Saturday, 3 June 2017

Minocycline as short term success or does it bite the dust?.

Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand'Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team. Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. N Engl J Med. 2017;376(22):2122-2133.

BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.
METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]).
RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.
CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).


Minocyline is a drug that is reported to be an inhibitor of microglial activation, where it was hoped that it could slow progression. It was looked at as part of Promise 2010 by a US based group.

This was reported in EAE as being useful. However, the effect reported was immunomodulatory and the neuroprotection could be secondary to that. Furthermore, the data may have been dogey, as we said to the scientists doing the work.

Minocyline is a very acidic compound and when injected into mice it was like injection of sulphuric acid into your belly. This must have been very irritating and must have stressed the animals out, which would stop their disease. However, this created an idea that it was active as an immune modulator. 

If it was given orally in animals, it didn't do much. Putting an acid into an acid stomach is not as irritating.

When we had a look, we (MD2 who noticed the issue with the acidity) adjusted its pH to get rid of the acidity before injection and it didn't do much, actually it did nothing as an immunomodulator, so would I be expecting big shakes as a immune modulator...Not really. It wasn't the best as a neuroprotector either and was not comaprable to the sodium channel blocking. We published this a few years ago.


Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Edith Chan AW, Amor S, Perkins V, Gerritsen WH, Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D. Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 2014;137(Pt 1):92-108.


So don''t blame the animals, but it must be said there is evidence for neuroprotection in proper neurodegenerative models. Anyway ignore the animal stuff about neuroprotection and plough-on with a clinical trial. This was aimed at showing whether minocycline is a disease modifying immunomodulator.

In this study the mimocycline they offered people with the first demyelinating event the option of placebo or mimocyline and at 6 months there was a slowing of the conversion to MS, however the other measures showed no significant effect, but the dreaded trend suggested some benefit that maintained itself for 12 months, but by 24 months there was no benefit. So a success in one way but not in another. ProfG is glass half-full and it would be good news, but you know me...a half-empty chap.

The trial had limitations, as the authors acknowledge. First, the small sample size could have led to the negative outcome at 24 months because the trial was powered to detect a clinical outcome at 6 months. 

However, is the failure an albatross that will hang round the neck of this agent? Furthermore, at baseline the minocycline group had fewer instances of spinal cord involvement and fewer enhancing lesions than the placebo group, which could have biased the results in favor of minocycline. There were some more adverse events in the minocycline group.

However, if we go back to the animals it has to be said that there are much better immunomodulators than mimocycline. If you want a cheap one there's......I'll shut up. The human dose in the trial used was about 40 times less than used in the animals. So if you did the experiment at a human equivalent dose in the animals, would the logic be like a carpet pulled from under your feet?

However, we have been saying that what we need are neuroprotectives, but first you have to deal with inflammation below this. If minocycline had been put on top of a strong disease modifying agent would the trial result have been different...Maybe not because the trial was not really targeting the neurodegeneration and a strong DMT may have done the trick. Put it on a weak DMT and minocylcine failed their too.

The problem is getting the correct trial design to show a neuroprotective effect, once you have that the tide will change. 

With the albatross around the neck of a fail by MRI and a clinical fail at 24 months, will their be round II for a trial?

If the trial had been a resounding success, what would happened next. With such a cheap off-patent drug will it be tried again, in two phase III trials.

7 comments:

  1. It makes little sense as to why this trial was approved by Health Canada and funded by MS Society of Canada for an antibiotic that treats intracellular bacteria by inhibiting protein synthesis in bacteria and has a possible inhibitory effect on microglia?

    Why was RRMS patients (CIS to clinically definitive MS) chosen when it works on inhibiting microglia. Progressive patients should have been enlisted for this trial concurrently to see if it is neuroprotective in nature and prevents progression of MS. We already have enough successful DMD that work better than minocycline anyways through immunosuppression and reduced inflammation.

    Canadian researchers, in the "hotbed of MS" called Canada, continue to disappoint and not deliver with publications like this.

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    Replies
    1. The EAE data was considered compelling.

      If I did a glass half full report would it be different, saying it worked at 6 months

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  2. Another wasted opportunity for progressive MS. What're we at, like fifteen RRMS DMDs? Eventually, even on these drugs, most patients progress to SPMS. So, first ten to fifteen years, handsome profits for big pharma while degeneration takes over with barely a different outcome in progression of disability. Sad

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    Replies
    1. "And so it goes...."

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    2. 100% agree with The God Effect.

      If a drug, over long term, is not shown to stop progression or stop conversion of RRMS to SPMS it is useless. It should not be approved, promoted or prescribed by a neurologist. This progression data, not only on MRI but actually clinically as well, should be a criteria for approval of any drug.

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    3. lol I think dogma killed logic and opinion is how clinicians interpret data and use it as part as clinical practice.

      But if clinicians are required to give their patients more information and decision making tools: that would overwhelm and distress the ms patients.

      You get the sense that the whole field is an egotistical pharma driven loop of which neuros are the integral part (pharma uses them to market to people with MS) - but now I'm just being outrageous with my suggestions.

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    4. For a drug to stop progression I.e. conversion to SPMS it should have neuro protective as well as immunomodulatory effects. What animal model would be used for neuro Protection? Also, the clinical would need to incorporate biomarkers of nerve damage/loss such as neurofilament levels in the CNS.

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