Multiple sclerosis (MS) is characterized by damage to the myelin sheath and is one of the most common inflammatory neurologic diseases in young and middle-aged adults.1 The symptoms of MS include limb weakness, gait ataxia, loss of bladder control, and cognitive dysfunction.2 The average age at onset is 34 years, and more women than men have MS.1,3 A recent study showed that more than 900,000 Americans had MS in 2017.3
The economic burden of managing MS is considerable—according to data from the National Inpatient Sample database, MS-related hospital admissions increase by approximately 540,000 annually, and the costs associated with MS care increase by approximately $7.3 million annually.1
MS comprises the 4 disease courses of clinically isolated syndrome, including relapsing-remitting MS, secondary progressive MS, and primary progressive MS.4 Clinically isolated syndrome is a first episode of neurologic symptoms that is characteristic of MS but does not yet meet the criteria for MS. Relapsing-remitting MS is the most common type, and is characterized by attacks of new or increasing neurologic symptoms (relapses), followed by episodes of partial or complete recovery (remissions). Patients with relapsing-remitting MS will eventually have secondary progressive MS, in which a worsening of neurologic function occurs over time. Primary progressive MS is characterized by worsening neurologic function from the onset of symptoms.4
Many pharmacologic therapies are approved for MS, including oral and injectable drugs. Ocrelizumab (Ocrevus) is the only approved disease-modifying therapy for primary progressive MS. US Food and Drug Administration (FDA)-approved drugs for relapsing forms of MS include beta interferon, glatiramer acetate (Copaxone, Glatopa), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), teriflunomide (Aubagio), siponimod (Mayzent), ocrelizumab, natalizumab (Tysabri), alemtuzumab (Campath, Lemtrada), and mitoxantrone (Novantrone).5,6
FDA Approves Mavenclad for Relapsing Multiple Sclerosis
On March 29, 2019, the FDA approved Mavenclad (cladribine; EMD Serono), a purine antimetabolite, for the treatment of adults with relapsing forms of MS, including relapsing-remitting disease and active secondary progressive disease.7,8 Cladribine is the first short-course oral therapy approved for relapsing forms of MS.9
“We are committed to supporting the development of safe and effective treatments for patients with multiple sclerosis,” said Billy Dunn, MD, Director, Division of Neurology Products, FDA’s Center for Drug Evaluation and Research.7 “The approval of Mavenclad represents an additional option for patients who have tried another treatment without success,” Dr Dunn added.7
Because of its safety profile, cladribine is recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternative drug for the treatment of MS.8
Mechanism of Action
Cladribine is a purine antimetabolite. Its mechanism of action in MS has not been fully elucidated, but cladribine is thought to impair DNA synthesis, resulting in the depletion of B and T lymphocytes, which are believed to play an important role in the pathogenesis of MS.8,10
Dosing and Administration
Cladribine is available as uncoated 10-mg tablets.
The recommended dosage of cladribine is 3.5 mg per kg of body weight, administered orally and divided into 2 annual treatment courses of 1.75 mg/kg per treatment course (see the full prescribing information for dosing per body weight).8 The cycle dose should be administered as 1 or 2 tablets once daily over 4 or 5 consecutive days.8
Each treatment course is divided into 2 treatment cycles.8 During the first cycle of the first treatment course, cladribine can be administered at any time. During the second cycle of the first course, cladribine should be administered 23 to 27 days after the last dose of the first cycle of the first course. During the first cycle of the second course, cladribine should be administered at least 43 weeks after the last dose of the second cycle of the first course. During the second cycle of the second course, cladribine should be administered 23 to 27 days after the last dose of the first cycle of the second course.8
Pivotal Clinical Trial: CLARITY
The approval of cladribine for MS was based on the 96-week, randomized, double-blind, placebo-controlled CLARITY clinical trial in patients with relapsing forms of MS who had at least 1 relapse in the previous 12 months.8,10
The patients’ median age was 39 years, and approximately twice more women than men were enrolled in the study.8 The median baseline neurologic disability across all treatment groups was 3, based on the Kurtzke Expanded Disability Status Scale (EDSS) score.8
The primary end point was the annualized relapse rate.8 Other outcome measures comprised the proportion of patients with confirmed disability progression, the time to first qualifying relapse, the mean number of magnetic resonance imaging (MRI) T1 gadolinium-enhancing lesions, and the presence of new or enlarging MRI T2 hyperintense lesions. The progression of disability was measured as a sustained change of 3 months in EDSS score of ≥1, if the baseline EDSS score was between 0.5 and 4.5 inclusively, or was ≥1.5 if the baseline EDSS score was 0, or ≥0.5 if the baseline EDSS score was ≥5.8
Overall, 1326 patients were randomized in a 1:1:1 ratio to placebo (N = 437), cladribine 3.5 mg/kg (N = 433), or to cladribine 5.25 mg/kg (N = 456) during the 96-week study period in 2 treatment courses.8 The patients in the 3.5-mg/kg dose arm received a first treatment course at weeks 1 and 5 of the first year and a second course at weeks 1 and 5 of the second year. The patients in the 5.25-mg/kg cumulative dose arm received additional treatment at weeks 9 and 13 of the first year.
Cladribine 3.5 mg/kg significantly lowered the annualized relapse rate by 58%, and 81% of patients were free of relapse after 2 years of cladribine therapy compared with 63% of patients who received placebo (Table).8
The most common (>20%) all-grade adverse reactions reported in patients who received cladribine versus placebo in the CLARITY clinical trial included upper respiratory tract infection (38% vs 32%, respectively), headache (25% vs 19%, respectively), and lymphopenia (24% vs 2%, respectively).8
Other notable adverse events that occurred more frequently in patients who received cladribine versus placebo included hypersensitivity reactions (11% vs 7%, respectively), alopecia (3% vs 1%, respectively), and serious seizures (0.3% vs 0%, respectively).8
Serious hypersensitivity reactions and/or those that led to the discontinuation of cladribine occurred in 0.5% of patients who received cladribine.8
Cases of myelodysplastic syndrome and fatal herpes meningoencephalitis have also been reported with cladribine therapy. One case of life-threatening acute cardiac failure with myocarditis, which improved after approximately 1 week, was reported with the use of cladribine therapy.8
Because of its safety profile, cladribine is not recommended for use in patients with clinically isolated syndrome.8
Cladribine is contraindicated in patients with current malignancy, HIV infection, active chronic infections, or a history of hypersensitivity to cladribine.8
Cladribine is also contraindicated in women who are intending to breastfeed during cladribine treatment and for 10 days after the last dose, in pregnant women, and in women and men of reproductive potential who do not plan to use effective contraception during treatment and for 6 months after the last dose in each treatment course.8
The concomitant use of cladribine with immunomodulatory, immunosuppressive, or myelosuppressive drugs is not recommended because of the risk for adverse reactions resulting from the additive effects of cladribine on the immune system. When cladribine and immunosuppressive drugs are used sequentially, the overlapping effects on the immune system should be considered.8
The concomitant use of cladribine with drugs characterized by hematologic toxicity may increase the risk for adverse events, and patients should be monitored for additive hematologic effects.8
The concomitant use of antiviral and antiretroviral drugs with cladribine should be avoided.8
Because breast cancer resistance protein or equilibrative nucleoside and concentrative nucleoside transport protein inhibitors may alter the bioavailability of cladribine, their concomitant use with cladribine should be avoided.8
Use in Specific Populations
The use of cladribine is not recommended in young patients aged <18 years because of the risk for malignancies.8
Clinical studies with cladribine did not include an adequate number of elderly patients (aged ≥65 years) to determine whether they respond differently from younger patients to cladribine. Cladribine should be used with caution in elderly patients because of the increased risk for decreased hepatic, renal, or cardiac function; concomitant diseases; and other drug therapies.8
No dose adjustment is recommended in patients with mild renal or hepatic impairment; cladribine should not be used in patients with moderate-to-severe renal or hepatic impairment.8
Warnings and Precautions
Cladribine has a boxed warning regarding the risk for malignancies and teratogenicity; as such, cladribine is contraindicated in patients with malignancy, in pregnant women, and in women and men of reproductive potential who do not plan to use effective contraception.8
Hematologic toxicity, including lymphopenia, serious cases of thrombocytopenia, neutropenia, and pancytopenia, has been reported with cladribine therapy. Patients’ complete blood count with differential, including lymphocyte count, should be obtained before, during, and after treatment with cladribine.8
Cladribine can increase the risk for infections, the most common serious infections being herpes zoster and pyelonephritis. HIV infection, active tuberculosis, and active hepatitis must be excluded before starting treatment with cladribine.8
In patients who require blood transfusion, the irradiation of cellular blood components is recommended to decrease the risk for transfusion-related graft-versus-host disease.8
Liver injury has been reported with cladribine therapy, but these abnormalities resolved after treatment discontinuation. Serum aminotransferase, alkaline phosphatase, and total bilirubin levels should be measured before the first and second treatment course of cladribine.8
Cladribine should not be used in patients with a history of hypersensitivity to cladribine.8
Patients should seek medical attention if they have symptoms of cardiac failure, such as shortness of breath, rapid or irregular heartbeat, or swelling.8
The approval of cladribine, the first short-course oral therapy for patients with relapsing forms of MS, including relapsing-remitting MS and secondary progressive MS, provides patients with a convenient new treatment option.
In the pivotal clinical trial CLARITY, cladribine significantly reduced the annualized relapse rate, and significantly more patients were free of relapses after receiving 2 years of cladribine treatment compared with those who received placebo.
- 1. Chen AY, Chonghasawat AO, Leadholm KL. Multiple sclerosis: frequency, cost, and economic burden in the United States. J Clin Neurosci. 2017;45:180-186.
- National Multiple Sclerosis Society. MS symptoms. www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms. Accessed June 18, 2019.
- Wallin MT, Culpepper WJ, Campbell JD, et al; for the US Multiple Sclerosis Prevalence Workgroup. The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019;92:e1029-e1040.
- National Multiple Sclerosis Society. Types of MS. www.nationalmssociety.org/What-is-MS/Types-of-MS. Accessed June 5, 2019.
- Mayo Clinic. Multiple sclerosis: diagnosis & treatment. April 19, 2019. www.mayoclinic.org/diseases-conditions/multiple-sclerosis/diagnosis-treatment/drc-20350274. Accessed June 5, 2019.
- Taşkapilioğlu Ö. Recent advances in the treatment for multiple sclerosis; current new drugs specific for multiple sclerosis. Noro Psikiyatr Ars. 2018;55(suppl 1):S15-S20.
- US Food and Drug Administration. FDA approves new oral treatment for multiple sclerosis. March 29, 2019. www.fda.gov/news-events/press-announcements/fda-approves-new-oral-treatment-multiple-sclerosis. Accessed June 4, 2019.
- Mavenclad (cladribine) tablets, for oral use [prescribing information]. Rockland, MA: EMD Serono; April 2019.
- Barrett J. First short-course oral therapy for relapsing forms of MS granted FDA approval. Pharmacy Times. March 30, 2019. www.pharmacytimes.com/news/first-shortcourse-oral-therapy-for-relapsing-forms-of-ms-granted-fda-approval. March 30, 2019. Accessed June 5, 2019.
- 10. Giovannoni G, Comi G, Cook S, et al; for the CLARITY study group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416-426.