Las Vegas—When the American Academy of Neurology (AAN) published its five “Choosing Wisely” recommendations earlier this year, recommendation No. 4 was the following: “Don’t prescribe interferon-β or glatiramer acetate [Copaxone, Teva] to patients with disability from progressive, nonrelapsing forms of multiple sclerosis [MS].”
Several prominent neurologists with expertise in MS criticized the recommendations soon after they were published online in the Feb. 20, 2013 edition of Neurology (doi: 10.1212/WNL.0b013e31828aab14). The specialists clearly were miffed at the proscription against the two injectable MS drugs, posting multiple comments on the “WriteClick” section of Neurology’s website. “This is an oversimplified recommendation that we strongly feel needs to be more nuanced,” argued representatives of the AAN’s Multiple Sclerosis Working Group. “Progressive MS patients with superimposed relapses can still benefit from these agents....”
As the controversy over the “Choosing Wisely” recommendations continues (sidebar), there is a need for guidance on how the “tried-and-true” injectable medications should be used, as well as how they stack up against a new generation of oral agents, according to Janet Nguyen, PharmD, BCPS, the vice president of network strategies for ModernHEALTH Specialty Pharmacy. At the recent Armada Specialty Pharmacy Summit, Dr. Nguyen offered some insights into the drug class and how it is affecting cost and other aspects of MS care.
Dr. Nguyen began with an overview of the new generation of MS drugs, starting with the first oral medication for the disease, fingolimod (Gilenya, Novartis), which entered the market in 2010, and continuing with oral teriflunomide (Aubagio, Genzyme), approved in fall 2012, and oral dimethyl fumarate (Tecfidera, Biogen Idec), approved in March 2013. Prescribers are still weighing the competing benefits and drawbacks of these three market newcomers, she noted. fingolimod has the best efficacy data, with an annual reduction in relapse rate of 54% in the two-year FREEDOMS study that led to its FDA approval, compared with a generally accepted 49% for dimethyl fumarate (the average of two trials) and 31% for teriflunomide, which is not significantly greater than the established 30% for the old standby self-injectables, she pointed out.
“Lots of physicians remain reluctant about fingolimod”—a hesitation that is often due to the cardiac side effects documented in the clinical trials, Dr. Nguyen said. “This drug may end up being used more often in a younger population, where the cardiovascular risks are not so significant.” (Biphasic bradycardia after the first dose of the drug was found in the clinical trial data, and the FDA has recommended that all patients starting fingolimod be monitored with hourly heart rate and blood pressure testing for at least six hours after the first dose. The FDA also recommends that the drug not be used for patients with certain preexisting heart conditions.)
Teriflunomide, on the other hand, does not appear to have significant cardiovascular risks; however, it is a pregnancy category X drug, meaning that it may cause significant birth defects, Dr. Nguyen noted. Data presented at the 2012 meeting of the AAN indicated that 10 women who carried pregnancies to term after first-trimester exposure to the drug had no structural or functional deficits in their newborns. (However, because 21 other women who became pregnant while on teriflunomide chose to terminate their pregnancies, and an additional nine experienced spontaneous miscarriage, these data are inconclusive at best). Teriflunomide continues to carry a boxed warning for women who are pregnant or trying to become pregnant, and a pregnancy registry has been established to monitor outcomes in women who accidentally become pregnant while taking teriflunomide. Given all of this, Dr. Nguyen posits that it will more likely be used in an older population.
And there’s no consensus from the neurology community as to what’s best. “We surveyed prominent neurologists from across the country and their opinions differed,” Dr. Nguyen said. Neurologists from one major center said that they were sure that oral medications would become first-line therapy and the self-injectables would become dinosaurs. “Another group said no, the self-injectables are the mainstay, we have 20 years’ experience with them and we know they work. And there was a middle group that said self-injectables are important but don’t work for everyone. It’s a crowded class, but we still need more options. MS is a very personal and individualized disease.”
Impact on Cost
Although questions thus remain regarding the optimal drug regimen for MS, a clearer picture has emerged on the effect the newer generation of drugs is having on the cost of treating the chronic condition. The spend on all three drugs is predicted to double, or nearly so, by 2017, according to Dr. Nguyen, from $1.2 billion in 2012 to $2.7 billion in 2017 for fingolimod; from an anticipated $389 million in 2016 to $917 million in 2017 for teriflunomide; and from an expected $1.7 billion in 2015 to $2.6 billion by 2017 for dimethyl fumarate.
In a study by Adelman et al, researchers quantified the cost burden of MS and found that direct and indirect costs associated with the disease ranged from $8,528 to $54,244 per patient per year (J Med Econ 2013;16:639-647). Some 77% of those were direct costs, and the majority of those costs comprised prescriptions.
Given the MS marketplace, these figures don’t indicate that any of these medications have been immediate blockbusters, Dr. Nguyen pointed out. “Health plans are being very cautious about these drugs,” she said, “perhaps because they want to see what other data [emerge].”
Robert Lisak, MD, Parker Webber Chair in Neurology at Wayne State University in Detroit and one of the MS Section members who raised concerns about the “Choosing Wisely” recommendations, outlined some of the issues that derailed consensus on this drug class during an interview.
“We do have evidence to indicate that [interferon-β and glatiramer acetate] are not particularly effective in a new, untreated patient with secondary or progressive MS, unless they have superimposed relapses or enhancements,” Dr. Lisak said. “But there are no randomized studies in patients who’ve become secondary progressive while already on one of these drugs, to see whether or not they get worse faster if you take them off it. Such a study would be almost impossible to do, but without that study and without more clarity on who we are calling progressive, you can’t say that staying on one of these drugs isn’t slowing progression somewhat in these patients.”
Commenting on the three market newcomers, the oral medications are likely to reduce, but not eliminate, the market for the tried-and-true self-injectables, Dr. Lisak noted. “There are people who are willing to stay with the self-injectables if they’re doing well,” he said.
In addition to the short-term adverse-event profile for the newer drugs, he pointed out that the self-injectables also have the advantage of at least a decade or more of additional long-term safety data. “We know that nothing serious has come out about glatiramer acetate since the 1980s, and even longer with the interferons. You can’t say that about these newer drugs, with data going back only 10 years or even less.”
Another problem in comparing the self-injectables with the newer oral agents: There actually have been very few head-to-head studies. fingolimod’s relapse rate beat that of a self-injectable formulation of interferon-β1a (Avonex, Biogen Idec) in a direct comparison trial, but dimethyl fumarate, on the other hand, has not yet been directly pitted against other existing MS medications in any major clinical trial.
As for the current state of the imbroglio over the “Choosing Wisely” recommendations, it was eventually determined that AAN’s Multiple Sclerosis Working Group that criticized the recommendation had, in fact, not actually seen the text, due to an oversight by AAN staff. The recommendation is now under review; as of mid-June, AAN representatives told Pharmacy Practice News, a decision had yet to be made on whether or not to revise the guideline.