Author Topic: (Abst.) Ocrelizumab vs. placebo, ocrelizumab vs. interferon beta-1a (NEJM)  (Read 202 times)

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Offline agate

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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:

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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.)

For discussion, see http://www.nejm.org/doi/full/10.1056/NEJMoa1606468?query=TOC#t=articleDiscussion.

The entire article can be seen here.

_________________________________________

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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.)

The entire article can be seen here.
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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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:

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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.
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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This news has been selected as one of the 10 top neurology stories of 2016 by MedPage Today:

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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."
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

 

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