Tuesday, 15 March 2016

The other drug - a marriage made in heaven?

Clin Neuropharmacol. 2016 Mar-Apr;39(2):102-111.

Something Old, New, Borrowed, Blue: Anthracenedione Agents for Treatment of Multiple Sclerosis.

Koffman BM, Hacker M, Gunning WT 3rd, Quinn A.

Abstract

OBJECTIVE:

This study aimed to present anthracenedione agents that have been used to treat multiple sclerosis (MS), problems related to their use, and knowledge gained from our experiences using these agents to develop more efficacious drugs with fewer adverse effects.

METHODS:

We review preclinical and clinical data during the development mitoxantrone, an anthracycline, for the treatment of MS; benefits and potential risks; and strategies to reduce complications of anthracyclines.

RESULTS:

Mitoxantrone had unacceptable and greater-than-anticipated toxicity for use in a chronic disease such as MS. Adverse effects included cardiotoxicity, treatment-associated leukemia, and amenorrhea. Toxicity was identified primarily in retrospect. Structurally related compounds include pixantrone (BBR2278) and BBR3378. Pixantrone is in clinical development in oncology. BBR3378 prevents the development of autoimmunity and experimental autoimmune encephalomyelitis and blocks experimental autoimmune encephalomyelitis even when given after the onset of autoimmunity.

CONCLUSIONS:

There remains a need for effective MS treatment, particularly for nonrelapsing forms of MS. Mitoxantrone was the first nonbiologic drug approved by the Food and Drug Administration for use in MS. Chromophore modification of anthracenedione agents yielded a novel class of DNA binding agents (aza-anthracenediones such as pixantrone and aza-anthrapyrazoles such as BBR3378) with the potential for less cardiotoxicity compared with mitoxantrone. There is a need for long-term observation for delayed toxicity among humans enrolled in pixantrone trials. Preclinical toxicity studies for delayed toxicities in rodents and other models are warranted before consideration of derivatives of anthracenediones, aza-anthrazenediones, or aza-anthrapyrazoles for use in human MS clinical trials.


Int Immunopharmacol. 2016 Feb;31:74-87. doi: 10.1016/j.intimp.2015.12.014. Epub 2015 Dec 18.

An aza-anthrapyrazole negatively regulates Th1 activity and suppresses experimental autoimmune encephalomyelitis.



Clark MP, Leaman DW, Hazelhurst LA, Hwang ES, Quinn A.

Abstract

Previously we showed that BBR3378, a novel analog of the anticancer drug mitoxantrone, had the ability to ameliorate ascending paralysis in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis, without the drug-induced cardiotoxicity or lymphopenia associated with mitoxantrone therapy. Chemotherapeutic drugs like mitoxantrone, a topoisomerase inhibitor, are thought to provide protection in inflammatory autoimmune diseases like EAE by inducing apoptosis in rapidly proliferating autoreactive lymphocytes. Here, we show that while BR3378 blocked cell division, T cells were still able to respond to antigenic stimulation and upregulate surface molecules indicative of activation. However, in contrast to mitoxantrone, BBR3378 inhibited the production of the proinflammatory cytokine IFN-γ both in recently activated T cell blasts and established Th1 effectors, while sparing the activities of IL-13-producing Th2 cells. IFN-γ is known to be regulated by the transcription factor T-bet. In addition to IFN-γ, in vitro and in vivo exposure to BBR3378 suppressed the expression of other T-bet regulated proteins, including CXCR3 and IL-2Rβ. Microarray analysis revealed BBR3378-induced suppression of additional T-bet regulated genes, suggesting that the drug might disrupt global Th1 programming. Importantly, BBR3378 antagonized ongoing Th1 autoimmune responses in vivo, modulated clinical disease and CNS inflammation in acute and relapsing forms of EAE. Therefore, BBR3378 may be a unique inhibitor of T-bet regulated genes and may have potential as a therapeutic intervention in human autoimmune disease.

 Pixantrone; Formula: C17H19N5O2 

Before natalizumab and alemtuzumab there was mitoxantrone. But it was not devoid of significant toxic side effects, especially those of leukaemia and cardiac toxicity and became quickly relegated to the sidelines, primarily being used as rescue therapy in select cases of progressive MS.

The story doesn't stop here, attempts have been made to produce less cardiotoxic second generation drugs with reduced potential for perpetuating oxygen free radical production felt to cause the cardiac toxicity. Pixantrone or BBR2778 (trade name Pixuvri, a blue compound, marketed by Novuspharma) is currently licensed in the UK for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma (a form of blood cancer). An open-label study has already been completed in RRMS and SPMS with promising findings: http://multiple-sclerosis-research.blogspot.com/2015/08/pixantrone-another-potent-dmt-similar.html. BBR3378 (second abstract) is another related compound that has been shown to impede the progression of naïve T helper cells (a form of T cells) to full effector status associated with the induction of EAE (the mouse model of MS). Moreover, increased dosages of BBR3378 were demonstrated to be associated with improved therapeutic impact, but without the concomitant increase in lymphopenia (low WBCs).

For those with progressive disease, the newer generation of anthracyclines may be a marriage made for heaven.

13 comments:

  1. So, from what I understand, Pixantrone and BBR3378 and has fewer side effects than their Mitoxantrone sister?

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    Replies
    1. Yes, at least as far as cardiotoxicity is concerned. Mitox without the side effects will swing the management of MS again

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    2. I might add that if I can give it as a one off induction regimen there may be some milage to it and then follow it up with the lesser toxic first line treatments to keep the immune system in check.

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  2. a toxic cancer therapy?? haven't you doctors got any better ideas?

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    Replies
    1. Ditto. They will keep pushing repurposed cancer therapies as long as no one stops pharma from setting their own prices. The skies the limit.

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    2. Most MS therapies at one stage or another have been tried in cancer, in particular the blood cancers; the fact that they also work in MS is telling do you not think? You need to see beyond what is directly in front of your eyes...

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    3. Yes, the MOA is to suppress your immune system so how many different ways can you do this? Is the goal to find a drug that suppresses your immune system with the least side effects or is it to find out why the immune system needs to be suppressed in the first place?

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    4. For me the former, deal with the problem you know about.

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  3. Because blood cancers and MS are somehow related to EBV?

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    Replies
    1. Hodkings Lymphoma, Burkitts lymphoma this is related to EBV

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    2. Well, so far as I know the Lymphomas are blood cancers.
      Some time ago I read this article that spoke of a possible genetic connection, as well as EBV infection, among Lymphomas and MS...

      http://www.healthline.com/health-news/ms-hodgkins-lymphoma-multiple-sclerosis-genetic-connection-110613

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    3. So this is the paradigm of the immune system: INFECTIONS-AUTOIMMUNITY-MALIGNANCY; it's a sliding scale and anyone of us can land somewhere on this scale.

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  4. One of my sons had leukaemia and the other has MS- just mad, bad immune systems, s**t luck or what?

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