Monday, 1 December 2014

Gilenya failing in PPMS, was it expected

What does ProfG mean? MD1:ProfG 0

The result of no effect in PPMS massively disappointing and does not bode well for the second half and further sends out signals that many immunologists may have to wake up and smell the roses.

Why is MD in the lead? This is because this was based on predictions from our animal model, so I draw your attention to a previous post of work done some time ago.


Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler. 2011;17:939-48

BACKGROUND: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination.

METHODS: The effect of FTY720 was assessed in relapsing-progressive EAE in mice.

RESULTS: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course.

CONCLUSIONS: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.



Gilenya (FTY720) is an S1P1 and S1P5 receptor modulator. S1P1 is involved in trapping white blood cells in the lymph nodes and stops relapsing remitting MS. It also stops relapsing-remitting EAE as we showed in this study. S1P5 is strongly expressed in the brain and has lead to the idea that Gilenya may promote repair and the hope that help in progressive MS. In our studies if we blocked relapses we could see that there was some recovery in mobility.

Was this due to the drug or was it because we had stopped disease and the the natural repair mechanisms kicked in? Maybe the former but we could not find evident that there was remyelination, maybe we weren't looking in the right place, maybe it was due to plasticity. Obviously if we blocked relapse it stopped the animals accumulating more nerve damage that occurs as a consequence of relapse. But could it stop progression that isn't attributed to relapsing disease?

It of course shows why we believe in treat early
Most people working with EAE do two to three week experiments. This is never going to tell us much, other than the effect on the inflammatory penumbra at best and maybe over interpretation at worse.
TeamG undertook the longest EAE experiment in history.

We set relapsing remitting disease in motion and allowed a few relapses to occur, more relapses than most researchers ever see. We then had to stop any more relapses occurring because if they occurred, it would obviously cause more nerve loss and disability and so Gilenya would stop relapses and would of course do better than placebo. So we stopped anymore relapses occurring using antigen-specific immunological tolerance induction.This involves a transient depletion of white blood cells followed by a tolerising injection of myelin and after that relapsing autoimmunity is essentially gone forever. Yep it really is that good.

Why people are trying to do immunological tolerance in MS without the prior the transient depletion that makes it really work escapes me. We shall see.

However, we have shown that if secondary progression, seen by worsening in disability, is occurring then blockade of relapsing autoimmunity is not enough to stop progression.

So back to the longest experiment, we stopped relapses then waited for white cells to return and then split the animals to one group to get placebo and another group to get gilenya. So months after starting the experiment, animals got a daily oral dose for a few months, again longer than most experiments in history. Progression accumulated slowly and unfortunately there was no apparent drug effect.

Massively disappointing. But the results are the results
Therefore, we have a concern that something similar could happen in MS, although we would expect it would inhibit gadolinium-enhancing progressive MS. Time will tell as S1P1 modulators are now in trial in both primary and secondary progressive MS, so this is what is important.

CoI: This work was supported by Novartis.

10 comments:

  1. "Gilenya failing in PPMS, was it expected"

    Since all previous drug trials that are effective in RRMS proved to be useless in progressive ms with the same endpoints, the answer is yes.

    Insanity: doing the same thing over and over again and expecting different results.

    Albert Einstein

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    1. "If you keep on doing what you've always done, you'll get the same as you always got before" - and this can be applied to so many situations!

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  2. Man, after the embarrassment that was the CUPID trials, and now the INFORMS project imploding even after Don Giovannoni's cocksure predictions last month, it goes to show just how clueless Team G remains. Bruv, maybe this MS research thang ain't really your game. You're kinda wasting your lives in laboratories hoping for miracles to occur. Perhaps you can get better jobs like in retail or something.

    It isn't really my style to kick a bloke when he's down, but your ongoing losses in MS research is startling. I'm telling you now that Campath-1H will be eventually revealed to be not fit for purpose in coming time. Trust me on that, I'm a doctor (of rap, that is).

    Oh well, at least MouseDoc can waste more public money in creating those pathetic advent calendar rodent figurines. One supposes at least that is more productive than his scientific work.

    Chin up, fellas. We're British and used to our average status in life. There's no shame, sirs. Take solace in the fact that even despite fingolimod's dire results, Novartis' shares are up 0.54 percent this morning.

    It could be worse. You could be Americans and convinced that your mediocrity is actually some form of grandness. That'd be even more embarrassing.

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    1. Dre, I so wanted to see a mock-up o Prof G in a biker jacket and tilted cap, a la Brando in The Wild One. That won't happen now.

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    2. Thanks for the kind words. You're an inspiration to us all.

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    3. "Man, after the embarrassment that was the CUPID trials,"
      Actually, if you analyse the data for the sub-group of MSers with a lower EDSS, the CUPID trial was positive. Trouble is there weren't enough of these and the placebo group did not progress as rapidly as predicted. A shame as it's unlikely this study will be repeated

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    4. After the seriously disappointing new with fingolimod this morning, I have to agree with Dre's scepticism.

      Maybe alamtuzamab won't cease progression. Perhaps disabling neurodegeneration cannot be prevented In MS once it's triggered. I mean, fingolimod had no benefit on progression. Alamtuzamab has no benefit on PPMS because PPMS is what MS truly is in its true form. These drugs are just dishonest.

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    5. I do not share your sceptism, but we already know that Alemtuzumab wont stop progression if you do not start early enough, if you do we will have to wait and see.

      as to Dre. The voice of the peeps. The rumours going round were that there was a positive effect and maybe ProfG picked up on this but he is a glass half full type of guy. However you are wayward in the assumption that we had control of the FREEDOM or the CUPID study. We would have targeted the more rapid progressors and if we they had done this and the results of the hundred plus people in the planned subgroup analysis replicated THC would be shown to be positive. However no-one is going to do a 7 year study again to repeat this and maybe the CUPID trialists should be made to do this, before moving onto their next bit of science to destroy.

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    6. In addition to lack of drugs for MSers, basic Science also suffers because now no one will be interested in S1P1 inhibitors for neuroprotection and just as the science of cannabinoid been killed by perceived failure of CAMS and CUPID

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    7. P.S. Bruv I thort being British was stiff-upper lip and being polite....

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