Why has the FDA so misunderstood induction therapies?

Are the FDA running scared? The tragic story of oral cladribine; let’s hope alemtuzumab does not go the same way. #MSBlog #MSResearch

“The post “Is alemtuzumab too risky?” has, not surprisingly, generated a lot of discussion about the FDA’s current position on alemtuzumab. Why has the FDA taken this position on alemtuzumab, and why did it reject cladribine? Both these drugs are induction agents, i.e. given as short courses, with the potential for long-term remission and in hopefully in some cases the possibility of a cure.”

“I am in Canada at the moment on a lecture tour and gave a talk last nigh to make the case for induction therapies. I have uploaded my slides below. The case I am making is for MSer choice. I see no reason why a well informed person with the disease cannot make a rational decision about risks and potential benefits of the various treatment themselves? Why should regulators act as gate keepers? If the FDA does not license alemtuzumab for treating MS it will be the second induction therapy they have turned down. Not having the option of an induction therapy will limit treatment options for MSers in the US. In slide 77 from the deck below I try and compare, and contrast, the differences between maintenance and induction therapy strategies.”

“The main differences is that induction therapies are irreversible, highly efficacious and are the only option that offers a potential for long-term remission and possibly a cure. The latter is based on the premise that MS is an autoimmune disease and that by rebooting the immune system you may get rid of the MS autoimmune response. For woman with MS induction therapies offer great advantages for having children; you can get on top of your MS disease activity and you can fall pregnant with the knowledge that no drug is in your body  that is potentially teratogenic. Induction therapies allows you to put yours and your unborn child’s interests on a par. I don’t think this latter attribute of induction therapies can be under estimated. There is one proviso in relation to alemtuzumab that needs to pointed out; auto-antibody mediated autoimmune diseases that may develop after alemtuzumab treatment may affect pregnancy. For example, antibodies that stimulate the thyroid gland may cross-over the placenta to affect the developing baby’s thyroid gland causing foetal hyperthyroidism. Although this will be a rare complication of alemtuzumab treatment it is something that needs to be considered. Fortunately, foetal hyperthyroidism is treatable.”

“I am still raw about the EMA’s and FDA’s decision on cladribine. Both regulatory agencies were concerned about the long-term cancer risk of cladribine-treated MSers. How do you resolve this?The only way would have been to given cladribine a conditional license with the requirement from the company who developed the drug to comeback with post-marketing surveillance to see what the long-term cancer risk was. Doing another phase 3 study would not have provided the information; long-term cancer risks can only come from long-term surveillance studies. The great tragedy is that Merck-Serono pulled the plug on their cladribine development programme before the results of their CIS, or clinically isolated syndrome, study were in. 

These results were stunning and the best CIS results to date. Would it not be a tragedy if a large proportion of those CISers treated with cladribine, who have flat-lined, never develop MS in the future? Imagine if we have thrown away the the chance of a potential MS cure for some CISers? The same may happen to alemtuzumab in the US. If you are an MSer who has received alemtuzumab and have done well you need to stand-up and be counted. Other MSers deserve the chance of saying yes or no to an induction therapy. I agree there are risks to these treatments, some of which are potentially life-threatening, but they are much lower than the risks associated with bone marrow transplantation, the most extreme form of induction therapy. Several countries are still running MS bone marrow transplantation programmes. Why does the EMA and FDA not close these programmes down?”

CoI: multiple

28 thoughts on “Why has the FDA so misunderstood induction therapies?”

  1. I'm finding the decisions of the FDA et al, increasingly bizarre. Anyone would suspect they have some vested interest in delaying progress in the treatment of MS. To delay treatment for those who have a narrow window before they develop irreversible disabilty is to my mind cruelty beyond belief.

  2. Why does it not close BMT down?..it is researchers rather than companies doing the studies?P.S. Clabribine does not cause the autoimmune problems of alemtuzumab, the cancer risk is no worse than with other DMT and in the CIS trials was lower than the placebo group.

  3. At least the EMA seems to be more enlightened than the FDA, who are presumably running scared after the PML/Tysabri episode. I guess we watch this space for further developments.

  4. If I had highly active MS, I think I would want the option to try induction therapy before major damage is sustained.However, it is concerning that with these induction therapies your CD4+ T cells never come back to baseline values and I don't think anyone knows what effect this will have on cancer sureveilance or the incidence of cancer down the road.So I think induction therapy should be an option for those with highly active disease or those that have failed first line therapy, but they should be advised what this treatment does to their immune system and that the consequences are not known at this point.

    1. Yes, your CD4+ T cells do not recover to the baseline levels you had prior to BMT as well.But these types of cells are part of the adaptive immune system, and like the mysteries of MS, scientists really do not yet know if these cells are vital at suppressing cancer at this point:http://www.annualreviews.org/doi/abs/10.1146/annurev-immunol-031210-101324So for me personally, I would use induction therapy as a last resort until more is known about the long term effects.

    2. Highly active induction therapy, BMT, HSCT and other stem cell therapies are relegated to the wealthy. If a person has the resources he or she will opt for the more efficacious, possibly curative therapy. Who would opt for a long term therapy that may only delay disability? The current paradigm is broken. Compared to short term cost of induction therapies and the high efficacy which would you choose if money was not an issue?

    3. Well, the high efficacy is based on the results of disease suppression after a two year study. This does not directly translate to long term prevention of progression.So for me, looking at the long term extension of the pivotal Copaxone trial, 57% of those on continuous therapy had stable or improved EDSS scores and 2/3rds did not progress to SPMS after 15 years. Clearly this drug does appear to work for some (known as super responders).http://www.ncbi.nlm.nih.gov/m/pubmed/20106943/So, from my point of view I would gladly inject this drug for the rest of my life if it will stop progression. But if I find myself progressing I would take the risks associated with induction therapy if it were an option.

    4. The question is at what point progression that is unresponsive to immunosuppression starts as you do not want to miss the boat. I do not know the answer to the question

    5. Well, I think if you hae highly active disease, Copaxone is not a good choice since it does not shut down activity immediately. However it appears that if you have a low EDSS score and start this drug and stay on it, you have a good chance of stopping the disease and your relapse rate seems to decline the longer you stay on it. I believe this is because it induces tolerance over time.So, to your original question what therapy would I choose if I had no restrictions on money or regulations if I had active disease? I would choose to go on Tsybari immediately while simultaneously taking copaxone. The Tsybari would hopefully shut-down disease activity quickly while the copaxone would induce tolerance.After a short time period, I would come off Tsybari to reduce the risk of PML and continue taking Copaxone for the long term. To me this is a form of induction therapy that does not delete large parts of your immune system and would be my preffered choice. Hopefully this combination can be investigated in the future.

    6. It wold be interesting to see what therapies people choose and their economic status. Would they choose maintenance or induction therapy? Neuros do not mandate the DMT and often let the patient have some input. When Jack Osbourne was recently diagnosed I thought that he chose to go to Germany for cell therapy.

    7. "After a short time period, I would come off Tsybari to reduce the risk of PML and continue taking Copaxone for the long term."If you do that, there is a significant risk of a rebound effect of a significant relapse on discontinuation of Tysabri that Copaxone will be very unlikely to mitigate.

    8. Possibly, but I think Copaxone may not start to work until an accumulation of GA specefic T-cells are produced. The same may also be true of the development of Tregs which there is evidence that GA develoopes.So the point is that since GA does not suppress the immune system or block cells from crossing the BBB, so I would suspect that if you take GA for at least a year before you stop Tsybari, your immune system will be primed for tolerance.Once you stop Tysabri, your BBB is open again allowing the tolerance mechanisms produced by GA to suppress further disease activity and hopefully prevent rebound.I think this is a reasonable combination to study.

    9. Actually and perhaps a more sensible approach was a study a while back by Mike Boggild and colleagues (in Liverpool at the time) which built on our extensive experimental tolerance studies) showed that an induction therapy with Mitoxantrone followed by Copaxone therapy showed some remarkably good results in his patients with a great reduction in relapse rate. http://www.ncbi.nlm.nih.gov/pubmed/16990994This seems to have been replicated in other studies. http://msj.sagepub.com/content/14/5/663.shortInterestingly the lead author on this second paper seems to have filed a patent on this treatment regimen not sure that's such a great thing to do.

    10. Yes, I saw these results also and that is one option I would consider as well. But there is a chance of leukemia with Mitoxantrone (1 person out of 27 had this in the first trial). So, I wold like to see if this approach also works with the combination of Tysabri and Copaxone as I described above without the cancer risks.

    11. Life has a cancer risk and cancers occur even if you have not drugs in your system. immunosuppression increases the risk as does age.The combination of tysabri and copaxone not sure about, as tysabri is not depleting cells just keeping them out of circulation whilst the drug is around. There will be people doing this as they want to stop tysabri because of risks of PML. Will data be collected in a way that it could be mined

    12. Yes, but If I get to that point I would probably opt for Campath instead of the Mitox/Copaxone combination since you would just need it for a short time and stop all medication after that.I agree that people will probably switch from Tysabri to Copaxone, however I think this will increase your risk of rebound.The important thing might be to have been on Copaxone for a long time prior to stopping Tysabri so that your immune system is primed prior to re-opening the BBB. I don't think most insurance companies would pay for this.

    13. Good point I agree with risk of rebound as it has been suggested that it takes time for Copaxone to take effect and the rebound will occur once the antibody effect wears off, I think that people tend to switch to Gilenya in ProfGs clinic we don't have option of BG-12 switch as it is not available in Europe.As to copaxone and tysabri combination I do not know of benefit or risks, besides further emptying the insurance coffers or your pockets, could the mechanism of tysabri impair the mechanism of copaxone, without knowing the safety profile one can't recommend it

    14. There was a study conducted on the combination of Tysabri and Copaxone taken simultaneously:http://clinicaltrials.gov/show/NCT00097760I remember seing a report on this, but I cannot find it. From what I remember there was basically no difference in the Ty+GA vs. the Ty alone arms.This makes sense to me. I think all of the effects of Copaxone such as Tregs and at GA specific T-cells would be prohibed from the CNS by the effect of Tysabri closing down the BBB.Its too bad these researchers couldn't have evaluated the rebound effect of the two arms of this study since they had the perfect opportunity to evaluate this.

    15. Tysabri doesn't close down the BBB but blocks the mechanism on T cells that enables them to cross the BBB leading to BBB disruption as a lesion is formed.

    16. Yes, i'm sure you are technically correct, but I think it prevents T-cells from crossing the BBB which in my mind is equivalent to closing it down.I guess this is why PML occurs if your are JC+ beacuse it blocks your immune system from getting into the CNS to fight it off.This may be the case also witht the combination of Tysabri and Copaxone. The regulatory mechanisms produced by Copaxone cannot access the CNS while on Tysabri. But if you build these mechanisms by taking Copaxone simultaneously with Tysabri, once you stop Tysabri the GA mechanism are available to hopefully suppress rebound and prevent future disease activity.I think it is clear that Copaxone is not a drug that works as soon as you start taking it which is why it does not have the efficacy results as other drugs based on immunsuppresion in a two year trial. But it you give it time it may make the transition off of Tysabri less problematic.

    17. There is a normal amount of lymphocytes present in the CNS for surveillance about 5/ul. Once lymphocytes are restricted by tysabri or because CD4 low as in AIDS latent infections such as JC virus become activated, oligos are targeted and PML results. MS is like a simmering flame whereas PML a raging fire.

    18. Exactly. MS is not caused by a breach in the BBB as many people think. The immune system needs access when you have an infection. But if you have an immune system that mistakes your brain for a virus it can cross the BBB and do its damage. BBB leakage is not the cause of MS, it is a consequence. This is why I think Tysabri is not a drug that should be taken for long periods of time. I think it is probably the best drug to quickly halt highly active disease without permanently deleting parts of your immune system. But you do need something to transition to for the long term and I think Copaxone may be a good drug if it is given enough time to introduce tolerance mechanism to your immune system.

  5. As mentioned above, the greatest tragedy was Cladribine was discontinued as an MS treatment.It needs to be revisited urgently.

  6. I would be upset if MSers were being pushed into induction therapy without a full understanding of the risks and I am just as upset if MSers are being not allowed induction therapy despite that full understanding. The more options the better.

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