Sunday, 24 February 2013

Combining glatiramer acetate with interferon-beta offers no merit

Epub: Lublin et al; for the CombiRx Investigators. Randomized study combining interferon & glatiramer acetate in multiple sclerosis. Ann Neurol. 2013 Feb 19. doi: 10.1002/ana.23863.

OBJECTIVE: A double-blind, randomized, controlled study to determine if combined use of interferon beta-1a (IFN) 30ug IM weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis (RRMS).

METHODS: 1008 participants were randomized and followed until the last participant enrolled completed 3 yrs. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics.

RESULTS: Combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The Combination was not better than either agent alone in lessening confirmed EDSS progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity free status (DAFS) compared to either single arm; driven by the MRI results.

INTERPRETATION: Combining the two most commonly prescribed therapies for MS did not produce a significant clinical benefit over three years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address if the observed differences in MRI and DAFS findings predict later clinical differences.

Combining beta interferon with glatiramer acetate (Copaxone) does not appear to add any benefit over either one alone. This is sort of disturbing because if they really have different mechanisms as could be inferred, you would have hoped that they would have some additive effect, but apparently not so.


  1. I believe there is evidence GA is effective at enhancing or producing Foxp3 regulatory T cells who's purpose is to shut-down overreactive immune cells in the CNS.

    The beta interferons and similar drugs seem to prevent immune cells from crossing the BBB altogether, so it is no surprise to me the combination of these two drugs is no more effective than one alone.

  2. But if you compare the level of effect compared to say Tysabri which blocks immune cells crossing the BBB, beta interferon is much less effective, so there is room for improvement.

    As for GA it has a new mechanism with each new round of dogma. Today Tregs, yesterday Th2, day before that...If GA is inducing T regs cells it is not doing as well as it could, because the new generation of immunomodulators are twice as effective at influencing relapse.

    Surely attacking two complementary pathways should improve efficacy I guess not.

  3. I think that the fact that GA improves the function of Tregs may not have been known is understandable since they were only verified to exist in the last 10 years. The same goes for the fact that people with MS have defects in the function of regulatory t-cells.

    But I guess it doesn't matter if you are talking about Tregs or Th2 cells, the point is that interferon beta's efficacy is based on the the dogma that MS is caused by a leaky BBB while GA is not. So why would you expect these two drugs to be additive when the function of one prohibits the mechanism of the other?

    1. Good point to explain the result, but we do not know the definative mechanisms of either. If it was obvious that was the expected outcome why do the study in the first place?

      Why not the dogma that interferon was used because of the dogma that MS is caused by a virus. The function of interferons is to prevent viral replication in cells hence ther name "interfere". They stop the need for cells to enter the CNS hence the apparent effect on BBB.

      My point is if either drug was good at halting its target mechanism and that mechanism was truely important then their level of efficacy would be much greater than they are. Maybe interferon betas are more effective than they appear because they fail due to the presence of neutralizing responsses.

  4. I guess in the end you have to run a trial to prove anything, but I would expect a better result from the combination of BG-12 and GA as opposed to Tsybari and GA since Tsybari also seems to function be shutting down the permeability of the BBB. Hopefully this will be thier next investigation.

  5. Is this where public funds should be directed? This trial was paid for by NIH


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