Monday, 24 August 2015

Pixantrone another potent DMT similar to Mitoxantrone without the cardiotoxicity

Gonsette R, Debouverie M, Sindic C, Ferré JC, Edan G.
Mult Scler. 2015 Aug 18. pii: 1352458515601902 Pixantrone: a B-cell-depleting immunosuppressant for multiple sclerosis patients with active disease. [Epub ahead of print]
BACKGROUND:Mitoxantrone has been approved for patients with worsening relapsing-remitting (RR) or secondary progressive multiple sclerosis(SPMS), but its long-term use is limited by its cardiotoxicity. Pixantrone (PIX) is an analog of mitoxantrone.
OBJECTIVES:The aim of this open-label, multicenter, noncomparative Phase I/II trial was to explore the immunosuppressive effect of PIX, its impact on clinical disease activity and cerebral gadolinium-enhanced (Gd+) lesions, and its safety.
METHODS:Eighteen patients with active RRMS and SPMS (⩾ 1 cerebral Gd+ lesion) despite approved immunomodulatory therapy received four intravenous PIX injections every 21 days. A neurological examination, hematology, lymphocyte subsets, and biochemistry were performed at Day 1, Weeks 3, 6 and 9, and Months 3, 6, 9 and 12. Echocardiography was performed before each infusion, at Months 3, 6 and 12. Cerebral MRI was performed at baseline, and at Months 6 and 12.
RESULTS:CD19+ cells were reduced by 95% at Month 3 and by 47% at Month 12. Gd+ lesions were reduced by 86% at Month 12 (p = 0.01). The annual relapse rate was reduced by 87% (p < 10-4). Two patients experienced a transient reduction in left ventricular fraction.
CONCLUSION: These preliminary data indicate the efficacy of PIX in active RRMS and SPMS.
It is interesting that as CD-20 immunotherapy appears to be coming to the market that a desirable feature of a drug is now B cell depleting rather than T cell depletion. However any drug that interfers with DNA synthesis is an anti-B cell agent and include drugs like cyclophosphamide. This is because B cells divide more than T cells and as they kill dividing cells then B cells seem more susceptible. However they also kill activated dividing T cells. 

This study looks at Pixantrone an anti-cancer drug, and analogue of mitoxantrone with fewer toxic effects on heart tissue, that limit the number of times that mitoxantrone can be given. 

There were 4 treatments a month apart and the drug induced marked depletion of B cells and reduced gadolinium and the relapse rate.

Pixantrone acts as a topoisomerase II poison and intercalating agent and therefore the big question what is the risk of leukaemia, which is rather high following the use of mitoxantrone. 

As we now how to do trials in relapsing MS, one would probably find that if any of the old anti-cancer drugs that kill dividing cells that failed in secondary progressive MS, because the element of SPMS being examined is unresponsive to the drug, then they would work in relapsing SPMS and RRMS.

6 comments:

  1. YAY!
    So will pateints who already receive Mitoxantrone profit from Pixantrone?
    E.g. switch to Pixantrone grom Mitoxantrone?

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    1. Good question...In UK neither pixantrone or mitoxantrone are approved, but one would say that this trial data is probably not good enough to warrant licencing as it was a phase I/IIa and involved n=18. Therefore it would be more studies are needed especially because of the leuakemia risk as this could be higher.

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  2. The risk of leukaemia with mitoxantrone is not insubstantial, so why would you choose this drug, pixantrone, over one of the other highly effective DMTs? Is it as a possible treatment for active SPMS?

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    1. You are correct the percieved risk of leukaemia is high.

      Why may you choose this drug....maybe if you are in an area with no access to DMT, but I would say cladribine would be a better option in this situation, however the 18 people consented for the treatment so some people can be persuaded.

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  3. Speaking of phase I/II trial. I stumbled upon articles about this new type of therapy done by ImCyse

    https://clinicaltrials.gov/ct2/show/study/NCT02427776?term=imcyse&rank=1#contacts

    I found almost no publication about this type of therapy. Maybe only this paper is loosely linked to this idea:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045366

    What do you think about it?

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    Replies
    1. This is a university type spin-out until we can see more pre-clinical data it is all speculation

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