Real-World Safety of Cladribine Matches Clinical Trial Development

Thomas P. Leist, MD, PhD

Using more than 250,000 person years (PYs) of exposure data, results from a recent analysis showed that the safety profile of cladribine (Mavenclad; EMD Serono), an FDA-approved medication for multiple sclerosis (MS), was consistent with findings from its clinical development program and previous safety updates. Encouragingly, cladribine did not show an increased risk of adverse pregnancy outcomes, further reinforcing its risk-benefit profile.¹

Presented at the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 28-31 in Phoenix, Arizona, the analysis examined adverse event (AE) rates in 251,900 PYs of exposure since the cladribine’s approval in 2017. Led by Thomas P. Leist, MD, PhD, division chief of Multiple Sclerosis/Neuroimmunology at Jefferson Health, PYs of exposure were estimated cumulatively (by quarter) from sales data using post-approval sources.

As of July 2024, the AE with the highest exposure adjusted reporting rate for cladribine treatment was hypersensitivity (1.13; 95% CI, 1.09-1.18), with 2858 reports. Other AEs observed were serious infections (0.50; 95% CI, 0.48-0.53; 1270 reports), herpes zoster (0.33; 95% CI, 0.31-0.35; 830 reports), liver injury (0.25; 95% CI, 0.23-0.27; 623 reports), malignancies (0.16; 95% CI, 0.14-0.17; 397 reports), serious lymphopenia (0.10; 95% CI, 0.09-0.12; 259 reports); seizures (0.06; 95% CI, 0.05-0.07; 160 reports); and tuberculosis (0.01; 95% CI, 0.01-0.02; 35 reports).

Cladribine is a unique medication, given at doses of 3.5 mg/kg over a 2-year period, with no additional treatment in years 3 and 4. In the analysis, there was a relatively small number of opportunistic infections other than progressive multifocal leukoencephalopathy (PML) and tuberculosis (0.02; 95% CI, 0.01-0.02), as well as no confirmed cases of PML. The lack of PML was in line with its previous safety profile, although caution is typically advised given its immunosuppressive mechanism.

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Leist et al also collected data on pregnancy outcomes in the analysis, identifying 474 pregnancies, 200 of whom had known outcomes. Of these, investigators recorded 127 live births without congenital anomalies, 36 spontaneous abortions, 30 elective terminations, 2 reports of ectopic pregnancy, 1 report of stillbirth with fetal defects, and 4 pregnancies resulting in live births with congenital anomalies. Those included 1 major anomaly of atrial septal defect and 3 other minor anomalies. Notably, the study authors relayed that the 5-year data was in line with the known safety profile as well, as cladribine-treated patients showed no new or unexpected AEs or risks.

Cladribine has been characterized as an effective disease-modifying therapy for MS, but requires careful patient selection and monitoring due to immune suppression risks. Contraindications for the medication include those with active chronic infections, a history of malignancy, and renal impairment. Some of the most common AEs have been lymphopenia, headache, nausea, and upper respiratory infections.

Since its 2017 approval, the drug has been evaluated in various research settings and trials. One study, also presented at CMSC 2025, showed that cladribine leads to low annualized relapse rates (ARR) after switching from prior injectable disease-modifying therapies (iDMTs). Known as the CLICK-MS study (NCT03933215), the observational, single-arm, phase 4 study showed that switching to cladribine led to a 24-month ARR of 0.02 (95% CI, 0.000-0.059), with at least 80.6% of patients remaining relapse-free over that period.²

Another phase 4 trial, CLARIFY-MS and its open-label extension (NCT04776213) highlighted the treatment benefits of cladribine on health-related quality of life and cognition in those with relapsing MS. In a 4-year period, investigators led by Andrzej Smyk, MD (Merck), compared changes from baseline and month 24 of the parent study. Among 265 patients, MSQoL-54 scores improved significantly in both physical (P = .003) and mental health (P < .0001) components with continued cladribine treatment. In addition, treated patients continued to show stable scores on various parameters of the Brief International Cognitive Assessment for MS, including Symbol Digit Modalities Test, California Verbal Learning Test, and Brief Visuospatial Memory Test-Revised.³

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REFERENCE
1. Leist TP, Yamout B, Harlow DE, et al. DMT42 - Post-Approval Safety of Cladribine Tablets in the Treatment of Patients with Multiple Sclerosis: 2024 Update. Presented at: 2025 CMSC Annual Meeting. May 28-31; Phoenix, Arizona. Abstract DMT42.
2. Katz J, Pace R, Miravalle A, Aldridge J, Chandler A. DMT19 - Real-World Effectiveness and Safety of Cladribine Tablets in Patients with Relapsing Multiple Sclerosis after Suboptimal Response to Prior Injectable Therapy. Presented at: 2025 CMSC Annual Meeting; May 28-31; Phoenix, Arizona. Abstract DMT19.
3. Langdon D, Brochet B, Havrdova EK, et al. P321. Improvements in Health-related Quality of Life and Preserved Cognitive Function in Patients With Relapsing Multiple Sclerosis: 4‑year Results From the CLARIFY-MS Extension Study. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT P321.