Monday, 15 December 2014

Testing anti-Virals in MS

Derfuss T, Curtin F, Guebelin C, Bridel C, Rasenack M, Matthey A, Pasquier RD, Schluep M, Desmeules J, Lang AB, Perron H, Faucard R, Porchet H, Hartung HP, Kappos L, Lalive PH.A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosispatients. Mult Scler. 2014 Nov 12. pii: 1352458514554052. [Epub ahead of print]

BACKGROUND:GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation.
OBJECTIVE:This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments.
METHODS: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, and MSRV RNA expression were studied.
RESULTS:All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected.  MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI.
CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.

We have just reported on the phase I studies (CLICK) and studies in animals (CLICK) hot on the heels are the phase II studies in MS. Please read the past post for the explanations. This is an antiviral treatment and the antibody appeared to drop evidence of active virus. The trial is too small and short to say what is going to happen.but another approach to give the Charcot project a run for its money. 

5 comments:

  1. Dear MouseDoctor,

    Could you please explain this sentence?
    "This is an antiviral treatment and the antibody appeared to drop evidence of active virus."

    It seems rather important. Does it mean MS is not caused by a virus?

    Thanks!
    Also for all your posts throughout the year.

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    Replies
    1. Thanks for your comments.

      No it does not say that MS is not caused by a virus.

      The drug is an anti-viral and if it is to work then you want to see evidence that it is getting rid of virus of stopping the activity of the virus. This is what the sentence is say is that there is evidence that the drug is having an antiviral effect. Is it enough I don't know.

      nine people had stable MRI so their disease was silent..is this real or chance then it will need a larger study. In the person who had MRI lesions is it because the drug failed or they would be less active than they would have been. We need to see a bigger study.

      Hope that answers your question

      Delete
  2. Hey MouseDoc.

    3 questions from me...

    1) Assuming the next phase of this trial (and your Charcot project) implicate a virus in the pathogenesis of MS, how long do you think it will be until this translates into a treatment being made available to MS patients?

    2) Would Acyclovir (which anyone post-HSCT is on for several months) have any effect on the viral targets being investigated (EBV and HERV)

    3) At best guess, do you envisage any antiviral treatment being a short-term induction therapy, or a lifelong maintenance therapy?

    Thanks
    Matt

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    Replies
    1. Would very interesting for me as well, if MD could answer to Matt post above...

      Delete
    2. (1) This is a phase IIa in about 10 people, next would be phase IIb in a lot more people imaging outcome 6 months to a year or clinical outcome 2 years so add another year to do, then one or two phase III depending on size of phase IIb and this will be at least 2 years (maybe 3 if regulators get their way) and add another 2-3 to recruit and readout and then another year to 18 months to get FDA approval. So the quickest way to assess this will be to be involved in a trial. Sorry if this seems like ages but this is the system the regulators have created

      2). Acyclovir is an anti Herpes virus drug so it gets rid of these types of virus by stopping viral DNA replication. People getting HSCT and alemtuzumab get anti-virals. HERV are a different type of virus and whilst EBV is a types of Herpes virus the value of acyclovir is debatable. http://www.ncbi.nlm.nih.gov/pubmed/20739216

      If getting rid of EBV was so easy it would have been tried already.

      3) If a virus is the problem and you get rid of it why keep treating. This is not how vaccines work...you give them and then give boosters every now and again. However HERVS are part of our genetic make up and are in every single cell so if this is the problem I would think life long.

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