Saturday, 27 January 2018

Trial in Remyelination is safe in humans

You want to hear about remyelination trials and here is one. The idea that there are naturally occurring antibodies that promote remyelination was suggested by the group of Moses Rodriguez at the Mayo clinic many, many years ago. 
They then generated an oligodendrocyte/myelin-specific recombinant human monoclonal IgM, rHIgM22. Apparently the antibody is well-endowed with strong anti-apoptotic and pro-proliferative effects on oligodendrocytes.

So this study says it is safe in humans
However, I must admit that I find the whole approach very weird. 
We know that to promote remyelination that the treatment has to enter the brain and bind the oligodendrocytes.
In the Lingo-1 studies they injected massive amounts of antibody such as up to 100mg/kg, which was was about 99.9% excluded from the target. But that tiny percent apparently did something. 
In this current study they used 50 to 100th less antibody and amazing 99.997%  was excluded although this increased to about 99.95 at 1mg/kg and 99.5 at 2mg/kg so again most of what injected went no where useful.
Surely the starting point needs to develop agents that get into the brain.  Maybe I'm just being thick again.

However, I guess other people think differently

Eisen A, Greenberg BM, Bowen JD, Arnold DL, Caggiano AO. A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. Mult Scler J Exp Transl Clin. 2017 Nov 21;3(4):2055217317743097.

OBJECTIVE:The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).
METHODS:Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.
RESULTS: rHIgM22 was well tolerated with no clinically significant safety signals. Non-compartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0-Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.
CONCLUSIONS: Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

10 comments:

  1. Does Clemastine fumerate and bexatrone get past the BBB?

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    1. Common side effects of clemastine fumarate include drowsiness, dizziness therefore it gets into the brain.
      Bexarotene is brain penetrant

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  2. Is it known MD if a remyelination agent will work better when there is inflammation vs. no inflammation in the environment?

    How can a monoclonal antibody ever pass the BBB to become effective in remyelination? Should be given by a different route or maybe use a drug carrier that crosses BBB?

    I have read for years about RhIgM22 and others like Clemastine, anti-Lingo, Vesicare, Miconazole, Clobetasol, Idebenone, Neureregulin-1, Benztropine, Retinoid Acid Receptor Agonist, Bexarotene etc. and nothing has panned out.

    Why do animal models not translate ever into human models? Do we need better animal models MD or better drugs or drug carriers of current drugs that help them cross BBB? Are you hopeful at all MD re: remyelination or even neurorestoration drugs ever becoming a reality in our lifetime?

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    1. Based on EAE studies we have Tregs promoting remyelination and macrophages also promote remyelination as they are needed to clear debris.

      Apparently shark antibodies can cross the BBB. Yes you could target the antibody to a transport molecule e.g. transferrin receptor

      I have read ...nothing panned out? It is too early to say this anti-LINGO1 is the only agent properly trialled.

      Why do animal models not translate into human studies.

      The human studies do not replicate the design of the animals studies as in most cases in the animals the tissue will remyelinate in a few weeks anyway without doing anything but in the human they try to affect long established demyelination. The human imaging tools to measure remyelination are also probably not good enough with lack of resolution and specificity. People may tae me to task on this.

      We have to use our animal models in a more sensible way and accept that it may take a few months to do the right experiements not a few weeks.

      Mice are not the best to look at demyelination as the nerves die, I would say the strain 13 guinea pig would be a useful model as you get good demyelination.

      Yes I am very hopeful as there are so many targets that may do the trick.

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    2. Also the trial design to show how to find positive agents has yet to be defined and history tells me that trial design and implimentation is one of the biggest killers of animal -supported ideas

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    3. Thanks for your thoughts MD, much appreciated.

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  3. Re BBB
    Clemastine yes. Old type antihistamine, causes drowsiness. No idea what bexatrone is.

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    1. Bexarotene activates retinoid X receptors (RXRs) and is in trial in Cambridge

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  4. Thanks AM. Bexatrone is old cancer drug. I think of all the trials currently running it's showing the most promise. I tried to get on the trail. But was told because I was on high efficacy drug tecfidera. Was ineligible. But i told them there trial is flawed as there is no chemical/Biological process in the universe where construction is faster than destruction. Due to law entropy. All ordered matter moves to disorder given time. I think they now have changed the trial criteria to include all ms people regardless of the DMT. Including Alemtuzumab. Scientifically trained. Hmmmm

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  5. Where are they doing the trial? I would like to be in. On my own I take Clemastine with my GP's help. Its not going to kill me and any hope better then none. Thanks for all you do Dr. Mouse.

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