Phase 4 CLADRINA Data Supports Transition From Natalizumab to Cladribine in Multiple Sclerosis

Olaf Stuve, MD, PhD

(Credit: UT Southwestern)

New 2-year data from the phase 4 CLADRINA study (NCT04178005) showed that transition to cladribine (Mavenclad; EMD Serono) within 4 weeks of their last infusion with natalizumab (Tysabri; Biogen) was safe among patients with relapsing multiple sclerosis (RMS), with patients showing stable disease progression and no progressive multifocal leukoencephalopathy (PML) or rebound disease activity.¹

The trial featured 40 patients with RMS, with a mean age of 41.3 years (SD, 10.2) at baseline, and a mean time of 12.2 days (range, 3.0-27.0) between natalizumab discontinuation and cladribine initiation. Presented at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida, investigators observed a reduction in annualized relapse rate (ARR) between baseline (0.10; 95% CI, 0.00-0.22) and 12 months (0.03; 95% CI, 0.00-0.08) following the transition to cladribine tablets, which persisted over 24 months.

Led by Olaf Stuve, MD, PhD, a professor of neurology at UT Southwestern Medical Center, the thought process behind the study was that a rapid transition from natalizumab to cladribine might reduce the risk of disease rebound from natalizumab, and may lead to sustained disease remission by depletion of encephalitogenic lymphocytes. In addition, as cladribine tablets have no association with PML, this particular transition might normalize patients’ PML risk.²

Natalizumab, a monoclonal antibody that blocks a4-integrin, was first approved in 2004 for RMS; however, it was temporarily withdrawn in 2005 because of cases of PML, a rare but serious brain infection. A year later, the therapy was reapproved with strict monitoring programs to manage PML risk. Cladribine, a lymphocyte-depleting oral treatment, is considered a convenient, short-course option with long-lasting effects for patients with RMS. It was originally approved for cancer, but later had its indication expanded to include patients with relapsing-remitting MS and active secondary progressive MS.

READ MORE: Phase 4 Study to Test Switch From Anti-CD20 Therapy to Ozanimod in Stable MS

At baseline, the median Expanded Disability Status Scale (EDSS) score was 2.3 (range: 0.0–5.5) and remained stable at 2.0 (range: 0.0–6.0) after 24 months. Among patients with RMS, 97.5% were free from T1 gadolinium-enhancing (Gd+) and new/enlarging T2 lesions at baseline, with 100% remaining free of T1 Gd+ lesions and 88.9% free of T2 lesions at 24 months. The overall MS disease activity score (MSDA) was either unchanged or improved following the switch from natalizumab to cladribine tablets across all assessed time points.

In terms of safety, the most common drug-related adverse events (AEs) were upper respiratory tract infection (12.5%), nausea (10.0%), and headache (7.5%). As mentioned, there were no cases of PML or rebound disease activity, and investigators concluded that cladribine was well-tolerated following the transition.

Previous studies on the transition from natalizumab to cladribine tablets have primarily been based on expert opinion or retrospective reviews. Research by Hersh et al. reported sustained disease activity for up to 24 months after natalizumab withdrawal, even with high-efficacy therapies like CD20 depleting agents.³ Mustonen et al. found that DMTs after natalizumab often failed to prevent MS reactivation, with longer washout periods (>3 months) linked to higher reactivation risk.⁴ Zanghì et al. observed a higher ARR in patients switching to cladribine tablets with extended washouts.⁵ In contrast, Pfeuffer et al., in a prospective study, reported increased disease activity in patients transitioning from natalizumab to cladribine, with a median washout period of 66 days.⁶

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REFERENCES
1. Sguigna P, Okai A, Kaplan J, et al. P147. Two-Year Findings on the Safety and Efficacy of Cladribine Tablets after Treatment with Natalizumab (CLADRINA Trial). Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT P147.
2. Sguigna P, Hussain RZ, Okai A, et al. Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design. Ther Adv Neurol Disord. 2024;4:17:17562864241233858. doi:10.1177/17562864241233858
3. Hersh CM, Harris H, Conway D, et al. Effect of switching from natalizumab to moderate- vs high-efficacy DMT in clinical practice. Neurol Clin Pract 2020; 10:e 53–e65.
4. Mustonen T, Rauma I, Hartikainen P, et al. Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation. Mult Scler Relat Disord 2020; 38: 101498.
5. Zanghì A, Gallo A, Avolio C, et al. Exit Strategies in natalizumab-treated RRMS at high risk of progressive multifocal leukoencephalopathy: a multicentre comparison study. Neurotherapeutics 2021; 18: 1166–1174.
6. Pfeuffer S, Rolfes L, Hackert J, et al. Effectiveness and safety of cladribine in MS: real-world experience from two tertiary centres. Mult Scler 2022; 28: 257–268.