Friday, 9 January 2015

Acute remyelination of MS lesions

A big thank you to innovators and risk takers behind the anti-lingo development programme. #MSBlog #MSResearch

"Should we be excited about yesterday's announcement by Biogen-Idec of the results of their anti-lingo trial yesterday? Their study took subjects with acute optic neuritis and treated them within 4 weeks to see if anti-lingo, a drug that blocks one of the inhibitors of remyelination, could improve visual outcome at 24 weeks. Although Biogen-Idec are claiming the trial is positive my interpretation is more guarded; I think it is negative. Why? The primary outcome is speed of conduction a marker of myelination; the results were borderline positive. However, if the drug was truly remyelinating the optic nerve fibres it should also protect some of vulnerable fibres from dying, or degenerating, and hence the retinal nerve fibre thickness should have been thicker on anti-lingo compared to subjects treated with placebo. Therefore, I am not convinced that this study is positive. My other concerns relate the the study design. We have always promoted the concept of a therapeutic pyramid in MS; i.e. anti-inflammatory to stop ongoing damage (not really relevant in this trial as the lesion had already developed), neuroprotection to keep the axons and nerves alive, remyelination of the surviving nerves and finally neurorestoration. No attempt was done to build a pyramid in this study."

"We have also shown in our animal model that neuroprotection in acute focal inflammatory lesions has to occur in a very narrow window; the so called inflammatory penumbra. In our animal model this is 3 days and correlates with the duration of blood brain barrier leakage. When we extrapolate this to MS we think the window is from 7 to 21 days; i.e the duration an acute MS lesion enhances with gadolinium on MRI. If you give a drug beyond this time window it will probably be too late and the axons that need protecting are probably too damaged and hence there will be nothing to remyelinate. This study does two things wrong; (1) it does not use a neuroprotectant and (2) it had a treatment window of 4 weeks, which according to our modeling is too long.  I think anti-lingo needs to be combined with a neuroprotectant (e.g. a sodium channel blocker) and needs to be given within a therapeutic window of  2 weeks. Anti-lingo is an antibody and hence is quite a large molecule; by giving the drug when the blood-brain-barrier is still open will allow it to cross and engage its target. Biogen-Idec will be able to do a post-hoc analysis to see if subjects treated within 2 weeks of symptoms onset did better than those treated in the 2-4 week window. We are currently testing the inflammatory penumbra concept with our phenytoin in acute optic neuritis trial and have set the treatment window at 14 days; this trial is now complete and the results will be presented in April this year."

"I am at a meeting with a large number of MS colleagues. At dinner last night the anti-lingo trial results dominated the conversation. One colleague made the comment that we neurologists know little about the significance of the results; he suggested that a much better indicator of whether the anti-lingo results are meaningful or not is what the markets think. He made the point that the market integrates information from many sources and hence it would be a better indicator than our opinions. The following share price plot shows Biogen-Idec share dipping slightly; I think the market's interpretation is compatible with my analysis."

"Whatever your interpretation of the trial results are I must congratulate Biogen-Idec for not being risk adverse and for taking on this study. Doing this study took guts and shows what a bold, brave and cutting-edge company Biogen-Idec is. Pharma companies who don't take risks, like Biogen-Idec have done with anti-lingo, shrivel and die. The only game in town is innovation and risk taking. To innovate you have to invest in R&D  and then translate your R&D into drugs that address the unmet needs of patients. Lingo and anti-lingo biology was discovered and pioneered by Biogen-Idec scientists. Biogen-Idec have then invested heavily in the clinical development of anti-lingo and in so doing are pioneering a new therapeutic strategy for MS. Every study is an experiment and we will all learn from this experiment. It is clear that anti-lingo programme needs to go forward; the unmet need, particularly in progressive MS, is still there. Finally, a big thank you to all the clinicians and people with optic neuritis who volunteered for this study; without their participation we would not be having this discussion."

CoI: multiple


  1. Hi Gavin, the issue here is the choice of VEPs as the primary outcome measure in AON; as a test it's only useful when you believe the visual loss to be functional! In clinical practice we use VEPs to confirm previous episodes of demyelination which are also often silent but persist for several years (an indication of the SD of this test).

  2. So eventually one of you neuros shows that a cheap available drug works as well as any of the expensive company drugs, so the company share price plummets. Does this mean the data is rubbish?

  3. Neuros developing drug ha ha, ProfG says only companies can do this

    1. Thank you for your kind comments. much appreciated!

  4. Re: Neuros developing drug ha ha, ProfG says only companies can do this.."

    I am being misquoted. What I said is that companies are the only ones with deep enough pockets, the ability to take on the financial risks and the expertise and systems to handle a phase 3 programme and to license drugs and maintain the license. Academia can't do the latter. Neuros and academics can develop drugs up to phase 2, but rarely beyond that.

  5. The fact that Team G has come out on record to rubbish this drug means that Biogen-Idec are on to a winner. Team G has the worst record at choosing winners. Everything they hail as a victor turns to crap.

    This anti-Lingo stuff must be the Holy Grail. Woo-hoo!

    1. There is no rubbishing here, except perhaps your comment :-). As to choosing and working on winners, I think we can be happy in this respect, most people never score a winner in helping develop a drug.

      1. COPAXONE: Pre-TeamG
      2. AVONEX: Pre-TeamG
      3. BETASERON:Pre-TeamG for MS but-Weissenbach J, Chernajovsky Y, Zeevi M, Shulman L, Soreq H, Nir U, Wallach D, Perricaudet M, Tiollais P, Revel M. Two interferon mRNAs in human fibroblasts: in vitro translation and Escherichia coli cloning studies. Proc Natl Acad Sci U S A. 1980;77:7152 (Cloned beta interferon).
      4. REBIF: Pre-TeamG..but to improve efficacy there was a new formulation to reduce neutralizing anibodies. Giovannoni G, Barbarash O, Casset-Semanaz F, King J, Metz L, Pardo G, Simsarian J, Sørensen PS, Stubinski B; Rebif New Formulation Study Group. Safety and immunogenicity of a new formulation of interferon beta-1a (Rebif New Formulation) in a Phase IIIb study in patients with relapsing multiple sclerosis: 96-week results. Mult Scler. 2009;15:219.
      5. MITOXANTRONE: Watson CM, Davison AN, Baker D, O'Neill JK, Turk JL. Suppression of demyelination by mitoxantrone. Int J Immunopharmacol. 1991;13:923.
      6. NATALIZUMAB: Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354:899.
      7.FINGOLIMOD-GILENYA: Prediction of Failure of Gilenya in Progressive MS (Failed 2014)
      Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler. 2011;17:939.
      8. SATIVEX: Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L.
      Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature. 2000;404:84.
      Hilliard A, Stott C, Wright S, Guy G, Pryce G, Al-Izki S, Bolton C, Giovannoni G. Evaluation of the Effects of Sativex (THC BDS: CBD BDS) on Inhibition of Spasticity in a Chronic Relapsing Experimental Allergic Autoimmune Encephalomyelitis: A Model of Multiple Sclerosis. ISRN Neurol. 2012;2012:802649.
      9. CLADRIBINE: Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ; CLARITY Study Group. A placebo-controll ed trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416.
      10. AUBAGIO
      11. ALEMTUZUMAB: Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012; 380:1819
      12: FAMPRIDINE
      13: TECFIDERA: Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN; BG-12 Phase IIb Study Investigators Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463.
      Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT; DEFINE Study Investigators.Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367:1098.
      14:DACLIZUMB (ALMOST LICENCED):Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, Stefoski D, Robinson R, Riester K, Rana J, Elkins J, O'Neill G; SELECT study investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial.Lancet. 2013;381:2167.