Novel therapy fails in MS trial
Current treatments for multiple sclerosis target different aspects of the immune response in an attempt to reduce inflammation in the brain and spinal cord. This inflammation causes damage to myelin, which insulates and protects nerve fibres. However, MS treatments don’t directly repair myelin, nor do they restore nerve function that has been lost.
So there’s a need for medications that promote myelin repair. Myelin is formed by specialized cells in the central nervous system called oligodendrocytes. This process of myelin formation is turned on and off by signalling proteins. One such signal is LINGO-1 (for leucine-rich repeat and Ig domain-containing, Nogo receptor interacting protein), which shuts down new myelin formation and the growth of nerve fibres (Mi and colleagues. CNS Drugs 2013;27:493-503). LINGO-1 has been shown to be especially active in situations when there is nerve damage, such as MS, Parkinson’s disease, and spinal cord injury. So the thinking was that if you could block LINGO-1, it would enable oligodendrocytes to do what they’re supposed to do – repair myelin and restore nerve function.
One way of doing this is to develop a monoclonal antibody that specifically targets LINGO-1. An example is opicinumab (also searchable as BIIB033) which completed two phase I studies in healthy subjects and people with MS (Tran and colleagues. Neurol Neuroimmunol Neuroinflammation 2014;1:e18).
Results from two phase II studies have now been reported. The first study was RENEW in people with optic neuritis (inflammation of the optic nerve), which is often an early symptom of MS. The study tested six doses of opicinumab administered by infusion (slow drip) once a month over 20 weeks to see if the drug could do either of two things: promote remyelination (as measured by the speed of electrical signals from the retina to the brain); and protect nerve fibres (as assessed by an eye exam that can measure the thickness of the retinal nerve fibre layer).
Neither of these measures showed significant improvement with opicinumab compared to a placebo (Cadavid and colleagues. AAN 2015; abstract P7.202). There was no evidence of neuroprotection, and vision didn’t appear to improve. However, there was cause for some optimism because there was a trend to a degree of remyelination. The speed of electrical signals along the optic nerve improved somewhat, and was more likely to be normalized in people on treatment compared to placebo.
The second phase II study was SYNERGY, which combined opicinumab with Avonex in people with MS over a 72-week period. Preliminary results are only available in a media release and haven’t been presented yet. The study was designed to test the effects of the drug on a grab-bag of measures that evaluated various types of physical and mental disabilities, such as walking ability (Timed 25-foot walk), upper limb function (9-hole peg test), disability (EDSS) and cognition (PASAT). Unfortunately, none of these measures showed improvement, nor was there a slowing of disability progression.
Biogen, the manufacturer of opicinumab (and Avonex), says the drug did have some effect so it will continue to study it. Higher or more frequent dosing may be needed, although the safety of chronic, high-dose treatment would need to be established.
The failure of these studies doesn’t mean that remyelination and regrowth of nerve fibres aren’t possible. Remyelination is a complex process involving many players, and other therapies will emerge that may prove to be more effective in restoring nerve function.
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