Why some patients continue with a relapsing and remitting course in multiple sclerosis and others develop progressive MS is unclear. Possible neurodegenerative mechanisms include chronic “smoldering” inflammation, microglial activation with oxidative damage, ion channel dysfunction and failure of energy in demyelinated axons, hypoxic injury, glutamate excess, mitochondrial failure, and accumulation of iron. It is unclear which of these are key. There are increasingly powerful medications, such as alemtuzumab and ocrelizumab, that are very effective against relapsing and remitting MS. They may have approached parity with stem cell transplants, and some researchers believe that we may have reached the limits of effectiveness of this class of medications.
Obviously, patients with progressive MS constitute an unmet need. A summary of completed and ongoing trials for this disorder follows.
Fingolimod (Gilenya) in phase III trials in patients with relapsing and remitting MS demonstrated an effect on brain atrophy. A class I trial termed INFORMS targeted primary progressive MS. It included almost 1000 patients. The primary endpoint was not met.
Ocrelizumab is not yet indicated by the FDA for multiple sclerosis, but approval is likely for use in 2017. It is a monoclonal antibody targeting CD20, a receptor on B-cells, and mechanism of action is similar to that of rituximab, which is off-label for MS though indicated for rheumatoid arthritis, and to ofatumumab, which is beginning phase III trials. Rituximab was of no benefit in disease progression in a phase III trial with PPMS, but a subgroup of patients younger than 51 years and those who had gadolinium-enhancing lesions at baseline seemed to benefit. A phase III trial of ocrelizumab called ORATORIO in PPMS was recently completed and reported. It showed a reduction of about 25% in clinical disability and less brain volume loss.
Biotin is a widely used supplement thought to improve hair and nail growth. It also activates an enzyme involved in synthesis of myelin. A phase III trial in patients with primary or secondary progressive MS was recently completed. A dose of 300 mg daily was used. Keep in mind that biotin is widely available, but highest capsule dose is 10 mg. Thus, a patient would need to take 30 pills daily. Thirteen percent of patients treated with biotin and none with placebo had improvement in a disability scale termed EDSS. Even though this was a low proportion of responders, the differences were statistically significant. There were no imaging data, and effects on atrophy are not known. Further trials are likely to proceed.
Ibudilast has potential neuroprotective properties and has been tested in Parkinson’s, without statistically significant benefit. In a phase II study in patients with relapsing MS, a dose of 30 or 60 mg a day had no effect on MRI or clinical relapses, but the 60 mg dose seemed to have protective effects on brain atrophy. These results led to an ongoing phase II trial termed SPRINT-MS. Results may be available in 2017.
Statins have been studied for years. Some trials have demonstrated an effect on new MRI lesions and brain atrophy. In one trial, however, adding simvastatin 80 mg a day to an interferon seemed to have deleterious effects on MRI for unclear reasons. A recent trial showed reduced atrophy by 43% compared to placebo. The medication is off patent, and there is thus no incentive for the pharmaceutical industry to fund a large phase III trial.
Natalizumab (Tysabri) was studied in a recently completed phase III placebo-controlled trial termed ASCEND in secondary progressive MS. Almost 1000 patients were studied. Results did not achieve statistical significance on the primary measure, but there seemed to be benefit on one of the components, termed the nine-hole pegboard test, which evaluates function of the upper extremities.
Lastly, an ongoing phase IIb multicenter trial in the UK termed MS-SMART is evaluating patients with secondary progressive MS. There are 4 treatment arms: placebo, amiloride 5 mg b.i.d. (widely used to treat hypertension), riluzole 50 mg b.i.d. (indicated and currently used to treat ALS), or fluoxetine (Prozac) 20 mg b.i.d., the first SSRI approved to treat major depression and still widely used. It is a 2-year study and the primary endpoint is change in brain volume. Of interest, the study involves potential neuroprotective rather than immunomodulating agents. Completion is expected in 2017.
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