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Anti-LINGO antibody appears to promote remyelination in optic neuritis

The investigational monoclonal antibody BIIB033 (Biogen Idec) appears not only to improve optic nerve latency in the affected eye of patients with acute optic neuritis (AON), often one of the first manifestations of multiple sclerosis (MS), but also has an impact on the unaffected eye, new research suggests... Read More - http://www.ms-uk.org/MSnews

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Anti-LINGO antibody appears to promote remyelination in optic neuritis
(20/10/15)

The investigational monoclonal antibody BIIB033 (Biogen Idec) appears not only to improve optic nerve latency in the affected eye of patients with acute optic neuritis (AON), often one of the first manifestations of multiple sclerosis (MS), but also has an impact on the unaffected eye, new research suggests.

The findings provide valuable information on the efficacy of this monoclonal antibody for remyelination and could mean that this agent has the potential to be the first neuroprotective therapy in this condition.

Results of two parallel studies of the investigational agent were presented here during the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015.

B11B033 is directed against LINGO-1, a central nervous system–specific membrane glycoprotein and suppressor of oligodendrocyte differentiation and myelination.

Optical nerve latency is a measure, in milliseconds (ms), of the time it takes for information to travel between the retina and the visual cortex in the back of brain. "Normally, it takes about 100 ms for that information to travel between these two points," Diego Cadavid, MD, Biogen Idec, Cambridge, Massachusetts, explained to Medscape Medical News in an interview.

Delayed latency of the visual evoked potential (VEP) is a major sequelae of AON. Recovery of VEP latency indicates remyelination.

AON is a common presentation in MS. Most patients with this condition — up to 80% — will eventually be diagnosed with MS.

The RENEW study included 82 patients at 33 sites who received treatment with 1 g of methylprednisolone for 3 to 5 days, had no history of MS, and were experiencing a first unilateral episode of AON with onset within 28 days of the baseline visit.

"This means that the optic nerve on one of the eyes was acutely inflamed with loss of myelin and damage to the axons and neurons, while the other eye — we call it the 'fellow' eye — was normal," explained Dr Cadavid.

These patients were randomly assigned to receive intravenous anti–LINGO-1, 100 mg/kg, or placebo every 4 weeks for 24 weeks.

The primary endpoint was improvement in optic nerve conduction latency by full-fluid (FF) VEP. An electrophysiologic technique routinely used by neurologists in assessing MS, FF-VEP measures latency. It also measures the strength of that information, or the amplitude.

Good Target

"One of the reasons we selected this endpoint was because it's well known that the human brain does not repair these optic lesions well," said Dr Cadavid. "On average, only about 20% of patients recover their latency, so it was a good target to look at for a treatment effect."

There were 69 patients in the study's per protocol (PP) population: 33 in the treatment group and 36 in the placebo group. In this PP population, the study showed that at week 24, the adjusted mean change in FF-VEP was 22.24 ms in the placebo group compared with 14.69 in the treatment group, for an average difference of –7.55 ms (95% confidence interval [CI], –15.12 to 0.01; P = .05).

"The fact that we observed that improvement on average is for us evidence that this drug is biologically active in humans," said Dr Cadavid. "That's something we never had before; we only had data from animal models."

For the intention-to-treat population of 82 patients, the results were less robust. The average between-group difference was –3.48 ms (95% CI, –10.61 to 3.65; P = .33).

At week 32, in the PP population the adjusted mean FF-VEP change was 22.35 ms in the placebo group vs 13.22 ms in the treatment group. Here, the average difference was a reduction of 9.13 ms (95% CI, –16.11 to –2.14; P = .01).

For the intention-to-treat population at 32 weeks, the average difference between the two groups was –6.06 ms (95% CI, –12.66 to 0.53; P = .07).

Further analysis showed greater latency in older patients. "We found that pretty much all the benefit from anti-LINGO was observed in the half of patients who were older, mean age 38 years, while the other half who were younger, mean age 25 years, seemed to recover on their own," commented Dr Cadavid.

In MS, it's clear that there's a failure of remyelination, but experts don't all agree on why this is, he added. "One theory blames it on aging; as we humans age, we lose the ability to repair."

Patients who were enrolled in the study earlier during the 28-day "window" from first symptom to first dose also seemed to do better, said Dr Cadavid. "People who received the dose on average during the third week vs the fourth week seemed is have a greater benefit." As well, those with more severe baseline visual acuity impairment also did better.

Dr Cadavid stressed that these subgroup analyses are "hypothesis-generating" only.

Parallel Study

In a separate paper, the researchers carried out a parallel multifocal (MF)-VEP substudy analysis of the fellow unaffected eye in 39 patients from the RENEW study: 18 in the placebo group and 21 in the anti–LINGO-1 group. MF-VEP, which covers a significantly larger area of the visual field, with each segment producing a different result, is better than FF-VEP for measuring amplitude changes.

For this analysis, researchers followed the "fellow" or normal eye visual pathway over 8 months. The change in MF-VEP amplitude at week 32 in the placebo group was –31.407 vs 1.926 in those receiving anti-LINGO, for an estimated difference of 33.333 (95% CI, 16.408 - 50.258; P =.004).

"We made a very interesting observation; the group randomized to placebo experienced a steady and gradual loss of amplitude — the strength of the signal," commented Dr Cadavid. "Within 8 months, this population was already having a measurable loss of amplitude."

This is important as this population "is as early as you can catch any patient with MS," he said.

Equally important, he added, was the observation that the group randomly assigned to anti-LINGO did not experience that loss.

The new research provides two important findings, said Dr Cadavid.

"First, that very early into the disease, even before patients could formally be diagnosed with MS, the brain, specifically the visual pathway, is experiencing damage. Second, that the group randomized to anti-LINGO appears not to have experienced that damage, so it's either being protected or being rapidly repaired."

Researchers are now carrying out another study — SYNERGY — that is testing four doses of the agent (3, 10, 30, and 100 mg/kg) and placebo in patients concurrently taking an anti-inflammatory treatment.

"We believe this will provide us with valuable information regarding the potential of anti-LINGO to hopefully one day help MS patients," said Dr Cadavid.

The study is fully enrolled, with results expected next year, he said.

The RENEW study was supported by Biogen. Dr Cadavid is an employee of and stockholder in Biogen.

Reference: Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015. Abstracts 165 and 231. Presented October 9 and 10, 2015.v Source: Medscape Multispeciality Copyright © 1994-2015 by WebMD LLC (20/10/15)