Tuesday, 30 July 2013

Rituximab review

Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013 Jul 2;8(7):e66308

BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.
OBJECTIVES:To evaluate the efficacy and safety of rituximab for MS treatment.
DATA COLLECTION:Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.
MAIN RESULTS:Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.

Anti-CD20 antibodies inhibit relapsing disease but does not appear to inhibit non-relapsing progressive MS

19 comments:

  1. Is rituximab out of patent? How does it compare with cladribine and alemtuzumab? If it is out of patent, is it never going to get any further like cladribine because of the costs of clinical trials?

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    1. Rituximab only comes of patent in 2015. It is however a biological therapy (antibody) and the rules for getting a biosimilar licensed are very different to generic small molecules. Biosimilars need phase 3 trials and data on whether or not they are safe and they hat don't induce antibodies against themselves (neutralizing antibodies or NABs). Therefore the hurdle for getting biosimilars to market are high. In or the words the price stays high.

      Yes, you are right rituximab probably punts in the same efficacy bracket as cladribine, alemtuzumab and ocrelizumab its daughter.

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    2. You know what Prof G, the fact that the effects of rituximab on disease progression in PPMS appears to be marginal makes me think that the pursuit of anti-CD20 monoclonal in the treatments of progressive MS will end in tears. I believe that the trails for ocrelizumab and fingolimod in PPMS will be a total disaster that will waste precious funds and resources. It will be mightily disappointing for us all when scientists at Barts' declare that valuable lessons will be learnt from erroneous trial designs and that they may get lucky next time.

      Also, the retrovirus pursuit of the Charcot Project is ringing alarm bells because of the Sol Spiegelman and Howard Temin failures of trying to link the causes of leukaemia in mammals with cancer-inducing viruses, and then discovering cancer being caused by retroviruses was a big and expensive mistake. I can see history being repeated here.

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    3. Re rituximab in PPMS. Yes, I agree with you that the results were not that impressive, which I why I am actively promoting the strategy of combining an anti-inflammatory with a neuroprotective agent. This is why you should not be so down beat about Fingolimod; it has very interesting biological effects and is both anti-inflammatory and there are hints that it is neuroprotective (brain atrophy data), it also may promote remyelination.

      I don't care about history repeating itself. If we don't try and do the experiment we won't get any answers. i deleted pessimism from my MS glossary a long time ago. The good news is that there is a lot of activity in the progressive MS space. It is only a matter of time before we will have something to offer you.

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    4. Pessimism Is For Losers!Tuesday, July 30, 2013 4:11:00 pm

      Blimey, Prof G! You sound like a man on a mission who will not take crap off of any naysayers. I like it. With a mind set like your current one, all may not be lost.

      I hope that you're right about fingolimod in treating PPPMS. If the results prove positive then we could have a bonafide medicine for progressive MS by the summer of 2015. That will be fantastic if it happens.

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    5. MouseDoctor is the one who is most pessimistic about fingolimod being efficacious in treating PPMS. He even said so on this blog. And he's a part of Team G!!

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    6. MouseDoctor is from Yorkshire and imbibed pessimism with his mother's milk! Just because he (and I) think this might not work extrapolating from our mouse study on fingolimod in our secondary progressive mouse study doesn't mean it may not be of use in PPMSers or SPMsers. In fact we hope we're wrong!

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    7. MD2, did you guys use anti-inflammatory with a neuroprotective agents when you tested fingolimod in mouse models of progressive MS?

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    8. We reinduced tolerance in the mice so they didn't have any more inflammatory events in the CNS then treated with fingolimod. We didn't use any other neuroprotectants in that study. It was just to see whether fingolimod had any neuroprotective effect on its own.

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    9. Re: Pessimism Is For Losers!

      So you reckon we'll have bonafide medicines for progressive MS by the summer of 2015? Hmm, keep hoping, son. They said the same thing in 2010 and will no doubt shift the goal posts in two years yet again.

      PPMS is as complex as cancer. The puzzle is just to grand to be beaten any time soon.

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    10. Re "It was just to see whether fingolimod had any neuroprotective effect on its own."

      Ah... so Prof G may be on to something. I am excited once again. In G we trust.

      Re Anon 5:37 "PPMS is as complex as cancer. The puzzle is just to[o] grand to be beaten any time soon."

      So hope you're wrong there, mate. There is too much pessimism in the world of PPMS.

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    11. If all the activity in progressive MS occurs behind the BBB with no active lesions present, then you would not expect rituximab or any other mAb to be able to get in there to work. Small molecules that pass into the brain and dosing mAbs directly into that compartment should have a better chance, shouldn't they?

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    12. Re 2015 or beyond. I don't want to make promises we can't keep. Yes, if the PPMS fingolimod trial is positive there will be something in 2015. If it is negative you will have to wait for the Ocrelizumab results in 2016.

      In addition, we are in the planning phase of a new PPMS trial. Recruitment should start in 2014.

      The point I want to make is that there is at least something happening in the field. A few years ago the field was barren. Let's hope it is bumper crop with not one but two positive options.

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    13. Our fingolimod in SPCREAE (secondary progressive chronic relapsing EAE) study was a very high bar to get over. The animals were allowed to become very disabled and then had the autoimmune inflammatory reaction switched off and allowed to progress. The equivalent would be take advanced SPMSers treat them with a course of mitoxantrone and then start fingolimod to see if it stops progression. The current trial is allowing fingolimod to be used earlier and in MSers that have not been treated with another anti-inflammatory. So I would give the trial a 50:50 chance of being positive. The reason why I am so positive is because of the impact that fingolimod has on brain atrophy and spinal fluid markers. Let's be patient and wait to see the results come in. However, the best treatment of SPMS is prevention; early highly effective treatments in the RRMS phase will almost surely delay or possibly prevent SPMS. For those who have PPMS we need also need to treat early; I would suggest doing a trial of cladribine with a neuroprotective agent added on top (for example laquinimod, simvastatin, ibudilast).

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    14. 50:50 is very good odds, Prof G. If you were a casino you'd be the most popular joint on the strip. Let's hope you're right. PPMS remains the great failure in MS research.

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  2. Re "rituximab appears overall safe for up to 2 years of therapy "

    What do we know about safety after 2 years?

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    1. We need a time machine/crystal ball. I guess we'll know about 5 year safety in 3 years time.

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  3. What's the trial you are planning this year for PPMS people? Have they finished recruiting?

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    1. The fingolimod trial has fully recuited and finishes this year.

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