Friday, 9 January 2015

215ON201 BIIB033 (Anti-LINGO-1!!) Phase II results In Acute Optic Neuritis (AON)

#MSResearch Hints of remyelination in Optic Neuritis Trial 

Official Title: A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects With First Episode of Acute Optic Neuritis

NCT01721161

Primary Outcome Measures: Change in optic nerve conduction velocity (NCV) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by full-field visual evoked potential (FF-VEP).

Secondary Outcome Measures: Change in thickness of the retinal nerve fiber layer (RNFL) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by spectral-domain optical coherence tomography (SD-OCT).

Change in thicknesses of the retinal ganglion cell layer/inner plexiform retinal layer (RGCL/IPL) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by segmentation of SD-OCT.

Change in low-contrast letter acuity (LCLA) at Week 24 from baseline as determined by 1.25% and 2.5% low contrast Sloan letter charts.

Number of participants with Adverse events (AEs) and serious adverse events (SAEs)

PK Parameters will be estimated based on Population based PK modeling.

Biological: BIIB033 (anti-LINGO-1 mAb)
100 mg/kg via IV infusion once every 4 weeks for 20 weeks (a total of 6 doses) versus placebo

There's not much out there in terms of hard data to peruse through yet, as I've lifted this news directly from the finance webpages! Biogen Idec (pharmaceutical) have reported a positive primary outcome on their Phase II study of anti-LINGO-1 in acute optic neuritis. An exciting finding.

Anti-LINGO-1 blocks LINGO-1 a transmembrane protein present exclusively in the brain and spinal cord. Now LINGO-1's role is to block axon regeneration by binding NgR and p75 (this is a normal mechanism in the brain to prevent uncontrolled nerve growth). Work in an animal demyelination model has previously shown that anti-LINGO-1 may promote myelin repair. There was then a Phase I safety study, and now the Phase II study in a focal demyelination model (acute optic neuritis). The findings are that there is in those who took the active drug (compared to placebo) an improvement in VEP's (majority of you would have had VEP's done as part of your diagnostic work up). VEP's measure the time taken for what you see at the back of the eye to be conducted to your visual centre in the brain (the occipital cortex). This conduction time is prolonged in optic neuritis predominantly due to demyelination.  This study would suggest that there is some remyelination.

However, results demonstrated a 34 percent improvement (p=0.0504. Note. This means it was not statistically different) in the recovery of optic nerve latency compared to placebo in the per-protocol population. The analysis of the intent-to-treat (ITT) population, which includes patients in both arms who did not complete the study, showed a positive trend but did not reach statistical significance.



Signalling pathway for LINGO-1

Now what would be interesting to know is, if the conduction in the unaffected fellow eye was also improved (as its well known that even the unaffected optic nerve demonstrates some problems in MS). 

Unfortunately, the study failed in all the secondary outcomes in particular the OCT data (retinal nerve fibre layer thickness), which indicates how much of the nerves are left after an ON attack. It lends support to the idea that remyelination without axonal neuroprotection is a crazy idea. It is the retinal nerve fibre layer thickness that determines how poor your vision is in the long run. Back to the drawing board I would say...Drug combinations will be needed

3 comments:

  1. Does this mean that other remyelination trials are doomed to fail?

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    Replies
    1. Absolutely not there is no reason to think remyelination is doomed as an enitity.

      This is the first drug used as a remyelination agent. They have got a sniff of activity but we need to learn as a community how to find agents and importantly we have to learn how to use them optimally.

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