Saturday, 10 October 2015

Breaking News from ECTRIMS

Generic minocyline has been tested in Clinically Isolated Syndrome to see if it effects conversion to clinically definte MS. It was found that minocylcine reduces the risk of developing MS by 27.4% and relative risk by 44.6%.  What will happen next...will they have to do another trial? Pharma would have to and so can the rules be bent.

However, what you want to know is what happens in the PPMSers trial treated with anti-CD20

People in the trial were younger people below 55 (mean 44 years) as was suggested from the rituximab trial. They were also only a mean of 3 years from diagnosis and so they loaded the trial with potential responders are waiting for this news. 

A differnece from placebo was noted within 12 weeks  of the beginning of the trial and the rate of progression was reduced by about 25%. The brain volume loss, when rebaselined to allow for pseudo atrophy, was also reduced.

The were a few infections but of note there were a number of cancers in group treated with the treated group and remembering what happened in the cladribine trial as the data does not look that disimilar, Will the regulators ask for another trial as they did with claribine. If they do that will delay things.

But as to the question we all really want to know is does this work for all PPMSers or just those with gadolinium enhancement...The issue was dodged and MRI was not really talked about...Why?. I

It was evident that over 25% had gadolinium lesions which is more than the average PPMSer and so and when asked they said they havn't done the analysis. Of course this would be the first thing you would do!!!. The trial was loaded with gadolinium enhancing people and therefore you have the conditions for a positive trial . That they did not properly address this makes me very cautious and therefore I withdrawn my apologies.

When the results were announced on the news I said I was wrong because I had predicted the trial would fail, with the previso that relapsing, gadolinium PPMSers would respond, so until I see the data I am going to stick to this opinion.

The company will not want get a sublicence and so will not want to release data that only the active PPMSers responded.

So it is a start remember when interferons arrived we have the 30% level of efficacy and now we are up to 70-80%  effective. It is a start but not enough to make me get my p45 yet and we still need to get neuroprotective drugs in addition to immune modulatory DMT

Conflixts None relevant however ProfG and DrK were involved in the trial design and undertaking the trial and they may want to say more, or may not be allowed to.


Next up is Anti-Lingo1 and its effect on visually evoked potential in optic neuritis. You shine a light in the eye and measure electrical response from the visual cortex of the brain. In the presentation there was a significant (P=0.05) improvement in the latency (a measure of improvement in myelination. The original press release was something like p=0.054 = non-significant:-) in the eye with optic neuritis. Now they looked in the other eye, without optic neurtis and there was loss in amplitude of the VEP. This is evidence of nerve loss and anti-LINGO-1 slowed this down. was it remyelinating subclinical demyelination or was it promoting neurogenesis and synaptic plasticity because remember the original function of LINGO-1 is an inhibitor of nerve growth. Block LINGO-1 and nerves may grow.

Conflicts: None ... ProfG multiple

Finally high dose biotin continued to show some benefit in Secondary Progressive MS, there is insufficient evidence to say it is of  any benefit in PPMS

Conflicts: None ... ProfG multiple

32 comments:

  1. Thank you. We need to know about the how the treatments have been tested, so that we can judge for ourselves. I wouldn't be convinced by a study over three years.

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  2. I would be more interested in reading a report from ectrims on the following, since I'm not a medication fan:

    1. biotin trial
    2. brain plasticity
    3. fatty acid diet

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    1. You can always read the abstracts which are online:-) Are you saying biotin is not a medication:-)

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    2. could you give a link to the abstracts? i have problems with finding them on the ectrims site. thanx.

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    3. Dear Anon, if you download the congress map which can be found on this address http://www.ectrims-congress.eu/2015/ectrims-2015.html#&panel1-1 on the right hand panel, then you can view the individual abstracts

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    4. thank you ndg.

      could find it now but the biotin trial i don't know how to interpret - is it a good result or just again a numbers game?

      anti-lingo looks promising or what do you think neuro doc?

      also, the plasticity stuff i can't find.

      lots of good stuff about vit d though.

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    5. Biotin trial - although they state the EDSS improved on their graph visually the biotin treated group showed initial improvement before stabilising, whilst those not on treatment continued to accumulate disability. Later in the trial when they all switched to biotin those not receiving biotin before also stabilised but did not return to what they were before they started to deteriorate (this implies there is a window of opportunity). You can see this when they say that the outcome was better in EDSS 4.5-5 (that is still walking) than EDSS 6/7 when you use a walking stick. Equally, again on their groups the main contributing group to the improvement in disability following biotin were the SPMS group rather than the PPMS group suggesting that it may be effective more in SPMS than PPMS. A large phase III study needs to be done across the world to see if these results can be reproduced but very interesting nonetheless. The fampridine bit might be an indication that the group on fampridine were more disabled and therefore biotin didn't work so well in them.

      Anti-LINGO is confusing; as you know that there was trend towards significance in VEP (this is a measure of the function of your visual capacity from the eye to the back of the brain) in the eye affected by optic neuritis in the anti-LINGO treated group. They now present results that there is also improvement in the VEP of the unaffected fellow eye (so if your right eye had optic neuritis, the left fellow eye doesn't have optic neuritis) in those treated with anti-LINGO vs untreated over time. The difficulty is that their assessment of the RNFL thickness (the nerve fibre layer at the back of the eye which captures what you see) was negative with no improvement in those treated with anti-LINGO - compare this with the phenytoin trial in optic neuritis which does show an improvement in RNFL thickness. The difficulty is after optic neuritis in one eye, the other unaffected eye also shows changes over time in VEPs. In this trial they have used a technique called MF-VEP which provides an assessment of the local retinal area, unfortunately this is not as good as using a technique called PERG which is more indicative of retinal ganglion cell dysfunction seen in optic neuritis. Which begs the question why they used the former measurement. They are saying that in the fellow unaffected eye there is improvement in the conduction velocity of the VEP following anti-LINGO. Again it is the amplitude of the VEP and not the conduction velocity which is more sensitive predictor of visual acuity (if you can read the bottom line of the reading chart at your optometrists you have good visual acuity). You can now see why I feel the results are confusing - the study needs a clinical neurophysiologist to decipher what exactly is going on!

      I didn't see much on stem cells at this ECTRIMS.

      Vit D is here to stay. There are new things such melatonin to explain seasonal variation in MS, fatty acids (or PUFAs) - an interesting study stating that there it was plant derived fatty acids and not fatty fish fatty acids i.e. cod liver oil which leads to an improvement in the MS activity! and also the gut microbiome.

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    6. NDG, if I understand right from your review, a study was presented relating to the improvement of MS by the action of vegetables instead of fatty acids derived from fish fatty acids? If so, if I understand it, it reminded me of the linseed oil ...

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    7. A huge thank you NeuroDoc - a wonderful summary.

      I guess by plant derived fatty acids one would mean for example seeds or nuts?

      I eat of lot of walnuts - always have - and believe they are doing lots of good.

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    8. Anything with high content of linolenic acid and linoleic acid; so seeds, nuts, vegetable oils.

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    9. Re vegetable oils - some caution should be exercised - many vegetable oils are highly processed, hydrogenated, and actually not very good for you. The whole "reduce sat fat" thing as an approach to reducing heart disease etc has had many people switch to vegetable oils, but much of what is on the supermarket shelves is so processed that it is often worse for you. Vegetable oils need to be cold pressed, not heat processed otherwise they are bad news. Even some well respected cardiologists in my country are saying that butter is better than highly processed vegetable oils. The key is to use products which are as unprocessed as possible.
      If you can - try to watch Jacques Perotti's "The men who made us fat" - it's a real eye opener into the food industry version of Big Pharma.

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  3. MD, for someone so sceptical, you were getting might excited about Cladribine.

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  4. MD, for someone so sceptical, you were getting mighty excited about Cladribine.

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    1. All for the right reasons. Ever since the Movectro programme was dropped, MD has been exploring the drug, the data and ways of making Cladribine available to people with MS.

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  5. "Finally high dose biotin continued to show some benefit in Secondary Progressive MS..."

    What is "some benefit"? Is this like, a little bit less progression maybe, probably of statistical significance, but then again, maybe not, and only in 9.5% of patients on Tuesdays?

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    1. A 10min talk without time to digest the data but they were looking a effects on edss,

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  6. "The trial was loaded with gadolinium enhancing people and therefore you have the conditions for a positive trial ."

    Is it actually realistic to expect that an immunomodulatory therapy could make any difference to older lesions which are not active? So how could this be a fair criticism of the trial?

    I'm not sure I feel that your assessment of Ocrelizumab is entirely neutral, scientific and non-biased.

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    1. What percentage of PPMS-ers never have enhancing lesions? Is it the majority? My understanding of PPMS is that although inflammation may play a role early on, many NEVER have an enhancing lesion. To load the trial the way Roche/Genentech did, then state they "didn't do the analysis" re. the subgroup with no enhancing lesions, I just think is extremely shocking. In fact, without the analysis on this blog, I never would have known this until my next neuro visits -- and maybe would not have known to press the issue. The press release and the news coverage after today are HIGHLY misleading. Why doesn't the http://www.progressivemsalliance.org/ issue a statement regarding how this has played out. It SHOULD be a major scandal. MS has never had a patient advocacy group as ruthlessly talented as the ACT UP group. Maybe it should.

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    2. There is no point treating someone with no lesions showing inflammation with an immunodulatory treatment, as far as I can see or understand. But I do not believe that people with PPMS have no inflammation. And this blog has said in the past that PPMS is very inflammatory. Possibly younger people in particular? Old lesions will need something else? But that does not mean that Ocrelizumab is not potentially a very useful therapy in many.

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    3. It would be useful to know how many of the PPMS were oligoclonal band positive and whether the treatment stopped their secretion - however there was no lumbar puncture in this study. The measurement of bands is a pathological indicator of inflammation in the cerebrospinal fluid.

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    4. We need to see the data when it is published getting a slide for a few seconds in a 10min talk. i think on averasge about 15% of PPMSers are gad positive so in the trial there were nearly twice. that, you want positive Lets see what happens they will have to do such analysis.

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    5. Dear NYC this analysis will have been done, but it was not reported, they will want to get licence for all of PPMS but i doubt the regulators or paper referees will want this to be addressed

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    6. So Professor Giovanonni's statement to the BBC was a bit disingenuous, or was he misquoted? Or are you guys not singing from the same hymn sheet?

      "Prof Gavin Giovannoni, one of the researchers involved in the trial at Barts and The London School of Medicine and Dentistry, told the BBC News website: 'These are very significant results, the drug is effective and the safety profile is very good. It's not going to fix the damage, it's going to slow the accumulation of more damage. We don't want to raise false expectation that it will reverse disability.'"

      http://www.bbc.co.uk/news/health-34475629

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    7. This makes me feel better - more nuanced coverage: http://www.medpagetoday.com/clinical-context/MultipleSclerosis/54037

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    8. Dear NYC this analysis will have been done, but it was not reported, they will want to get licence for all of PPMS but i doubt the regulators or paper referees not will want this to be addressed they will want to see this data (slip up) on missing not


      Someone was taking pictures or has been given the slides press release there is no way anyone could get this detail without extra time the disclosures are shown for a nanosecond.

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    9. It seems enhancing lesions may be more prevalent in the early stage of PPMS, so possibly this is why this was chosen as an inclusion criteria:

      http://www.ncbi.nlm.nih.gov/pubmed/20203148

      It seems these patients are simply primary relapsing MSers with that have silent relapses or were perhaps improperly dxed as PPMS. Immunosuppression has been shown to be effective in PPMS previously so it looks as though
      this is the case here also.

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    10. Anon 11:55: Now you _are_ making sense.


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  7. Why do you doubt the regulators or paper referees would want "this" to be addressed? Do you mean the subgroup analysis? I hope that you meant to say "I DON'T doubt" -- because otherwise I am flabbergasted. I'm an academic - it seems the paper referees would *require* it to be addressed. Why do you doubt that the academic referees would want that? How could the FDA allow this for all of PPMS without subgroup analysis? If there is no evidence from the trial that the drug can help 85% of PPMS patients, then it's a big deal -- a scandal -- to move forward to get a license for all of PPMS without the evidence to support it. I am really angry about this.

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    1. ihave no doubt they will want this to be addressed there was a missing word.

      Writing on a phone in a cafe and somtimes words slip and you can't read what youve written However reactions like yours will ensure the truth comes out. well spotted .

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  8. So what of Prof. Giovanonni's statement to the BBC????????

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    1. No idea whatt that was....I haven't seen a TV in days

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    2. If I can get home I will check but 6h in an airport is no fun

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