Ocrelizumab (Ocrevus) not the answer in PPMS - far from it.

[Cliffhanger]

Hi!

I am a new member at this page. But I have been reading this page for several years. So today I pull myself together and registered It is a way to get more actively involved instead of being just passive.

So then, I was diagnosed with PPMS 8 years ago. And of course I am longing for a favourable agent that will give a good risk/benifith ratio. Now this agent Ocrelizumab (brand name Ocrevus) had produced some buzz lately among pwMS´s. Some have aired hopes in connection to this agent. But I want to air some serious doubts regarding this agent.


OCRELIZUMAB - NOT A WALK IN THE PARK
I don´t think that the Ocrelizumab will be a walk in the park. Clearly it seems to have some serious safety problems with regard to malignancies. Also it has some dark history with regard to PML in previous halted trials in SLE (lupus) and RA.

The AAN 2016 Conference did not give any some light on the high incidence of malignacies (read: cancer) with with Ocrelizumab in PPMS, namely 11 patients - incidence 2.3%.
All in all, From that based on stuff presented or discussed at AAN 2016, it was 9 malignancies (or the 11 cancers reported) verses 0 in placebo and I think 6 breast cancer verses 0 in only one trial ...(!)

Now If we think it was only 3 malignacies v 0 in the cladribine (European originated drug) trial and this got rejected by the FDA what will they do to this American oriniated drug?
Therefore licencing may not be a slam dump

OCRELIZUMAB - SERIOUS ISSUES WITH REGARD TO SAFETY
Clearly, 2.3 % incidence of malignacies during the 2 year study with Ocrelizumab raises some serious questions about safety connected to Ocrelizumab.

Also what will happend in the long run when you put B cells on hold, a question that Professor Mark Freedman, a MS neurologist in Ottawa raised in this video from Ectrims oct 2015 (*Prof Mark Freedman starts talking about Ocrelizumab at the 3:50 mark of the video*): http://bit.ly/1T5XXDJ

And to be noted, what professor Steve Hauser stated after Ectrims Óct 2015 with regard to Ocrelizumab´s sister Rituximab (also CD-20 antagonist) efficacy with regard to keep RRMS patients away from SPMS, Quote:
" However, my initial enthusiasm for ocrelizumab has been dampened, giventhat a large number of my patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea. "

OCRELIZUMAB - HAS A DARK HISTORY
Also, the history with Ocrelzumab is not so light: Both in lupus and in RA Ocrelizumab were halted due to serious infections, some of them deadly, such as PML. So then, both studies were stoped due to severe infections, several cases of the deadly PML.
So, there bound to be some incidence of PML sooner or later in MS, as rituximab was not free from PML events, nor Ocrelizumab in the previous halted trials in RA and SLE.

OCRELIZUMAB - SISTER OF RITUXIMAB
These are he Box Warnings that came up Rituximab CD-20 in Non-Hodgkins lymfom (NHL): http://bit.ly/1T8IpnS (*Scroll down a bit on the page*)

The safety experience was made, to my best understanding, when it was given as a single agent in NHL and the doses used, to my understanding, are lower than those used in the phase III with Ocrelizumab. Now Roche would say, that would differ Rituximab CD-20 antagonist from Ocrelizumab antagonist (... everyone talks for their sick mother ...) in that Rituximab is a chimeric antibody and Ocrelizumab is humanised antibody.

But I would buy any sutch argument that Ocrelizumab should not earn the same Box Warnings as Rituximab, unless hardcore proof will show rational for this. Nor will independant well respected neurologs buy this argument either.

And these 8 to 0 malignancy events that occoured in the PPMS Ocrelizumab trial does not make the picture any better. Furthermore, Genentech/Roche have all the reason in the world to alienate themselves from Rituximab, since it would pose a threat for the company´s profit ambitions with Ocrelizumab ...

MY OWN CONCLUSION:
Now, I have personal doubts about Ocrelizumab safety in PPMS and in general. The efficacy in PPMS is very low. Also, the study were "pimped" or rigged with very early PPMS patients and with non aggressive version of it. With regard to RRMS ca 75% of the patients were naive; i.e. they have a rather benign version of RRMS. So both trials were loaded with responders.

Despite what Roches marketing department says, Ocrelizumab have some serious safety issues to deal with, especially with the high incidence of malignancy events (2.3% in PPMS trial), the history of severe deadly infections, PML in previous halted trials with Ocrelizumab in SLE/Lupus and RA, and the obvious bridge over the Rituximab and the safety issues with this very closely related agent.

So, I Think it would be vice for everybody to hold your horses for a while, with regard to Ocrelizumabs safety. It will never be a first line agent in RRMS. Furthermore, its use among PPMS will be limited, given its low efficacy and the high risks that goes with long term use of this heavily immunosupressive agent

No, Roche marketing department have been very skilled in creating positive Buzz about Ocrelizumab in the MS-Community. But I have my doubts about this agent. But more importantly, several prominent Neurologs have also doubts about risk /benifith ratio connected to Ocrelizumab, as aired above.

As for me, I am still waiting for a PPMS drug to be developed, with reasonable risk/benifith ratio. But Ocrelizumab (brand name: Ocrevus) is not the answer for me in my PPMS sickness.

[David1949]

As I understand it Ocrelizumab is an immune suppressant, just like many of the other disease modifying drugs.
https://en.wikipedia.org/wiki/Ocrelizumab

Its not surprising that it would make the patient more susceptible to infections and cancers.

I've had PPMS for 20 years. I don't use any of that junk and I'm still able to hobble around with my cane and leg brace.
Yeah I'd like to be free of MS but I don't want to get PML or cancer in the process.

[Cliffhanger]

Thanks for comment David1949.

Yes true, Ocrelizumab is an heavy immune suppressant - or heavy artillery. Now, to completely deplete all the CD-20 B cells will not be good in the long run. And as Professor Dr Mark Freedman, Neurologist in Ottawa, says in the video, it will be risky. And the Ocrelizumab in PPMS showed a high incidence rate of cancer (2.3%). Also, Ocrelizumab´s sister, Rituximab had several PML cases. And to be noted, Ocrelizumab was halted in SLE and RA due to cases of PML and other opportunistic infections.

No, as you David, I will stay away from Ocrelizumab, and instead use my cane.

[1eye]

Dr. Mark Freedman was my neurologist. Then I had a CCSVI procedure. I begged him to put me on any disease modifying therapy. He was convinced I had converted to Secondary Progressive, and refused, saying it would not help. I was on Copaxone. I started mitoxantrone. Since then, a study has come out saying it is synergistic with copaxone. But that had not happened yet, and through my drug store, I was unilaterally taken off copaxone. I have not had any disease modifying therapy since. But I have had a heart attack, which I blame on the mitoxantrone. I now have a prescription for Sativex.

I am still without any disease modifying therapy. I was supposed to be on a Gilenya trial, back when my SPMS status was questionable, but that never happened. If it had happened, I would probably be able to walk, and drive, neither of which I can do now. Dr. Freedman prevented my participation in that trial, just before I was to be randomized.

Around that time, the whole Tysabri/PML thing happened. I had better results from my CCSVI procedure than I ever had with any drug.

Now I am on 300mg/day of biotin, with 300mg rice bran filler. I still have progressive MS, but I would no more take a monoclonal antibody than go back to seeing Dr. Freedman. In case anyone is interested, and I know no neurologists are, I believe I am having a relapse at the present moment. SPMS, my @$$! The diagnosis of SPMS has nothing to do with whether or not you have relapses or remissions. It is given based on your ability to walk, and whether you can do it without a cane. I could then, but I can't now. I had a very long remission of a lot of my MS symptoms after my CCSVI procedure. I have had a number of relapses, none of which required a doctor. I wish I had a specialist of some kind for the one I am having now, as it is affecting my balance, and I wish to avoid falls. I still would refuse monoclonal antibodies. Life, for us MS patients, can get complicated.

[CureOrBust]

SPMS by definition means you will still have relapses.

[NHE]

SPMS by definition means you will still have relapses.

Yes. See the chart below.

[1eye]

Yes I have seen that chart before. Several times drawn by hand when a neurologist was explaining that I would still get relapses. So why am I not still relapsing-remitting? Because I can't walk? None of it makes any sense to me. I don't think my disease is any different. I prefer to call it symptom progression. There is no difference in the disease or its cause, and the fact that treatments don't work because they never did.

[CureOrBust]

So why am I not still relapsing-remitting? Because I can't walk? None of it makes any sense to me.

There is no single consensus on the distinction between the different sub-groups. And hence it is confusing as different sources/neurologists use different criteria and will therefore possibly place you in a different category. It may also get confusing (my opinion here) as the "transition" between the phases are probably not simple "click" over, but a slow transition. I would say that its simply a line in the sand as you move between each phase, drawn by your neurologist. And as above, another neurologist may place you in a different group (ie a different side of the line in the sand). eg I think it was the Ocrelzumab trial that had PPMS participants which had enhancing lesions.

My first label of SPMS was made by a neurologist because I had some (ie any/slight) residual symptoms (ie weakness) from a previous relapse. huh? would anyone pass as RRMS after a relapse?

[Cliffhanger]

I so wish that a MS drug without immunosuppression features would eventually be developed ... because we need it.

There is always a price to be paid for long term immunosuppression:


So this is what I read today in a newly published paper - and it relates to all drugs that have immunosuppression as a charactersitica:

" AIDS-related cancer seen in someone treated with Fingolimod (Brand name: Gilenya) . This case highlights potential risks associated with immunosuppression with this medicine and ongoing need for vigilance in assessing for such complications. !


Source:
http://multiple-sclerosis-research.blog ... +Research)

[1eye]

I am glad now that I was kept out of the Gilenya trial (aka FTY 720) not because if I had been allowed in the trial, I would likely still be able to walk, drive, and play guitar. The reason I am glad, is that I would have been risking PML or leukemia. I have enough problems without those.

The theory (and it is no more than a theory) that MS has anything to do with an overactive immune system, will, soon I hope, be consigned to history's rubbish-heap. It may dawn on people that there is a good reason why decades of money-spending have had little effect. There is good, powerful scientific evidence that MS is genetically caused.

[HarryZ]

The theory (and it is no more than a theory) that MS has anything to do with an overactive immune system, will, soon I hope, be consigned to history's rubbish-heap. It may dawn on people that there is a good reason why decades of money-spending have had little effect. There is good, powerful scientific evidence that MS is genetically caused.

I've been following MS research since the mid 60's. Despite all the money spent and all the research done, there still is not any known cause for MS. A lot of various speculation and the drug companies for years have tried to force the immune system theory on the world of MS medicine. It's been good business for them since the early 90's when the DMDs started to surface but it hasn't been much relief for MS patients. The DMD's time and time again have been proven to provide little if any help for MS patients in the long run.

And now the monoclonal anti-bodies have arrived and with them huge costs and an array of nasty side-effects, some of which are lethal. And where is most of the research money still going...the development of immune system altering drugs that continue to chase the auto-immune theory.

In the last ten years there has been other venues of research that have more or less introduced more questions about the causes of this lousy disease but here we still are....no known cause and very little in the way of a solid treatment. I really hope some day in the near future that some scientist stumbles upon THE answer. After waiting over 50 years for really great news....well, I'm still waiting!!

[centenarian100]

I am glad now that I was kept out of the Gilenya trial (aka FTY 720) not because if I had been allowed in the trial, I would likely still be able to walk, drive, and play guitar. The reason I am glad, is that I would have been risking PML or leukemia. I have enough problems without those.

This is an odd comment because there is absolutely no evidence that gilenya has any benefit in progressive multiple sclerosis.

It failed miserably to demonstrate any benefit compared to placebo in a PPMS trial (http://msology.ca/gilenya-fails-in-prim ... e-ms-trial)

I don't know why you blame your doctor. Do you expect doctors to prescribe medications with serious side effects just to appease a patient if they don't think the drug will be effective?

[centenarian100]

SPMS by definition means you will still have relapses.

This is not correct. People will multiple sclerosis often have less relapses and less accumulation of new MRI lesions as they get older, and they are more likely to have a slow insidious worsening of symptoms. "progression" is a very confusing term, but it simply refers to a slow worsening-most commonly a gradual decline in gait. This is distinct from rapid worsening which occurs in the setting of a relapses. Relapses also often improve completely or incompletely over time or with treatment (solumedrol, plasmapheresis, et cetera)

"progression" has nothing to do with the level of disability. Young people with RRMS can have devastating relapses with poor recovery. People can have PPMS for many decades and have relatively mild problems if the progression is very slow. One typical history of primary progressive multiple sclerosis is a middle aged man saying, "I can't keep up with my wife any longer."

The term "progression" is very confusing and is misleading to patients and neurologists alike. People with aggressive relapsing multiple sclerosis with high disability and poor or slow recovery often are diagnosed wrongly with progressive multiple sclerosis (this is likely what happened with Dr. Terry Wahls)

-Cent

[centenarian100]

Cliff hanger: you make an excellent post.

I think the question at hand is, "are you hot, or are you not?" In other words, is active inflammation driving disability, or is a slow degenerative processes (axonal loss, neuronal death, mitochondrial failure, brain/spine atrophy) driving disability.

Ocrelizumab/rituximab (essentially identical drugs when talking about drug efficacy) are only going to help with inflammation related acquisition of disability. They are not neuroprotective, and they are certainly not promoting regeneration. Most likely, if you are young, have superimposed relapses, or have new or gad+ MRI lesions, you have a better chance to respond to these treatments. If you are old, have an insidious decline without relapses, and have a static MRI, you are less likely to respond to these drugs. This is essentially what was shown in the OLYMPUS trial (for rituxan at USCF). Whether or not the potential benefit is worth the risk is a different discussion.

[CureOrBust]

SPMS by definition means you will still have relapses.

This is not correct. People will multiple sclerosis often have less relapses and less accumulation of new MRI lesions as they get older, and they are more likely to have a slow insidious worsening of symptoms. "progression" is a very confusing term, but it simply refers to a slow worsening-most commonly a gradual decline in gait. This is distinct from rapid worsening which occurs in the setting of a relapses. Relapses also often improve completely or incompletely over time or with treatment (solumedrol, plasmapheresis, et cetera)

"progression" has nothing to do with the level of disability. Young people with RRMS can have devastating relapses with poor recovery. People can have PPMS for many decades and have relatively mild problems if the progression is very slow. One typical history of primary progressive multiple sclerosis is a middle aged man saying, "I can't keep up with my wife any longer."

The term "progression" is very confusing and is misleading to patients and neurologists alike. People with aggressive relapsing multiple sclerosis with high disability and poor or slow recovery often are diagnosed wrongly with progressive multiple sclerosis (this is likely what happened with Dr. Terry Wahls)

You appear to have confused PPMS (Primary Progressive) with SPMS (Secondary progressive). In PPMS you have no relapses, but SPMS you still have relapses. see NHE's post above.

SPMS by definition means you will still have relapses.

Yes. See the chart below.

You also use the language "have less relapses". Less relapses means you are still having relapses. Most diagrams I have seen and descriptions i have read show that people "progress" (ie move) from RRMS to SPMS to PPMS, as they reduce in frequency of relapses and move to a general decline. As in the diagram above linked by NHE. You will also note that the relapses are less distinct in the above diagram once you move to SPMS. But they are still happening.

The actual definition between the stages of RRMS/SPMS/PPMS (and also PRMS etc etc) is not absolutely defined/agreed/acepted between Neurologuists, and hence I heard that there were PPMS patients in the Ocrelizumab trial who had enhancing lesions, which other neurologists would not consider valid for a PPMS diagnosis.