Research: Oral Tysabri Analogue

BACKGROUND:Monoclonal antibody therapy against α4β-integrin is efficacious in patients with multiple sclerosis (MS) with some safety concerns. We assessed the safety and efficacy of firategrast, a small oral anti-α4β-integrin molecule, in patients with relapsing remitting MS.

METHODS:We did a multicentre, phase 2, randomised, double-blind, placebo-controlled, dose-ranging study in participants with clinically definite relapsing-remitting MS. A 24-week treatment period was followed by 12 weeks of core follow-up and 40 weeks of extended follow-up. Participants were randomly assigned, via computer-generated block randomisation in a 1:2:2:2 ratio, to receive one of four treatments twice a day: firategrast 150 mg, firategrast 600 mg, or firategrast 900 mg (women) or 1200 mg (men), or placebo. Brain scans were obtained at 4-week intervals to the end of core follow-up. The primary outcome was cumulative number of new gadolinium-enhancing brain lesions during the treatment phase and was analysed using a generalised linear model with an underlying negative binomial distribution, adjusted for sex, baseline number of new gadolinium-enhancing lesions, and country. This study is registered with, NCT00395317.

FINDINGS:Of 343 individuals enrolled, 49 received firategrast 150 mg, 95 received firategrast 600 mg, 100 received firategrast 900 mg or 1200 mg, and 99 received placebo. A 49% reduction (95% CI 21·2-67·6; p=0·0026) in the cumulative number of new gadolinium-enhancing lesions was seen for the 900 mg or 1200 mg firategrast group (n=92, mean number of lesions 2·69 [SE 1·18]) versus the placebo group (90, 5·31 [1·18]). In the 600 mg group (86, 4·12 [SE 1·19]), a non-significant 22% reduction (95% CI -21·3 to 49·7; p=0·2657) occurred in mean number of new gadolinium-enhanced lesions relative to placebo; for the 150 mg group (47, 9·51 [SE 1·24]), a 79% increase (95% CI 4·1-308·1; p=0·0353) occurred relative to placebo. Firategrast was generally well tolerated at all doses. The frequency of all adverse events was similar across all treatment groups except for an increased rate of urinary tract infections in the high-dose firategrast group. No cases of progressive multifocal leukoencephalopathy or evidence of reactivation of JC virus were identified.

INTERPRETATION:This study showed efficacy on imaging endpoints for firategrast at the highest dose tested, and suggests that further investigation of oral short-acting α4β integrin blockade therapies is warranted.


Following the success of Tysabri in stopping relapses and the marked effect of stopping gadolinium enhancing lesions by over 80% compared to placebo, it was obvious to develop a pill that does the same thing as Tysabri. This works by blocking the molecule that lets white blood cells get in the brain.

These would have the advantage that the drug is oral rather than a monthly infusion with tysabri. Also importantly you can get rid of these type of drugs quickly by natural breakdown-mechanisms compared to antibodies such as tysabri that hang around for weeks-months. This is important because we know that PML is a risk of antibody blockage by Tysabri. So if things go wrong you want to get rid of it.

The question we now need to know is does it work to do anything clinically. We have already had one of these types of drugs, which is an oral VLA-4 Antagonist called CPD323, fall by the wayside because it did not work. This study shows an inhibition of new lesions by about 50% at the high doses ( of around 1000mg). This is a lot lower than Tysabri. Will this be enough?.

Also it is perhaps of a worrying note that the low dose (150mg) was associated with 80% MORE lesions than placebo and it will be interesting to see how this relates to clinical disease as there will be follow-up.

About the author



  • You are quite correct this trial was started in december 2006 and completed in August 2010 and was reported at ECTRIMS in Fri 15 Oct 2010 on 14.55 when it hit the web on medscape.

    At the moment I can't get to the journal to see when it was actually submitted maybe some one with access can tell us. Because this will tell use when it was submitted and when it was accepted for publication.

    But lets say the paper was written first around Oct 2010 it would need to circulated round the authors in spain germany USA etc that can easily take a few months and the company GSK sponsoring the study will have an input in this.

    Then it gets submitted maybe it takes the editor abit of time to send it out to peer reviewers(it get set to about 2-3..recently one in Team G was sent to 9…). One reviwer does not review it on time (Many people are very busy you do not get paid to do it. Maybe you have a few a week to do).

    Maybe they just sit on it whilst they do similar work or worse they quickly repeat the study as they now know what to do as the paper they are reviewing tells you what to do…Trust me it happens) This process can be a month or 4 you are normally given 2-4 weeks to do it.

    The reviewers then want changes made and a month or 3 could laspe whilst you do the things that the reviewers want.

    It then goes back to the editor who sends it back to the original reviewers (or new ones that come up with new questions) who maybe takes another month to deal with it. They are happy and it goes back to the editor the manuscript is accepted

    The manuscript then must be typeset at the publishers. A few weeks go by, you then have to review this and correct any mistakes and then it may be put online then take quite a few more months for it to be published. So most of the year gone.

    It normally takes a minimum of 6 months.

    Now lets have the common scenario you send it to one journal (you aim high and work your way down the pecking order) it goes through the reviewing process and then gets rejected after being reviewed once, twice maybe three times. Therefore months have gone by and you are back to square one.

    You then go through the process again and sometimes again.

    So it is not hard to take a year to get something published.

    The internet has greatly facilitated this process as you don't need to relie on snail mail to send things back and forward to the journal and the reviewers.

    I once had a paper made out of rubber (bouncing between differnt journals). I had the idea presented it a meeting (it wasn't ECTRIMS) a guy read it. Maybe he already had the idea maybe not. Whilst we spent time showing it was revelant to established disease the guy did a quick and dirty experiment of no direct relevance to disease, in an immunologically sexy way and put in a flash journal. We spent many years working on this before it was published.

    For this reason most people do not present stuff at a meeting until it is already published or has already been accepted for publication.

    For others they want to talk about new data and when presented at a meeting. Some of the data may be finished a few days/weeks before the presentation so not alot of time to ge the manuscript ready for publication.

    For clinical meetings there are always journalist around looking for a story so things can quickly get put on the web.

    For clinical trials the worry of being pipped with the scoop is not so much of an issue because they take years to complete and so even if you had a cometitor it would take them years to do it. Also because of patents it is often that no-one else can do the work because access to the drug it is controlled by the drug company.

    That must be about the longest reply

  • Long reply but very informative, thank you
    In a case like this I hope ph 3 trials don't have to wait till ph 2 is in print

  • No waiting for stuff to come in print as for big pharma-time is money wasted.

    However for small entities it is a way of advertising for raising funds for the next phase of work.

    For this product there have been no obvious activitiy on clinicaltrial. gov and I did not find follow-up abstracts about the phase II that went beyond this.

    Therefore may 50% reduction of MR lesions was not enough to have clinical value.

    Maybe it was a casualty of GSK closing neuroscience down in the UK and moving it to China

    Maybe I am full of hot air and the phase III is round the corner.

    Prof G will probably know the story.

  • Re: "Maybe I am full of hot air and the phase III is round the corner."

    No hot air; the drug is dead as far as MS is concerned.

By MouseDoctor



Recent Posts

Recent Comments