1

Treatment of highly active

MS

Mahmoud M Hasan Al Ewaidy

Professor Of Neurology
Al-Azhar University

Confidential – internal use only

 2

Multiple sclerosis (MS) is a serious, lifelong disabling disease with

unpredictable outcomes.

The clinical presentation and phenotype of MS are variable between

patients and over time. It can encompass various degrees of severity.

Minority of patients exhibit either a benign course with little disability

accrual over time or an ‘aggressive’ course with frequent, severe relapses,
incomplete recovery and rapidly accumulating and permanent disability.

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 3

The efficacy of available disease-modifying therapies (DMTs) for

relapsing multiple sclerosis (rMS) and progressive (primary
progressive MS (PPMS) and secondary progressive MS (SPMS))
have been insufficiently studied in aggressive disease courses.

For some available DMTs, regulatory approval and insurance

coverage mandate that patients must be considered not responsive
(based on ongoing clinical or radiological disease activity) or
intolerant to first-line therapies before receiving access to more
effective treatment.

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Patients with aggressive MS may be better treated if given rapid

access to therapies considered to be more effective at slowing or
preventing disability accrual.

Therefore, early identification of subjects with aggressive disease at

onset or with disease that becomes more aggressive over time is
essential to both aid treatment recommendations and decisions
making.

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 5

Definition of highly active MS

- Approximately 8% of patients with MS experience more aggressive or hyperacute
disease course.

- Some of these patients can be categorized as having highly active relapsing–remitting

multiple sclerosis (HARRMS), although its definition remains debatable.

- European Medicines Agency (EMA) defined patients with HARRMS as treatment

naïve patients with at least two disabling relapses in the last 1 year and at least one
gadolinium-enhancing lesion or significant increase in T2-lesion load.

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Definition of highly active MS

- Patients who have failed to respond to an adequate course of at least one disease-
modifying therapy (DMT), presenting with at least one relapse in the previous year while on
therapy and at least nine T2-hyperintense lesions or at least one gadolinium-enhancing
lesion, were also characterized as having HARRMS.

- Early initiation of effective immunotherapy is considered to be important in this group of

patients due to a narrow therapeutic window for anti-inflammatory agents.

- Most of the conventional first-generation DMT may be ineffective in avoiding rapid

accumulation of fixed disability.

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Aggressive MS
Fulfilment of at least one criterion within first 5 years of multiple
sclerosis:

≥2 relapses with incomplete recovery within 12 months.

≥2 MRI with new or enlarging T2 lesions or gadolinium

enhancing (GD+) lesions during 12 months on DMT.

No treatment effect during first year of DMT.

Confirmed EDSS ≥ 4.0 after 5 years of disease onset.

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Aggressive MS
“Patients that reached an EDSS of 6.0 within 5 years from onset” (Form 1).

“Patients that reached an EDSS⩾6.0 at the age of 40 years” (Form 2)

“Patients who entered SPMS phase within 3years after rMS onset” (Form 3)

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 9

Aggressive MS
- Malignant MS
“A disease with a rapid progressive course, leading to significant disability in
multiple neurologic systems or death in a relatively short time after disease onset”

Ever malignant MS
“Patients that reached an EDSS of 6.0 within 5 years from onset.”

Aggressive onset MS
“MS patients with:
(a) ⩾2 relapses in the year after onset and ⩾2 Gd+ lesions on brain MRI scan or
(b) one relapse within 1 year after onset if it results in sustained baseline EDSS score of 3.0 along with ⩾2 Gd+ lesions”.

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EDSS
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What is “highly active MS”?

A universally accepted definition for highly active
MS does not exist.

The term highly active MS has not been precisely

defined but the most important features include
frequent relapses with incomplete recovery,
and/or high radiological burden of disease, rapid
accrual of disability after disease onset, with
otherwise typical features of MS.

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Selection of disease modifying treatment vary

in highly active MS
For patients identified as having highly active MS, most efficacious agents
should be used early despite increased risk of adverse events.

The treatment algorithm must be adjusted based on the estimated level of

risk, but in general patients with highly active MS will benefit from early
aggressive anti-inflammatory treatments selected to maximize the likelihood
of disease control.

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 13

Selection of disease modifying treatment vary in

highly active MS
For patients identified as having highly active MS, our most efficacious
agents should be used early despite increased risk of adverse events.

The treatment algorithm must be adjusted based on the estimated level of

risk, but in general patients with highly active MS will benefit from early
aggressive anti-inflammatory treatments selected to maximize the likelihood
of disease control.

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 14

Selection of disease modifying treatment vary in

highly active MS
For patients identified as having highly active MS, our most efficacious
agents should be used early despite increased risk of adverse events.

The treatment algorithm must be adjusted based on the estimated level of

risk, but in general patients with highly active MS will benefit from early
aggressive anti-inflammatory treatments selected to maximize the likelihood
of disease control.

Confidential – internal use only

 15

Which Patients with RRMS Should Be Considered for

Cladribine Tablets?
The first scenario considered patients with newly diagnosed RRMS, with
evidence of recent highly active MS, such as a higher level of recent MS
disease activity, a combination of relapse with radiological activity, MS
activity in the brainstem, cerebellum, or spinal cord, or with other adverse
prognostic factors (e.g. motor symptoms presentation or MRI findings in
high-risk regions).

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 16

What medications should be used to treat highly

active MS?

Use of oral medications such as fingolimod(Gilenya) and dimethyl

fumarate(Tecfidera) can be considered for patients with highly active MS.
The use of fingolimod or dimethyl fumarate as first line agents in patients with
highly active MS should be considered, especially among JCV seropositive patients.

The starting dose for TECFIDERA is 120 mg twice a day orally. After 7 days, the
dose should be increased to the maintenance dose of 240 mg twice a day.

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What medications should be used to treat highly

active MS?

Natalizumab(TYSABRI) is a highly effective medication for MS and is one

of the most used medications to treat highly active forms of MS.

The use of natalizumab should be considered early in the disease course of

highly active MS.

JC virus (JCV) serology (including titer) can help determine the safety of the
medication and in JCV negative patients it can be considered as a first line
agent. (with repeat JCV serology every 6 months) with low risk of PML.

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 19

TYSABRI: ONE-HOUR IV INFUSION ONCE EVERY 28

DAYS 

Recommended dose: 300 mg every 28 days.

Observe patients during the 1-hour IV infusion

and for 1 hour after the infusion is complete.

How supplied: 300 mg in a 15 mL, sterile,

single-dose vial.

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LEMTRADA (Alemtuzumab)

Recommended Dosage
The recommended dosage of LEMTRADA is
12 mg/day administered by intravenous
infusion for 2 treatment courses:

First Treatment Course: 12 mg/day on 5

consecutive days (60 mg total dose).

Second Treatment Course: 12 mg/day on 3

consecutive days (36 mg total dose)
administered 12 months after the first
treatment course.

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 21

What medications should be used to treat highly

active MS?
Anti- CD20+ B-cells

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What medications should be used to treat highly

active MS?

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What medications should be used to treat highly

active MS?

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Ofatumumab (Kesimpta)
• The U.S. Food and Drug Administration (FDA) approved Kesimpta
in August 2020 for treating adults with relapsing forms of MS,
including clinically isolated syndrome (CIS), relapsing-remitting
MS (RRMS), and active secondary progressive MS (SPMS).

• In March 2021, the European Commission approved Kesimpta for

the treatment of relapsing MS in adults with active disease.
• The therapy also is approved in Canada, Switzerland, Australia,
and Japan, among other countries.

• Kesimpta (20 mg subcutaneous) every

four weeks

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Cyclophosphamide
• Intravenous monthly cyclophosphamide
has been used to treat highly active forms of
MS.
• Cyclophosphamide is used monthly for 6
months with dosage based on white blood cell
count followed by a prolongation strategy
(doses at every 6 months) or transition to
other medication.
• An alternative approach involves high dose
induction therapy.
• Risks include hemorrhagic cystitis,
amenorrhea, and myelosuppression.

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Myeloablation
Myeloablation with autologous hematopoietic stem cell rescue
(“bone marrow transplantation”), although effective does carry a
significant risk of mortality ranging from 3 to 10%.

Bone marrow transplantation may be attempted in cases with high

disease activity despite use of most aggressive treatments.

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 28

Cladribine(Mavenclad)

2019,The U.S. Food and Drug Administration approved Mavenclad

(cladribine) tablets to treat highly active relapsing forms
of multiple sclerosis (MS) in adults.

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 29

Cladribine(Mavenclad)
Immune Reconstitution Therapies (IRT)

The persistence of efficacy beyond the apparent pharmacological

effects of the treatment is the hallmark of an IRT-like mechanism

IRTs differ from other DMTs used in MS in that they are not given
continuously. Rather, cladribine tablets and alemtuzumab IV are
given in two short courses 1 year apart .

The administration of a pharmacological IRT causes a marked

reduction in the number of circulating immune cells that recovers
slowly over time.
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 30

Cladribine(Mavenclad)
Immune Reconstitution Therapies (IRTs)

Specifically, there is a profound and rapid reduction in B (CD+19) cells

following treatment with cladribine tablets, which occurs over several
weeks and recovers over a period of about 1 year, with a slower and
smaller reduction in T cells, which recovers over about 18 months .

Treatment with cladribine tablets appears to exert little effect on

components of the innate immune system (e.g. monocytes or dendritic
cells) , while alemtuzumab may exert a larger effect on this component of
immunity.

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 31

®
MAVENCLAD is:
 An analog of the purine
nucleotide deoxyadenosine

 Designed by adding 1 chlorine

atom to deoxyadenosine

 Largely protected from degradation by deoxyadenosine MAVENCLAD®

adenosine deaminase (ADA) DEGRADED PROTECTED
BY ADA FROM ADA

Leist T, Weissert R. Clin Neuropharmacol 2011;34:28-35.

Confidential – internal use only

 32

How does cladribine reduce lymphocytes?

❷
ACCUMULATES
❶ intracellularly
ENTERS cell due to protection
via nucleoside from ADA
transporter

❸
ACTIVATED by
specific kinases

❹
APOPTOSIS induced
only by activated
cladribine

ADA = adenosine deaminase

*One of the kinases is deoxycytidine kinase (dCK). The phosphatase is 5’-nucleotidase
Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35.
 33

Current hypothesis for the long-term effect of MAVENCLAD on the immune system in MS ®

IRT with MAVENCLAD®

naive/mature
lymphocyte
Baseline Post-Reduction Post-Reconstitution
memory
lymphocyte

monocyte
B cells1,2,4

neutrophil

T cells1,2,5,6

Monocytes1
Neutrophils1,3
Illustrative concept of information published in:
1. Baker D, et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e360. 2. Sorensen PS, et al. ACTRIMS 2018 [P084].
3. Giovannoni G, et al. N Engl J Med 2010;362:416–426 [Suppl Materials]. 4. Ceronie B, et al. J Neurol 2018;265:1199–1209.
5. Stuve O, et al. ECTRIMS 2017 Abstract A-858-0029-01165 Poster P667. 6. Stuve O, et al. Mult Scler J 2018 p 398 P-50.
 34

MAVENCLAD is proposed to be classified as an

®

Immune Reconstitution Therapy (IRT)

Short-course dosing
with MAVENCLAD ® REDUCTION1,2 RECONSTITUTION3,4

transient long-term qualitative

lymphocyte reduction immune changes

short-term long-term
efficacy efficacy

1. Sorensen PS, et al. ACTRIMS 2018 [P084]. 2. Giovannoni G, et al. N Engl J Med 2010;362:416–426.
3. Ceronie B, et al. J Neurol 2018;265:1199–1209. 4. Giovannoni G, et al. Mult Scler J 2017 DOI: 10.1177/1352458517727603 p 1-11.
 35

Cladribine therapy* results in qualitative changes

in memory B cells 1 year after dosing
Mature Immature
Memory B Cells Naive B Cells Naive B Cells

Absolute
Number of
Memory
B cell subsets
x 106/L

Unswitched Switched CD25+ Mature Immature

Memory B cells Memory B cells Memory B cells Naive B cells Naive B cells

* Cladribine administered subcutaneously to 40 patients with MS off-label on compassionate grounds

Ceronie B, et al. J Neurol 2018;265:1199–1209.
 36

MAVENCLAD therapy results in qualitative changes in memory

®

and regulatory* T cells 48 weeks after dosing1,2

Memory CD4+ CD4+/CD25+/CD127-/RA-
T Cells T Cells

Median
Percentage
Number
of nTreg
of Cells
cells
per μL

Central Memory Effector Memory Th1-type Memory-like

T Helper Cells T Helper Cells T Helper Cells nTreg Cells

Oral cladribine 3.5 mg/kg given to patients with a first clinical demyelinating event in ORACLE-MS trial. Subset of 41 patients in ORACLE-MS study who
received at least one dose of Cladribine Tablets 3.5 mg/kg and had at least one lymphocyte surface marker (LSM) analysis using flow cytometry.
Longitudinal evaluation of peripheral blood lymphocyte subtypes using LSM at baseline and at 48 weeks
1. Stuve O, et al. ECTRIMS 2017 Abstract A-858-0029-01165 Poster P667. 2. Stuve O, et al. Mult Scler J 2018 p 398 P-50.
 37

CNS-compartmentalized inflammatory injury is hypothesized to play a key role in the pathophysiology of MS

• Peripheral- and CNS-compartmentalized

inflammatory injury both play important roles in
the pathophysiology of MS1
• Local inflammation and neurodegeneration
in the CNS compartment can be relatively resistant
to peripheral immune intervention and may
become dominant later in the disease process1
• MS therapies vary in their ability to penetrate the
blood–brain barrier2

CNS, central nervous system

1. Bar-Or A. Semin Neurol 2008;28:29–45. 2. Cheng Z, et al. Drug Metab Dispos 2010;38:1355–1361.
 38

Cladribine has the potential to penetrate the blood–brain barrier and enter the CNS compartment1-4

Blood

Blood–brain barrier
CSF

Cladribine CSF
concentration is
up to 25% of blood
concentration*

* In small study of cancer patients

CNS, central nervous system; CSF, cerebrospinal fluid

1. Liliemark J. Clin Pharmacokinet 1997;32:120-131. 2. Kearns C, et al. Cancer Res 1994;54:1235-1239.
3. Santana V, et al. Blood 1994;84:1237-1242. 4. Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35.
 39

Characteristics of MAVENCLAD that may explain its high and ®

sustained efficacy
Reduction & reconstitution of Qualitative immune changes that persist Potential to penetrate BBB
T and B lymphocytes1,2 beyond dosing period 3,4 and enter CNS5,6
naive/mature memory
lymphocyte lymphocyte

T and B cells play central Long-term qualitative changes in lymphocyte Not all DMDs are capable of
role in MS pathophysiology subsets appear to occur during reconstitution penetrating into CNS

1. Baker D, et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e360. 2. Sorensen PS, et al. ACTRIMS 2018 [P084].
3. Ceronie B, et al. J Neurol 2018;265:11 99–1209. 4. Stuve O, et al. ECTRIMS 2017 Abstract A-858-0029-01165 Poster 667.
5. Liliemark J. Clin Pharmacokinet 1997;32:120-131. 6. Cheng Z, et al. Drug Metab Dispos 2010;38:1355-1361.

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 40

Cladribine(Mavenclad)
Immune Reconstitution Therapies (IRT)

• Treatment with cladribine tablets is given at a

total cumulative dose of 3.5 mg/kg over 2 years .
• This involves two periods of 10 mg tablets 4–
5 days (depending on body weight) of oral
treatment 1 month apart at the start of
treatment, with the same regimen repeated 1
year later.
• The European labelling for cladribine tablets
states that “Following completion of the 2
treatment courses, no further cladribine
treatment is required in years 3 and 4”.
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 41

Cladribine(Mavenclad)
washout periods

• - No washout is needed following withdrawal of

interferons, dimethyl fumarate, or glatiramer
acetate, and cladribine tablets can be initiated
immediately.
• - Typical washout periods between withdrawal of
the prior DMT and initiation of cladribine tablets
are at least 4 weeks for fingolimod or
teriflunomide, about 4–8 weeks for natalizumab,
and at least 6–12 months for ocrelizumab or
alemtuzumab.

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 42

MS Activity after the First Dose of Cladribine

There is no formal clinical evidence base to guide therapy for patients who experience a
MS relapse during the first year of treatment with cladribine.

The treatment with cladribine tablets should be continued in this eventuality, rather
than switching to an alternative DMT, based on the assumption that the full efficacy of
the treatment would not be apparent until the full 2-year course had been given.

Thus, there is also no evidence-based guidance for the management of a patient with
RRMS who relapses during the second year of treatment, i.e. soon after the full dose of
cladribine tablets has been given.

The relapse would be treated with corticosteroids, in the normal way.

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 43

Cladribine(Mavenclad)
Administration and Monitoring
• The lymphocyte count must be in the normal range before treatment initiation and must have recovered to at least
800/mm2 before administering the second course (delay the second course if necessary, to allow recovery of
lymphocytes).
• It is important to screen for latent or pre-existing infections, particularly varicella/herpes zoster, hepatitis B or C,
tuberculosis, or HIV.
• Active infections (including TB, hepatitis B or C, PML, or HIV) are contraindications to the use of cladribine tablets.
• Patients who have not been exposed to Varicella zoster virus (by an antibody test) can be vaccinated against this virus
at least 4–6 weeks before starting treatment.
• Active malignancy and moderate or severe renal or hepatic impairments are further contraindications and must be
screened for and excluded in advance of treatment.
• Finally, an MRI scan should be performed at (or soon after) the time of treatment initiation to provide a new baseline
for evaluation of the therapeutic respons

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 44

Cladribine(Mavenclad)
Administration and Monitoring
• Special Consideration-Latent Tuberculosis
• Special attention must be made to the labelling requirement to exclude latent TB infection. Latent TB infection is not
uncommon in the countries of the Middle East, particularly where residents have travelled to TB-endemic areas or
have been in contact with others who have .
• It is recommended to prescribe the 3-month isoniazid/rifapentine protocol for a patient with latent TB, starting
treatment 1 month before initiating cladribine tablets and continuing for 2 months after.

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 45

Pregnancy and DMTs

• A patient who develops significant MS disease activity at this time presents a difficult challenge for clinical
management, as the risk to the pregnancy from a severe relapse must be balanced with perceived risks from
treatment with a DMT.
• If the physician concludes that a DMT is required, interferon beta is now indicated in Europe for use during
pregnancy.
• If a high-efficacy DMT is needed, most physicians would consider the use of natalizumab during pregnancy up to
week 30, based on experience in pregnant women and the lack of a formal contraindication for this treatment in
Europe or the USA.
• It should be noted that the continued use of natalizumab to delivery risks the development of haematologic
abnormalities in the neonate.

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Pregnancy

• The possibility of pregnancy must be excluded before starting treatment, and the labelling requires the
use of adequate contraception during treatment with cladribine tablets and for 6 months
after the last dose.

• It is currently unknown that Mavenclad may reduce the effectiveness of systemically acting hormonal
contraceptives. Therefore, women of child bearing potential, using systemically acting hormonal
contraceptives, should add a barrier method during cladribine treatment and up to 4 weeks after the last
dose.

• Accordingly, Men and women must use effective contraception during MAVENCLAD treatment.

Confidential – internal use only

 47

Pregnancy

• Many pregnancies are unplanned, however, and it is inevitable that some will be exposed to
treatments contraindicated at this time.

• Clinical experience on pregnancies exposed to cladribine tablets is limited to a survey of 64

pregnancies, which did not report an increased risk of adverse maternal or foetal outcomes .

• Women who become pregnant within 6 months of a dose of cladribine tablets who wish to
continue their pregnancy should be monitored carefully.

• If a patient becomes pregnant after the first treatment course of cladribine tablets, the
second course must be withheld until after delivery.

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 48

Breastfeeding
• During and one week after the last dose

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 Vaccination Narrative

Naïve or first 1. MAVENCLAD is the first and only high-efficacy DMT to

switch demonstrate a full antibody response to COVID-19 vaccine1
similar to healthy subjects and untreated people with MS,
regardless of lymphocyte count2

2. After starting cladribine tablets, live and attenuated

vaccines can be given after the lymphocytes return to
normal levels.

3. Vaccines that are not live nor live attenuated can be

administered any time , prior to or after starting
Mavenclad3

1. First-ever real-world data on the efficacy for MS patients to develop antibody response following Pfizer-BNT162b2-COVID-19 vaccination.
2. Achiron A et al. Ther Adv Neurol Disord. 2021;14:1-8.
3. Mavenclad SmPC
 Vaccination Narrative
Three key messages

Naïve or first 1. The European and US labels recommend that treatment with
switch cladribine should not be initiated within 4 to 6 weeks after
vaccination with live or attenuated live vaccines.

2. Live-attenuated vaccines should not be given to

patients who have received cladribine tablets while
lymphocyte counts are depressed.

1. First-ever real-world data on the efficacy for MS patients to develop antibody response following Pfizer-BNT162b2-COVID-19 vaccination.
2. Achiron A et al. Ther Adv Neurol Disord. 2021;14:1-8.
3. Mavenclad SmPC
 51

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 52

1. Giovannoni G, et al. N Engl J Med 2010;362:416–426.

2. Giovannoni G, et al. Mult Scler J 2017 DOI: 10.1177/1352458517727603 p 1-11.
3. Leist TP, et al. Lancet Neurol 2014;13:257–267.
4. Montalban X, et al. Neurol Neuroimmunol Neuroinflamm 2018;5:e477 DOI:10.1212/NXI.0000000000000477.
5. Cook S, et al. CMSC 2017 Poster DX69.

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 53

MAVENCLAD had an adverse event profile that was similar

®

to placebo except for lymphopenia

Discontinuation rate Most Frequently Reported MAVENCLAD® 3.5 mg/kg Placebo

due to AEs: 3.5%1 Adverse Events N = 430 N = 435

Any adverse event 80.7% 73.3%

Most common adverse events*

Headache 24.2% 17.2%

Lymphocytopenia1 21.6% 1.8%
Nasopharyngitis 14.4% 12.9%
Upper respiratory tract infection 12.6% 9.7%
Nausea 10.0% 9.0%
Any serious adverse events 8.4% 6.4%
Infections and infestations 2.3% 1.6%
Neoplasms¶ 1.4% 0.0%
Death 0.5% 0.5%
Data shown is from CLARITY trial only
*
Listed are symptoms that were reported by at least 10% of the patients in each group.
¶
Benign, malignant, and unspecified. Includes 5 patients with benign uterine leiomyoma and one each of stage 0 cervical in situ carcinoma (considered precancerous), melanoma, ovarian
carcinoma, pancreatic carcinoma, and myelodysplastic syndrome; the last was probably reactive bone marrow changes caused by tuberculosis infection and not true myelodysplasia.
1. Giovannoni G, et al. N Engl J Med 2010;362:416–426. 2. MAVENCLAD® SmPC Jul 2018.
 54

M AV E N C L A D ® H A S A MAXIMUM O F 2 0 D AY S O F O R A L D O S I N G 1

Discontinuation rate
due to AEs: 3.5%1

with 0% due to
Lymphopenia.

1. Giovannoni G, et al. N Engl J Med 2010;362:416–426.

 55

In up to 10 years of follow-up, the overall risk of infection with

MAVENCLAD was similar to placebo except for herpes zostera
®

Incidence of infections1,2

No increased risk of
infection1,3

No increased risk of No cases of PML reported

severe infection3 in patients receiving
MAVENCLAD® for MS
8,650 patient years2
0.6 additional cases of herpes
zoster per Placebo (n=641)
100 patient-years2 MAVENCLAD® (n=923)

Figure adapted from data in Cook S et al. ECF 2017 Poster & MAVENCLAD® EMA Assessment Report EMA/435731/2017.
a
All studies that used MAVENCLAD® monotherapy, matching the recommended dose: CLARITY, CLARITY EXT and ORACLE-MS + follow-up in PREMIERE.
b
Vaccination of varicella zoster antibody-negative patients is recommended prior to initiation of MAVENCLAD® therapy. Initiation of treatment with MAVENCLAD®
must be postponed for 4 to 6 weeks to allow for the full effect of vaccination to occur. Source: MAVENCLAD® SmPC
AE, adverse event; PML, progressive multifocal leukoencephalopathy.
1. Cook S, et al. EAN 2018 [EPO1082]. 2. MAVENCLAD® EMA Assessment Report EMA/435731/2017.
3. Giovannoni G, et al. N Engl J Med 2010;362:416–426.
 56

In up to 10 years of follow-up, the demonstrated rate of malignancies with

MAVENCLAD was almost identical to that of a matched reference population1
®

In clinical studies and long-term follow-up of patients

No. of No. of
treated with MAVENCLAD® 3.5 mg/kg, events of
malignancies were observed more frequently in
EXPECTED OBSERVED MAVENCLAD® -treated patients compared to patients
malignancy SIR: 0.97 malignancy who received placebo

events (95% CI 0.44–1.85)a events All studies that used MAVENCLAD®

monotherapy, matching the recommended dose:
CLARITY, CLARITY EXT and
ORACLE-MS + follow-up in PREMIERE

Unique Events
of Malignancya No haematological malignancies
were observed in the entire MAVENCLAD®
development programme2

No clustering of types of malignancies2

Expected Events Observed Events
reference population monotherapy oral cohort (3.5 mg/kg)
N=923 PY=3432.65
a
SIR calculated against the GLOBOCAN reference population (GLOBOCAN 2012,http://globocan.iarc.fr/default.aspx);
non-melanoma skin cancer excluded due to inconsistent reporting in GLOBOCAN 1. MAVENCLAD® EMA Assessment Report EMA/435731/2017
2. Galazka A, et al. EAN 2018 [EPO1083]
 57

MAVENCLAD has the lowest monitoring requirement of

®

all high-efficacy DMDs in a 4-year horizon1-6,a

Year 1 Year 2 Years 3 and 4
Before initiation of therapy Before continuation of therapy If last lymphocyte count is normal,
Normal blood lymphocyte counts (≥1000/mm3)7 Lymphocyte count ≥800/mm³ no further monitoring is required

2 months 6 months 2 months 6 months

after initiationb after initiationb after continuationb after continuationb

1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12

Month

Blood test Infection screeningd

The schedule for initiation and continuing therapy with MAVENCLAD® Weight-based dosing. Recommended treatment over 2 years. 1 treatment course per year, followed by observation for another
may need to be adjusted based on absolute lymphocyte counts1 2 years. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of
the second month of the respective year. A total of between 8 and 10 days of treatment is needed per treatment course based on
Treatment course in Year 2 can be delayed for up to 6 months patient weight.
to allow for recovery of lymphocytesc
a
Correct as of December 2017. bIf the lymphocyte count is below 500 cells/mm³, it should be actively monitored until values increase again.
If the lymphocyte count is below 200 cells/mm³, anti-herpes prophylaxis acccording to local standard practice should be considered during the
time of grade 4 lymphopenia. cIf recovery takes more than 6 months, the patient should not receive further treatment with MAVENCLAD®.
d
HIV infection, active TB and active hepatitis must be excluded before initiation of MAVENCLAD® in Year 1 and Year 2 DMD, disease-modifying drug. 1.
MAVENCLAD® SmPC Jul 2018. 2. Tecfidera® SmPC Nov 2017. 3. Gilenya® SmPC Apr 2018. 4. Lemtrada® SmPC Dec 2017.
5. Tysabri® SmPC Apr 2018. 6. Ocrevus® SmPC Mar 2018. 7. Cook S, et al. Mult Scler J 2010 DOI: 10.1177/1352458510391344 p 1–16.
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MAVENCLAD has a low burden of treatment

®

Year 1 Year 2
Dose Free Dose Free
Patients do not need to
remember to take
medication daily or weekly,
Low Dosing Burden 1 or undergo
Maximum 20 days of ORAL treatment in 2 years
IV line placement

Patients do not need

1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 laboratory monitoring of
liver enzymes, renal
Month function or other testing
Blood test Low Monitoring Burden 1

Infection screeninga Only requirement is total lymphocyte count 3 times per year for 2 years

HIV infection, active TB and active hepatitis must be excluded before initiation of MAVENCLAD® in Year 1 and Year 2
a

MAVENCLAD® SmPC Jul 2018.

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HIGH EFFICACY* ACROSS KEY CLINICAL PARAMETERS IN PATIENTS ON MAVENCLAD®

WITH HIGH DISEASE ACTIVITY**1
2 Year CLARITY in high disease activity patients (n=289)

82%
reduction in disability progression1
6-month confirmed EDSS progression
67%
reduction in ARR1

1. Giovannoni G et al. Mult Scler 2019; 25:819–827.

Confidential – internal use only

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A cohort study of therapy adherence and risk of relapse

• The proportion of participants remaining relapse-free

for 24 months increased with increasing MPR and the
proportion of those with one or more relapses declined
with increasing levels of MPR (p<0.0008).

MPR: Medication Possession Ratio

B.A. Cohen et al.76 Multiple Sclerosis and Related Disorders (2015)4,75–82

Confidential – internal use only

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Only a minority received a subsequent DMD after treatment with

MAVENCLAD
• A post-hoc analysis of patients with relapsing MS treated
with cladribine tablets 3.5 mg/kg as monotherapy (in
CLARITY, CLARITY Extension or ORACLE-MS and followed up
in PREMIERE) suggested that only a minority received a
subsequent DMD (for any reason) after treatment with
cladribine tablets. At 4 years after last dose of cladribine
tablets, the Kaplan-Meier estimated proportion of patients
who had initiated another DMD was 26.8%.

S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167

Confidential – internal use only

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Thank you

Confidential – internal use only