Robert J. Fox, MD: The interferon class of medicines was the first class developed for the treatment of MS [multiple sclerosis], and they were originally intended to treat MS as a viral infection. It turns out that these probably don't work as antivirals, but instead work directly on the immune system through the interferon receptor to lead to immune modulating effects, downregulation of inflammatory cytokines, and other immune system responses.
Glatiramer acetate was originally developed in the laboratory to induce MS in animals. What was found, surprisingly, is that it didn't induce MS in animals, but instead prevented MS in animals and treated an animal model of MS. Glatiramer acetate is a random polypeptide based on 4 amino acids that are contained in the myelin protein.
Myelin is the sheath that surrounds axons, of course. Glatiramer acetate is a random polymer of about 40 to 80 amino acids in length of a random assortment of those 4 amino acids. The way it works is not entirely known, but is probably a combination of an immune mimic to induce tolerization against myelin peptides. It may compete in the MHC [major histocompatibility complex] class 1 molecule so that myelin peptides are not presented to the immune system.
It also induces regulatory response—this so-called Th2 [T helper type 2] downregulatory response—and protective cytokines decrease inflammation and may actually induce neuroprotection.
When we think about the different classes of MS therapies, we start with the injectables because, historically, they were the first to develop. They are generally modestly effective. They clearly have efficacy, but their efficacy is limited. Their tolerance is also limited. Because they’re injections, the interferons induce flu-like adverse effects. Glatiramer acetate induces skin reactions and divots in the skin. Therefore, tolerance is variable.
Now, for some patients these drugs work well and are tolerated well. But in a lot of patients, treatment with these drugs is either insufficient or their adverse effects are not sufficiently tolerated. Oral therapies such as dimethyl fumarate, fingolimod, and siponimod appear to be more effective than injectable therapies, and are often more acceptable to patients given their oral administration route compared to injections. They are generally considered to be more effective than the injectable therapies, although they have slightly more safety concerns.
There are more safety concerns in terms of GI [gastrointestinal] adverse effects, lowering of the white blood cell count, and there is an increased risk of infections depending on which medicine we're referring to. That said, in general, many neurologists are using the oral drugs ahead of the injectable drugs because of their better efficacy and their better acceptance profile. Infusion therapies are generally considered to be more effective than oral therapies, although there are some patients who are fully controlled with either oral therapies or injection therapies.
Nonetheless, for patients who don't tolerate or don't respond sufficiently to the oral or injectable therapies, infusion therapies are a very good option. They are highly effective and are generally safe, although they do have some safety concerns.
A big question in the field is whether the infusion therapies, those highly effective therapies, are the best therapies to start with right at the beginning of MS. Or is it better to start with a less effective drug, such as an injectable or an oral therapy, and then move up to the infusion therapy as needed, depending on patient tolerability or disease activity?
There is some evidence from the rheumatology literature that suggests that treating rheumatoid arthritis with aggressive therapy right out of the gate is better. That is what has gotten us in the MS field wondering if we should be doing the same thing. There are a few studies ongoing now that are asking that exact question. They are randomizing patients to the highly effective versus the modestly effective therapy and are following them over the long term to see how patients do. We await the results of those studies before we really know which strategy is best at the time of diagnosis.
Fred D. Lublin, MD: One could, under the right circumstances, use almost any of our given agents as a first-line therapy. I think early on you want to make sure that you're maintaining safety, but you also need to maintain efficacy. One of the challenges to the clinician is trying to gauge the individual prognosis of a patient. We're not very good at that. Nevertheless, we do it. And so, if someone comes in, even with a first attack that was a really bad attack, and they have a lot of activity on their MRI [magnetic resonance imaging] scan, and they haven't made a good recovery, one would use a more aggressive, highly effective therapy there.
On the other hand, there are other times when you could use almost any of the agents. The orals are a good starting point. One of the things that one has to take into consideration: What's the patient interested in taking? Some patients are more concerned with safety than they are with efficacy. So we have to meet their needs, as well, by giving them an agent that they're comfortable taking.
The decision-making process is long. It takes us about an hour to go through this with a patient. Again, we have to assess what we think the aggressiveness is of their course, as well as what risks and [adverse] effects they're willing to take or not willing to take, and what drug administration route they prefer—whether it be injectable, intravenous, or oral. Again, family planning. Comorbidities are also very important to consider. Do they have other diseases—diabetes, heart disease, liver disease—that may affect the choice of agent? So, all of these are considerations in choosing among all of the drugs that are on the table. There's not 1, and there shouldn't be any 1 drug that someone always starts with. There ought to be a tailored conversation with the individual to come up with the right drug for them.