Abstract

Cladribine tablets (CladT) were initially approved for use in people with highly active relapsing multiple sclerosis (RMS) in 2017. However, following review of the clinical development programme and subsequent long-term efficacy and safety data, the Medicines and Healthcare products Regulatory Agency granted a label expansion, in March 2024, to include patients with active RMS. Based on the research and our multidisciplinary experience, we recommend that healthcare professionals consider CladT in disease-modifying treatment (DMT) conversations with all patients who have active or highly active RMS. In our experience, CladT are well suited as a first-line therapy for newly diagnosed and treatment-naïve patients, for those who require an alternative to chronic, continuous immunosuppression, such as older patients with RMS and those with comorbidities. CladT are a valuable high-efficacy DMT with a dosing and monitoring schedule that is conducive to family planning, employment and increasing accessibility for those with barriers to frequent hospital visits.

The cladribine tablets license extension

In 2017, cladribine tablets (CladT) were approved by the European Medicines Agency as a treatment for patients with highly active relapsing multiple sclerosis (RMS) [1]. The restriction to “highly active” RMS resulted from concerns related to lymphopenia and the imbalance in reported malignancies between active and placebo arms during Phase 3 trials [2, 3]. However, an independent meta-analysis comparing the original Phase 3 data with other disease-modifying treatments (DMTs) [4], new data and analyses from Phase 3 [2,3,5] and Phase 4 studies [6-8], a post-approval observational study [9], and real-world evidence [10,11] found the benefit-risk ratio to be more favourable than initially noted. Additionally, of five high-efficacy DMTs available for RMS, a time and motion study found CladT resulted in the lowest administration and monitoring burden to NHS MS services over 4 years [12]. As a result, in March 2024, the Medicines and Healthcare products Regulatory Agency (MHRA) granted a label expansion for CladT, which now includes an indication for adults with active RMS [13].

Here, we share our experience and views on how to navigate the expanded use of CladT, by considering the value of CladT to different patient cohorts (Table 1) and highlighting relevant supportive data.

Patient cohorts

Consideration of CladT for all patients with RMS

In our opinion, the newly expanded label enables the discussion about possible CladT use for most patients with RMS. In addition to the simple dosing and monitoring of CladT [1], which is less burdensome than other DMTs [14-19], this recommendation is based on CladT’s substantial and sustained efficacy [2,3,5,8], and favourable safety profile [9].

The original Phase 3 CLARITY [2] and CLARITY-EXT [3] trials are well documented. They showed that CladT significantly decreased annualised relapse rate (ARR) [2,3], the number of gadolinium-enhancing T1 and active T2 lesions, and the risk of sustained progression of disability, compared to placebo [2]. These benefits were largely maintained throughout Years 3 and 4 [3]. The subsequent CLASSIC-MS study found that those treated with CladT in the original trials experienced sustained mobility and disability benefits over a median of almost 11 years [8].

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In a long-term safety analysis of the CladT clinical development programme, and the prospective, observational PREMIER registry, 14.4% of patients receiving CladT experienced at least one serious treatment-emergent adverse event versus 10.6% of patients receiving placebo [9]. However, over 8 years of observation, the risk of infections, other than herpes infections, was not increased in the CladT versus placebo groups [9] and progressive multifocal leukoencephalopathy was not observed [9]. A drop in lymphocyte counts is expected due to the mechanism of action of CladT so the occurrence of mild to moderate lymphopenia is common. However, the drug label stipulates the total lymphocyte count must reach 800 cells/mm3 before commencing the second year treatment course, limiting the risk of severe lymphopenia [1].

Newly diagnosed and treatment naïve patients

Our clinical experience suggests that CladT are a suitable first-line DMT option for treatment-naïve patients with RMS. As with any immunotherapy, patients at this stage of their disease respond better than those switching from another DMT. Our experience is underpinned by a post-hoc analysis of CLARITY [20], alongside CLARIFY-MS, an open-label, Phase 4 study [7], which showed the ARR of qualifying relapses was approximately 50% lower in treatment-naïve participants versus those who used another DMT prior to CladT. Our recommendation for early use of CladT is additionally supported by a post-hoc analysis [21] of ORACLE-MS [5], a double-blind, randomised, Phase 3 trial, that found CladT can reduce the risk of a definitive diagnosis of RMS if given at the stage of clinically isolated syndrome (CIS) [21]. Please note, however, CladT are not indicated for CIS.

Patients with RMS planning a family

Family planning is another area in which both our experience and the trial data support the discussion of CladT as an early DMT option. Although CladT should not be taken during pregnancy or whilst breast feeding [1], its unique posology makes it a good option for those wishing to conceive. CladT are administered orally as two, 4 or 5-day courses, approximately 1 month apart. This dosing cycle is then repeated in Year 2, with – in the vast majority of cases – no further dosing required during years 3 and 4 [1]. Although pregnancy is contraindicated throughout the dosing period and for at least 6 months following the final dose of CladT in Year 2 [1], a significant amount of time opens up in years 3 and 4 to plan conception, pregnancy and birth, whilst still being protected by the DMT effect of CladT. Thus, compared to other DMTs that require continuous dosing and where pregnancy is commonly contraindicated in the label [15-18], CladT enables individuals with active or highly-active RMS who wish to have children, access to an induction treatment that allows them to plan drug-free pregnancies without the risk of relapse inherent in pausing other DMTs.

Elderly or immunosuppressed patients

We also consider CladT an excellent option for older people with RMS. These individuals often bear the burden of multiple comorbidities, chronic conditions and polypharmacy. They are also more exposed to the adverse effects of ongoing immunosuppressive therapy and the risk of drug interactions. We have used CladT as an “exit” strategy after treatment with other high-efficacy DMTs, and as a first choice in patients newly diagnosed at the age of 50 and beyond.

Unlike many high-efficacy DMTs for RMS that function through continuous immunosuppression [14-18], the short-dosing schedule of CladT minimises contributions to polypharmacy and may improve treatment adherence in a population potentially experiencing cognitive decline or frailty. This unique posology is possible due to CladT’s transient and semi-selective targeting of the adaptive immune system, followed by characteristic repopulation dynamics, which largely preserves immune competency [22,23]. Like anti-CD20 monoclonal antibody DMT, CladT leads to considerable reduction of CD19+ and CD20+ B cells, particularly memory B cells, which remain depleted for at least 96 weeks [23,24], and probably considerably longer, a mechanism thought to be key for lasting MS disease control [25,26]. Conversely, naïve and maturing B cells, important for early immune responses, recover towards baseline from Month 3 after CladT administration [23]. Natural killer and T cell sub-populations show a more gradual and moderate decline compared to B cells [23], with CD4+ T cells reaching normal levels within 36–48 weeks of the start of Year 2 treatment [27].

Patients with RMS from underserved populations: facilitating equality

The short dosing of CladT are not only beneficial for the older patient population. Many high-efficacy DMTs for RMS deliver their effect by continuous immunosuppression, requiring uninterrupted daily, monthly or 6-monthly dosing and require patient monitoring [14-19]. The treatment burden of maintenance DMTs can be considerable and may be difficult to adhere to; many patients, such as those living in rural or remote communities, travel significant distances to reach services for regular treatment administration and/or frequent monitoring, which can disrupt daily life. This burden can be particularly challenging for some individuals, including people who have insecure housing or are experiencing homelessness, members of the travelling community and people who find travel more difficult due to for example, lower incomes or disabilities.

The combination of an induction therapy and short course, oral delivery of CladT may improve treatment adherence and allows people who have poor social determinants of health or who live far from specialist centres to access effective treatment that does not require frequent travel, with associated time and financial costs. This has the potential to improve equality of treatment access across the UK, which is beneficial from a wider health equalities perspective.

The value of CladT to the healthcare service

MS teams managing the provision and monitoring of DMTs are under mounting pressure to deliver complex monitoring regimes in an increasingly resource-constrained NHS and as mentioned, CladT has the lowest administration and monitoring burden compared to other high-efficacy DMTs [12]. Moreover, CladT may also contribute to NHS  green initiatives and the goal of delivering a net zero NHS by 2045 [28]. Unlike injectable and infusion DMTs, CladT are a short-course oral tablet that benefit patients and services by enabling care closer to home, while also reducing the volume of carbon-driven deliveries and medical waste.

Conclusions

The MHRA reviewed the submitted long-term efficacy and safety data for CladT and in March 2024, it granted a label expansion that now includes adults with active RMS [13] in addition to highly active RMS [1]. We have been using CladT regularly since its approval in 2017 and following this expansion, this expert group recommends that CladT are discussed by the multidisciplinary team as a treatment option for every patient diagnosed with active or highly active RMS. We believe that CladT should be used early after diagnosis and considered as a first-line DMT in treatment-naïve patients with RMS, where it can maintain function and quality of life in a large proportion of patients [29]. The posology of CladT makes it an excellent option for family planning and we suggest considering CladT for individuals wishing to start a family. CladT also provides a versatile choice for people with RMS aged 50 and beyond, and we propose CladT as either a first-line DMT for patients newly diagnosed at that age or as an exit strategy from prior high-efficacy and regular immunosuppressive DMTs. Crucially, the oral formulation, infrequent administration and monitoring burden associated with CladT means it is a key option for ensuring MS healthcare equality in the UK for all the reasons listed above.

References

  1. Merck. Mavenclad® (cladribine). Summary of Product Characteristics. Last updated 20 August 2024. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mavenclad
  2. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-26. https://doi.org/10.1056/nejmoa0902533
  3. Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult Scler. 2018;24(12):1594-604. https://doi.org/10.1177/1352458517727603
  4. Pakpoor J, Disanto G, Altmann D R, Pavitt S, Turner B P, Marta M, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e158. https://doi.org/10.1212/nxi.0000000000000158
  5. Leist T P, Comi G, Cree B A, Coyle P K, Freedman M S, Hartung H P, 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 randomised trial. Lancet Neurol. 2014;13(3):257-67. https://doi.org/10.1016/s1474-4422(14)70005-5
  6. de Stefano N, Barkhof F, Montalban X, Achiron A, Derfuss T, Chan A, et al. Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS. Neurol Neuroimmunol Neuroinflamm. 2022;9(4):e1187. https://doi.org/10.1212/nxi.0000000000001187
  7. Brochet B, Solari A, Lechner-Scott J, Piehl F, Langdon D, Hupperts R, et al. Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study. Mult Scler. 2023;29(14):1808-18. https://doi.org/10.1177/13524585231205962
  8. Giovannoni G, Boyko A, Correale J, Edan G, Freedman M S, Montalban X, et al. Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study. Mult Scler. 2023;29(6):719-30. https://doi.org/10.1177/13524585231161494
  9. Leist T, Cook S, Comi G, Montalban X, Giovannoni G, Nolting A, et al. Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis. Mult Scler Relat Disord. 2020;46:102572. https://doi.org/10.1016/j.msard.2020.102572
  10. Brownlee W, Amin A, Ashton L, Herbert A. Real-world use of cladribine tablets (completion rates and treatment persistence) in patients with multiple sclerosis in England: The CLARENCE study. Mult Scler Relat Disord. 2023;79:104951. https://doi.org/10.1016/j.msard.2023.104951
  11. Spelman T, Ozakbas S, Alroughani R, Terzi M, Hodgkinson S, Laureys G, et al. Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry. Mult Scler. 2023;29(2):221-35. https://doi.org/10.1177/13524585221137502
  12. Rog D, Brownlee W, Carod-Artal F J, Kalra S, Barker N, Lowndes C, et al. Quantifying the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis in the United Kingdom: A time and motion study. Mult Scler Relat Disord. 2024;82:105380. https://doi.org/10.1016/j.msard.2023.105380
  13. Merck. Great Britain is first across Europe to get regulatory approval of MAVENCLAD® (cladribine tablets) as the only short course oral treatment for active Relapsing Multiple Sclerosis patients. 2024. [updated 27 March 2024]. Available from: https://www.merckgroup.com/uk-en/press-releases/GB-Mavenclad-27-Mar-2024-Local-Press-Materials-for-Announcements-press-release-for-the-label-expansion.pdf
  14. Biogen. Tysabri® (Natalizumab). Summary of Product Characteristics. Last updated 17 October 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/tysabri-epar-product-information_en.pdf
  15. Novartis. Kesimpta® (Ofatumumab). Summary of Product Characteristics. Last updated 12 July 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/kesimpta-epar-product-information_en.pdf
  16. Novartis. Gilenya® (Fingolimod). Summary of Product Characteristics. Last updated 18 December 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf
  17. Juvisé Pharmaceuticals. Ponvory® (Ponesimod). Summary of Product Characteristics. Last upated 22 October 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/ponvory-epar-product-information_en.pdf
  18. Roche. Ocrevus® (Ocrelizumab). Summary of Product Characteristics. Last updated 11 Dember 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf
  19. Sanofi. Lemtrada® (Alemtuzumab). Summary of Product Characteristics. Last updated 22 April 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/lemtrada-epar-product-information_en.pdf
  20. Vermersch P, Galazka A, Dangond F, Damian D, Wong S L, Jack D, et al. Efficacy of cladribine tablets in high disease activity patients with relapsing multiple sclerosis: post hoc analysis of subgroups with and without prior disease-modifying drug treatment. Curr Med Res Opin. 2021;37(3):459-64. https://doi.org/10.1080/03007995.2020.1865888
  21. Freedman M S, Leist T P, Comi G, Cree B A, Coyle P K, Hartung H P, et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017;3(4):2055217317732802. https://doi.org/10.1177/2055217317732802
  22. Comi G, Cook S, Giovannoni G, Rieckmann P, Sørensen P S, Vermersch P, et al. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis. Mult Scler Relat Disord. 2019;29:168-74. https://doi.org/10.1016/j.msard.2019.01.038
  23. Wiendl H, Barkhof F, Montalban X, Achiron A, Derfuss T, Chan A, et al. Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study. Frontiers in Immunology. 2025;16. https://doi.org/10.3389/fimmu.2025.1512189
  24. Ammoscato F, Wafa M, Skonieczna J, Bestwick J, Monero R, Andrews M, et al. Cladribine tablets in relapsing-remitting multiple sclerosis preferentially target B-cells. Clin Immunol. 2024;269:110380. https://doi.org/10.1016/j.clim.2024.110380
  25. DiSano K D, Gilli F, Pachner A R. Memory B Cells in Multiple Sclerosis: Emerging Players in Disease Pathogenesis. Front Immunol. 2021;12:676686. https://doi.org/10.3389/fimmu.2021.676686
  26. Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50. https://doi.org/10.1016/j.ebiom.2017.01.042
  27. Giovannoni G, Coyle P K, Vermersch P, Walker B, Aldridge J, Nolting A, et al. Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets. Front Immunol. 2021;12:763433. https://doi.org/10.3389/fimmu.2021.763433
  28. NHS England. Delivering a ‘Net Zero’ National Health Service. July 2022. Available from: https://www.england.nhs.uk/greenernhs/a-net-zero-nhs/
  29. Afolabi D, Albor C, Zalewski L, Altmann D R, Baker D, Schmierer K. Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis. Mult Scler. 2018;24(11):1461-8. https://doi.org/10.1177/1352458517726380
  30. Boyko A N, Boyko O V. Cladribine tablets’ potential role as a key example of selective immune reconstitution therapy in multiple sclerosis. Degener Neurol Neuromuscul Dis. 2018;8:35-44. https://doi.org/10.2147/dnnd.s161450
  31. Möhn N, Skripuletz T, Sühs K W, Menck S, Voß E, Stangel M. Therapy with cladribine is efficient and safe in patients previously treated with natalizumab. Ther Adv Neurol Disord. 2019;12:1756286419887596. https://doi.org/10.1177/1756286419887596