You might say the dizzying array of options multiple sclerosis (MS) clinicians have to choose from is a good problem to have, and the “problem” just got larger. In late March, the US Food and Drug Administration (FDA) approved two new therapies for MS, bringing the total number of disease-modifying therapies (DMTs) for MS available in the United States to nearly 20.
The two new drugs are both oral medications: siponimod, a once-daily tablet approved for clinically isolated syndrome, relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS); and cladribine that has a novel dosing regimen comprising eight to 10 days in each of two years of treatment.
Approved for RRMS and active SPMS but not clinically isolated syndrome, cladribine has a significant safety profile that includes malignancies and is generally recommended for patients who have been unsuccessful with other MS therapies.
“Having all these medications available gives us more options to treat our patients, but it also makes the picture more complicated,” said Mitchell T. Wallin, MD, MPH, director of the US Department of Veterans Affairs' Multiple Sclerosis Center of Excellence-East, and associate professor of neurology at George Washington University and the University of Maryland School of Medicine.
Dr. Wallin recently published a national algorithm-based analysis in the March 5th Neurology that puts MS prevalence at its highest report to date and suggests that between 851,749 and 913,925 people in the US today are living with MS.
“With more and more agents approved, even at major MS centers it has become more taxing to determine who should be getting which medication when,” Alex D. Rae-Grant, MD, FAAN, professor of neurology at the Cleveland Clinic and lead author of the AAN's 2018 updated practice management guideline on disease-modifying therapies in MS, said.
“I think that each MS clinician needs to try to be comfortable with some reasonable subset of the medicines and know them very well. You should be ready to use the other agents, but have a group of them that you know inside out to offer your patients appropriate choices. The analogy might be [comparable with] treating hypertension. I'm sure my general internist doesn't know 600 anti-hypertensives in detail, but he may have a reasonable list that he knows well, and I think that's where we are transitioning to in the treatment of MS.”
The Three Buckets
So how are leading MS experts choosing from the ever-growing array of available DMT options, and what are they advising their patients?
“When I discuss therapies with a newly diagnosed patient or a patient who may need to change medications, I generally categorize them into three buckets,” said Tanuja Chitnis, MD, FAAN, director of the Partners Pediatric MS Center at Massachusetts General Hospital for Children and chair of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. “The first is the older injectables, which have lots of long-term safety data and tend to be low-risk, but their efficacy also tends to be on the lower end. The second category is the newer oral treatments, of which there are now at least five. They are in the moderate range in terms of efficacy, but they all come with their own side effects and screening requirements. And then there are the newer IV treatments, which appear to have the highest efficacy but also [have] a more significant risk profile.”
Older, Safer, Milder
The older DMTs include interferon beta-1a (Avonex, Plegridy, Rebif), interferon beta-1b (Betaseron, Extavia), and glatiramer acetate (Copaxone) and its biosimilar, Glatopa. The mainstays of MS treatment, these self-injectable agents have been taken by hundreds of thousands of patients over more than two decades, Dr. Chitnis said.
In the 1990s, these drugs were tested against placebo, and all demonstrated similar efficacy for the prevention of relapses, with a mean reduction of about 30 percent. Major trials in the 2000s showed that there were no significant differences among these drugs in terms of relapses, MRI lesions, or progression on the Expanded Disability Status Scale (EDSS).
Their exact dosing regimens and side effect profiles vary, Dr. Chitnis said, but in general, the first-generation agents are well tolerated, with injection-site reactions, flu-like symptoms, and headaches, as well as blood count and liver test abnormalities, as the most common events. These are all generally mild and temporary.
A newer self-injectable, daclizumab (Zinbryta), was withdrawn from the market in 2018, two years after its approval after the European Medicines Agency raised new safety concerns regarding reports of inflammatory encephalitis and meningoencephalitis.
The Newer Orals
Newer oral agents for the treatment of MS include fingolimod (Gilenya), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio). “These drugs tend to have moderate efficacy, ranging generally between 35- and 65 percent in the reduction of relapses,” said Dr. Chitnis. “Of course, they all come with their own side effects and screening requirements.”
Cases of progressive multifocal leukoencephalopathy (PML), a rare, often fatal brain infection, have been reported among a handful of patients taking either fingolimod or dimethyl fumarate. Clinicians are advised to withhold the drug at the first symptoms of PML, which include clumsiness or progressive weakness on one side of the body, vision disturbances, and memory impairment, confusion, and personality changes.
Both fingolimod and dimethyl fumarate also are associated with significant reductions in lymphocyte count, so a baseline complete blood count (CBC) and regular monitoring are required, she said. Fingolimod also poses a risk of bradycardia and AV conduction delays following the administration of the initial dose, so patients must be monitored by medical personnel for six hours following that first dose. This agent also has a risk of macular edema and fungal infections. The risks of dimethyl fumarate also include severe allergic reactions and skin reactions.
Teriflunomide has fewer side effects and adverse events than the other two oral agents, but it does pose the risk of acute liver damage, decreases in white blood cell counts, and tuberculosis, so baseline liver and CBC counts and a tuberculin test should be done before starting therapy, Dr. Chitnis said. It is also contraindicated in pregnancy, rated “pregnancy class X” by the FDA. Its efficacy profile is less than the other oral agents, being more comparable to the platform injectables.
Siponimod is the latest entrant in the oral category. In the phase 3 EXPAND study which led to siponimod's approval, the annualized relapse rate decreased by 55 percent compared with placebo. Risks include macular edema, bradycardia, infection, and declines in liver function, Dr. Wallin said.
“Siponimod is hopefully a kinder, gentler fingolimod with more selective affinity for the sphingosine-1-phosphate receptor,” said Dr. Wallin. “At least you don't have to do the extended monitoring with the first dose. The real-world experience will be important to watch, but hopefully, it will make it easier to start people on therapy with fewer side effects.”
Newer IV Treatments
“The newer infused agents are, so far, our most effective therapies at treating relapsing forms of MS,” said Rebecca Spain, MD, associate director of clinical care for the US Department of Veterans Affairs' Multiple Sclerosis Center of Excellence-West and associate professor of neurology at Oregon Health & Science University. Reductions in the annualized relapse rate for RRMS with these drugs range from 50 to 80 percent.
These drugs include natalizumab (Tysabri), alemtuzumab (Lemtrada), ocrelizumab (Ocrevus), and, off-label, rituximab. “While highly effective, they also tend to pose the highest risk of significant adverse events, with the possible exception of ocrelizumab,” Dr. Spain said. Cladribine, while an oral agent, also falls more into the category of high risk and high efficacy, she said. (Another drug, mitoxantrone, is approved for MS but rarely prescribed because of the significant potential for heart damage and leukemia.)
Alemtuzumab is associated with the risk of autoimmune diseases, malignancies, immune thrombocytopenia (ITP), and rare cases of ischemic stroke, hemorrhagic stroke, and arterial dissection. Natalizumab and rituximab both carry black-box warnings for PML. Natalizumab is also associated with other serious risks such as infections (including pneumonia) and liver damage, while rituximab has been linked to serious infections such as pneumonia and septic arthritis. And in both phase 3 trials of ocrelizumab, patients taking the drug had higher rates of cancer than the control group.
Cladribine has its own black box label, warning that resuming or supplementing dosing after two years of care could increase the risk of developing malignancy. It also carries risks of liver damage, hematologic toxicity, and infection. Because of this, it is approved as a second-line agent, for those unable to tolerate or inadequate response to a first MS therapy.
For both cladribine and siponimod, only time will tell if the efficacy and safety profiles seen in the clinical trials that led to their approval will bear out in the real world. “We typically need two to three years to get a better sense of the import and frequency of rare but critical adverse events, something that is very hard to evaluate in the clinical trials,” Dr. Spain said.
The Balancing Act
The AAN practice management guideline provides recommendations on balancing the patient's preferences for efficacy and safety, along with route of administration, lifestyle, cost, common adverse events, and tolerability when choosing a treatment. That guideline was released before the approval of siponimod and cladribine, however. For people with highly active MS, the AAN guideline recommends that clinicians prescribe alemtuzumab, fingolimod, or natalizumab, depending on patient-specific factors.
“It's up to us as neurologists to help our patients find a therapy with a risk vs. benefit ratio that works for them,” said Dr. Spain. “We don't have perfect algorithms for determining early on in the disease which patients are at high risk for having a more aggressive course, but we do have some pretty good clinical and radiographic markers that predict more disability down the line. If a patient has many relapses early on, poor recovery from those relapses, and/or more MRI activity with more enhancing lesions, that suggests that we may want to consider a higher-efficacy treatment early on.”
But other patients may have a relatively indolent disease course. “If someone's MS is more benign, perhaps with more of a sensory start to it, involving milder symptoms such as optic neuritis, I would tend to be more conservative and start them on an injectable or oral agent,” said Dr. Wallin. “But in a patient with more aggressive disease and higher risk, I pull out all the stops. For example, an abstract presented at the 2018 AAN Annual Meeting reported evidence that MS progresses more quickly in African-Americans than in Caucasians, and in men than in women. If I have an African-American male patient who's experiencing significant neurological symptoms and has an active brain MRI early in the disease course, I'd recommend natalizumab or ocrelizumab right out of the gate.”
The availability of such a wide range of disease-modifying drugs also opens up more possibilities for switching therapies sooner when one does not work, Dr. Spain noted. “Instead of waiting two to five years to try something different, as we might have back when we had only injectable drugs, now our threshold for making a switch if a drug is not effective is more at the six-, 12- or 18-month mark.”
Cost of care must also be taken into consideration when discussing a new therapy or changing therapies. According to the National Multiple Sclerosis Society, the average median price of MS DMTs in 2018 was $80,000; in 2013 the average was less than $60,000. Combine that with the fact that an increasing number of patients are on high-deductible insurance plans, which are more often requiring coinsurance rather than copays, and it's no surprise that some people with MS are paying $2,500 or more every month out of pocket for their treatments.
“For clinicians, it's particularly tricky because there isn't a good way to know when you're prescribing a new drug, what a particular patient will pay out of pocket,” Dr. Rae-Grant said.
Seeking Better Answers
Even for the “lower efficacy agents,” Dr. Spain noted, long-term studies do suggest ongoing benefits. “The University of California, San Francisco has a cohort of 500-plus people they have followed for more than a decade, the MS EPIC study. When this study started, the only agents available were the earlier-generation injectable drugs. What it shows, very reassuringly, is that even with these medications, time to disability is much longer and disability levels are lower than in the natural history studies from before those therapies. That tells us we're on the right track in treating MS.”
The same group at UCSF is also developing a more precision medicine-based approach to predicting MS progression and selecting therapy with a data-driven algorithmic tool called BioScreen. This platform, the developers write, “gathers all relevant MS data from different sources, including clinical, imaging, and biomarker information, visually represents the disease course of an individual with MS from a front-end interface, and frames this course within the context of a large cohort of patients treated according to contemporary standards. The goal is to inform more precise clinical decisions, and empower patients to participate more actively in their clinical care.” It's not yet ready for widespread clinical use, however.
In addition, the Patient-Centered Outcomes Research Institute has sponsored two major randomized controlled trials comparing escalation treatment—starting with a lower-efficacy agent with fewer side effects and moving to a more aggressive agent if relapses or new lesions occur—to early treatment with more highly effective agents. The TREAT-MS trial is based at Johns Hopkins University and includes more than 45 centers participating nationwide, while the DELIVER-MS trial is led by the Cleveland Clinic and will be conducted at 24 centers across the US and the United Kingdom. Both trials are still recruiting patients.
Patients may also not need to be on high-efficacy, high-risk treatments for decades. “There's an emerging approach to considering scaling back treatment at a certain age,” said Dr. Chitnis. A 2017 meta-analysis in Frontiers in Neurology found that high-efficacy drugs outperform low-efficacy drugs in arresting MS disability only in patients 40 and younger, and that for those 53 years old and over, the average patient gets no benefit from immunomodulatory DMTs.
“There may come a point where we pare down treatment and go to something with more modest efficacy, or even stop at some age,” Dr. Chitnis said. “ With that understanding, patients with the more aggressive disease are more likely to think about trying something high efficacy in the beginning, and to my mind, that is really critical to arresting the process of disease progression.”
Drs. Wallin, Spain, and Rae-Grant declared no conflicts. Dr. Chitnis has received consulting fees from Alexion, Biogen, Novartis, and Sanofi-Genzyme; she receives support for research studies from Serono and Verily.