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MECHANISM OF ACTION

MAVENCLAD Proposed MOA

MAVENCLAD is thought to preferentially target B and T lymphocytes, and is associated with a reduction and subsequent recovery in lymphocyte count.1-3

In RMS, there are multiple treatment approaches to consider

Graphic representing immunomodulation

IMMUNOMODULATION4

  • Continuous administration
  • Ongoing modulation of immune function during active treatment without immunodepletion
Graphic representing chronic immunosuppression

CHRONIC IMMUNOSUPPRESSION4,5

  • Continuous administration
  • Ongoing suppression of immune function during active treatment
Graphic representing immunodepletion followed by repopulation

IMMUNODEPLETION FOLLOWED BY REPOPULATION2,5

  • Therapy administered intermittently as a short course
  • Dosing followed by depletion and repopulation

Effect of MAVENCLAD on total lymphocytes

MAVENCLAD selectively depletes lymphocytes.6,7 After 2 months, most immune cells begin to recover toward normal levels.3,8

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.5,6

Lymphocyte counts were measured as part of routine clinical laboratory evaluations in patients in clinical studies.8 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.6

In patients treated with MAVENCLAD as monotherapy, lymphopenia observed was transient and mostly mild to moderate.8 The median duration of severe lymphopenia was 6.0 weeks to improvement to Grade ≤2 and 28.1 weeks to recovery to Grade ≤1.8 26% and 1% of patients had nadir absolute lymphocyte counts less than 500 and less than 200 cells/μL, respectively.6 At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells/μL.6
 

Chart showing the effect of MAVENCLAD® on total lymphocyte count
Chart showing the effect of MAVENCLAD® on total lymphocyte count

 

Post hoc analysis, percentage of patients who had median ALC at Grade 1 lymphopenia or within normal limits3‡§:

#1

Week 13 of year 1

  • Normal to Grade 1: 82.2%
  • Grade 2: 16.4%
  • Grade 3: 1.3%
  • Grade 4: 0.0%
#2

Week 48 of year 1

  • Normal to Grade 1: 89.1%
  • Grade 2: 10.9%
  • Grade 3: 0.0%
  • Grade 4: 0.0%
#3

Week 12 of year 2

  • Normal to Grade 1: 64.5%
  • Grade 2: 28.9%
  • Grade 3: 6.7%
  • Grade 4: 0.0%
#4

Week 48 of year 2

  • Normal to Grade 1: 88.3%
  • Grade 2: 10.4%
  • Grade 3: 1.3%
  • Grade 4: 0.0%

Due to the post hoc nature of this analysis, no statistical significance between treatment groups can be drawn.
 

*Grade 1, <LLN-800/μL; 2, <800-500/μL; 3, <500-200/μL; 4, <200/μL.10

Visits with sample size ≥30 are displayed.3

Data were derived from a post hoc analysis of the 2 courses in patients receiving MAVENCLAD in CLARITY.3

§Percentages were calculated as a proportion of all patients with laboratory values at each time point. A total of 1.7% of patients (3/176) experienced ≥1 episode of Grade 4 lymphopenia at any time point during the entire trial period.3

ALC: absolute lymphocyte count; LLN: lower limit of normal; MOA: mechanism of action; RMS: relapsing multiple sclerosis.

MAVENCLAD proposed MOA

MAVENCLAD is associated with a reduction, and subsequent recovery, in lymphocyte count

Graphic representing reduction of B and T lymphocytes
  • The mechanism by which MAVENCLAD exerts its therapeutic effects in 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 by apoptosis or programmed cell death6
  • Its targeted effect on B and T lymphocytes is thought to interrupt the cascade of immune events central to MS1
  • In addition to lymphopenia, decreases in other blood cells and hematological parameters (neutrophils, hemoglobin, and platelets) have been reported with MAVENCLAD in clinical studies6
  • Pooled clinical trial data: MAVENCLAD treatment resulted in sharper depletion, followed by recovery of CD19+ B cells, compared to T cells3,7
Graphic representing recovery of B and T lymphocytes
  • Lymphocytes generally recovered over several months or more. Lymphocyte reduction and recovery are shown on the chart above6

MAVENCLAD has an estimated terminal half-life of approximately 24 hours and is eliminated from the body in ~1 week1,6,9

MAVENCLAD is a prodrug that is preferentially activated in B and T lymphocytes1

The reduction of B and T lymphocytes by MAVENCLAD is believed to interrupt the immune cascade central to MS1-3

Graphic representing MAVENCLAD® mechanism of action
  1. Inactive MAVENCLAD enters the lymphocyte via nucleoside transporters1,11
  2. Inactive MAVENCLAD becomes active in the cells upon phosphorylation to its 2-chlorodeoxyadenosine triphosphate (cd-ATP) metabolite6
  3. Activated MAVENCLAD accumulates in B and T lymphocytes due to protection from adenosine deaminase1,12
  4. Activated MAVENCLAD depletes lymphocytes through cell death1,11,12§

§Cladribine is activated by specific kinases (ie, deoxycytidine kinase).
Activated cladribine is inactivated by a specific phosphatase (ie, 5’-nucleotidase).

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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.
  • Risk of 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 if clinically significant 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 of 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.