Aggressive or Progressive MS?

[myoak]

One treatment possibility is Rituximab

From the first study below it appears rituximab can be effective against aggressive MS.

Rituximab appears in the second study to be a superior drug to some other MS meds after Tysabri is discontinued.

From the third study it appears that rituximab is highly effective in RRMS; fairly effective in SPMS and has some, but very limited effectiveness in PPMS. Those are my own characterizations; the important thing is to become familiar with the studies to form your own opinion.

The last study listed here is a systematic review, however, it is older than the first three studies; those 3 may hold particular interest for those affected by aggressive MS, those wondering about an effective drug should they stop taking Tysabri, or the results of using rituximab for 285 patients with RRMS, SPMS, or PPMS.

Management of Fulminant Multiple Sclerosis with Rituximab: A Case Report.
http://www.ncbi.nlm.nih.gov/pubmed/2...?dopt=Abstract

Rituximab Following Natalizumab Withdrawal in Relapsing Remitting Multiple Sclerosis
http://onlinelibrary.ectrims-congres...3989/undefined

Safety, Tolerability, and Efficacy of Rituximab in the Treatment of Multiple Sclerosis: 285 Patients Treated in a Single Center. (P3.262)
http://www.neurology.org/content/84/...plement/P3.262

Rituximab in Relapsing and Progressive Forms of Multiple Sclerosis: A Systematic Review
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699597/

Rituximab goes off-patent later this year; the new patentable version is called ocrelizumab and is currently being trialed. To a number of people ocrelizumab appears to have a few more safety issues than rituximab, however, since they are similar drugs I expect the safety profiles will be somewhat similar when Phase III trials results are published.

Likely, ocrelizumab will be far more expensive that rituximab, though unlikely to be more effective. I also expect ocrelizumab to be maximized for recurring revenue, that is, many more doses will have be taken to achieve to what rituximab achieves as an induction therapy in just two doses. But I hope I am wrong about cost and number of doses.

Time will tell. The good news is that rituximab offers possibilities for a number of MSers if their neuro is knowledgeable about current studies and willing to consider off-label use of a medicine FDA approved for other conditions. A surprising number will not even consider off-label, content to offer their patients palliatives which have no influence on disease course. Others are more progressive but those must be sought out.

Large scale rituximab trials required for FDA approval for MS will not occur because it goes off patent this year. There is no financial incentive for pharma to trial it, disease societies receive money and counsel from pharma so they aren’t inclined to go against pharma's interests by agressively pursuing inexpensive alternatives, and government agencies behave more like pharma lap-dogs than pharma watchdogs because of political donations to politicians of both parties.

So, if your doctor isn’t willing to prescribe rituximab off-label you have no chance of getting it. First, you would have to find a doctor knowledgeable enough to use it and willing to prescribe it if you believe rituximab may be worth trying. Of course, there may be sound reasons why it is not right for you personally from a safety perspective. A doctor who prescribes rituximab would give the best counsel because those not using it probably aren't as well informed about it, IMO.

From the limited studies presented here I marvel that more MSers are not utilizing a drug which seems to have benefitted many MSers using it. Unacceptable situation for those who have few to no alternatives offered, IMO.

[Cvfactor]

I agree, Rituximab seems to be an effective drug and I was looking into what is required to take it.

One of the hurdles is to get your insurance company to pay for it let alone getting a doctor to prescribe it.

I have since decided on another option, but below is an article about how Rituximab was abandoned:

https://neuroimmunology.wordpress.co...ple-sclerosis/

[Suebee]

This information is good to be aware of. I appreciate all the info that is posted. Unfortunately, off label likely means no insurance coverage. So that would be a big consideration if if I found I needed to switch things up. But I found a good overview of use of this rituximab of label/ treatment protocol for MS from Cleveland Clinic. I will keep it in my files. http://my.clevelandclinic.org/ccf/me...mab12-2010.pdf
Is there anyway to help get a trial funded? Will any pharm be interested in it after off patent ? It just seems so wrong to have been dropped.

[myoak]

Don't resign yourself to believing you cannot get this drug if needed, Sue. You were one of the specific people in mind when I thought about posting on rituximab.

There are a number of MSers on rituximab so getting it is possible. Also, the fact that one MS Center used it with 285 MSers signals it is getting attention from clinicians. More people are becoming aware of rituximab's use in MS.

Getting insurance coverage should not be overly difficult and having a good strategy is important to that end. A strategy to get insurance coverage for Rituxan (rituximab) should include getting the support of a prescribing doctor. Doctors are integral in explaining to an insurance company why a particular patient requires a particular medicine.

Another help is Genentech, the company making Rituxan. They have “Rituxan Cost Assistance” which can be Googled for patient assistance and information.

No one should be reluctant to approach their doctor or Genentech for assistance in getting insurance coverage. Often, doctors handle this directly and w/o patient involvement. Many insurance companies would cover Rituxan for MS based purely on the fact that it costs far less than any of the current MS meds because it is given less frequently. It will require an informed doctor making the case because insurance companies are willing to save money.

I would urge MSers not to let their doctor off the hook if he/she says your insurance won’t cover it. Insurance won’t cover it because he/she hasn’t made the case and either doesn’t know enough about it to make a case or doesn’t have time or willingness. Getting another doctor would be the best solution. Contacting Genentech for their assistance would be another approach and should be done by anyone considering Rituxan and cost.

Also, there is a wealth of information about rituximab on various websites. One of my favorites is “Patients Like Me”. Member Jazz 1982 is an MSer who talks about her experience getting rituximab infused every 6 months post-Tysabri and getting along even better than she did on Tysabri.

Just so you know, I have no interest in Genentech or Patients Like Me beyond that of a caregiver for my wife with MS and those who may benefit from the little I have learned. I have studied MS and treatments since my wife was diagnosed in 1982, which oddly enough appears to be the year Jazz 1982 at Patients Like Me was probably born. I would urge anyone coming off Tysabri to not miss Jazz 1982’s testimony; she is knowledgeable and articulate.

There are many other patient reviews of rituximab out there, also. Google is a wonderful thing.

Sue, rituximab will continue to be used and available after it comes off-patent late this year because it is employed in several maladies. The reason ocrelizumab is being developed (by a different company, Biogen) for MS is because rituximab is so effective. Ocrelizumab is tweaked rituximab with enough difference to get a patent. The story is similar to Biogen tweaking Fumaderm and patenting Tecfidera; its the same drug with one molecule tweaked for patent protection. Both ocrelizumab and tecfidera result from the monetization of drugs already effective in MS.

If (rather,when) ocrelizumab gets FDA approval it will have to establish a few years of safety data before I would be comfortable with it. Rituximab already has a safety record established from years of use outside MS.

Sorry that likely there will never be large trials required for FDA approval of rituximab in MS. The NMSS has a budget of about $100 million a year; they are not going to do a Phase 3 trial for a single drug costing a minimum of $50 million, or half their budget.

Unfortunately, in spite of PR to the contrary, disease societies, government, and pharma are players in the same game with pharma influencing most of the calls, IMO.

We have to deal with things as they are. Rituximab has a stellar record in MS although large trials have not taken place. Because a drug coming off patent cannot be monetized as well as a patented one, rituximab will never be trialed on a scale large enough to get FDA approval for MS, IMO.

But where there is a will to use this medicine there is a way. Rituximab is being used by MSers all over the world including the USA. Seek and ye shall find endures even in the modern age.

Also, to be considered is that ocrelizumab may sail through FDA approval an become a highly effective MS med within two years or so. Although, for our household it will need a couple years more to establish a real world track record. On the horizon at this point. Rituximab is here now.

TY for the link, Cvfactor.

[Cvfactor]

Also, it is quite difficult to underatand all of the possible treatments for MS and when they should be used.

I like this presentation by Dr. Timothy Vollmer that gives an overview of all the meds (including Rituximab) and how to decide which to use. This is his opinion, but there is a good comparison towards the end.

http://www.ucdenver.edu/academics/co...%20Vollmer.pdf

[myoak]

TY, Cvfactor for the great link, very educational!

I need to correct my previous post, Roche is developing ocrelizumab, not Biogen. Today, Roche released this good news about ocrelizumab: http://www.roche.com/investors/updat...015-06-30b.htm

They will probably go for FDA approval in 2016.

[Suebee]

Thank you Myoak and CVfsctor. I appreciate your posts. I don't feel I have to fight MS alone. Suebee

[myoak]

Sue, thank you for the link you provided to the pdf on the Rituxan treatment protocol. I had not seen that before. I do the same as you… gather and save information to keep abreast of treatment options.

Rituximab is going to evolve into ocrelizumab rather quickly, I believe. The trials with ocrelizumab are looking quite good and have been in the news the last few days; you can Google them if you like.

I have read that Biogen is funding trials of ocrelizumab. First, Genentech was developing ocrelizumab with Biogen but Roche bought Genentech. Now it appears that Roche and Biogen may co-market the drug so I have to correct my previous correction… both companies are involved in developing ocrelizumab! Sorry for my confusion.

The important issue is how effective and how safe is ocrelizumab for MS? The trials look good and Roche indicated they may submit ocrelizumab for FDA approval in 2016. It isn’t unusual for the FDA to take 6 months or more to make a ruling on drug approval. Probably, ocrelizumab will become available very late in 2016 or 2017. Not that far off.

Sometimes it can feel like we are alone in this fight even though we know full well that many others face the same battle and are actively pursuing knowledge which may help. Lots more readers than posters, I suppose. It’s great to have a forum where anyone who wishes may post freely and those who enjoy reading may do so at their leisure.

Everyone appreciates your posts, Sue. Thank you for making your thoughts and study available to us.

Oh hey, one last thing… I was so happy to see a grant be given to study MS from a metabolic point of view. Google “National MS Society Awards WSU Professor With Grant to Develop New MS Research Model”. I’m no fan of the NMSS and have plenty of reason not to be but kudos for awarding this grant. Metabolic dysfunction has a huge impact in several diseases, I believe.

Thomas Seyfried’s book, Cancer as a Metabolic Disease is a very powerful book along that line. Studying cancer and multiple sclerosis over the past several years for family members has lead me to believe metabolic dysfunction contributes mightily to both. Brings to mind Terry Wahls’ book Minding Your Mitochondria. I see she has a TED talk of the same title on youtube; pretty good one, too.

Metabolic dysfunction may/probably not be all of the MS story but is part of it, IMO. Throw in activated HERV with metabolic dysfunction and you are well on the way to unraveling the etiology of MS, IMO.

[Cvfactor]

I also believe that the degenerative nature of progrssive ms is linked to a change in energy supply in the damaged axon.

One of the papers that got me to think about this is the one below:

http://www.ncbi.nlm.nih.gov/pubmed/19233038

In essence this describes the observation that demyelinated axons undergo changes in mitochondrial function. Mitochondria are the powehouses of a cell that provides the energy it needs to function.

It seems the demyelinated axon requires much, much more energy to transmit signals than normal nerves and it is thought this increased energy demand might set-up a state of hypoxia in the neuron eventually leading to the death of the axon.

This makes sense to me because fatigue is one common symptom in MSers and I suspect this increased axonal energy demand might be the cause of this overwhelming fatigue.

[AMFADVENTURES]

Cv, I suspect you are on to something there, I've noticed that taking an extended break from my exercise routines is needed to restore function and I often thought this was related to some kind of neuronal fatigue. Damaged mitochondria could explain it.

However I don't think it explains the mind crushing MS fatigue so many of us have experienced because of the number of studies which report exercise as a mitigating factor for the classic MS fatigue syndrome. If that were the case, seems like exercise would make MS fatigue worse, not better.

[Suebee]

This is an interesting issue. I found an article published around same time in 2009 re possible involvement of mitochondria in ms. It theorized that there is a "pre active" state of lesions in ms and I think it suggests that the axonal destruction is what determines the secondary progressive part of the disease. The article Gives an interesting but very esoteric detailed explanation of how the authors hypothesize the mitrochronia is damaged, if you are curious. It also gave a synopisis of findings by other researchers, including certain genes that have been identified as causing disease. But what caught my eye was this paragraph about one treatment that targets mitochondria: "Intravenous mitoxantrone (novantrone) treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing–remitting or secondary progressive disease [187]. Regarding the action mechanisms of this approved immunosuppressant mitoxantrone, a synthetic analog of anthraquinone, at least in tumor cells, the mitochondrial PTP targeted mechanism is involved [188]."
http://www.sciencedirect.com/science...2544390900146X

I am relieved to see That science is finally realizing and documenting the destruction ms causes to the brain is at an axonal or mitochondrial level and hopefully will seek to find therapeutic treatments to prevent such damage. With re to AM's comment about MS fatigue, I have similarly observed, and I also don't have a clue as to why. 😝

[Cvfactor]

There are a ton of papers that discuss the problems with mitochondria and ms. My thought about the increased energy demand by demyelinated axons is that it is sucking energy all of the time and really is not related to physical exertion.

In my case I would go to work and be completely exhausted by the end of the day. I would sleep 12 hours at night but I would always feel tired regardless.

For me, I started taking a supplement that seems to support mitochondrial health. I found out about this from other msers who it seemed to help (at least some of them):

http://www.msworld.org/forum/showthr...ha-lipoic-acid

This combination was tested in rats and has a positive effect:

http://www.ncbi.nlm.nih.gov/pubmed/18846423

It has worked for me so I think there is something to this notion that there is a problem with mitochondria in MS. Hopefully there will be FDA approved treatments in the near future.

[Suebee]

Supplements for fatigue / mitrochondrial damage

CVfactor, thanks so much for passing along the link to thread on supplement
1,000 mg of acetyl L-carnitine and 200 mg of alpha lipoic acid daily. Is this available at most drugstores? I haven't tried this but it looks worth a try. My fatigue is overwhelming at times. My youngest daughter will lie down with me when I rest and whisper how much she hates ms. It's heart wrenching. I've tried co-q10 in different compositions and never noticed a difference so stopped that rather pricey supplement. Have you used co-q10 with it?
I understand better what you meant by the increased energy demand from the axonal damage seen in progressive ms. The so called preactive ms lesions in rrms shows axonal changes too, which could explain why rrms can have ms fatigue as a main symptom, ...I think, if I have followed your line of thinking.
Regardless, I will try the supplement! Suebee
Happy 4th!

[Cvfactor]

Yes, this combination is already available over the counter. I take two of these a day:

http://www.amazon.com/gp/aw/d/B003G2...z4L&ref=plSrch

I also take 500mg CoQ10. The local drug store has this bUT they are expensive for some reason. But I buy 400mg and 100mg capsules from Amazon.com which arequires pretty reasonable. I read a paper that 500mg COQ10 was tested in msers and it had a positive effect. Ill post it if I can find it.

I should say that there are people with genetic mitochondrial dysfuction for which there is no cure. There is a support foundation that has reccemdations on how to treat this disease:

http://www.umdf.org/site/pp.aspx?c=8...7LUG&b=7934635

It is interesting that sone of the supplements they recommend are things like Coq10 and Alpha Lipoic Acid and Acetyl-L-Carnitine. So if the degenerative phase of ms is a result of mitochondrial abnormalities it is not a surprise these supplements help some people. Not to say the is a proven treatment but the evidence seems to be accumulating.

P.S. here is the study on CoQ10:

http://www.ncbi.nlm.nih.gov/pubmed/24621064

I was taking 400mg/day prior to this and this seems the max dosage the mitochondrial foundation recommends for my weight. I can't say if it is the CoQ10 or AlA/AC that helps me with the fatigue but I'm happy with the results I'm seeing.

[Suebee]

CVfactor, you're awesome! Thanks so much with passing on supplement info. I'm going to start ASAP. I'll wait a bit on coq-10 so I can see if I have a benefit. It gave me a boost just to know I have something to try out. It
Makes me feel more proactive. I'll keep you posted. Suebee