The Shift in MS Care as Biologics and BTK Inhibitors Advance

In this edition of Pipeline Projections, Roy Moore breaks down the rapidly evolving landscape of multiple sclerosis treatments—highlighting the shift from injectables to orals, the rise of monoclonal antibodies, and the promise of innovative biologics like BTK inhibitors poised to reshape future care.

Let’s start with an overview— what’s the current landscape of biologics and advanced disease modifying therapies (DMTs) in the US Food and Drug Administration (FDA) pipeline for MS? What trends are you seeing in development focus or mechanisms of action?

Roy Moore: To begin, we should probably step back and say what exactly is the landscape currently, and how it has evolved for MS.

I've been looking at this for 15 years, so I've seen it evolve in real time. Initially, you had what were called the platform injectables. These were the self-administered, injected therapies like Betaseron, Avonex, and Copaxone, those were the standard of care for quite a long time. Now, a lot of those drugs have since gone generic; we've just seen a genericization of that class, so mostly generics there.

The second bucket you have are the oral therapies, and that began in 2010 with the launch of Gilenya. It was the first oral therapy for MS. That also changed the game because oral therapy is preferable for both the patients and the physician. You saw the rise of new therapies there—Aubagio and other therapies as well, even some of the more recent ones like Mavenclad. The first ones of those have since gone generic, like Gilenya, like I mentioned, and the payers, of course, are pushing those generics over the brands because they're just going to be cheaper from a net cost standpoint, although there are still some brands there.

That means that the brands that are remaining that don't have a generic equivalent are typically covered under either a nonpreferred tier or specialty tier, or they may be preferred if there is some sort of contract in place. That's an evolving class, and we're seeing activity there that continues to evolve. It's not as set in stone as platform injectables because there is still not quite the genericization there.

The last class we want to talk about is the physician-administered drugs. These are the monoclonal antibodies, drugs like Tysabri, Lemtrada, and Ocrevus. These have been on the market, in the case of Lemtrada and Tysabri, for many years. This is a class that has not had genericization. We are going to see a biosimilar version of Tysabri launch sometime soon, and that will reshape that market completely.

All that to say, we have those 3 buckets for the drugs, and we are going to see changes to the overall treatment options with the launch of new therapies that are in pipeline. We published a report just recently looking at the pipeline for these and how payers and physicians view them.

We're going to see the launch of new drug classes. That's exciting because payers and physicians want new drug classes because this is a heterogeneous population. MS is a collection of different populations—relapsing MS (RMS), primary progressive MS (PPMS), etc. They want these drugs with novel mechanisms of action (MOA) that can allow them to treat patients with a different method if a current treatment isn't working. We're going to see the Bruton's tyrosine kinase (BTK) inhibitors. We're going to see additional monoclonal antibodies that use a slightly different MOA.

Lastly, there's one drug that's in development that we were looking at that looks like it has 2 different pathways toward addressing multiple sclerosis. So, exciting times in pipeline.

How could these emerging biologic therapies influence the positioning of existing MS treatments, particularly among high-efficacy DMTs already in use?

Moore: To be honest, I don't think it will affect it all that much. Yes, you will see patient share lost because more patients will use the newer drugs. But again, these drugs that are in development have novel MOAs. If a patient is already succeeding on a current treatment, physicians aren't going to switch them off unless there's a good reason for it. What these do is offer an option for new patients.

Additionally, because they're in a different class and have a different MOA, they're not really competing head to head with these drugs necessarily. Those drugs are competing with each other within class. The new drugs that are coming on will be taking some share, but I think it will be mostly from patients who are not responding to current treatment or patients who are newly diagnosed. That's what's going to be the impact of these new therapies.

Which biologic DMT candidates are generating the most attention in late-stage trials or real-world data—and how might they reshape clinical decision-making or access pathways?

Moore: We looked at 5 different drugs that are in development that are going to launch between this year and 2029. The ones that stand out to me are the BTK inhibitors. That's Sanofi's tolebrutinib and Roche's fenebrutinib, as well as a monoclonal antibody from Sanofi called frexalimab. We already have monoclonal antibodies on the market, but they target CD20. This new one will be targeting CD40L, so it's a slightly different drug. Those are the ones that stand out to me.

What I should point out with these emerging therapies, though, is that in addition to surveying payers and physicians, I do interviews with payers themselves to really dig deep on some of the Target Product Profiles (TPPs) and profiles for these drugs. They did point out some interesting things.

One of the things that stands out is that the data we have right now are just phase 2, so we don't really know exactly how effective these drugs are. They are in phase 3 development now, so they're in trial, but in many cases, they are either going to be pitted against placebo or a drug that's not standard of care. That creates hurdles. Payers don't know how good these drugs are because they can't really compare them head to head with what's considered the standard of care. Yes, they can do indirect comparison, but that just creates more fuzziness or more uncertainty with their analysis. That's how they're looking at the data.

What they're going to be doing is waiting for the drugs to get approved. They will almost certainly reimburse them because, as I mentioned before, if it's a novel MOA, they're going to reimburse it because they want to give physicians as much latitude as possible to prescribe what they need for their patients. In fact, that's exactly what the payers told us. They said, "We want to give them as much latitude as possible. We'll reimburse everything because we know this is a heterogeneous population."

They'll be waiting for the drugs to launch, they'll reimburse them, and then they will be tracking them through real-world evidence collection to see how well they work in real time, as well as, of course, their impact on—in addition to efficacy—adherence, to make sure the patients are staying on the drug. If patients are falling off the drug, they know there's probably a safety or tolerability issue that needs to be addressed.

What clinical, safety, or cost-effectiveness data should stakeholders—including payers and providers be watching as these therapies advance? Are there any signs of meaningful differentiation yet?

Moore: Not yet, as there have not been any signs of meaningful differentiation—for obvious reasons. As I said, these drugs are still in phase 2 trial, so we don't even have the comparative effectiveness yet, much less the cost effectiveness.

Payers are sensitive to costs. They tell us, of course, hospitalization is going to be a big key. That is something they will be tracking. If you can do any real-world evidence generation around that—preferably with an Integrated Delivery Network (IDN) or someone like that who has captive claims and electronic medical record (EMR) data—all the better, but it's really going to come down to the drug price.

I should point out that this is a highly contracted space. I believe the rebates are in the teens in many cases. They're going to be looking at the list price and then, of course, how they get the net price lower. Those are the areas that they're going to be focused on. We won't necessarily be doing a cost-effectiveness analysis, because even if you have the data, we don't live in a cost-per-quality world here in the United States. They'll be looking more around the net drug cost and, of course, any kind of budget impact, like I mentioned with the hospitalization.

What are the biggest challenges to integrating newer biologic DMTs into the MS treatment landscape, especially when it comes to formulary access, prior authorizations, or step therapy requirements?

Moore: There are going to be some hurdles. I should say that there are prior authorization (PA) rules in place; they typically are to label. That's not something that manufacturers need to worry about, because that's what your trial is for.

There are step therapy things in the sense that if a drug has gone generic, the payers are going to obviously prefer the generic, unless there is some sort of contract in place. If the physician does write the prescription for the brand and the generic is there, it'll be switched at the pharmacy. That's obviously something that currently exists.

Speaking largely, though, about the newer therapies, the challenge is that you already have a disease state where some of the current treatments have been on the market and trusted for years, and they're low cost because they have generics. You're competing against drugs that are extremely low cost, and those prices act as an anchor on payers' willingness to pay what they see as a drug's value. Here's the efficacy, is this new drug all that more effective than this generic we have right here where the price is so much less? That will become a hurdle to access, certainly.

That's going to mean that the new therapies will probably be placed on nonpreferred or specialty tiers. Payers can do that. If you put it on a specialty tier, you're looking at a co-insurance, and these drugs are not inexpensive. That's more cost on the patient. If there's more cost on the patient, that's going to lead to physicians saying, "Okay, I need this patient to actually take this drug and stay on this drug and adhere to it. I'll probably go with the lower-cost drug." That's going to create new hurdles.

Now, that's something that can be overcome. We do know that when it comes to the multiple sclerosis market, couponing is common, and that's, of course, legal in commercial insurance. That's something I'm sure these drug companies who have products in development are going to be instituting. That is something to look at. But the cost to patients is going to be a hurdle, particularly because we know it'll be put on a nonpreferred or specialty tier, especially if you have these low-cost drugs and generics that act as a price anchor in the minds of the payers themselves.

Is there anything else you hope the audience will take away from this?

Moore: One of the drugs that I'm looking at here is from Munich Therapeutics. I have not talked about it. It's called vidofludimus calcium. What is interesting here is that, with a lot of these drugs, the data the payers are looking at is going to be: Can it stop disease progression? Could it, ideally, reverse disease progression? Or does it affect the number of lesions?

One of the endpoints that they're monitoring for this upcoming phase 2 trial was an endpoint called serum neurofilament light chain levels. This is interesting. It sparked the interest of a payer that I was talking to. It would be nice if there were other endpoints besides number of lesions and disease progression that maybe can actually signal that this drug works that much faster than relying on these other endpoints.

I found that to be an interesting take. I know that, from the payer perspective, they're not going to say surrogate endpoints are great in and of themselves, you have to tie that to actual efficacy. That will be something that will be interesting to monitor over the years. I did think that was an interesting change when it comes to one of these therapies that's in development.