ARTICLE IN BRIEF
Members of the AAN Multiple Sclerosis Section comment on the controversies, challenges, and opportunities facing the field.
Treating a patient with multiple sclerosis (MS) requires a commitment to the often-elusive concept of personalized medicine — an understanding that in a multifaceted disease, where there is no “one size fits all” prognosis or management, a universal approach to prescribing drugs and tracking disease progression simply won't cut it.
The 850 members of the AAN Multiple Sclerosis Section know these issues all too well — especially as they seek to decipher an expanding array of new treatment choices and paradigms.
Neurology Today spoke with members of the section's executive committee to highlight some of the most pressing issues in the field right now — including recent controversies involving the economics of DMTs, the promise of new outcome measures for disease progression, and the hope for new treatments that promote neuroprotection and neural repair.
THE RISING COST OF DMTS
Since the first DMT won US Food and Drug Administration approval in 1993, 11 new drugs in eight different classes have been approved for MS. The expansion of treatment options is a boon for MS patients and their physicians, but it comes with a cost — namely, the escalating price tag for these therapies.
The average annual wholesale price of these 12 DMTs has risen substantially over the years and now averages around $60,000, MS Section Chair David E. Jones, MD, an assistant professor of neurology at the University of Virginia, told Neurology Today. “This is unsustainable.” [For a related story on the cost of MS drugs, see “Supreme Court Ruling on Patent Case Will Give Teva Pharmaceuticals More Time to Market Copaxone for MS without Generic Drug Competition” on page 8 of this issue.]
These rising costs — among newer and older DMTs alike — have prompted health care payers and pharmacies to institute restrictions, or step edits, on prescribing certain medications. For instance, “they might say, you must try an injectable before you can get an oral drug, or you must try Drug A before you can try Drug B,” said Dr. Jones. He added that some health care payers now require treatment changes, even if patients are stable on a treatment, because of changes in the formulary.
But “there's absolutely nothing in the clinical trials or in any research that's been done that provides a rationale for that,” said section Vice Chair Jeffrey E. Dunn, MD, FAAN, a professor of clinical neurology and division chief of clinical neuroimmunology at Stanford University Medical School.
“The data are very clear that early therapy is better than later therapy, so it may not be appropriate to wait to escalate to a more effective therapy if you fail first-line therapies,” added Dr. Jones.
The MS Section has been vocal about opposing these step edits. “Our concern as MS specialists is that these step edits mean that [the decision to prescribe a new drug] is not a decision that the doctor makes in conjunction with the patient,” but rather, it is based on factors beyond our control, which don't necessarily relate to choosing the best medical therapies, said David H. Mattson, MD, PhD, FAAN, a professor of neurology and director of the Neuroimmunology/Multiple Sclerosis Program at Indiana University. “We should be able to make that decision without having step edits or restricted formularies get in the way.”
In response to these concerns, the AAN convened a summit in December 2014 — bringing together the AAN President, President-elect, executive leadership team, members of the MS Section, and members of the Consortium of MS Centers. Together, they developed an action plan. When the state of Minnesota attempted to restrict the DMT formulary in 2013, for example, AAN CEO Catherine M. Rydell, CAE, with encouragement from the MS Section and other members of the AAN, sent a letter to Minnesota Medicaid advocating for the inclusion of all MS DMTs on the preferred drug list. A similar letter was sent to Colorado Medicaid in 2014. These letters were successful in keeping more open formularies in both states.
Another recent concern among members of the MS Section was a draft review of the evidence for discontinuation of long-term DMTs, released in October 2014 by the US Agency for Healthcare Research and Quality (AHRQ). The draft paper argued that there was little evidence that long-term therapy with disease-modifying drugs carries any greater risks or harms than short-term therapy, but added that there was also little evidence to support the long-term benefits of DMTs for patients with relapsing-remitting MS.
“We were not involved in the AHRQ review until very late” in the draft process, said Dr. Mattson. Indeed, many MS specialists questioned whether the paper's authors, whose names were withheld at the discretion of the AHRQ, were leading experts in the field.
Several patient and research organizations, including the National Multiple Sclerosis Society and the Multiple Sclerosis Coalition, submitted comments that were highly critical of the paper. Their main concern was that health care payers and patients might misinterpret the review as a blanket recommendation to discontinue long-term treatment with DMTs, when in fact many MS specialists have seen firsthand evidence of the benefits of long-term treatment. In the case of health care payers, this misinterpretation could also lead to restricted coverage and more step edits for long-term DMT use, they argued.
Many experts among the MS Section also questioned the review's methodology. The paper restricted its review to long-term studies lasting more than three years, yet most long-term studies are limited to two to three years because of cost, Dr. Jones noted. “By their methods, the AHRQ eliminated a lot of the data that supports the use of disease-modifying therapies,” he said.
The MS Section has also requested that the AAN update its 2002 guidelines on disease-modifying therapies; the AAN Practice Committee is currently reviewing the request. While certain gaps in the research literature remain — for example, data from clinical trials comparing the relative efficacy of newer DMTs are lacking — an update to the available information would be immensely helpful, Dr. Jones said. “It's okay to highlight what we don't know in these guidelines,” he added.
“The policy paper on how best to prescribe disease-modifying treatments is more than 10 years old now,” said Dr. Dunn. “It doesn't take into account many of the newcomers to the MS armamentarium. These newly approved DMTs are of considerable consequence: they're administered differently, they work by different mechanisms of action, and there are issues of sequencing prescriptions. The old recommendations have to be updated to take into account these new and important medications that are so increasingly being prescribed.”
Still, Dr. Dunn acknowledged that guidelines are simply that. For optimum practice, “Ideally the practicing neurologist could make decisions according to personalized medicine,” which a standardized set of recommendations neither promotes nor affords. “Ideally we'd have biomarkers that can predict what a given patient would respond to in an optimal way, but we don't have that yet,” he said. “So we take into account all sorts of things: availability, tolerance, adherence, financial issues, patient comfort.”
Ultimately, having an updated set of guidelines may help MS specialists answer some of the big questions, but it will continue to take a back seat to the knowledge and experience of the MS expert and the needs and preferences of the patient.
‘NO EVIDENT DISEASE ACTIVITY’
As the formulary continues to expand, the concept of “no evident disease activity” (NEDA) has gained traction as an outcome measure both in clinical trials and clinical practice. A recent study presented at the October 2014 joint meeting of the Americas Committee on Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS) defined NEDA as no relapses, no progression of disability, no gadolinium-enhanced lesions, and no new or enlarged T2 lesions on MRI. [See the Neurology Today article, “News From the Joint Meeting of ACTRIMS/ECTRIMS: No Evident Disease Activity — How It Appears in Clinical Trials and Clinical Practice”:].
NEDA is “the highest bar we can set for our patient treatment response by our present metrics,” said Dr. Dunn.
The use of NEDA has become more popular “in parallel to our increasing therapeutic choices,” he said. “When we only had interferon and glatiramer as therapeutic options, people were more willing to accept some degree of breakthrough as acceptable. We knew the medicines weren't curative. But now, because we're aware of the potential for super-responders to individual medications, the hope is that we might find a treatment for a given patient that can induce NEDA.”
As a clinical endpoint, NEDA is attractive because it takes into account a number of different measurements and offers a fairly holistic picture of a patient's disease and disability status. “It's hard to argue with no attacks, no progression, no new T2 lesions,” said Dr. Mattson. “It's a clean endpoint.”
But the concept could still use some refinement. “The big thing I believe is missing from NEDA is atrophy measurements,” said Dr. Jones. “We haven't standardized those, but presumably loss of brain tissue is not in anyone's best interest.”
And a simple, inexpensive test or biomarker that could more accurately predict remission would be extremely welcome, Dr. Dunn added. He compared the concept of NEDA to hemoglobin A1C, a biomarker that lets endocrinologists monitor a diabetic patient's blood glucose level quickly and painlessly. “The MS doctor doesn't have a blood pressure cuff or an A1C, and yet we still have the responsibility of making sure these important and potentially harmful disease-modifying treatments are achieving their target,” he said. “How do we do that? NEDA is one model, and it sets the highest bar for us to follow. Its effect on the community has been to raise the bar in terms of what we can accept as disease breakthrough.”
EXPERTS: ON MS DISEASE-MODIFYING THERAPIES
NEW STRATEGIES FOR NEUROPROTECTION AND REPAIR
MS specialists have watched intently and with great enthusiasm as several new studies have offered the promise of uncovering drugs that act as neuroprotective agents or promote neural repair — suggesting that it may be possible to not only stop MS in its tracks, but actually reverse some of the damage.
“We've got a lot of drugs that seem to work on the inflammatory aspect of MS, so they're helpful early in the relapsing phase,” said David H. Mattson, MD, PhD, FAAN, a professor of neurology and director of the Neuroimmunology/Multiple Sclerosis Program at Indiana University School of Medicine. “But what's left is the smoldering progression: the atrophy, the neurodegeneration. Some of that is prevented by earlier prevention of inflammation, but there's still a piece left over. And there are people with primary-progressive MS who don't have much in the way of inflammation. We need drugs to help them as well.”
Several existing drugs have shown promise as potential neuroprotective agents, but so far, none are ready for the clinic. For instance, a recent study showed that simvastatin (Zocor), a commonly prescribed statin, could reduce brain atrophy in patients with secondary- progressive MS. [See the Neurology Today article, “A Statin Is Found to Ameliorate Late-Stage Disability in MS: Experts Call for Phase 3 Trial,”].
Statins are a particularly exciting treatment option because they might help patients with progressive MS, a form of the disease for which treatment options are less well defined, and because these drugs have already been approved for treating high cholesterol and physicians are already quite comfortable using them, said Barbara S. Giesser, MD, FAAN, a neurologist at the University of California, Los Angeles and a former councilor for the MS Section.
“The only kicker is that if you start using these high doses of statin drugs, it can cause other issues like muscle or liver problems,” said Dr. Mattson. “So you don't want to do those high doses unless your cholesterol requires it, or until it's proven for MS.”
Drugs that have failed as neuroprotective agents for stroke may offer promise in MS, he added. Stroke is an acute condition that requires immediate resolution. “In stroke, they're dealing with minutes to hours; we have days or weeks or months,” he said. “So, some of the drugs that don't help acute stroke neuroprotection may help in more chronic MS.”
Another potential neuroprotective strategy currently in the pipeline is anti-LINGO-1, a monoclonal antibody that may be able to promote remyelination, Dr. Giesser said.
“We're getting pretty good at stopping or greatly decreasing inflammation in MS. The next step is to affect neural repair,” she said. “That's the next great frontier.”