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MECHANISM OF ACTION

Impact on Lymphocyte Subsets

MAVENCLAD efficacy was demonstrated across key clinical and MRI endpoints in the pivotal trial1,2

MAVENCLAD effectiveness was studied in CLARITY, a Phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial vs placebo in patients with RRMS. Patients were recruited from 155 clinical centers in 32 countries.2 Out of 1,326 patients randomized, 1,184 patients completed the study at 96 weeks (2 years).2
 

Figure showing the study design and the randomization of the phase 3 pivotal trial, CLARITY.

Primary endpoint2

  • Annualized relapse rate at 96 weeks‡

Key secondary endpoints2

  • Proportion of relapse-free patients
  • Time to 3-month confirmed disability progression§
  • Mean number of T1-Gd+ and active T2 lesions

*The approved dose for MAVENCLAD is 3.5 mg/kg. Cladribine 5.25 mg/kg dose is not included in MAVENCLAD Prescribing Information clinical study results; no data will be discussed.1


Patients were eligible if they met certain criteria, including at least 1 MS relapse within the past 12 months, EDSS scores ≤5.5, and <2 prior DMT failures.2

Select exclusion criteria included2,3:

  • Patients who received:
    • Immunosuppressive therapy at any time before study entry
    • Cytokine-based therapy, intravenous immune globulin therapy, or plasmapheresis within 3 months before study entry
  • Presence of systemic disease (eg, hepatic or renal disease or HIV)
  • Prior or active malignancies
  • History of persistent anemia, leukopenia, neutropenia, or thrombocytopenia after immunosuppressive therapy
     

†In CLARITY, the baseline demographics and clinical characteristics were well balanced across study groups, except for mean disease duration, which was shorter in the MAVENCLAD group (7.9 years) than the placebo group (8.9 years) (P=0.005).2

‡A relapse was defined as a 2-point increase in ≥1 functional system of the EDSS or a 1-point increase in ≥2 functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for ≥24 hours and preceded by ≥30 days of clinical stability or improvement.2

§Disability progression was measured in terms of a 3-month sustained change in EDSS score of at least 1 point, if the baseline EDSS score was between 0.5 and 4.5 inclusively, or at least 1.5 points if the baseline EDSS score was 0, or at least 0.5 point if the baseline EDSS score was at least 5, over a period of at least 3 months.2

CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging; RRMS: relapsing- remitting MS; T1-Gd+: T1 gadolinium-enhanced.

MAVENCLAD selectively depletes lymphocytes.1,4 After 2 months, most immune cells begin to recover toward normal levels.5,6

The proposed mechanism by which MAVENCLAD exerts its therapeutic effects (MAVENCLAD MOA) in patients with multiple sclerosis (MS) is not fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.1

Lymphocyte counts were measured as part of routine clinical laboratory evaluations in patients in clinical studies.6 MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course.1

In patients treated with MAVENCLAD as monotherapy, lymphopenia observed was transient and mostly mild to moderate.6 The median duration of severe lymphopenia was 6.0 weeks to improvement to Grade ≤2 and 28.1 weeks to recovery to Grade ≤1.6 26% and 1% of patients had nadir absolute lymphocyte counts less than 500 and less than 200 cells/μL, respectively.1 At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells/μL.1
 

Graph showing effect of MAVENCLAD® on total lymphocyte count
Graph showing effect of MAVENCLAD® on total lymphocyte count

 

IIGrade 1, <LLN-800/μL; 2, <800-500/μL; 3, <500-200/μL; 4, <200/μL.9
Visits with sample size ≥30 are displayed.5

MAGNIFY-MS**: Quantitative B cell changes were observed in patients with highly active MS†† taking MAVENCLAD, including sustained decrease of memory B cells, and maintenance of regulatory B cells, following each treatment course10
 

Graph showing B-cell changes over time in the phase 4, open-label MAGNIFY-MS study


Study Limitations

  • MAGNIFY-MS was a Phase IV, open-label, single-arm, multicenter study
  • The primary endpoint of MAGNIFY-MS was to determine the onset of action of MAVENCLAD in patients with highly active relapsing MS††
  • The data presented here are based on a poster that has not been peer-reviewed


Due to the study limitations listed above, no definitive conclusions of efficacy can be drawn from these results and no treatment decisions should be made from these data.

**MAGNIFY-MS was a Phase IV, open-label, single-arm, multicenter, 2-year study to determine the onset of action of MAVENCLAD, as measured by combined unique active lesions. These data illustrate the longitudinal evaluation of peripheral blood immune cells in patients receiving MAVENCLAD. Patients with highly active relapsing MS (N=270) received 2 courses of active treatment (week 1 and week 5 of year 1, week 1 and week 5 of year 2).

††Highly active relapsing MS was defined by having 1 relapse in the previous year and ≥1 T1-Gd+ lesion, or ≥9 T2 lesions, while on therapy with other DMTs, or ≥2 relapses in the previous year, whether on DMT treatment or not.

‡‡Median percentage change from baseline.

BL: baseline; DMT: disease-modifying therapy.

Expand

INDICATION and IMPORTANT SAFETY INFORMATION for MAVENCLAD® (cladribine) tablets

MAVENCLAD® (cladribine) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS.

Limitations of Use: MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES and RISK OF TERATOGENICITY

  • Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
  • MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant.

CONTRAINDICATIONS

  • Patients with current malignancy.
  • Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during and for 6 months after the last dose in each treatment course. May cause fetal harm.
  • Patients infected with human immunodeficiency virus (HIV).
  • Patients with active chronic infections (e.g., hepatitis or tuberculosis).
  • Patients with a history of hypersensitivity to cladribine.
  • Women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose.

WARNINGS AND PRECAUTIONS

  • Malignancies: Treatment with MAVENCLAD may increase the risk of malignancy. After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. In clinical studies, patients who received additional MAVENCLAD treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
  • Risk of Teratogenicity: MAVENCLAD may cause fetal harm when administered to pregnant women. In females of reproductive potential, exclude pregnancy before initiation of each treatment course of MAVENCLAD and prevent by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.
  • Lymphopenia: MAVENCLAD causes a dose-dependent reduction in lymphocyte count. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before, during, and after treatment.
  • Infections: Serious, including life-threatening or fatal, infections have occurred. MAVENCLAD reduces the body's immune defense, and an increased risk of infections has been observed in patients receiving MAVENCLAD. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies; serious or severe infections occurred in 2.4% of MAVENCLAD- treated patients and 2.0% of placebo-treated patients. The most frequent serious infections included herpes zoster and pyelonephritis. Fungal infections were observed, including cases of coccidioidomycosis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. 
    • Screen patients for active and latent infections (tuberculosis, hepatitis B or C). Delay treatment until infection is fully resolved or controlled.    
    • Vaccinate patients who are seronegative for varicella zoster virus (VZV) prior to treatment. Vaccinate patients who are seropositive to VZV with recombinant, adjuvanted zoster vaccine either prior to or during treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter.
    • Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections.
    • Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with parenteral cladribine for oncologic indications. No case of PML has been reported in clinical studies of cladribine in patients with MS. Obtain a baseline magnetic resonance imaging (MRI) within 3 months before initiating the first treatment course of MAVENCLAD. At the first sign of PML, withhold MAVENCLAD and perform an evaluation.
    • Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD due to risk of infection.
  • Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. Obtain complete blood count (CBC) with differential including lymphocyte count before and during treatment, periodically thereafter, and when clinically indicated.
  • Graft-versus-Host Disease with Blood Transfusions: Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications. In patients who require blood transfusion, irradiation of cellular blood components is recommended.
  • Liver Injury: In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) compared to 0 placebo patients. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment. Discontinue MAVENCLAD if clinically significant liver injury is suspected.
  • Hypersensitivity: If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine.
  • Cardiac Failure: In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

Adverse Reactions: The most common adverse reactions (incidence of >20%) are upper respiratory tract infection, headache, and lymphopenia.

Drug Interactions: Concomitant use with immunosuppressive or myelosuppressive drugs and some immunomodulatory drugs (e.g., interferon beta) is not recommended and may increase the risk of adverse reactions. Acute short-term therapy with corticosteroids can be administered. Monitor for additive effects on the hematological profile with use of hemotoxic drugs. Avoid concomitant use of antiviral and antiretroviral drugs.  Avoid concomitant use of BCRP or ENT/CNT inhibitors as they may alter bioavailability of MAVENCLAD.

Use in Specific Populations: Studies have not been performed in pediatric, or elderly patients >65 years, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono, Inc. at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

 

References

  1. MAVENCLAD. Prescribing Information. EMD Serono, Inc; 2024
  2. 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(5):416-426.
  3. Data on file. Merck KGaA, Darmstadt, Germany.
  4. Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e360.
  5. Comi G, Cook S, Giovannoni G, et al. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis. Mult Scler Relat Disord. 2019;29:168-174.
  6. Data on file (NDA, Summary of clinical safety).
  7. Leist TP, Weissert R. Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol. 2011;34(1):28-35.
  8. Benet LZ, Zia-Amirhosseini P. Basic principles of pharmacokinetics. Toxicol Pathol. 1995;23(2):115-123.
  9. CTCAE Version 5, November 17, 2017.
  10. Wiendl H, De Stefano N, Barkhof F, et al. Blood biomarker dynamics in highly active relapsing multiple sclerosis patients treated with cladribine tablets: results of the 2-year MAGNIFY MS study. Poster presented at: Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2023 Forum; February 23-25, 2023.
Expand

INDICATION and IMPORTANT SAFETY INFORMATION for MAVENCLAD® (cladribine) tablets

MAVENCLAD® (cladribine) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS.

Limitations of Use: MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES and RISK OF TERATOGENICITY

  • Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
  • MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant.

CONTRAINDICATIONS

  • Patients with current malignancy.
  • Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during and for 6 months after the last dose in each treatment course. May cause fetal harm.
  • Patients infected with human immunodeficiency virus (HIV).
  • Patients with active chronic infections (e.g., hepatitis or tuberculosis).
  • Patients with a history of hypersensitivity to cladribine.
  • Women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose.

WARNINGS AND PRECAUTIONS

  • Malignancies: Treatment with MAVENCLAD may increase the risk of malignancy. After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. In clinical studies, patients who received additional MAVENCLAD treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
  • Risk of Teratogenicity: MAVENCLAD may cause fetal harm when administered to pregnant women. In females of reproductive potential, exclude pregnancy before initiation of each treatment course of MAVENCLAD and prevent by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.
  • Lymphopenia: MAVENCLAD causes a dose-dependent reduction in lymphocyte count. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before, during, and after treatment.
  • Infections: Serious, including life-threatening or fatal, infections have occurred. MAVENCLAD reduces the body's immune defense, and an increased risk of infections has been observed in patients receiving MAVENCLAD. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies; serious or severe infections occurred in 2.4% of MAVENCLAD- treated patients and 2.0% of placebo-treated patients. The most frequent serious infections included herpes zoster and pyelonephritis. Fungal infections were observed, including cases of coccidioidomycosis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. 
    • Screen patients for active and latent infections (tuberculosis, hepatitis B or C). Delay treatment until infection is fully resolved or controlled.    
    • Vaccinate patients who are seronegative for varicella zoster virus (VZV) prior to treatment. Vaccinate patients who are seropositive to VZV with recombinant, adjuvanted zoster vaccine either prior to or during treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter.
    • Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections.
    • Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with parenteral cladribine for oncologic indications. No case of PML has been reported in clinical studies of cladribine in patients with MS. Obtain a baseline magnetic resonance imaging (MRI) within 3 months before initiating the first treatment course of MAVENCLAD. At the first sign of PML, withhold MAVENCLAD and perform an evaluation.
    • Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD due to risk of infection.
  • Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. Obtain complete blood count (CBC) with differential including lymphocyte count before and during treatment, periodically thereafter, and when clinically indicated.
  • Graft-versus-Host Disease with Blood Transfusions: Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications. In patients who require blood transfusion, irradiation of cellular blood components is recommended.
  • Liver Injury: In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) compared to 0 placebo patients. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment. Discontinue MAVENCLAD if clinically significant liver injury is suspected.
  • Hypersensitivity: If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine.
  • Cardiac Failure: In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

Adverse Reactions: The most common adverse reactions (incidence of >20%) are upper respiratory tract infection, headache, and lymphopenia.

Drug Interactions: Concomitant use with immunosuppressive or myelosuppressive drugs and some immunomodulatory drugs (e.g., interferon beta) is not recommended and may increase the risk of adverse reactions. Acute short-term therapy with corticosteroids can be administered. Monitor for additive effects on the hematological profile with use of hemotoxic drugs. Avoid concomitant use of antiviral and antiretroviral drugs.  Avoid concomitant use of BCRP or ENT/CNT inhibitors as they may alter bioavailability of MAVENCLAD.

Use in Specific Populations: Studies have not been performed in pediatric, or elderly patients >65 years, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono, Inc. at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

 

US-MAV-02020
Last update 03/2024

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