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What’s Next in MS Care: Guidelines & Pipeline Disclosures

My name is Patricia Coyle. I'm a Distinguished Professor of Neurology, Vice Chair for Academic Affairs and Head of the MS Comprehensive Care Center at Stony Brook University on Long Island in New York. I'm delighted to be here with you.

AAN Guidelines: Initiating DMT

In 2018, the American Academy of Neurology, AAN, put out their guidelines on use of the disease‑modifying therapies. It would be great, I think, if they updated them on a regular basis, that's not being consistently done. So the AAN guidelines that were put out for concepts to really be pertinent to initiating a DMT for the first time is they endorsed access to all the approved DMTs, not limited access.

It is so important to get on the right DMT that it should be discussed at a dedicated visit for initiating a disease‑modifying therapy, choosing and then initiating it. They said you need to use shared decision making with the patient, that it's an ongoing dialogue about the optimized treatment, that the subject with MS had to have realistic expectations. You're not expected to get better. It's not expected to treat a symptom. The disease‑modifying therapy is invisible therapy in that it's designed to minimize future damage to the central nervous system. So you don't want somebody going in with the expectation, this is going to make me better, this is going to reduce my fatigue, this is going to reduce my pain issue. Those are not realistic expectations. It could happen, particularly with some of the high dose treatments, but that's never an expectation. They have to really appreciate, is this patient ready for treatment, ready for following the schedule of how they're going to be evaluated?

And then you really want to focus on counseling on the importance of identifying comorbid conditions and optimize management of them, avoiding or getting rid of adverse health choices like not smoking, not vaping and any drug interactions. And then evaluate and counsel on the importance of adherence, that once the patient chooses the treatment, they should really continue it. These are all key things to analyze in initiating a disease modifying therapy.

Treatment Issues: Treatment Naive

And in a treatment ‑naive individual, issues that come up are obviously the education and expectation is very important, the shared decision-‑making, high efficacy is to be encouraged. The data is accumulating that using a high efficacy early is the best thing to avoid late disability. You really want to treat to target concept. What's going to be unacceptable? What will raise the possibility of making a switch? It does take a little bit of time for any new DMT to be fully operational. I will generally counsel patient on 8 to 10 weeks. 8 to 10 weeks, that it's not fully operational initially and so there may be some disease activity during that early time. And you want to spell out the monitoring plans and make sure that the patient understands them and will buy into that, and that's for their own safety and being able to do a risk benefit analysis on a regular basis.

AAN Guidelines: Switching DMT

With regard to switching a disease‑modifying therapy, the AAN guidelines also made statements on that. They said if you're on a treatment for a year or more and there's one or more clinical attacks, or there's the development of disability worsening on the neurological exam, or you have two or more new MRI lesions form, not in that immediate period but later on, that should trigger a discussion about switch. So it's very interesting. They said if there's one or more clinical attacks, you should discuss the possibility of switching your disease-‑modifying therapy. If the patient is worsening on their neurological exam, you should discuss the potential of switching their DMT. And if they have two or more lesions, so they didn't say one lesion, okay, they said two or more lesions that might trigger doing the surveillance MRI scan sooner than annually, let's say, that should trigger a discussion about switching.

When you're switching for breakthrough activity you need to consider how active is the MS. Is the patient adhering to it? What is the adverse event profile and mechanism of action?

Other reasons for switching might be needle fatigue. Somebody might might say, I've been doing fine on my immunomodulator, but I'm tired of the needle. I would like to make a switch from that. And that would be a valid reason to consider switching. Or medication adverse events or persistent laboratory abnormalities might – might come up.

You want to counsel on PML risk, on infection and malignancy, maybe things that immunosuppressing an individual can be increased. On somebody on natalizumab, you're typically doing a JC virus antibody index at a regular interval. We do it every three months. And if the patient seroconverts, then there needs to be a new risk-‑benefit analysis on their personal risk of PML and what do they want to do. And there are certain agents that rebound, this is fingolimod and this is natalizumab. So when you come off, you have to get them on a new treatment pretty quickly because there's the possibility of a temporary rebound with increase in activity. These are all considerations.

Treatment Issues: Switch

So when we're talking about treatment switch issues the reason for switch matters, particularly if there's breakthrough activity, because that's potentially damaging the patient and that is potentially setting them on a future course. Listen, when we start treating MS, we can't cure the disease. It's a lifelong disease, but we can see a change in MS. In the pre‑treatment era, it was a Russian roulette. You didn't know who was going to be bad, who was going to wind up in a wheelchair, etc. In the post‑treatment era, I think we can tell people if we get to you quickly, if you follow a healthy lifestyle, if you get on a high ‑efficacy agent, we can keep you out of a wheelchair. You can have a normal life. I really do believe that that's something that we can tell people, but they have to be cooperative and buy in.

So breakthrough activity is a key reason to switch. Needle fatigue, valid. A change in the risk‑benefit ratio. Pregnancy issues, valid. Tolerability and laboratory abnormality.

If the breakthrough activity is the cause for the switch, then really you want to move to a new mechanism of action and a higher efficacy agent. You should be moving to a higher efficacy agent in that case.

Treatment Issues: Switch

So let's – let's talk about what's becoming available. And let's start with the BTK inhibitors.

The BTK inhibitors are oral agents that have been proposed as treatment for relapsing MS and also progressive MS. All the BTK inhibitors being studied in MS have been CNS penetrant. So they can target microglia and B‑cells within the central nervous system, as well as B‑cells and monocytes and macrophages outside the nervous system.

The first BTK inhibitor to report out was evobrutinib, and it reported on two completed phase III trials that were identical trials in relapsing MS.

The next to readout was tolebrutinib, once a day BTK inhibitor that read out on two identical phase III relapsing trials and one phase III non‑active secondary progressive trial, and they have just completed preliminarily their phase III primary progressive trial.

Fenebrutinib is the third one that has just given preliminary data on one completed phase III relapsing trial and their completed phase III primary progressive trial.

And then we have remibrutinib, which is ongoing in their phase III relapsing trials.

Orelabrutinib, which has primary progressive and secondary progressive MS trials planned.

And BIIB091 that has a small combination study with dimethyl fumarate and a BTK inhibitor. So let's talk a little bit further.

How Could BTKi Be Used?

How could you use a BTK inhibitor? Well you could propose it as monotherapy to treat MS, particularly if you have progressive MS or prominent PIRA, progression independent of relapse activity. You could propose using a BTK as a follow up therapy after you had them on presumably a high efficacy relapsing component for a finite period of time, and it seemed like the relapsing focal ‑inflammatory component of the disease was well controlled. Or you might use it as combination therapy with a DMT for the relapsing component to treat both pathologies simultaneously. And that very small study with dimethyl fumarate is doing that. You'd have to have a study for combination therapy quite, quite frankly.

Evobrutinib

Well, the bottom line was that the two phase III evobrutinib relapsing trials failed. Why did they fail? Evolution Relapsing MS 1 and 2 entered 2,290 relapsing patients, and they were randomized to oral BTK inhibitor evobrutinib or oral teriflunomide. So teriflunomide was chosen as an oral agent to treat relapsing MS, and the primary outcome had to show superiority for the BTK inhibitor in suppressing relapses compared to teriflunomide. It didn't. They both had a really low relapse rate, 0.15 versus 0.14 in one relapsing trial, and 0.11 for both arms in the other relapsing trial. That's a pretty good annualized relapse rate. That's one attack every, you know, 8 to 9 years there.

But to be positive, the BTK inhibitor had to beat teriflunomide. It didn't. So this was a negative study. It was a negative study. The primary outcome was not met and so the other outcomes really had no impact. But we'd say that you didn't see better suppression of contrast lesions or new or enlarging lesions, you really didn't see much of a difference between the two arms or in the development of disability. And as a result, evobrutinib was abandoned and is not going anywhere.

Tolebrutinib Phase III Trials

These are the tolebrutinib studies, the HERCULES phase III secondary progressive trial, Gemini 1 and 2 phase III relapsing trials, and just reporting out on PERSEUS, which is the phase III primary progressive trial against placebo.

HERCULES Primary Endpoint: Time to 6‑Mo CDP

So this is the HERCULES primary endpoint. It was positive. This was a time to six month confirmed disability progression, 31% risk reduction with the BTK inhibitor versus placebo. So this was a positive primary outcome. And that's exciting because we don't have a lot of phase III positive progressive trials. This was a positive study in slowing progression in secondary progressive MS.

HERCULES: Liver Safety

Now, there were liver issues, liver enzyme issues. So what they found, it was in a small percentage, 0.5%, but they had 0.5% of the BTK inhibitor cohort compared to the placebo cohort that had greater than 20‑fold ALT in the upper limits of normal. That occurred in the first 90 days and then when you stop the drug, most resolve without any sequelae at all. So this is an adverse event signal that the FDA and the company are wrestling with at the current time. I think the proposal has been to check weekly liver enzymes for the first 90 days for this treatment. Remember, this BTK inhibitor is not on the market at this point in time, they're negotiating with the FDA.

GEMINI 1 and 2 Key Secondary Endpoint: Time to 6‑Mo CDW

What was interesting was the relapsing trials. GEMINI 1 and 2 did not show a significant difference between this BTK inhibitor and teriflunomide. So that particular primary outcome was negative in the phase III relapsing trials.

However, if you looked at time to six month confirmed disability worsening in this relapsing cohort, the line separated in favor of the BTK inhibitor, in favor of the BTK inhibitor versus teriflunomide. Okay, so it kind of gave support for the concept that if this is worsening due to PIRA, even though it's a relapsing population, the BTK inhibitor performed better than teriflunomide, so that was like a pretty good sign that there was a real impact on progression in this CNS penetrating agent.

Initial Tolebrutinib Assessment

Now, what have they said about the phase III primary progressive trial? And this will be presented at the next big MS meeting in Athens coming up in a few weeks. This is PERSEUS, a phase III trial where tolebrutinib for placebo was evaluated. And we've heard that the primary outcome in slowing progression was not met. Not met. They are applying to the FDA for approval for tolebrutinib for non‑relapsing secondary progressive MS and those negotiations are ongoing. So we'll need to take a wait to see, to see what happens.

Fenebrutinib Phase II Conclusions

Fenebrutinib has also conducted a phase II trial that was quite good. The open label extension went out to 48 weeks. It really knocked out MRI activity. This is the fenebrutinib BTK inhibitor study. You saw very little in the way of clinical or MRI activity out to the open label extension.

12‑Wk CSF Fenebrutinib Impact Chronic Progressive MS

In the phase II trial, they looked at fenebrutinib levels in spinal fluid and found them elevated above the Ic50 and Ic90. So this is really documented to be a CNS penetrant treatment.

Fenebrutinib Phase III Trials

So what happens with the phase III fenebrutinib trials? They've just announced, they've not shown the data, that one of the two phase III relapsing trials ended and was positive in that fenebrutinib, this BTK inhibitor, was able to show a significantly better relapse rate decrease compared to teriflunomide. The second phase III relapsing trial is ongoing and will read out this year.

Secondly, they talked – they had a phase III primary progressive trial where PPMS was – was randomized to the BTK inhibitor or ocrelizumab. Okay. And they said that the BTK inhibitor was – was statistically not inferior to ocrelizumab and might have been, quote, “numerically better from week 24 onward”. They'll be presenting the actual data at this next meeting, so people are eager to hear about that.

Orelabrutinib in MS

Orelabrutinib has committed to phase III trials in both primary progressive MS and secondary progressive MS, showing the need for really seeing and getting treatments for progressive MS.

Open Questions

So some open questions about the BTK inhibitors. Will tolebrutinib be approved for non‑relapsing SPMS? For fenebrutinib, will the second relapsing MS trial also be positive in beating teriflunomide and how impressive will the primary progressive data be? Could the oral agent be as good or better than ocrelizumab for PPMS? How much will class related early liver issues be a factor? Remibrutinib has been approved for chronic spontaneous urticaria, this will read out around April in the phase III relapsing MS trials, but it's already on the market for a different disorder. And that small fusion study is testing combination therapy with an oral DMT and a BTK inhibitor. So stay tuned, that's going to be coming out in this area.

Frexalimab

Frexalimab is another new treatment being developed. It's a second generation monoclonal antibody that binds to CD40 ligand. It disrupts that costimulatory pathway, affecting both adaptive and innate immune responses that are responsible for a number of things. They had a positive phase II trial that shut down clinical and MRI disease activity very well. There are ongoing phase III trials in relapsing MS, FREXALT, and non‑relapsing secondary progressive MS, FREVIVA. This is given intravenously on a monthly basis. Brand new treatments, so we'll see what the data shows, that is being tested in relapsing and non‑relapsing secondary progressive MS.

Summary

So to summarize, early disease‑modifying therapy is strongly supported, particularly for relapsing forms of MS. The data is accumulating on that. If you're going to use a high efficacy therapy, probably should use it very early on if you decide that that someone deserves to be treated, and virtually all active MS patients should be on a disease‑modifying therapy, in my opinion.

People need to be closely followed on their therapy and they need to follow the program of surveillance, MRI scan typically done once a year in the first couple of years, and regular blood work that's done in a routine that should be discussed up front.

Again, accumulating data really says use high efficacy early, don't start with mild efficacy and then need to move up. You get the best results if you use that high efficacy agent early.

It's clear that we need better detection of progressive MS and better therapies for progressive MS. So we have ocrelizumab approved for primary progressive MS. We're looking to, I think right now, the BTK inhibitors to maybe see if we're going to get some agents that penetrate the CNS, that are impacting on the activated microglia in a positive fashion. And would they be available to treat progressive MS?

Then you need to identify early on, I mean, ideally before you have the clinical progression features, this is a patient that's at risk for going into or developing progressive disease. I need to get them on a treatment. I need to be treating them right now. So we need better detection of progression and better therapies for it. And this is a big research emphasis now.

And of course, don't forget CNS repair strategies. To have better recovery or to improve fixed deficit would be a wonderful thing, not being driven just by MS, but by virtually every major neurologic disorder and neurologic type of insult, you really want and need CNS repair strategies.

Thank you very much.