The EMD Serono therapy’s resubmission was accepted after a 2011 CRL, with the new NDA supported by the findings of a 5-study clinical development program.
Belén Garijo, MD, PhD
The US Food and Drug Administration (FDA) has accepted the resubmission of a New Drug Application (NDA) for cladribine tablets (Mavenclad, EMD Serono) for the treatment of patients with relapsing forms of multiple sclerosis (MS).
The therapy has been approved in 38 countries as of this filing. Originally, EMD Serono received a Complete Response Letter (CRL) from the FDA in 2011, with the agency requesting additional data to better inform it about the safety risks and the overall risk-benefit profile.
"We are delighted the FDA has accepted cladribine tablets for filing," said Belén Garijo, MD, PhD, a member of the Executive Board and CEO Healthcare of Merck KGaA, EMD Serono’s parent company, in a statement.1 "Our goal is to offer cladribine tablets to patients and physicians in the U.S. as a new treatment paradigm for relapsing MS, and we look forward to working closely with the FDA throughout the review process."
The therapy was accepted based on data from a large clinical development program consisting of 5 studies: CLARITY, a phase III trial of the tablets as monotherapy in patients with relapsing-remitting MS (RRMS), and its extension study, CLARITY EXT; ORACLE MS, a phase III trial of cladribine tablets in patients at risk of developing MS; ONWARD, a phase II trial testing the therapy in those with relapsing forms of MS who have experienced breakthrough disease while on established ß-interferon therapy; and PREMIERE, a long-term follow-up study of the therapy’s safety in patients with MS who participated in the program’s studies.
In total, the clinical trial program consisted of 12,000 patient-years of data from more than 2700 patients, with a total of follow-up of up to 10 years in some patients.
CLARITY, a 2-year trial, consisted of 1326 patients, randomized 1:1:1 to receive either 3.5 mg/kg (n = 433) or 5.25 mg/kg (n = 456) of cladribine, or placebo (n = 437) for 96 weeks.2 Among those that received either the 3.5 mg/kg or 5.25 mg/kg dose of the intervention, there was a significantly lower annualized rate of relapse than the placebo group—0.14 and 0.15, respectively, compared to 0.33 (P <.001 for both). Additionally, both doses were associated with a higher relapse-free rate (79.7% and 78.9%, respectively) than placebo (60.9%; P <.001 for both), and a lower risk of 3-month sustained progression of disability (3.5 mg hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02; 5.25 mg HR, 0.69; 95% CI, 0.49 to 0.96; P = .03). Brain lesion counts were reduced on magnetic resonance imaging (MRI) as well (P <.001).
In ORACLE MS, the therapy was tested in a group of 616 participants, also randomized 1:1:1 to either 3.5 mg/kg (n = 206) or 5.25 mg/kg (n = 204) of cladribine, or placebo (n = 206) for a 2-year study period.3 At trial termination, the therapy was associated with a risk reduction of clinically definite MS with a HR of 0.38 for the 5.25-mg dose (95% CI, 0.25 to 0.58; P <.001) and a HR of 0.33 for the 3.25-mg dose (95% CI, 0.21 to 0.51; P <.0001) in comparison to placebo.
The effects of cladribine were similar in the ONWARD study, which randomized patients to 3.5 mg/kg cladribine plus interferon-ß (n = 124) or placebo plus interferon-ß (n = 48).4 Ultimately, the trial revealed that patients with active relapsing MS, despite treatment with interferon-ß, were 63% less likely to have a relapse than the placebo group (relative risk, 0.37; 95% CI, 0.22 to 0.63; P = .001). Additionally, T1 gadolinium-enhancing lesions were 95% less likely to increase with the therapy and combined unique active lesions were 59% less likely to appear.
In CLARITY, the most commonly reported adverse event (AE) in patients treated with cladribine was lymphopenia, which occurred in 48.3% of patients in the intervention arm compared to 42.5% of patients given placebo, with 99.1% to 99.0% of them rated mild-to-moderate by investigators, respectively. This finding was similar in both ORACLE MS (5% of the 5.25-mg group, 2% of the 3.5-mg group) and ONWARD (40.3% with therapy compared to 0% with placebo).
"Most available MS therapies require continued, regular dosing of medication. A treatment approach consisting of short, infrequent oral treatment cycles may help lower the treatment burden for patients," said Thomas Leist, MD, PhD, Director of the Comprehensive Multiple Sclerosis Center at Jefferson University Hospitals. "Based on additional clinical research in recent years, we know more about the treatment course, safety, and impact of cladribine tablets across several key measures of MS and hope it will be made available to the U.S. MS community."
1. FDA Accepts File for Cladribine Tablets as Potential Treatment for Relapsing Forms of Multiple Sclerosis [press release]. Rockland, MA: EMD Serono; July 30, 2018. prnewswire.com/news-releases/fda-accepts-file-for-cladribine-tablets-as-potential-treatment-for-relapsing-forms-of-multiple-sclerosis-829471781.html. Accessed July 30, 2018.
2. Giovanni G, Comi G, Cook S, et al. A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis. N Engl J Med. 2010;362(5):416-426.
3. Leist TP, Casset-Semanaz F, Scaramozza M, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomized trial. Lancet
4. Montalban X, Leist TP, Cohen BA, et al. Cladribine tablets added to IFN-β in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neruoinflamm. 2018;5(5):e477.