Real-world data continues to support the safety and effectiveness of Mavenclad (cladribine tablets) in treating multiple sclerosis (MS), and several studies underway will help scientists gain in-depth understanding of how Mavenclad works, its impact on the immune system, and the durability of its benefits, an executive with EMD Serono said in an interview.

Mavenclad, marketed in the U.S. by EMD Serono (known as Merck KGaA outside the U.S. and Canada), was approved by the U.S. Food and Drug Administration (FDA) in March to treat adults with relapsing forms of MS, including relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS).

The therapy is taken as two short treatment courses over two years. Each course consists of two treatment weeks, spaced one month apart, at the beginning of each treatment year.

Mavenclad’s approval was backed by findings from controlled clinical trials involving a total of 1,976 MS patients, followed for up to eight years. Data from these studies showed that more than half (58%) of those treated with Mavenclad had a significant reduction in relapse rates, compared with placebo, and that fewer experienced disability progression.

New real-world data and post-hoc trial analyses were presented at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) that concluded Sept. 13 in Stockholm.

Results to date, John Walsh, MD, vice president of U.S. medical affairs in Neurology & Immunology at EMD Serono, said in an interview with Multiple Sclerosis News Today, are “very consistent with what we saw in the clinical trials.”

Effectiveness and mode of action

As support, Walsh cited some of the real-world studies underway.

Data from one — CLARINET-MS, following 80 relapsing MS patients in Italy treated with Mavenclad in its pivotal trials— were presented at ECTRIMS. They showed that 57% of the patients analyzed had no new relapses, and 64% had no evidence of disability progression, five years after their last dose of Mavenclad.

John Walsh, EMD Serono’s vice president of U.S. medical affairs in Neurology & Immunology. (Photos by MS News Today)

Mavenclad is an immunosuppressant that works by reducing the number of certain immune cells, called lymphocytes (i.e., B-cells and T-cells), circulating in the blood. As a result, fewer of these immune cells are available to provoke inflammation and damage the nervous system.

This mechanism of action is “very unique from other therapies that are currently available for MS,” Walsh said.

Upon finishing a Mavenclad course, the number of lymphocytes in blood circulation drops. Afterward, there is a phase of reconstitution, or replenishment, of these cells — a process addressed in a poster presented at ECTRIMS, Walsh said.

Its data showed that 96 weeks after Mavenclad treatment, patients had higher levels of naïve B-cells but lower amounts of memory B-cells compared to patients on placebo, suggesting that Mavenclad causes the immune system to “shift towards an anti-inflammatory” state, its researchers wrote.

In other words, Walsh said, Mavenclad seems to work by “resetting” the immune system. “To say that [treatment is] resetting the immune system may be a step too far at this point in time; it might be a little over-reaching,” he said, adding that a fuller understanding of Mavenclad’s mechanism of action and its immune system impact is a company priority.

“We continue to generate data that will suggest what that reconstitution looks like. And in fact, this poster is one piece of that.”

EMD Serono has a number of studies ongoing into its action and likely reconstitution profile, which may better explain the durability seen with treatment, Walsh said.

He spotted a new U.S. study, called CLOCK-MS (NCT03963375; not recruiting yet), that will look at “key markers” in patients’ blood and cerebrospinal fluid to gain insight into the effects of Mavenclad on the immune system. This collaborative and co-sponsored study involves Greg Woo, MD, PhD, and Ann Cross, MD, both with Washington University in St. Louis.

“We’re really happy about this because people are often asking us what returns in that reconstitution phase,” Walsh said. “So again, to say we reset is probably premature. But as we develop more data, we’ll understand that more fully.”

Safety

A “very consistent” safety profile for Mavenclad, Walsh said, is evident in data from 8,400 patients examined in clinical practice (a real-world setting), and from the long-term safety study PREMIERE (NCT01013350). In other words, safety seen in practice and over the long-term matches that seen in clinical trials.

Common side effects of treatment include headaches, common cold symptoms, and lymphocytopenia (low white blood cell counts). The therapy is also associated with an increased risk of infections with herpes zoster (such as shingles or cold sores), and an increased risk of cancer.

“In clinical trials, we did see a very, very small numerical difference between infections in the cladribine [Mavenclad] group versus placebo, which were predominantly driven by a small increase of herpes zoster, where it was about 6% versus 2% in placebo,” Walsh said.

Concerning cancer, he emphasized the U.S. “boxed warning that speaks to the risk of malignancy, where the overall rate is 0.23 per 100 patient-years.”

So far, no differences in malignancy rates are evident in real-world compared to clinical trial data, “so we’re very confident that we’re capturing the right data” Walsh said, adding that people being treated in clinics will continue to be monitored to track the therapy’s safety profile.

Acceptance and support

In a recent report by Spherix — based on a survey of nearly 100 neurologists across the U.S. — Mavenclad was seen as likely first option for RRMS patients who failed an initial therapy. Currently, it’s advised for those who have had an inadequate response, or are unable to tolerate, another MS therapy.

“It’s certainly very interesting and exciting to hear that physicians … understand the potential benefit that Mavenclad can offer,” Walsh said of the report. “It matches much of what we see in the way of the utilization today, so we’re very encouraged by that.”

Regarding its acceptance by the medical and patient communities since its March approval, Walsh mentioned that “every time there is a new therapy that comes to market, the patient community becomes excited because it offers an extra option for them. We’ve certainly seen that with Mavenclad; we’ve definitely had interest … which has gradually been increasing over time since our launch.”

Another oral therapy, Mayzent, marketed by Novartis, was also approved by the FDA to treat relapsing forms of MS in March 2019. Although no head-to-head study has compared these two oral therapies, we asked Walsh about Mavenclad’s specific benefits or features that could influence people to choose it over Mayzent.

Merck’s booth at ECTRIMS 2019.

“It’s very hard to make an apples-to-apples comparison,” Walsh said, “but I really believe that the attributes that we see with Mavenclad is what will drive the interest and the reason for people to want to use it.”

One such attribute he emphasized, in addition to its “unique mechanism of action,” is Mavenclad’s short dosing schedule — 10 days in the first year, plus another 10 days in the following year. “For patients, I think that represents a paradigm shift in the way drugs are administered in MS today,” he said.

“We really believe that Mavenclad has a great benefit-risk profile, and [is] a great option for many patients.”

EMD Serono offers a support program in the U.S., MS LifeLines, that provides one-on-one assistance to people prescribed an EMD Serono/Merck therapy, including Mavenclad. The service answers questions related to a medication, and also helps patients navigate insurance coverage and payments.

Walsh said Serono is “very, very proud” of MS Lifelines, a service it’s “been doing it for about 16 years” and continuing to expand.

Looking ahead

Among ongoing studies of Mavenclad’s effectiveness and safety, Walsh highlighted CLASSIC-MS (NCT03961204), which will explore the long-term outcomes and the durability of Mavenclad’s effectiveness in people who participated in the pivotal ORACLE MS (NCT00725985), CLARITY (NCT00213135) and CLARITY extension study (NCT00641537).

CLASSIC-MS will help answer “what’s happened with those patients from the time that the trial ended until today?” Walsh said. “We want to understand what’s been their experience.”

Enrolled patients will be followed to assess changes in disability, and for possible genetic markers and disease biomarkers. “We really want to understand what the durability of effect could look like in many people well beyond the ending of our pivotal trials,” he said.

Two observational trials now enrolling in the U.S. — MASTER-2 (NCT03933202) and CLICK-MS (NCT03933215) — will study patients who switch to Mavenclad from another disease-modifying therapy, injectable or an oral. Its goal, Walsh said, is to establish a profile for such transitions and to “understand what does changing from one drug to another look like in this current environment.” Both are recruiting patients; information is available on their respective trial documents.

For EMD Serono, “the theme really is where does real-world evidence meets high science, and that’s our endeavor with this product moving forward,” Walsh said. “We know people have many questions, in particular, we’re very, very prudent about making sure follow on with safety and efficacy data.”

Merck and Serono are also developing a potential new oral therapy, called evobrutinib (also known as M2951). Two parallel studies — EVOLUTION-1 (NCT04032158) and EVOLUTION-2 (NCT04032171) — were recently launched to address its safety and efficacy, compared to Avonex (interferon-beta-1a), in relapsing MS patients. A first person was enrolled on Sept. 10, Walsh said.

“We’re excited about the possibility of bringing another new drug with a novel mechanism of action, having a BTK [Bruton’s tyrosine kinase] inhibitor on the market,” he said. The BTK protein is involved in the development and maturation of immune cells, particularly B-cells, which play a major role in driving inflammation in MS.

“We’re obviously committed to MS, and will remain in that space,” Walsh concluded. “All in all, we’re proud of where we are.”