Details Behind the Phase 3 MyClad Study of Cladribine in Myasthenia Gravis

Henry Kaminski, MD

Identifying effective disease-modifying therapies for neurological diseases remains an important challenge in drug discovery and development. Drug repurposing attempts to determine new indications for pre-existing compounds and represents a major opportunity to address this clinically unmet need. While there has been significant expansion in the available options for patients with myasthenia gravis (MG), the field is still trying to identify new treatments for those who’s disease may not be adequately controlled.

At the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, a poster presentation focused on a new phase 3 study assessing cladribine (Mavenclad; EMD Serono), a previously approved therapy for multiple sclerosis, in MG. The study, a 3-year, double-blind, placebo-controlled trial, plans to recruit 240 participants to better understand the meaningful clinical benefits of cladribine in this patient population. Like many MG trials, it will use change in Myasthenia Gravis-Activities of Daily Living as the primary end point, observed over a 24-week period.

During the meeting, NeurologyLive® sat down with lead investigator Henry Kaminski, MD, to overview the unique style of the trial and how its conducted. Kaminski, the Meta A. Neumann Professor of Neurology at George Washington University, spoke on the idea behind testing cladribine in MG, including those seronegative subtypes of the disease. He laid out some of the main points of the trial, and how it speaks to the progress made in treating MG over the past decade.

NeurologyLive: Why do we believe that cladribine can be an effective medication for myasthenia gravis?

Henry Kaminski, MD: Yeah, well, some obvious reasons, right? Myasthenia gravis is B cell-mediated, but it also requires T cell help. So what does cladribine do? It inhibits DNA synthesis in rapidly activating cells, like B cells, and it also seems to have effects on T cells. From a biological standpoint, one would think this agent should be effective. Plus, we already have some background with it from its use in multiple sclerosis, so we’re not going into this blindly. That’s the rationale.

Anecdotally, what have we seen about cladribine’s use in myasthenia gravis?

I haven’t had personal experience with it, but there’s been an open-label study in fairly treatment-resistant patients, and it showed some efficacy. So, you know, that gives us even more human rationale to use the drug.

What does the trial design look like?

I think that's another interesting part of this. Many clinical trials in myasthenia gravis have been restricted to antibody-positive patients, and for good reasons in some cases, but here it’s open to AChR-positive, MuSK-positive, and even seronegative patients—although the seronegative group will be very strictly defined. But, you know, we understand that the underlying pathophysiology in all these cases involves B cells and T cells, and that’s where the drug will likely work.

In terms of the trial design, it’s pretty cool. There’s a first phase with two drug doses and a placebo, and they’ll do a 24-week readout using the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, which is standard in clinical trials now. But then there’s a blinded extension period, where those on placebo will get randomized to one of the two drug doses. So if you're a patient coming into the trial, you’ll know that at some point you’ll get the active drug, which is an advantage.

Then, patients who got the active drug will be followed, so we’ll get an idea of how long the drug acts. And that’s not the end. There’s also an open-label extension where patients can be re-dosed and monitored, so we’ll have a much clearer picture of how this drug works in the long term and how it can fit into regular clinical practice compared to other treatments. I really like how thoughtfully this has been developed over time.

What is the significance of having seronegative patients included in the study?

I think it's a frustration for patients with seronegative myasthenia that they usually can’t participate in clinical trials, right? So, it’s good for our patient population to see that we care about them too. And with the way this medication works, we have a good idea that it should help seronegative patients. We have effective ways to confirm the diagnosis there—like single-fiber EMG and repetitive nerve stimulation. These patients have already been seen by experts and look like they have myasthenia gravis, so we can be confident we’re treating actual cases of seronegative myasthenia. Hopefully, in the end, we’ll have a drug approved for this group that’s not otherwise being overlooked. This is a rigorous trial that can properly evaluate the medication in this population.

How does this trial speak to the progress in treating patients with myasthenia gravis?

That’s a complicated question. Ten years ago, we wouldn't be having this conversation. There are exciting new agents now—like FcRn inhibitors and complement inhibitors—which are really promising, but we’re not there yet. Some patients, even in my own practice, don’t respond to these agents, but we know a lot more about the disease mechanisms now, thanks to investigators who have been working on this since the 1970s.

For pharmaceutical companies and startups, it's exciting to see myasthenia gravis becoming more of a focus, and this could extend to other autoimmune diseases. That said, it’s frustrating that these drugs are expensive, and there are issues with access. Many patients can’t get these drugs or face long waits for insurance approvals. It’s also tough to see the heavy marketing of these agents—to both doctors and patients—when not everyone can benefit from them yet.