Beginning of the end of the injectables?
The year 2013 will likely see the launch of two new oral agents for multiple sclerosis (MS) – teriflunomide (already available in the U.S. as Aubagio), and BG-12 (which may be called Synaplin). They will join fingolimod (Gilenya), the first of the oral MS drugs (following the withdrawal of oral cladribine). Depending on where you live, Gilenya is indicated as a first- or second-choice therapy. Teriflunomide and BG-12 are also expected to be accorded first- or second-line status following their review by regulators.
Will these new oral drugs become the standard of care? Or will doctors stick to the ABCs (Avonex/Betaseron/Copaxone/Rebif)?
The year 2013 marks two important milestones in MS treatment. It was 30 years ago that Dr. Kenneth Johnson (1932-2011) first wrote about a plan to test an injectable interferon in MS (Johnson KP. Arch Neurol 1983;40:681-682). As it turned out, the type of interferon he used (interferon-alpha) wasn’t effective (Camenga et al. Arch Neurol 1986;43:1239-1246). And his second choice, interferon-gamma, made things worse (Panitch and colleagues. Lancet 1987;1:893-895). But at the same time he was working on a pilot study of interferon-beta, which did seem to have an effect (Knobler and colleagues. J Interferon Res 1993;13:333-340).
This coincided with the second milestone 20 years ago now – the IFNB MS Study Group’s trial of interferon-beta in MS (Neurology 1993;43:655-661) – which resulted in the approval of Betaseron as the first of the injectable MS drugs. Dr. Johnson then turned much of his attention to glatiramer acetate, becoming the lead author of the pivotal trial that led to the approval of Copaxone in 1996 (Johnson and colleagues. Neurology 1995;45:1268-1276).
The past two decades have given people a good idea of the strengths and weaknesses of these first-generation meds. The main advantage of the interferons and Copaxone are their remarkable safety records. Their chief advantages are a reduction in relapses by about one-third, and some improvement on disease activity seen on MRI. These are nice-to-haves, but are somewhat beside the point. The key question is: do these disease-modifying therapies actually modify disease? In other words, do they affect whether a person develops disability down the road?
Here the results are more mixed. Some studies suggest that every relapse has a cost – that each relapse causes a little bit of damage that doesn’t go away. Some have said that up to 50% of people will have a noticeable loss of function after a relapse, and some of this disability doesn’t always get better (Lublin and colleagues. Neurology 2003;61:1528-1532; Hirst and colleagues. J Neurol 2008;255:280-287).
Others have suggested that relapses are important only in the first 2-5 years after you’re diagnosed (Scalfari and colleagues. Brain 2010;133:1914-1929; Tremlett and colleagues. Neurology 2009;73:1616-1623). And recent studies have questioned whether interferons will prevent disability down the road (Shirani and colleagues. JAMA 2012;308:247-256. See Interview with researcher Helen Tremlett for more on this study.)
These studies raise two important questions. Is the idea of reducing inflammation the right approach in slowing or preventing the development of disability? And if so, would a more potent medication have better long-term effects?
The second-generation drugs should help to answer both of these questions. Thus far, studies directly comparing the new oral drugs to the ABC drugs have found that the orals are at least as good at reducing relapses, MRI lesions and disability progression. In the TRANSFORMS trial, the relapse rate in people taking Gilenya was less than half of that seen among those taking Avonex (Cohen and colleagues. N Engl J Med 2010;362:402-415; free full text at www.nejm.org/doi/pdf/10.1056/NEJMoa0907839). Gilenya also produced greater reductions in the number of MRI plaques. Almost one-half (46%) of those taking Gilenya showed no MS activity – meaning no relapses, no progression and no MRI activity – in the first year of treatment compared to one-third in the Avonex group (Khatri and colleagues. American Academy of Neurology annual meeting 2012).
BG-12 was compared to Copaxone in the CONFIRM trial (Fox and colleagues. N Engl J Med 2012;367:1087-1097). In terms of reducing the rate of relapses, the higher dose of BG-12 (240 mg three times a day) was significantly better than Copaxone; the lower dose of BG-12 (240 mg twice a day) was about the same as Copaxone. Both doses of BG-12 were better than Copaxone with respect to the number of MRI lesions. But neither of the drugs had much effect on disability in this trial, which may be due to the low number of people who progressed during the study.
The comparative trials for the other two orals, Aubagio and laquinimod, were a little less impressive. In the TENERE study comparing Aubagio with Rebif, Rebif was better than the oral in reducing relapses (Vermersch et al. CMSC/ACTRIMS 2012). In the BRAVO trial, laquinimod was no better than Avonex in terms of reducing the frequency of relapses.
So the take-home message is that teriflunomide and laquinimod are roughly comparable to the injectable drugs, BG-12 may be a little better, while Gilenya appears to be the most potent of the oral drugs. If you’re taking an injectable and aren’t having any problems, then sticking with the program may be your best option. But for those who aren’t responding well, or can’t handle the injections and side effects, at least a wider range of options is opening up.
The most obvious advantage of oral drugs is that they’re easier to take – no more messing about with needles and searching for a place to inject. That may help people stay on therapy. For at the moment, the number of people who go off their injectable is high. A study looking at people with MS in British Columbia found that most had stopped treatment or switched to another drug within three years (Evans et al. Clin Ther 2012;34:341-350). Similarly, the MSBase Incident Study found that about 40% (over 50% in Canada) stopped their injectable within 2-3 years – and about one-third of people didn’t start another treatment after that (Meyniel et al. PLoS One 2012;7:e38661; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3387159/pdf/pone.0038661.pdf). The reasons: side effects and the disappointed feeling that the drug wasn’t working. When surveys ask people about how they’re doing (which they do, occasionally), many will say they’re simply fed up with treatment (Rinon et al. Patient Prefer Adherence 2011;5:629-643; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3259078/pdf/ppa-5-629.pdf).
The side effects with the injectables are well known: pain, skin reactions and, in the case of the interferons, flu-like symptoms that drag on for years. So it’s little wonder that people give themselves drug holidays, go off treatment from time to time, switch drugs or quit altogether.
It’s still too early to say if day-to-day side effects will be any better with the oral meds. With Gilenya, some precautions are needed with the first dose because of how the drug affects the heart. The drug can also affect the eyes so a follow-up eye exam is needed. With BG-12, many people experience flushing and the drug can be hard on the stomach, which has led to high dropout rates in clinical trials. For Aubagio, there’s a small risk of liver damage, and about 1 in 10 will develop hair loss. In a seven-year follow-up of Aubagio, most had dropped out of the study so it’s hard to draw any conclusions at this stage (Confavreux et al. Mult Scler 2012;18:1278-1289).
More work is needed to identify who is the best candidate for which drug. And more information is needed on the long-term safety of the new drugs. The hope is that the inevitable balancing of effectiveness and side effects will tilt favourably, but we’ll need to see if the orals do a better job in limiting disability over the long haul.
It’s also important to keep in mind that the orals are just one wave in the floodtide of MS treatments. The second wave is the infusion drugs. We already have Tysabri, which has been highly effective so far. The key concern is PML (progressive multifocal leukoencephalopathy), a calamitous and potentially fatal brain disease caused by the JC virus. About 50% of people with MS have not been exposed to the JC virus, and they’re good candidates for Tysabri for as long as they remain unexposed. The three other infusion drugs in the pipeline are alemtuzumab, ocrelizumab and daclizumab – and the early results with all three have been very promising.
As more treatments become available, it’s likely that the current injectables will become taxi therapies – a means of getting where you need to go. At least until health plans, insurance companies and regulators clear the way for the new generations of drugs that have the potential to do a better job of controlling MS.
We’ll learn more about the new MS medications at the upcoming annual meeting of the American Academy of Neurology (AAN). Let us know what you’d like to see at My Voice.
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