
sclerosis.
"It's hard to tell in some patients" whether they're
relapsing-remitting or primary progressive, Riley said. "What we
need so desperately is a drug that will address both of those
issues."
And John Corboy, MD, co-director of the MS center at the
University of Colorado Denver, noted that ocrelizumab could be
taken infrequently, would be well tolerated, with high efficacy
and very good safety: "We will always be interested in a drug
like that," he said.
Ocrelizumab is not the first anti-CD20+ monoclonal antibody
tested in progressive as well as relapsing-remitting MS. The
pioneering drug in this class, rituximab (Rituxan), has also
been tested in both progressive and relapsing-remitting MS and
showed promise, but Roche/Genentech chose not to fund further
trials.
Wolinsky noted that the new drug is a humanized monoclonal
antibody, whereas rituximab is chimeric, and it binds more
tightly to its target than the older drug.
In the ORATORIO study, which will be presented on Saturday
during a late-breaking trials session by Xavier Montalban, MD,
PhD, of Vall d'Hebron University Hospital in Barcelona,
investigators enrolled 732 patients with primary progressive MS
who were randomized to placebo or to 600-mg IV infusions of
ocrelizumab every 6 months, given as two 300-mg infusions 2
weeks apart.
They found that patients on the drug had a significant 24%
decrease in disease progression as measured by EDSS scores
compared with those on placebo over 12 weeks (P=0.0321) -- the
primary endpoint of the study -- and a comparative 25% decrease
at 24 weeks (P=0.0365), according to the Roche/Genentech
release.
Those on the drug also had less worsening on the timed 25-foot
walk test over 120 weeks compared with placebo (P=0.0404).
Although new lesion formation occurs less often in primary
progressive disease than it does in relapsing-remitting disease,
the investigators also saw significant improvement in the volume
of hyperintense T2 lesions, with a reduction of 3.4% over 120
weeks compared with an increase of 7.4% on for those on placebo
(P<0.0001).
The drug also reduced the rate of whole brain volume loss over
120 weeks by 17.5% compared with placebo (P=0.0206), according
to the company release.
Wolinsky said the incidence of adverse events was similar in
both groups, with the most common being mild-to-moderate
infusion-related reactions (39.9% versus 25.5%).
The incidence of serious adverse events, such as serious
infections, was similar between groups (20.4% and 22.2%), and
there were no cases of PML, Wolinsky said.
In the OPERA I & II trials, which will be presented on Friday by
Stephen Hauser, MD, of the University of California San
Francisco, researchers randomized a total of 1,656 patients with
relapsing-remitting MS to a 600-mg IV infusion of ocrelizumab
every 6 months or to interferon beta-1a (Rebif) given as 44-mg
subcutaneous injections three times per week.
They found that the investigational agent reduced the annualized
relapse rate by about 50% over 2 years compared with interferon
(P<0.0001 for both studies).
The investigational drug also slowed progression as measured by
EDSS scores by about 40% at both 12 and 24 weeks compared with
interferon in both studies.
Ocrelizumab-treated patients also had significant reductions in
the number of T1-gadolinium-enhancing lesions at 24, 48, and 96
weeks compared with those on interferon (by about 90% between
groups), as well as about an 80% reduction in T2 hyperintense
lesions at all those time points compared with interferon,
according to the company data.
Overall adverse events were similar in both groups in both
trials at about 83%, but infusion-related reactions were higher
in the ocrelizumab group (34.3% versus 9.7%). There were similar
rates of serious adverse events including serious infections
(6.9% and 8.7%), and there were no cases of PML, Wolinsky said.
Many experts interviewed by MedPage Today noted that 2-year data
may be insufficient to detect all of the potential safety issues
with the drug.
Roche had previously stopped a trial of ocrelizumab in
rheumatoid arthritis after seeing an increased risk of serious
and opportunistic infections, some of which were fatal. Patients
in the MS population, however, may be getting a different dose
of the drug and may be younger and healthier than those in the
RA studies.
The study also raises the question of whether more physicians
will now seek to use rituximab off-label in both forms of MS --
a practice that is already not uncommon. (At least half a dozen
presentations are scheduled at the 2015 ECTRIMS meeting that
describe clinical experience with rituximab in MS and related
conditions such as neuromyelitis optica.)
Roche and Genentech are no strangers to having two competing
drugs for a single condition, with one offered at a
significantly cheaper price. The companies manufacture both
bevacizumab (Avastin) and ranibizumab (Lucentis) for a host of
ophthalmic conditions, and physicians have long preferred the
cheaper bevacizumab, especially after studies largely showed
equal efficacy and safety profiles between the two.
Whether such a situation will arise with rituximab-ocrelizumab
remains speculative, but biosimilars for rituximab are expected
to be introduced eventually, at which point market pressures may
force Roche/Genentech to drop the price for rituximab.
___________________________
Reviewed by Robert Gross, MD Multiple Sclerosis Fellow, Corinne
Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School
of Medicine at Mount Sinai, New York, NY[/quote]
The article can be seen here
HTML http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/54012?xid=nl_mpt_DHE_2015-10-10&eun=g345846d0r.
#Post#: 971--------------------------------------------------
Ocrelizumab works in PPMS but is it enough? (MedPage Today)
By: agate Date: October 13, 2015, 1:20 pm
---------------------------------------------------------
Another article in MedPage Today, October 12, 2015 (emphasis
added):
[quote]Ocrelizumab Works in PPMS, But is it Enough?
Experts questions magnitude of benefit in positive ORATORIO
trial results
by Kristina Fiore
Staff Writer, MedPage Today
BARCELONA -- Enthusiasm for an investigational monoclonal
antibody that targets B cells for primary progressive multiple
sclerosis (PPMS) was muted despite positive trial results during
a late-breaking presentation here.
In the ORATORIO study, the anti-CD20+ therapy ocrelizumab
significantly reduced the proportion of patients (mean age 44.6
age baseline) who had 12-week confirmed disability progression
by 24% compared with placebo (P=0.0321), according to Xavier
Montalban, MD, PhD, of Vall d'Hebron University Hospital in
Barcelona, and colleagues.
The drug also significantly reduced 24-week confirmed disability
progression, T2 lesion volume, and whole-brain volume loss and
preserved scores on the Timed 25-Foot Walk test compared with
placebo, Montalban reported at the European Committee for
Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting.
But MedPage Today contacted several experts, none of whom were
involved in ORATORIO, who said the primary progressive data were
less impressive than those seen for relapsing-remitting disease
in the OPERA studies that were also presented at the meeting.
"While anti-CD20+ treatment for relapsing-remitting disease
looked like a home run, these data in primary progressive
disease are not nearly as impressive," said David Hafler, MD, of
Yale University in New Haven, Conn.
Dennis Bourdette, MD, of Oregon Health & Science University in
Portland, called the 24% reduction in confirmed progression "not
great. "This is a younger group with shorter duration than in
previous trials in PPMS. It is also not representative of most
PPMS patients that neurologists are seeing today. It should
encourage us to identify PPMS earlier in their course."
Most of the experts said they wanted to wait to see planned
subgroup analyses before drawing further conclusions about the
data. Indeed, one of the first questions to Montalban after the
presentation was how the results looked when separated by groups
with and without gadolinium-enhancing lesions. It will also be
important to look at the results by age and gender, they said.
Still, Montalban stated that he was encouraged by the findings.
"We can discuss the magnitude of the effect, but I have to say I
am very happy with the results," he said.
Trial Details
Ocrelizumab is not the first anti-CD20+ monoclonal antibody
tested in progressive as well as relapsing-remitting MS. The
pioneering drug in this class, rituximab (Rituxan), has also
been tested in both progressive and relapsing-remitting MS and
showed promise, but Roche/Genentech chose not to fund further
trials.
The ORATORIO investigators used the lessons from those earlier
rituximab trials to shape their studies, with a particular focus
on patient selection -- picking younger patients who were in an
earlier stage of primary progressive disease.
Another difference is that rituximab is chimeric, whereas the
ocrelizumab is a fully humanized monoclonal antibody that binds
more tightly to its target than the older drug, the
investigators said.
Montalban and colleagues enrolled 732 patients with PPMS who
were randomized to placebo or to 600-mg IV infusions of
ocrelizumab every 6 months, given as two 300-mg infusions 2
weeks apart.
In addition to the significant reduction in the proportion of
patients who had 12-week confirmed disability, there was a
similar comparative 25% decrease at 24 weeks (P=0.0365).
Those on the drug also had less worsening on the Timed 25-Foot
Walk test over 120 weeks, by 29% compared with placebo
(P=0.0404).
Although new lesion formation occurs less often in primary
progressive disease than it does in relapsing-remitting disease,
the investigators also saw significant improvement in the volume
of hyperintense T2 lesions, with a reduction of 3.4% over 120
weeks compared with an increase of 7.4% on for those on placebo
(P<0.0001).
The drug also reduced the rate of whole-brain volume loss over
120 weeks by 17.5% compared with placebo (P=0.0206), Montalban
said.
The incidence of adverse events was similar in both groups, with
the most common being mild-to-moderate infusion-related
reactions (39.9% versus 25.5%). Montalban said these were worse
with the first dose and declined over the course of the study.
The incidence of serious adverse events, such as serious
infections, was similar between groups (20.4% and 22.2%), and
there were no cases of progressive multifocal
leukoencephalopathy (PML).
But Montalban noted that there were numerically more
malignancies among those in the drug group. There were 11
cancers among those on ocrelizumab compared with only two in the
placebo group, something that deserves further monitoring, he
said.
There was also a numerical imbalance in deaths, with four in the
drug group and one in the placebo group.
Safety Issues
Experts told MedPage Today noted that 2-year data may be
insufficient to detect all of the potential safety issues with
the drug.
Roche had previously stopped a trial of ocrelizumab in
rheumatoid arthritis after seeing an increased risk of serious
and opportunistic infections, some of which were fatal. Patients
in the MS population, however, may be getting a different dose
of the drug and may be younger and healthier than those in the
RA studies.
The study also raises the question of whether more physicians
will now seek to use rituximab off-label in both forms of MS --
a practice that is already common, as at least half a dozen
presentations are scheduled at the current ECTRIMS meeting that
describe clinical experience with rituximab in MS and related
conditions such as neuromyelitis optica.
Roche and Genentech are no strangers to having two competing
drugs for a single condition, with one offered at a
significantly cheaper price. The companies manufacture both
bevacizumab (Avastin) and ranibizumab (Lucentis) for a host of
ophthalmic conditions, and physicians have long preferred the
less costly bevacizumab, especially after studies largely showed
equal efficacy and safety profiles between the two.
Whether such a situation will arise with rituximab-ocrelizumab
remains speculative, but biosimilars for rituximab are expected
to be introduced eventually, at which point market pressures may
force Roche/Genentech to drop the price for rituximab.
Some experts remained hopeful about ocrelizumab's future in
primary progressive disease. "It's hard to tell in some
patients" whether they're relapsing-remitting or primary
progressive, said Claire Riley, MD, of the MS Center at Columbia
University Medical Center in New York City. "What we need so
desperately is a drug that will address both of those issues."
Bourdette acknowledged that the ORATORIO are important because
the drug is indeed the first to be able to affect the course of
primary progressive disease.
John Corboy, MD, of the University of Colorado Denver,
reiterated that the subgroup analyses will be important to tell
how generalizable the results will be for all primary
progressive disease, which may be a challenge given that the
overall cohort was younger and had shorter disease duration.
"The main point for me is that...if you treat MS at a young age
-- any MS -- patients benefit from presently available
medications," Corboy said.
_________________
The study was funded by F. Hoffmann-La Roche. Some co-authors
are employees of the Roche Group.
Montalban disclosed relevant relationships with Roche/Genentech,
Bayer Schering Pharma, Biogen, Merck Serono, Genzyme, Novartis,
Sanofi, Teva, GlaxoSmithKline (GSK), Hoffman La Roche, and
Almirall.
Some co-authors disclosed relevant relationships with F.
Hoffmann-La Roche, Novartis, Bayer Schering, Merck Serono,
Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech.
Genzyme, the Archives of Neurology and Experimental Neurology,
Teva Pharmaceutical, Five Prime Therapeutics, Metanomics,
Acorda, EMD Serono, Accera, NIH, National Multiple Sclerosis
Society, AbbVie, Bayer HealthCare, Biogen, Canbex, FivePrime, GW
Pharma, Protein Discovery Laboratories, Roche, Synthon, Teva
Neuroscience, UCB, Vertex, Ironwood, Merz, Elsevier, Bayhill
Therapeutics, BioMS, Diogenix, Eli Lilly, Guthy-Jackson/GGF, Ono
Pharmacia, Innate Immunotherapeutics, MedImmune, Mitsubishi
Pharma, Receptos, Alkermes, Athersys, EMD Serono, Forward
Pharma, and XenoPort.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of
Medicine, University of California, San Francisco and Dorothy
Caputo, MA, BSN, RN, Nurse Planner[/quote]
The article can be seen here
HTML http://www.medpagetoday.com/clinical-context/MultipleSclerosis/54037?xid=nl_mpt_DHE_2015-10-12&eun=g345846d0r.
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