Thursday, 23 April 2015

AAN 2015: successful remyelination of the optic nerve

The first positive results of a remyelination trial. #AAN2015 #MSResearch #MSBlog

"One of the highlights of the AAN 2015 meeting so far was Biogen's results of their anti-Lingo-1 trial presented yesterday. In short in the per protocol analysis, i.e. study subjects who completed the treatment as defined by the protocol, showed an average change in their electrical conduction speed in their affected optic nerve of 13.2 msecs compared to 22.4 msecs in the placebo-treated subjects. Treated nerves conducted electrical signals faster and hence are thought to have been remyelinated. What is interesting, and important, is that there was no difference in the so called retinal nerve fibre layer thickness between the eyes. In other words anti-LINGO-1 did not prevent nerve fibre loss. Dr Cadavid who presented the data made the comment at how surprised he was at how quickly the nerve fibres are lost in acute optic neuritis. He shouldn't be surprised, we knew this fact from our animal model when we defined the so called inflammatory penumbra. We suspect this is probably in the order of 14-21 days in human optic neuritis. In the anti-Lingo-1 trial study drug could be given up to 4 weeks after the onset of optic neuritis; too late in our opinion and clearly too late to save optic nerve fibre loss, but early enough to improve the remyelination state of the surviving axons."

"I personally think this data suggests the drug works and promotes remyelination but it will need to be given in combination with a neuroprotective compound in future. We need to protect and save nerve fibres to remyelinate them."

"Until yesterday, I hadn't appreciated how high the dose of anti-LINGO-1 was that was used in this trial; i.e. 100mg/kg iv every 4 weeks. In other words a 70kg MSer will get 7g of anti-LINGO-1 antibody monthly. This is a such a large dose that it may be working like high-dose intravenous immunoglobulin (IVIG), in other words it may be saturating the so called neonatal Fc receptor and reducing the half-life of other circulating antibodies. The dose may result in other problems not too dissimilar to what we see with high-dose IVIG; thromboses, renal dysfunction, headaches, aseptic meningitis, infusion reactions, etc."

"Despite my guarded scepticism about remyelination strategies, congratulations to Biogen for taking this forward. This is truly innovative science and may make a difference to people with progressive MS. If I am not mistaken these are the first positive results of a trial of an agent specifically targeting remyelination."

Visual evoked potentials: the shorter the so called latency the faster the electrical conduction. In demyelinated nerves  this is slow and when it is remyelinated it speeds up. The difference in so called latency between treated and untreated MSers indicates that anti-LINGO-1 improved remyelination. 

Cadavid et al. Efficacy Analysis of the Anti-LINGO-1 Monoclonal Antibody BIIB033 in Acute Optic Neuritis: the RENEW Trial. AAN 2015: P7.202.
OBJECTIVE: To determine the efficacy of the anti-LINGO-1 antibody BIIB033 in subjects with a first episode of acute optic neuritis (AON).

BACKGROUND: The demyelination and axonal injury during AON usually results in permanent structural and functional visual deficits. Although corticosteroid treatment can accelerate the rate of spontaneous recovery, no reparative treatment is available to reduce sequelae of AON. LINGO-1 is a CNS-specific membrane glycoprotein that suppresses oligodendrocyte differentiation and myelination. BIIB033 is a fully human monoclonal antibody which selectively antagonizes LINGO-1, is efficacious in preclinical models of remyelination, and was found to be safe and well tolerated in Phase 1 studies.

DESIGN/METHODS: RENEW (NCT01721161) is an ongoing, randomized, double-blind, placebo-controlled, parallel-group study in healthy subjects with a first episode of unilateral AON (treated with high dose IV methylprednisolone prior to randomization). Subjects (aged 18 to 55 years) were randomized 1:1 to receive 100 mg/kg BIIB033 IV or placebo once every 4 weeks (6 doses total). All key efficacy endpoints are assessed at 4 weekly intervals from randomization through week 24 and include: latency of optic nerve conduction measured by full-field visual evoked potential (primary endpoint); thickness of the retinal nerve fiber layer measured by spectral-domain optical coherence tomography (SD-OCT); thickness of the retinal ganglion cell layer/inner plexiform retinal layer measured by segmentation of SD-OCT, and change in low-contrast letter acuity from baseline measured by Sloan charts.

RESULTS: Eighty-two subjects were randomized to receive BIIB033 or placebo. Detailed descriptions of the efficacy assessments in RENEW will be presented.

CONCLUSIONS: Results from the RENEW study will provide evidence for the efficacy of BIIB033 in improving recovery from AON when dosing starts within 28 days of disease onset.

Study Supported by: Biogen Idec

9 comments:

  1. Thanks for this summary. I had multiple bouts of optic neuritis at the outset of MS. My OCT images look like a bomb site. Had HSCT last year. Is this therapy likely to be suitable for people like me (ie at this stage, a year on, could I still benefit from a remyelination drug?) to improve my latencies? Or is there no benefit after the penumbra has passed?

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    1. maybe. the next biotin trial is in optic neuritis

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    2. is the next biotin trial done by the same ground which now has the data presented at aan?

      is the trial phase 2 or phase 3?

      mouse how long do YOU think it will take for biotin (if proven neuroprotective) to arrive as pills for us to take?

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    3. yes the same group the results are at the end of this year if positive the company hope to be ready by 2017

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  2. When Biogen made the press release the data was not quite significant, has this changed in the three months since the announcement

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    1. No it hasn't changed! But they did have a poster on their synergy trial with anti-LINGO in RRMS that is their step 2 with this drug. The primary outcomes are clinical, whilst MRI is secondary- make what you may of this.

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  3. Given that there was a queztion mark on trial design and the results of alemtuzumab do you thing that these results are on thin ice too. Because so little antibody gets in the brain they gave massive amounts of antibody and then compared it with nothing. Could the results be associated with blockade of macrophage function just like intravenous immunoglobulin which is not inert. Is this gong to believeable unless the control is something like an anti lingo antibody that is engineered not to bind?

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  4. Failed. Sorry Everyone.

    -BIIB

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