Mavenclad (cladribine) tablets stand out as a treatment for relapsing forms of multiple sclerosis (MS), providing two years of proven efficacy with a maximum of 20 days of oral treatment, a top executive with EMD Serono says.

After being approved in more than 50 countries worldwide, including the European Union, Australia, and Canada, Mavenclad is now also available in the U.S., following its March 29 approval by the U.S. Food and Drug Administration (FDA) for relapsing-remitting (RRMS) and active secondary progressive disease (SPMS).

These U.S. indications are less restrictive than in Europe, where Mavenclad is only indicated to treat highly active relapsing forms of MS.

“We’re really excited about the FDA approval,” John Walsh, MD, EMD Serono’s vice president of neurology and immunology, U.S. medical affairs, and interim head of North America medical affairs, said in an interview with Multiple Sclerosis News Today. “This is a great time not only for EMD Serono but most importantly for patients, and we’re really, really proud to offer this therapy because it’s the only short-course oral treatment where physicians can treat patients with RRMS as well active SPMS.”

Mavenclad is given in two treatment courses of two weeks each, separated by approximately one year. In each course, the patient receives eight to 10 tablets, for a maximum of 20 tablets over two years. The exact number of tablets a patient receives depends on his/her body weight, with a targeted cumulative dose of 3.5 milligrams per kilogram.

Due to its safety profile, Mavenclad is recommended for patients who failed to respond or were unable to tolerate other MS treatments.

“We really believe that making sure that patients and prescribers have options that fit the needs of different patients is important, and we think that Mavenclad certainly can offer options to people who may be looking for different therapies,” Walsh said.

Different measures supporting efficacy

The safety and efficacy of Mavenclad were evaluated in Phase 2 and 3 trials in more than 2,700 relapsing MS patients, some of whom were followed for more than 10 years.

Pooled data from Phase 3 trials — CLARITY (NCT00213135), the CLARITY extension study (NCT00641537), and ORACLE-MS (NCT00725985) — revealed that Mavenclad provided a 58% reduction in the annualized relapsed rate (the number of confirmed relapses per year) compared with a placebo.

In addition, 81% of Mavenclad-treated patients remained free of relapses over the following two years, compared with 63% of patients in the placebo group. Treatment with Mavenclad was also associated with a lower risk of developing new brain lesions or aggravating existing ones, as well as a 33% reduction in confirmed disability at three months.

But in patients with high disease activity taking part in CLARITY, the reduction in relapses was even more significant — 67% compared with placebo. These patients also had an 82% lower risk of six-month confirmed disability progression versus placebo, according to Walsh, more than the 47% difference seen in the overall study population. These benefits continued throughout the third and fourth year.

In CLARITY — which included 1,326 patients with relapsing MS — high disease activity was defined through clinical and radiographic measures, namely by having two or more relapses in the previous year regardless of receiving another disease-modifying therapy, or at least one relapse and an increased number of brain lesions while on treatment at the beginning of the study.

The team conducted further analyses in groups with Expanded Disability Status Scale (EDSS) scores below 3 or above 3.5, which is the cut-off supported by several MS studies as indicating the transition from RRMS to SPMS, Walsh said.

Patients with a score greater than 3.5 — which generally refers to those with difficulty walking and moderate to significant disability — had a 57.1% relapse reduction relative to placebo, according to Walsh. This group also showed a greater proportion of patients with no evidence of disease activity — NEDA, which means no relapses, evidence of disease activity, or new or active lesions — relative to the overall CLARITY population (48.6% vs. 44%).

Altogether, these benefits seen in clinical and imaging measures make the company “pretty confident” about Mavenclad’s efficacy, Walsh said. This efficacy, combined with a 20-day maximum dosing period over two years, “is something that helps differentiate Mavenclad,” he added.

Understanding benefits versus risks

Mavenclad’s approval in the U.S. was not straightforward. EMD Serono, known as Merck KGaA outside the U.S. and Canada, filed an initial submission in 2008, but the FDA considered its information insufficient. Then, an application in 2011 was rejected, with the agency requesting a better understanding of the treatment’s safety risks and the overall risk-benefit profile.

In its latest — and ultimately successful — application, EMD Serono filed more than 12,000 patient-years of data from its Phase 3 trials, as well as from a registry study called PREMIERE (NCT01013350) and from the ONWARD Phase 2 trial (NCT00436826). “We’ve put a lot of work into doing further analyses,” Walsh said.

Regarding safety, data from CLARITY showed that the most common adverse events associated with Mavenclad included upper respiratory tract infections, with the difference from placebo being driven by herpes — experienced by 6% of patients on Mavenclad and 2% of those on placebo.

Other frequent side effects were headaches and low white blood cell counts, or lymphopenia. “Clearly, lymphopenia was expected given that that’s how the mechanism of the drug works,” Walsh said.

Specifically, Mavenclad exerts its effects by reducing the number of immune B-cells and, to a lesser extent, T-cells, in the bloodstream, two types of lymphocytes that cause nerve degeneration in MS. “We believe that this could be the factor that contributes to [its] overall clinical efficacy,” Walsh said.

Lymphocytes are depleted within two to three months after each treatment cycle, but their levels ultimately return close or back to normal, according to Walsh. This gradual cell repopulation could help explain Mavenclad’s efficacy beyond the immediate dosing period, he said, although more needs to be known about its mechanism of action.

In addition, due to the reconstitution of B- and T-cells, “very few, if any, patients should have any persistent lymphopenia based on the data that we see at this time,” he added. Still, the FDA recommends monitoring the levels of lymphocytes and using anti-herpes prevention if they fall below 200 cells per microliter.

Serious adverse reactions found in CLARITY included the occurrence of malignancies (0.27 per 100 patient-years), and infections by herpes zoster (shingles; 2%) or oral herpes (2.6%). This increase in herpes zoster was still observed in post-marketing results in Europe, but was mild and well-resolved, “which is very reassuring,” Walsh had said in a previous interview.

All treatment risks associated with Mavenclad, including malignancy and fetal harm, are found in a boxed warning on the product label.

“We had a great opportunity to work closely with the FDA and add a label that we believe informs patients and prescribers about what the risks and benefits of the product are, Walsh said, adding that the FDA approval “really speaks to the fact that the benefit does outweigh the risks.”

The company encourages doctors and patients to discuss the treatment’s efficacy and its safety concerns.

“We remain very committed to making sure that we educate on safety, as pointed out on our label, and most importantly, we remain committed to better understanding of that,” he said.

Transitioning between therapies

Similar to other companies in the MS field, EMD Serono is working to understand how best to transition between different therapies. The company is conducting a trial called CLASSIC-MS, which will be assessing patients who took part in the company’s pivotal studies and switched from Mavenclad to other options.

The team will also conduct Phase 4 studies looking at patients who made the opposite switch — from other therapies to Mavenclad.

According to Walsh, EMD Serono already has data from patients who transitioned to Mavenclad, but these trials were conducted about 10 years ago, which means they do not cover a substantial number of treatments made available in the meantime.

“Just like most of the other therapies today, [we] don’t have complete conclusive evidence, but we certainly know that we have some and we’re developing more,” Walsh said.

In parallel, the company is addressing requests from the FDA asking for additional data on the therapy. One study will assess drug-to-drug interactions, namely with contraceptives. Another will address the risk of malignancy over time, “something the company continues to be very vigilant about watching and making sure that we characterize,” Walsh said.

Details on the studies’ design and when they will start will be defined during the company’s ongoing dialogue with the FDA. A study in pediatric patients is not part of current plans at this point, according to Walsh.

EMD Serono will also work on a pregnancy registry, which is “pretty standard with many MS products,” Walsh said, although Mavenclad is not recommended for pregnant women. Effective contraception is also advised for six months after each treatment course.

Mavenclad’s value proposition

Mavenclad comes in at an annual list price of $99,500 in the U.S., while current prices in the EU and countries such as Canada and Australia are lower or include discounts. But Walsh cautioned against direct price comparisons, saying that the U.S. system is “quite complex” due to differences between insurers, and the fact that discounts and rebates are negotiated on an individual basis with payers.

Making sure that patients have access to Mavenclad is a major priority for the company, Walsh said. Express Scripts added the therapy to their national formula industry for approval, representing coverage for a large number of patients in the U.S.

“We’re pleased that an industry leader like Express Scripts would recognize the value of the product and understand how it could benefit their patients,” Walsh said.

Ultimately, coupling Mavenclad’s price with not having to take a single tablet for almost one year “is where payers will need to decide what the value proposition looks like,” he added.

To provide assistance to MS patients, MS LifeLines, EMD Serono’s U.S. patient support program, will be expanded to include Mavenclad. The program, which currently includes Rebif (interferon beta-1a), offers personalized support “in navigating questions that [patients may] have clinically or around reimbursement, for instance,” Walsh said.

Additional data on Mavenclad will be presented at the upcoming 2019 American Academy of Neurology Annual Meeting May 4–10 in Philadelphia, he said.