Despite considerable advances in the understanding of MS pathogenesis, unmet needs remain to achieve long-term therapeutic success. Two major areas of unmet need are reducing or preventing neurodegeneration and further delaying disability progression.
At ECTRIMS Paris, Professor Gavin Giovannoni discussed the many elements within the process of preventing neuroaxonal loss, including both MS specific and MS non-specific factors. The MS-specific factors can be considered as a therapeutic pyramid, where anti-inflammatory effects form the base and then neuroprotection, remyelination and neuro-regeneration are sequential factors. MS non-specific factors to consider regarding neuro-recovery relate to brain health, and include normal brain biology, plasticity and ageing mechanisms, and the influence of these on MS development and progression.
A number of therapies have been developed in recent years to address the MS-specific mechanisms of preventing neuroaxonal loss. Potent anti-inflammatories such as natalizumab, alemtuzumab and ocrelizumab given early in the disease course can maintain or improve function soon after initiation, however it may take several years to achieve the full improvements in disease progression. The ASCEND trial of nataluzimab in secondary progressive MS is a good example of this, in which no improvement in function was observed in the lower limbs at the end of the three year study period, while function was retained or improved in the upper limbs. This is due to the fact that the upper limbs have a greater neural reserve and therefore a greater capacity to regain function than lower limbs. It is likely that if the trial duration had been longer then improvement in lower limb function would have also been observed.
The remyelination of neurones in patients with MS is being specifically targeted with a number of therapies that are currently under development, showing promising results. One example is opicinumab, an anti-Lingo-1 therapy which has demonstrated remyelination effects in proof of concept studies. Patients in the early stages of the disease experienced a response versus placebo, however a significant treatment response was not seen in the whole active treatment population versus placebo. It was proposed that this may be because those with less extensive axonal damage had a greater capacity to recover than those with more advanced disease. This highlights the importance of sub-population analyses in order to identify sub-groups achieving a strong therapeutic response even when the whole population does not. High-dose biotin has also demonstrated very promising remyelination results in patients with progressive MS, with measurable efficacy soon after treatment initiation. It was suggested that this may have important implications for the design of future trials of remyelination therapies; if a response is seen within a year then trials could be shorter than currently thought, potentially allowing more rapid approval of effective new therapies.
Ultimately, the goal of neuroregeneration is to enhance plasticity, however even in a healthy brain this is an uphill struggle, due to factors such as the progressive volume loss experienced by all from 35 years onwards, resulting in a loss of brain reserve. According to Professor Giovannoni, a major focus in future drug discovery should be on age related neurodegeneration mechanisms. Given the rate of current advancements, it is certainly possible that the future holds therapies available to specifically target and prevent age-related processes linked with MS pathology, as well as normal aging patterns.
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