Author Topic: (ECTRIMS abst.) Efficacy and safety of ocrelizumab in PPMS...  (Read 347 times)

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Offline agate

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Ocrelizumab works in PPMS but is it enough? (MedPage Today)
« on: October 13, 2015, 09:20:07 am »
Another article in MedPage Today, October 12, 2015 (emphasis added):

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.