Author Topic: (ECTRIMS abst.) Efficacy and safety of ocrelizumab in PPMS...  (Read 236 times)

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Offline agate

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(ECTRIMS abst.) Efficacy and safety of ocrelizumab in PPMS...
« on: October 10, 2015, 02:35:32 pm »
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.
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Offline agate

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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

The article can be seen here.
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Offline agate

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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

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

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