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Mavenclad – Safety & Tolerability

MAVENCLAD® USE IS SUPPORTED BY OVER 13 YEARS OF CLINICAL STUDY EXPERIENCE IN MS1,2,4,6-8

*High-efficacy, defined by the Association of British Neurologist as “[DMTs] with an average relapse reduction substantially more than 50%14
The length of the arrows in this diagram indicated the total duration of each study, including patient enrolment and follow-up.
Studies in orange=efficacy and safety results considered for indication; blue=safety results considered for indication; grey=safety results considered for indication
ABN=Association of British Neurologists; DMT=disease-modifying therapy; MS=multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis

MAVENCLAD® is generally well-tolerated. Only 3.5% of patients discontinued treatment due to adverse events

In the CLARITY trial, incidences of the most commonly reported AEs for MAVENCLAD® were comparable to placebo, with the exception of lymphopenia1-3

*There were 4 deaths (2 each in the MAVENCLAD® and placebo groups). Causes of death during the study were suicide and haemorrhagic stroke (placebo), and acute myocardial infarction and metastatic pancreatic cancer (MAVENCLAD®)
**1 each melanoma, pancreatic cancer, ovarian cancer
AE=adverse event

MAVENCLAD® has a well-characterised safety profile with no cases of PML or autoimmunity over 8 years of follow-up in the premiere safety registry1,4,22-26

LYMPHOPENIA

Transient, mostly mild-to-moderate lymphopenia was observed1,22

<1%

patients** treated with MAVENCLAD® developed grade 4 (<0.2 x 109/L) lymphopenia2

Patients generally recover to either normal lymphocyte counts or grade 1 lymphopenia within 9 months2

Transient, mild-to-moderate lymphopenia was observed following MAVENCLAD® dosing1,2,23,27,28

 

  • Median lymphocyte count remained within normal range in Year 127
  • Grade 4 lymphopenia was observed in <1% of patients1
  • There were no cases of grade 4 lymphopenia at the end of either treatment years28
  • There was minimal impact on innate immune function1,3,9-11
Data from the 2-year CLARITY trial
*Pooled data from CLARITY, CLARITY Extension and PREMIERE
**Lymphocyte counts (lymphopenia) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE):3 Grade 1: <LLN–800 cells/mm3; Grade 2: <800–500 cells/mm3; Grade 3: <500–200 cells/mm3; Grade 4: <200 cells/mm3
LLN=lower limit of normal

INFECTIONS

Overall risk is comparable to placebo – except herpes zoster22-24

MAVENCLAD® may increase the likelihood of infections2

The overall risk of infections with MAVENCLAD® was similar to placebo.22-24
With the exception of herpes zoster

In CLARITY, over 2 years

Infections

• Infections were reported in 47.7% of patients receiving MAVENCLAD® 3.5 mg/kg (n=430) vs. 42.5% of patients receiving placebo (n=435)23

Serious infections occurred in:2

• 10 patients (2.3%) treated with MAVENCLAD®
• 7 patients (1.6%) treated with placebo

The risk of infections was correlated with lymphocyte count; patients should be screened for latent infection and patients with a lymphocyte count <0.5 x 109/L should be monitored for signs of infection1

MAVENCLAD® may increase the likelihood of infections1

Herpes zoster

Consider vaccination in antibody-negative patients prior to treating with MAVENCLAD®1

If patients receive a live or attenuated live vaccine (including those for herpes zoster), MAVENCLAD® should be postponed for 4-6 weeks

If lymphocyte counts drop below <0.2 x 109/L, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia1

PML

Over 8 years of follow-up in the PREMIERE safety registry, there were no cases of PML reported during the clinical trial programme for MAVENCLAD®1

Cases of PML have been reported for parenteral cladribine* in patients treated for hairy cell leukaemia with a different treatment regimen1

Analysis of all patients receiving a cumulative dose of MAVENCLAD® 3.5 mg/kg in CLARITY or CLARITY EXT, including time in the MAVENCLAD® PREMIERE safety registry

MALIGNANCY

No increased risk compared with the general population4,25

Expected vs. observed malignancies with MAVENCLAD® †25,26

In clinical studies, malignancies were observed more frequently in MAVENCLAD®-treated patients compared to patients who received placebo

The rate of malignancy with MAVENCLAD® is similar to other DMTs29

Third-party analysis of malignancy rates in the treatment arms of clinical trials of DMTs29

By meta-analysis, the rate of malignancy with MAVENCLAD® was similar to that reported with other DMTs in pivotal trials:

  • MAVENCLAD®: 0.34%
  • Other treatment arms: 0.6%, p=n.s.
  • The rate of malignancy in the placebo arm of CLARITY was lower than that in other trials

DMT=disease-modifying therapy; IFN=interferon

Pregnancy and breast-feeding1

  • MAVENCLAD® is contraindicated in pregnant women
  • Based on experience with other agents that inhibit DNA synthesis and evidence of teratogenicity with cladribine in animal studies, MAVENCLAD® could cause congenital malformations1
  • Highly effective contraception is recommended for female and male patients during treatment and for 6 months after completing each treatment course1
  • Before initiation of treatment both in year 1 and year 2, women of childbearing potential and males who could potentially father a child should be counselled regarding the potential for serious risk to the foetus and the need for effective contraception1
  • It is not known if cladribine is excreted in breast milk. Patients should not breastfeed during the MAVENCLAD® treatment weeks and for 1 week after the last dose1
  • Women using systemically acting hormonal contraceptives should add a barrier method during MAVENCLAD® treatment and for at least 4 weeks after the last dose in each treatment year
Data from the 2-year CLARITY trial
SIR is calculated in post-hoc analysis by dividing the observed number of cancers during the study by the number of expected cases, according to rates from a reference population
*In the clinical study database (1,976 patients, 8,650 patient-years) no case of PML has been reported, accurate at date of creation – May 2018. However, a baseline MRI should be considered before initiating MAVENCLAD® (usually within 3 months). This is particularly recommended if patients are switched from other MS agents that have a risk of PML
†Integrated safety analysis of CLARITY, CLARITY EXT, ORACLE-MS, PREMIERE (oral monotherapy cohort) compared to global malignancy database GLOBOCAN 20126
††SIR calculated against the GLOBOCAN (2012) reference population; non-melanoma skin cancer excluded due to inconsistent reporting in GLOBOCAN 2012 (http://globocan.iarc.fr/default.aspx)
CI=confidence interval; MRI=magnetic resonance imaging; MS=multiple sclerosis; PML=progressive multifocal leukoencephalopathy; PY=patient-years; SIR=standardised incidence ratio

 

VIEW REFERENCES

1. MAVENCLAD® Summary of Product Characteristics. Merck.
2. Giovannoni G, et al. N Engl J Med. 2010;362:416–26.
3. Giovannoni G, et al. N Engl J Med. 2010;362:416–26 (Supplementary information).
4. Giovannoni G, et al. Mult Scler. 2018;24:1594–1604.
5. Data on file CLAD005
6. Montalban X, et al. AAN. 2016;[P3.029].
7. Leist TP, et al. Lancet Neurol. 2014;13:257–67.
8. PREMIERE Clinical trials registry. Available at: https://clinicaltrials.gov/ct2/show/NCT01013350 [Accessed 19th November 2018].
9. Baker D, et al. Neurol Neuroimmunol Neuroinflamm. 2017;4:e360.
10. Soelberg-Sørensen P, et al. ENS. 2009;[P359].
11. Soelberg-Sørensen P, et al. ENS. 2010;[P442].
12. Giovannoni G. Neurotherapeutics. 2017;14:874-7.
13. Giovannoni G. Curr Opin Neurol. 2018;31:233–43.
14. Scolding N, et al. Pract Neurol. 2015;15:273–9.
15. Cook S, et al. AAN. 2016;[P3.058].
16. Giovannoni G, et al. Lancet Neurol. 2011;10:329–37.
17. Giovannoni G, et al. Mult Scler. 2018;doi: 10.1177/1352458518771875.
18. Giovannoni G, et al. ECTRIMS. 2017;[P1143].
19. Alemtuzumab Summary of Product Characteristics. Sanofi Genzyme.
20. Natalizumab Summary of Product Characteristics. Biogen.
21. Ocrelizumab Summary of Product Characteristics. Roche.
22. Cook S, et al. EAN. 2017;[P0543].
23. Cook S, et al. Mult Scler. 2011;17:578–93.
24. Cook S, et al. ECTRIMS-ACTRIMS. 2017;[P1142].
25. Galazka A, et al. ECTRIMS-ACTRIMS. 2017;[P1878].
26. MAVENCLAD® European Public Assessment Report, September 2017.
27. Soelberg-Sørensen P, et al. EAN. 2017;[EP3120]
28. Data on File, CLAD001 – Incidence of Lymphopenia, June 2018.
29. Pakpoor J, et al. Neurol Neuroimmunol Neuroinflamm. 2015;2:e158.
30. Stuve O, et al. ECTRIMS. 2017;[P690].
31. Soelberg-Sørensen P, et al. ECTRIMS. 2017;[P1141].
32. Cvetanovich GL, Hafler DA. Curr Opin Immunol. 2010;22:753–60.
33. Ceronie B, et al. J Neurol. 2018;265:1199–1209.
34. Leist TP, et al. Clin Neuropharmacol. 2011;34:28–35.
35. Giovanni G, et al. Mult Scler. 2017; doi:10.1177/1352458517727603.
36. Giovanni G, et al. EAN. 2017; [PO542].
37. Giovanni G, et al. ECTRIMS. 2016.

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Reporting Adverse Events
Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk. In the Republic of Ireland information can be found at www.hpra.ie. Adverse events should also be reported to Merck Serono Limited – Tel: +44(0)20 8818 7373 or email: medinfo.uk@merckgroup.com.