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:
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.