Multiple sclerosis (MS) remains a leading cause of neurologic disability in the young. MS usually relapses and remits before entering a progressive phase. We still don’t know the precipitating cause of MS – consequently we have no cure. Our best approach right now is to try to reduce relapse rate by using drugs that we broadly call disease-modifying agents. Unfortunately, these medications aren’t perfect.
If you were diagnosed with MS in the past couple decades and decided to be treated, you were probably started on either an interferon or glatiramer acetate. These drugs slow relapse rates by about 30%. Since these medications require injection, many patients must deal with daily subcutaneous administration, needle anxiety, refrigeration of the drug, skin reactions, and flu-like symptoms. Yet the drugs continue to be first-line therapies, simply because we haven’t had many other great options.
Things have changed in the past several years. The drug natalizumab given by intravenous infusion monthly, shows high efficacy, however, its usage has been hampered by about one in 3000 patients developing a condition known as progressive multifocal leukoencephalopathy (PML) – an often fatal central nervous system infection.
Neverthless, natalizumab does have a place in treating cases of aggressive MS.
The first oral drugs have also recently arrived. The FDA approved fingolimod in 2010 for treating MS, a drug which reduces rates of relapse by more than 50%. However, fingolimod also has been associated with serious adverse events, including cardiac arrythmias, infections, and some cancers. This September, the FDA just approved another novel agent, teriflunomide, with recent phase III studies showing positive results.
Now, another new oral agent enters the pharmacopia. Succinctly titled BG-12, or dimethyl fumarate, this medicine has been used for over 30 years to treat another autoimmune disease, psoriasis. Researchers now report in this week’s issue of NEJM two new positive trials – DEFINE and CONFIRM – that show BG-12 also works in MS, reducing the annualized relapse rate by about 50% over placebo. While DEFINE compares BG-12 to placebo, CONFIRM compares BG-12 to glatiramer acetate and reveals that the new oral drug also has an efficacy comparable to established first-line therapy. In the latter study, patients who received BG-12 at two different dosing schemes had significantly reduced rates of MS relapse and lower disease activity as measured on MRI.
We still don’t know if BG-12 is better than glatiramer acetate or other MS therapies, since CONFIRM was not designed to detect the superiority of BG-12 over its comparator. Furthermore, like glatiramer, BG-12 also did not show a significant effect on disability progression compared to placebo, but this observation might result from the low rates of disability evolution in the placebo group. But there’s a lot to like here. BG-12 appears to be at least as efficacious as glatiramer acetate and the drug can be taken orally. The most common adverse events due to BG-12 are gastrointestinal distress and flushing, and neither study reports any serious infections or cancers. Because BG-12 has been used to treat psoriasis for many years, we can be more confident of its relatively benign adverse event profile, although adverse events in patients with MS may differ.
Whether patients who are currently on injectable medications should switch to BG-12 or other oral agents is a hard question to answer. Neither DEFINE nor CONFIRM address this issue. Nevertheless, the arrival of BG-12 will invigorate this discussion in MS clinics across the country, requiring the physician and the patient to balance the benefits of therapy with the potential side effects. Multiple therapeutic options always invite debate – but thankfully, when it comes to treating MS, this is a conversation we have long been waiting for.
See also the related editorial, from Dr. Allan Ropper at Brigham & Women’s Hospital in Boston.