September 24, 2015 | News | MS Treatments

What does “higher efficacy” mean?

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For just over a decade, the only medications to treat the MS disease process were the interferon-beta drugs (Avonex, Betaseron/Extavia, Rebif) and Copaxone. These medications had three things in common: all needed to be injected, they generally weren’t associated with serious side effects, and they were only modestly effective. The frequency and severity of relapses did improve for some people, but it has been very difficult to show that these drugs have much of an impact on disability over the longer term. Low risk meant that people were encouraged to start treatment. Low benefit meant that most quit taking their medication within the first few years (Wong and colleagues. Can J Neurol Sci 2011;38:429-433).

The approach to treatment began to change a decade ago with the introduction of Tysabri, the first of the “higher-efficacy” medications. Betaseron reduced relapses by one-third (IFNB Study Group. Neurology 1995;45:1277-1285); Tysabri reduced relapses by two-thirds (Polman and colleagues. N Engl J Med 2006;354:899-910). Moreover, switching from an injectable to Tysabri was also beneficial in terms of achieving better control of the disease (Kalincik and colleagues. ECTRIMS 2014; abstract P288). These benefits appear to be sustained for at least five years, although long-term data for Tysabri are very sketchy (Butzkeuven and colleagues. J Neurol Neurosurg Psychiatry 2014;85:1190-1197).

Whether it’s safe for a person to take Tysabri for five years is another matter. Tysabri is associated with PML (progressive multifocal leukoencephalopathy), and the risk of developing this potentially fatal brain infection increases with cumulative exposure to the drug. For people with all of the known risk factors, there’s a 1-2% chance of developing PML in years 2-4 of treatment, and this risk probably continues to increase thereafter.

Because of this concern, Tysabri is generally kept in reserve for people who really need it – those with frequent, severe relapses and worsening disability early on, and those who haven’t responded well enough to other MS medications. Its main advantage is its ability to shut down inflammation in the brain and spinal cord very quickly, and so it has proven to be an invaluable stop-gap for people who are running into trouble. The chief disadvantage is that because of the cumulative risk of PML, it’s often best to stop the drug within the first two years – and weaning off Tysabri is no easy matter. For most people, whatever gains that have been made will be lost when treatment is stopped – even if another treatment is started (Sangalli and colleagues. Mult Scler Relat Disord 2014;3:520-526). Some have argued that this is a good reason not to stop Tysabri (Clerico and colleagues. JAMA Neurol 2014;71:954-960), but it may be a better argument not to start.

The trade-off of greater benefits and greater risks may be acceptable if your MS is likely to worsen soon, and if there are no other options. However, three medications are available or in development that provide some good alternatives.

The first is Gilenya, which has been shown to be significantly more effective than Avonex in a head-to-head trial (Cohen and colleagues. N Engl J Med 2010;362:402-415). It also appears to be effective when coming off Tysabri if the switch is done quickly enough – with no more than a 2-3 month gap between therapies (Kappos and colleagues. Neurology 2015;85:29-39). The main issues with Gilenya are its effects on the heart when it’s first started, which requires a six-hour observation period when you take the first dose; and some people develop eye problems, so regular eye exams are needed. An emerging issue is PML. To date, there have been 11 cases of PML in people with MS who switched from Tysabri to Gilenya (Putzki and colleagues. ECTRIMS 2014; abstract FC3.1), which in some cases appeared to be a holdover from exposure to Tysabri. An additional three cases of PML have also been reported in people taking Gilenya with no prior Tysabri use. The PML risk with Gilenya appears to be very small (about 1 per 10,000) but needs to be considered.

The most potent MS medication is Lemtrada, which essentially acts to reboot the abnormal immune response. Two clinical trials have shown that Lemtrada is about 50% more effective than Rebif in controlling relapses (Cohen and colleagues. Lancet 2012;380: 1819–1828; Coles and colleagues. Lancet 2012; 380:1829–1839). The drug is given as a series of infusions over the course of a week, with a second course administered one year later. Thus far, most people have only required two treatment courses, although it’s likely that additional therapy (either another course of Lemtrada or another drug) will be needed at some point.

The main advantage of Lemtrada is its impact on disability. At four years (i.e. two years after the last dose in most cases), about 75% of people had no worsening of their disability (Havrdova and colleagues. AAN 2015; abstract P7.276)). In fact, 40% of people had less disability than before starting Lemtrada. No PML cases have occurred with Lemtrada, but there is a risk of other types of infections, including viral infections (e.g. cold sore flare-ups). About one-third experience a problem with their thyroid, which may require treatment (Hartung and colleagues. ECTRIMS 2014; abstract P043). Regular blood tests are also needed because the drug can have potentially serious effects on the blood and liver.

The third high-efficacy options are drugs (called ocrelizumab and ofatumumab) that target the abnormal B cell (rather than T cell) response. Final data haven’t been presented yet, but the preliminary results appear to be very promising. In the OPERA studies, ocrelizumab was shown to provide better disease control compared to Rebif. Full results will be presented in October 2015. In the MIRROR study of ofatumumab, there was a substantial reduction in inflammatory lesions in the brain (Sorensen and colleagues. ECTRIMS 2014; abstract P048). No effect was seen on relapses or disability, but this will need more study once the most effective dose has been established.

It isn’t known yet how safe the B cell drugs will be. Both have been used to treat other diseases, and PML cases have been reported. Reactivation of other viral diseases can also occur, so this issue will need to be followed closely. Other safety issues are a risk of fatal infections, which led to the cancellation of ocrelizumab as a treatment for rheumatoid arthritis.

While safety is always a concern, closer monitoring – regular blood tests and other exams – can help to ensure that people don’t develop problems. The added tests may be inconvenient, but the trade-off is the possibility of more fully controlling the MS disease process, maintaining day-to-day function and slowing the development of disability.

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