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MECHANISM OF ACTION

The Roles of Immune Cells in MS and in MAVENCLAD Treatment

Understanding the roles of immune cells can help when evaluating benefit/risk of treatment approaches.1,2

Immune cells are key drivers of MS neuroinflammation. These cells also defend the body from invasive pathogens. A deeper understanding of the roles of immune cells in disease and treatment can help when evaluating the benefit/risk of MS treatment approaches.1-3

Innate immune cells serve as immune surveillance and the first line of defense1

NK cells

Induce apoptosis in virus-infected cells1

MAVENCLAD and select NK cells

  • May play a role in MS pathogenesis4
  • MAVENCLAD treatment resulted in median NK cell counts remaining within normal limits in patients5

POST HOC ANALYSIS: Median levels of NK cells remained within normal limits through MAVENCLAD treatment5*†‡ 

Graph showing median levels of NK cells through MAVENCLAD® treatment
Graph showing median levels of NK cells through MAVENCLAD® treatment
  • Reduction in median NK cell counts followed by recovery, but median cell counts remained within normal limits throughout treatment5


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

*204 patients from a post hoc analysis of CLARITY ([n=98] placebo, [n=101] MAVENCLAD) had lymphocytes and additional blood cells analyzed.5

Decreases in blood cells, other than lymphocytes, and hematological parameters have been reported with MAVENCLAD in clinical studies.7

In general, mild to moderate decreases in neutrophil counts, hemoglobin levels, and platelet counts were observed. Severe decreases in neutrophil counts were observed in 3.6% of patients treated with MAVENCLAD, compared with 2.8% of placebo patients.7

CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; LLN: lower limit of normal; NK: natural killer.

 

Neutrophils

Phagocytose bacteria and fungi1

MAVENCLAD and select neutrophils

  • The role of neutrophils in MS is still emerging8
  • MAVENCLAD treatment resulted in a mild to moderate effect on neutrophils9,10 
    • Median counts remained within normal range throughout the treatment period

POST HOC ANALYSIS: Median levels of neutrophils remained within normal limits through MAVENCLAD treatment9,10§ 

Graph showing median levels of neutrophils through MAVENCLAD® treatment
Graph showing median levels of neutrophils through MAVENCLAD® treatment
  • Mild to moderate effect on neutrophils9,10
    • Median counts remained within normal range throughout the treatment period


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

§Post hoc analysis of patients taking MAVENCLAD (n=103) and placebo (n=101) from CLARITY had lymphocytes and additional blood cells analyzed.9,10

LLN: lower limit of normal.
 

Monocytes

Phagocytose pathogens and present antigens1

MAVENCLAD and select monocytes (macrophages and dendritic cells)

  • May have a pro-inflammatory role in MS2
  • MAVENCLAD treatment resulted in mild to moderate effects on platelets and monocytes9,10
    • Median counts remained within normal range throughout the treatment period

POST HOC ANALYSIS: Median levels of monocytes remained within normal limits through MAVENCLAD treatment9,10|| 

Graph showing median levels of monocytes through MAVENCLAD® treatment
Graph showing median levels of monocytes through MAVENCLAD® treatment
  • Mild to moderate effect on platelets and monocytes9,10
    • Median counts remained within normal range throughout the treatment period


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

||Post hoc analysis of patients taking MAVENCLAD (n=103) and placebo (n=101) from CLARITY had lymphocytes and additional blood cells analyzed.9,10

LLN: lower limit of normal.
 

Adaptive immune cells, the second line of defense, drive MS neuroinflammation1-3

B cells
  • Differentiate into antibody-secreting plasma B cells, including in response to vaccines12,13
  • Memory B cells have an increased longevity and are involved in cytokine and antibody production as well as antigen presentation. In MS, increased memory B cell levels are associated with higher lesion activity and neurodegeneration14

MAVENCLAD and select B cells

  • In MS, can produce antibodies that lead to myelin damage13,15 and also present antigen to active T cells12
  • MAVENCLAD treatment resulted in sharper depletion, followed by recovery, of CD19+ B cells, compared to T cells9,16

POOLED CLINICAL TRIAL DATA: MAVENCLAD treatment resulted in sharper depletion, followed by recovery of CD19+ B cells compared to T cells9,16¶**††

Graph of pooled clinical trial data showing the effect of MAVENCLAD® on B cells
Graph of pooled clinical trial data showing the effect of MAVENCLAD® on B cells
  • Treatment resulted in sharper depletion, followed by recovery of CD19+ B cells, compared to T cells9,16

 

Pooled data from CLARITY, CLARITY EXT, and PREMIERE.16

**Median CD19+ B cells reached a nadir at 2 months (median 0.018 × 109 cells/μL) and then gradually increased.16

††MAVENCLAD and placebo were administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). Each course consisted of 2 treatment weeks: 1 at the beginning of the first month and 1 at the beginning of the second month. Data from patients randomized to placebo in CLARITY or who received a cumulative dose of MAVENCLAD for 2 years in CLARITY or CLARITY EXT were included. Any relevant follow-up in CLARITY EXT and PREMIERE is also reported.7,16

LLN: lower limit of normal.

 

CD4+ T-helper cells, CD8+ cytotoxic T cells
  • Help regulate the immune response and release pro-inflammatory proteins1
  • Attack cells (eg, virus/bacteria-infected cells, tumor cells), able to respond to re-exposure quickly1

MAVENCLAD and select CD4+ T-helper cells, CD8+ cytotoxic T cells

  • In MS, contribute to central nervous system inflammation and damage, do not function correctly, and are widely implicated as pro-inflammatory cells2,3
  • MAVENCLAD treatment resulted in reduction in T cells16
    • CD4+ cells were more sensitive to MAVENCLAD than CD8+ cells
    • Median CD8+ counts remained within normal range throughout the 96-week treatment period

 

POOLED CLINICAL TRIAL DATA: CD4+ cells were more sensitive to MAVENCLAD than CD8+ cells, and median CD8+ T cell counts remained within normal range16‡‡§§
 

CD4+ T-helper cells

CD4+ helper T cells

  • Median CD4+ T cell counts decreased followed by recovery16
Graph of pooled clinical trial data showing the effect of MAVENCLAD® on CD4+ T cells
Graph of pooled clinical trial data showing the effect of MAVENCLAD® on CD4+ T cells
CD8+ cytotoxic T cells

CD8+ cytotoxic T cells

  • Median CD8+ T cell counts decreased but remained above the lower limit of normal16
Graph of pooled clinical trial data showing the effect of MAVENCLAD® on CD8+ cytotoxic T cells
Graph of pooled clinical trial data showing the effect of MAVENCLAD® on CD8+ cytotoxic T cells


 

‡‡Pooled data from CLARITY, CLARITY EXT, and PREMIERE.16

§§MAVENCLAD and placebo were administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). Each course consisted of 2 treatment weeks: 1 at the beginning of the first month and 1 at the beginning of the second month. Data from patients randomized to placebo in CLARITY or who received a cumulative dose of MAVENCLAD for 2 years in CLARITY or CLARITY EXT were included. Any relevant follow-up in CLARITY EXT and PREMIERE is also reported.7,16

LLN: lower limit of normal.

With MAVENCLAD, median counts of NK cells, monocytes, and CD8+ cytotoxic T cells remained within normal range throughout the treatment period5,9,10,16

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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.