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Thread: Ocrevus (ocrelizumab) has FDA approval

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    Distinguished Community Member agate's Avatar
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    Default Ocrevus (ocrelizumab) has FDA approval

    From the New York Times, March 28, 2017. Ocrevus (ocrelizumab) has FDA approval now and may be available soon for people with RRMS and PPMS:

    F.D.A. Approves First Drug to Treat Severe Multiple Sclerosis

    By Katie Thomas


    The Food and Drug Administration approved on Tuesday the first drug to treat a severe form of multiple sclerosis, offering hope to patients who previously had no other options to combat a relentless disease that leads to paralysis and cognitive decline.

    The federal agency also cleared the drug to treat people with the more common, relapsing form of the disease.

    “I think that this is a very big deal,” said Dr. Stephen Hauser, the chairman of the neurology department at the University of California, San Francisco, and leader of the steering committee that oversaw the late-stage clinical trials of the drug, ocrelizumab. “The magnitude of the benefits that we’ve seen with ocrelizumab in all forms of M.S. are really quite stunning.”

    The drug, which will be sold under the brand name Ocrevus by Genentech, showed the most notable results in patients with relapsing multiple sclerosis, appearing to halt progression of the disease with few serious side effects. In patients with the more severe form, primary progressive multiple sclerosis, the drug only modestly slowed patients’ decline, but medical experts described it as an important first step.


    “This sort of opens the door for us,” said Dr. Fred D. Lublin, who was a crucial investigator for the clinical trial and is director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Hospital in New York. “Once we open that door, then we do better and better and better. It’s a very encouraging result.”

    Genentech, which is owned by the Swiss pharmaceutical giant Roche, said Tuesday that it would charge a list price of $65,000 a year, which — though expensive — is 25 percent less than an existing drug, Rebif, that was shown to be clinically inferior to Ocrevus in the two clinical trials that led to Ocrevus’s approval.


    Rebif, sold in the United States by the German company EMD Serono, carries a list price of about $86,000. In a statement, Genentech noted that the price of drugs to treat multiple sclerosis had risen sharply in recent years.

    “We feel that the industry needs to start to reverse this trend, and believe that pricing Ocrevus 25 percent less than the comparator in our trials is an important first step,” the company said.

    Although people with the relapsing form of the disease have more than a dozen treatment options, many of the most effective drugs also come with significant side effects, which means that doctors often wait to prescribe them until a patient’s disease has advanced significantly. Ocrevus is viewed as relatively safe: Side effects included reactions at the injection site (the drug is infused every six months), and more upper respiratory infections and cold sores.

    As a result, “it represents a new treatment option that has the potential to be used earlier,” said Dr. Peter Chin, the group medical director of neuroscience at Genentech, who was closely involved in developing the drug.


    An estimated 400,000 people have multiple sclerosis in the United States, and about 15 percent have the primary progressive form of the disease.

    In the trials that studied the relapsing form of the disease, which involved 1,656 patients, those taking Ocrevus saw a 47 percent reduction in their rate of relapses compared with patients who were taking an existing treatment, Rebif. In the clinical trial for people with primary progressive multiple sclerosis, which involved 732 patients, those on the drug had 24 percent less risk of their disability progressing compared with patients who were taking a placebo.

    Ocrevus works by depleting a specific type of a patient’s B cells, which circulate in the blood and are part of the immune system. While they normally help the body fight off infections, they are believed to malfunction and contribute to central nervous system damage in people with multiple sclerosis.

    “I think if the safety holds up, it will become the leading M.S. therapy,” said Dr. Steven L. Galetta, the chairman of the department of neurology at NYU Langone Medical Center, who is an expert in multiple sclerosis and who was not involved in the clinical trials. But, Dr. Galetta said, the medical community will be watching to see how the drug performs once it is widely available. The clinical trial showed a slightly heightened rate of tumors in patients with primary progressive multiple sclerosis, which he said needed to be monitored closely. “There can be side effects, but you just didn’t have enough patients initially to confirm that signal,” he said.

    Jerrie Gullick, one of the patients who received Ocrevus in the clinical trial, said the drug had significantly slowed the progression of her primary progressive multiple sclerosis since she began taking it about three and a half years ago.

    Ms. Gullick, who is 51, had been declining steadily since she learned she had the disease in 2010. At the time she learned she had multiple sclerosis, Ms. Gullick was an active 45-year-old who walked six miles a day between her home in Park Slope and her office in Downtown Brooklyn, where she worked as the chief financial officer of a technology start-up.

    But her condition quickly deteriorated, and the drugs she was given appeared to do little to help her. She lost the ability to walk more than two to three blocks at a time, and she had to move out of her third-floor walk-up to an elevator building. Fatigue led her to leave her job, and she began to notice cognitive decline.

    Ms. Gullick said that at first she hoped she was on the placebo because while she noticed her disease slowing, her condition did not improve. “From a patient perspective, what you want is to get back what you’ve lost,” Ms. Gullick said. “What this drug seems to do is to stop what was happening.”

    Now, she said, she is thankful that Ocrevus appears to have bought her more time. “I was figuring another five years, and I was going to be bed-bound, and one day I realized I might have 20 or 30 more years of this,” she said. “It’s like I was on a bullet train, and I was transferred to a local.”


    Link to the article about the trial involving 732 patients that is mentioned above, "Ocrelizumab vs. placebo in primary progressive multiple sclerosis" (New England Journal of Medicine, January 19, 2017):


    http://www.nejm.org/doi/10.1056/NEJMoa1606468













    Last edited by agate; 03-29-2017 at 06:50 AM.
    MS diagnosed 1980. Avonex 2002-2005. Copaxone 6/07 - 5/10.
    Member of this MS board since 2001.

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    Distinguished Community Member BBS1951's Avatar
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    Thank you agate. I will watch closely reports of serious side effects once in the market. How could it not have sig side effects if one is mucking around with B cells, I wonder?

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    Thanks!
    My understanding has been that it is similar to rituximab (rituxan). I always thought it was a repackaging of rituxan but that is not the case. Still, the two are similar. I would love it if one of the scientists here gave me links to follow about the difference? Maybe not since I do not know what I am asking!

    However, I think it has a safety profile like rituxan. This would be very good.
    Linda~~~~

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    Distinguished Community Member Howie's Avatar
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    I hope someone here, or that comes along soon, will be on it so we can keep track of how they are doing with it. Folks just starting off with MS could really benefit.

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    Distinguished Community Member agate's Avatar
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    Virginia, I'll butt in and say I wasn't sure I heard right on that either but I went back and listened several times. He definitely mentioned SPMS and definitely said Ocrevus would be available for all types of MS.
    MS diagnosed 1980. Avonex 2002-2005. Copaxone 6/07 - 5/10.
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    Default Ok..I looked for information on the different between rituximab and ocrelizumab ...

    It appears the difference is in how the monoclonal antibody is developed? I copied the following part from "Neuro Immunology" which is exactly what I was looking for..:

    "
    "It turns out that Rituximab patent expires in the US in 2015. This means that, by the time the phase III is over, the patent will be over too. So, no profit then in doing such an investment. To surpass this inconvenience Genentech invented a new drug, antiCD20 as well, but humanized (Rituximab is chimeric), called Ocrelizumab, and started the whole process again. Then, obviously, we got a phase II trial with ocrelizumab in MS. Results have not been published yet but have been presented at 2010 ECTRIMS meeting and show,as expected, an almost equal efficacy profile to that of rituximab. But a patient died on the ocrelizumab arm from an unexpected “systemic inflammatory syndrome”. That could be chance and still hope larger studies to be assured… but it was not chance. Several rheumatoid arthritis trials with ocrelizumab have been terminated because “the overall benefit to risk profile of ocrelizumab was not favorable in RA” what it really means that 7 patients died unexpectedly in the high ocrelizumab dose arms of the trials.

    So, what have we now? Rituximab, an extraordinarily effective therapy, used for quite a long time now, pretty safe but that will never be approved for MS if phase III trials are not performed (and phase III trials are not planned to be performed) because that drug has become unprofitable. On the other hand we have an equally effective therapy, tested in phase II trials, to date showing a pretty less safe profile (to the point of having been stopped in other diseases) but potentially profitable if the company overcomes the safety issues. Guess wich one will be approved in a few years.

    This is terrible. We don’t have so many choices to give our patients to throw away the best ones or have to wait several more years. But it’s terrible not only for MS patients… Rituximab has been tested in small case series of myasthenia gravis, neuromyelitis optica, NMDAR encephalitis, Lambert Eaton myasthenic syndrome, CIDP, anti-MAG neuropathy… diseases that, if MS may not have rituximab phase III trials, they won’t for sure. And, in those case series, it has shown pretty good results that need to be confirmed in order to be approved and used routinely. If a bad commercial decision halts rituximab development or commercialization for all those diseases, MS included, it will be the most shameful story in neuroimmunology. So, if not big pharma, a consortium of neuroimmunology departments should perform that expected phase III trial and bring rituximab back to neuroimmunology therapy.

    If, in the meantime, ocrelizumab, ofatumumab or any other treatment can be developed and results positive it will be welcomed, but not a single effective drug should be left behind."

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    Distinguished Community Member agate's Avatar
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    This is weird. I was replying to a post by BBS here but BBS's post has disappeared. It probably would have been right before mine.
    MS diagnosed 1980. Avonex 2002-2005. Copaxone 6/07 - 5/10.
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    Distinguished Community Member BBS1951's Avatar
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    Thanks Laz. Now we know. Ocrevus does have some bad SEs including death. And is less safe than Rituxan.

    When the patent runs out on Rituxan, can't a generic company like Teva, produce it?

    Who wrote the article?

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    Quote Originally Posted by BBS1951 View Post
    This quote is hidden because you are ignoring this member. Show Quote
    Thanks Laz. Now we know. Ocrevus does have some bad SEs including death. And is less safe than Rituxan.

    When the patent runs out on Rituxan, can't a generic company like Teva, produce it?

    Who wrote the article?
    Hi,
    While trying to find the URL for the previous article I posted, I found this article which the scientists on this board will understand!
    "

    Tl;dr Ocrelizumab is a newly designed antibody that works with a similar mechanism as Rituximab but is expected (some preliminary data confirms it) to have a better safety and efficacy profile.

    Let's start with Rituximab (RTX) -

    RTX is a chimeric IgG1 antibody (Fc domain is humanized but Fab is Murine) that targets the CD20 protein on B-cells. The antibody induces CD20 positive B-cell lysis by different pathways (see below). Since CD20 is expressed on the surface of almost all B cells, RTX can be used to target all pathological conditions with overactive or dysfunctional B cells - Lymphoma and Leukemia.

    RTX - Mechanism of Action:


    However, there are few of problems with Rituximab -

    RTX causes infusion reactions in 50% of the patients. [1]
    RTX induces serum sickness in some (rare) patients due to the mouse antibody reaction. [2]
    As with most cancer drugs, prolonged use of RTX results in treatment resistance through unclear (but we have some hints) mechanisms. [3]
    Here comes Ocrelizumab,

    Ocrelizumab is also a CD20-targeting antibody but with some key differences. It is a humanized (90–95% human) antibody that recognizes (and binds to) a overlapping but different site on CD20 protein. It is expected to not produce the murine antibody reaction.

    Additionally, the antibody is designed to have more activity (2–5 times higher than RTX) through Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and less activity (3–5 times lower than RTX) through Complement-mediated Cytotoxicity (CMC).[4] The complement regulatory proteins as one the mechanisms shown to induce resistance to RTX treatment. This new design feature in Ocrelizumab should prevent (or delay) the development of drug resistance.

    Wait there is more…

    As you see in the picture above, RTX induces ADCC through Fc-γ-R but has better effect in patients with homozygous for Fc-γ-RIIIa with V158 mutation and works poorly in patients with one or two copies of F158 mutation.[5] On the other hand, Ocrelizumab (its Fc domain) is designed to bind to both high affinity and low-affinity (Fc-γ-RIIIa CD16) Fcγ receptors. This has already been confirmed in a Ph II clinical trial.[4]

    Notes:


    Footnotes
    [1] Infusion reactions to therapeutic monoclonal antibodies used for cancer therapy
    [2] http://onlinelibrary.wiley.com/d...
    [3] http://www.ncbi.nlm.nih.gov/pmc/...
    [4] Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma
    [5] Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H ph... - PubMed - NCBI

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    Quote Originally Posted by BBS1951 View Post
    This quote is hidden because you are ignoring this member. Show Quote
    Thanks Laz. Now we know. Ocrevus does have some bad SEs including death. And is less safe than Rituxan.

    When the patent runs out on Rituxan, can't a generic company like Teva, produce it?

    Who wrote the article?
    Here's the url to the first post I made about the patent:

    http://www.multipleexperiences.org/2...ximab-rituxan/
    Linda~~~~

    Be the kind of woman that when your feet hit the floor each morning the devil says:"Oh Crap, She's up!"

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