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Demonstrated efficacy

Only MAVENCLAD can deliver proven efficacy with a maximum of 20 days of treatment over 96 weeks.1,2

Indication

MAVENCLAD® (cladribine) tablets 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.


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

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

See the CLARITY study design

Graph indicating the CLARITY study design

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

*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

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; T1-Gd+: T1 gadolinium-enhanced.

MAVENCLAD significantly reduced ARR vs placebo1,2

In CLARITY, MAVENCLAD significantly reduced the annualized relapse rate vs placebo at 96 weeks.1,2

Bar graph showing a 58% relative reduction with MAVENCLAD®
MAVENCLAD® kept 81% of patients relapse free for 96 weeks vs 63% on placebo

ARR: annualized relapse rate; CI: confidence interval.


MAVENCLAD significantly reduced EDSS progression vs placebo1,2

In CLARITY,MAVENCLAD significantly reduced the risk of 3-month confirmed EDSS progression vs placebo1,2

Chart showing a 33% reduction in disability progression with MAVENCLAD® treatment
87% of MAVENCLAD® patients remained  EDSS progression free for three months

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

CI: confidence interval; EDSS: Expanded Disability Status Scale; HR: hazard ratio.


MAVENCLAD significantly reduced the median number of lesions across MRI endpoints vs placebo1

In CLARITY, MAVENCLAD significantly reduced the median number of T1-Gd+ and active T2 lesions vs placebo at 96 weeks.1

Placebo had .33 more active T1-Gd+ lesions compared to MAVENCLAD® patients
Placebo had .67 more active T2 lesions compared to MAVENCLAD® patients
86% relative reduction of active T1-Gd+ lesions
73% relative reduction of active T2 lesions

The mean relative reduction reflects that not all patients had lesions. At 96 weeks, 57/433 (13.2%) patients in the MAVENCLAD group had T1-Gd+ lesions vs 226/437 (51.7%) patients in the placebo group. At 96 weeks, 166/433 (38.3%) patients in the MAVENCLAD group had active T2 lesions vs 313/437 (71.6%) patients in the placebo group.3

CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; T1-Gd+: T1 gadolinium-enhanced.


Significantly more patients on MAVENCLAD achieved NEDA (no evidence of disease activity) vs placebo4

In a post hoc analysis of CLARITY, significantly more patients taking MAVENCLAD achieved NEDA compared to placebo.4

44% of MAVENCLAD® patients achieved no evidence of disease activity (NEDA)

Of the 870 patients in the CLARITY study who received MAVENCLAD 3.5 mg/kg or placebo, 781 were assessable for NEDA at 96 weeks. MRI scans were obtained at the prestudy evaluation and at 24, 48, and 96 weeks.4

NEDA was defined in CLARITY as patients who4:

  • were relapse free
  • had no 3-month sustained change in EDSS score
  • had no new T1-Gd+ lesions
  • had no active T2 lesions

*The 3-month EDSS progression–free component of the NEDA analysis included the 407 patients in the MAVENCLAD arm and 388 patients in the placebo arm who were assessable for NEDA.4

CI: confidence interval; CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; EDSS: Expanded Disability Status Scale; OR: odds ratio; T1-Gd+: T1 gadolinium-enhanced.


MAVENCLAD demonstrated efficacy in a subgroup of patients with high EDSS1,5

Secondary progressive multiple sclerosis (SPMS) is a process characterized by progression of disability independent of relapses.6

Active SPMS

In the first few years of this process, many patients continue to experience relapses—a phase of the disease described as active SPMS. Active SPMS is one of the relapsing forms of MS (RMS).6-8

Non-active SPMS

Many patients with SPMS stop experiencing relapses, but disability continues to progress—a phase called non-active SPMS.7

EDSS score as a proxy for active SPMS

One proposed definition for active SPMS is that relapsing MS patients with an EDSS ≥3.5 can serve as a proxy of active SPMS.6,8-10

 

Timeline of proven results in patients with active SPMS

Active SPMS subgroup in CLARITY

Approximately 40% (n=335/870) of MAVENCLAD and placebo patients in the CLARITY trial met the active SPMS proxy criteria of EDSS ≥3.5 (all patients in CLARITY were required to have at least 1 relapse in the previous 12 months) and EDSS score ≤5.5.1,5

CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; EDSS: Expanded Disability Status Scale; RRMS: relapsing-remitting multiple sclerosis.


MAVENCLAD significantly reduced ARR in active SPMS vs placebo5

In a post hoc analysis of CLARITY, MAVENCLAD significantly reduced the annualized relapse rate vs placebo in patients who met the proxy criteria for active SPMS.5

Chart indicating a 57% relative reduction in ARR in active SPMS

ARR: annualized relapse rate; CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; EDSS: Expanded Disability Status Scale; SPMS: secondary progressive multiple sclerosis.


Significantly more patients with active SPMS achieved NEDA with MAVENCLAD vs placebo4*

In a post hoc analysis of CLARITY, significantly more patients who met the proxy criteria for active SPMS achieved NEDA (no evidence of disease activity) with MAVENCLAD vs placebo.4*

49% of MAVENCLAD® patients with active SPMS achieve NEDA

*The definition of NEDA is consistent with that used for the overall population as outlined above.

CI: confidence interval; CLARITY: CLAdRIbine Tablets treating multiple sclerosis orallY; OR: odds ratio; SPMS: secondary progressive multiple sclerosis.


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 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 while taking MAVENCLAD tablets 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. 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. 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. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before and during treatment, periodically thereafter, and when clinically indicated.
  • Infections: MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies. The most frequent serious infections included herpes zoster and pyelonephritis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. In patients treated with parenteral cladribine for oncologic indications, cases of progressive multifocal leukoencephalopathy (PML) have been reported. No case of PML has been reported in clinical studies of cladribine in patients with MS.
  • Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. 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 MAVENCLAD-treated patients, compared to 2.8% of placebo patients. 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.
  • 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: In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD, occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. 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. 

Adverse Reactions: The most common adverse reactions with an incidence of >20% for MAVENCLAD are upper respiratory tract infection, headache, and lymphopenia.

Drug Interactions/Concomitant Medication: Concomitant use of MAVENCLAD 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.

Avoid concomitant use of certain 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, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

Please see the full Prescribing Information, including boxed WARNING for additional information.

INDICATION

MAVENCLAD® (cladribine) tablets 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 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 while taking MAVENCLAD tablets 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. 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. 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. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before and during treatment, periodically thereafter, and when clinically indicated.
  • Infections: MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies. The most frequent serious infections included herpes zoster and pyelonephritis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. In patients treated with parenteral cladribine for oncologic indications, cases of progressive multifocal leukoencephalopathy (PML) have been reported. No case of PML has been reported in clinical studies of cladribine in patients with MS.
  • Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. 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 MAVENCLAD-treated patients, compared to 2.8% of placebo patients. 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.
  • 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: In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD, occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. 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. 

Adverse Reactions: The most common adverse reactions with an incidence of >20% for MAVENCLAD are upper respiratory tract infection, headache, and lymphopenia.

Drug Interactions/Concomitant Medication: Concomitant use of MAVENCLAD 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.

Avoid concomitant use of certain 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, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

Please see the full Prescribing Information, including boxed WARNING for additional information.

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