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![Subgroup at baseline HR (95% CI)
Definition Overall (N=870) 47% RR 0.53 (0.36, 0.79)b
HRA
Patients with ≥2 relapses during the year
prior to study entry, regardless of prior
use of DMD
HRA (n=261) 82% RR 0.18 (0.08, 0.44)c
Non-HRA (n=609) 19% RR 0.81 (0.51, 1.28)
HRA+TNR
As for HRA plus patients with ≥1 relapse
in the year prior to study entry while on
DMD and ≥1 T1 Gd+ or ≥9 T2 lesions
HRA+TNR (n=289) 82% RR 0.18 (0.07, 0.43)d
Non-HRA+TNR (n=581) 18% RR 0.82 (0.51, 1.30)
HR (95% CI)
6-month confirmed EDSS progression
Favours oral cladribine Favours placebo
High relapse activity subgroup of oral cladribine indicated reduced
relative risk of disease progression by 82% compared to placebo
28
Oral cladribine had a greater effect in patients in both the HRA and HRA+TNR subgroups on study
aAll HDA analyses were post-hoc and not prespecified; no multiplicity adjustments were done to the resulting p-values. All comparisons where the p-value was less than 0.05 by statistical testing
should be regarded as nominally significant; bp<0.0001; cP=0.0002; dP=0.0001. RR and associated 95% CIs were estimated using a Poisson regression model with fixed effects for treatment group, the
number of relapses in previous year as covariate and with the log of time on study as the offset variable. CI, confidence interval; DMD, disease-modifying drug; EDSS, Expanded Disability Status Scale;
HDA, high disease activity; HRA, high relapse activity; HRA+TNR, high relapse activity plus treatment non-response; RR, relative risk.
Giovannoni G, et al. EAN 2017 [EP1157].
10 0.5 1.5 2](https://image.slidesharecdn.com/sirtoslo1feb2018-180202071032/75/Sirt-oslo-1_feb2018-28-2048.jpg)
![40
Totallymphocytecount3
Median(Q1–Q3)lymphocytecount(109/L)a
Grade 1b
Grade 2
Grade 3
Grade 4
CLARITY CLARITY-EXT
c
Error bars represent 5–95 percentile range for cell counts at each time point.
aPooled data from CLARITY, CLARITY EXT and PREMIERE; figure includes treatment gap. Visits with sample size ≥30 are displayed; +Reductions in absolute
lymphocyte counts (lymphopenia) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE): 1, <lower limit of normal–
800/mm3; 2, <800–500/mm3; 3, <500–200/mm3; 4, <200/mm3; cPatients who received placebo in CLARITY and did not enter CLARITY EXT but were
registered in PREMIERE; dPlease note that lymphocyte count data were not available for all patients at every observation.
CP, Cladribine tablets (3.5 mg/kg) in CLARITY, placebo in CLARITY EXT.
Year 1 Year 2 Year 3 Year 4
434
683
415
645
263
437
378
624
358
574
86
298
94
265
69
167 147 131 116 106 66 32
Number of
patientsd
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 24 48 72 96 120 144 168 192 216 240 264 288 312
Weeks
Cladribine Tablets
Placebo
No further treatment
CP
MAVENCLAD® demonstrated durable efficacy beyond total lymphocyte
count recovery
Proportion of patients
qualifying as relapse free (%)1
77.8 75.6
0
20
40
60
80
100
CLARITY CLARITY EXT
MAVENCLAD®
(Cladribine tablets
3.5 mg/kg)
Years 1 & 2
MAVENCLAD®
(Cladribine tablets
3.5 mg/kg Years 1 & 2)
Placebo | Years 3 & 4
1. Figure adapted from Giovannoni G, et al. ECTRIMS 2016 [Abstract 553; Poster P636];
2. Giovannoni G, et al. ECTRIMS 2016 [Abstract 554; Oral 164];
3. Figure adapted from Soelberg-Sørensen P, et al. ECF 2016 [abstract and poster].](https://image.slidesharecdn.com/sirtoslo1feb2018-180202071032/75/Sirt-oslo-1_feb2018-40-2048.jpg)
![LYMPHOPENIA
INFECTIONS
MALIGNANCY
MAVENCLAD® has a well-characterised safety profile, with no cases of PML or
autoimmunity over 8 years of follow-up in the PREMIER safety registry1–8
47
• In clinical studies, malignancies were observed more frequently in MAVENCLAD®- treated
patients compared to patients who received placebo
• In the CLARITY trial, the SIR of malignancy was 0.99 (95% CI 0.25, 2.70) for MS patients
treated with MAVENCLAD® vs matched general population8
• In a meta-analysis, the malignancy rate for MAVENCLAD® in the CLARITY trial (0.34%) was
similar to that reported with DMTs in other trials (0.6%, p=ns)8
LYMPHOPENIA
INFECTIONS
MALIGNANCY
Transitory, mostly
mild-to-moderate1
Overall risk is similar to
placebo – except for
herpes zoster7
Malignancy incidence
is generally similar to
other DMTs8
• Grade 4 lymphopenia seen in <1% of patients5
• In clinical studies, 20–25% of patients developed transient Grade 3 or 4 lymphopenia5,6
• Patients generally recover to either normal lymphocyte counts or Grade 1 lymphopenia
within 9 months5
• Lymphocyte monitoring is required before and during treatment5
• Herpes zoster infection was more frequent in patients treated with MAVENCLAD® vs
placebo (1.9% [8/430] vs 0% [0/435])7
• All cases were dermatomal and only one was rated as serious (the patient was treated in
hospital with anti-viral therapy)7
• MAVENCLAD® may increase the likelihood of infections5
1. Giovannoni G, et al. N Engl J Med 2010;362:416–26; 2. Montalban X, et al. AAN 2016 [P3.029]; 3. Leist TP, et al. Lancet Neurol. 2014;13:257–67;
4. PREMIER Clinical trials registry. Available at: https://clinicaltrials.gov/ct2/show/NCT01013350 [Accessed November 2017];
5. MAVENCLAD® EU Summary of Product Characteristics; 6. Giovannoni G, et al. N Engl J Med 2010;362:416–26 (Supplementary information);
7. Cook S, et al. Mult Scler. 2011;17:578–93; 8. Pakpoor J, et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158.
CI, confidence interval; DMTs, disease-modifying therapy; ns, non-significant;
PML, progressive multifocal leukoencephalopathy;
SIR, standardised incidence ratio.](https://image.slidesharecdn.com/sirtoslo1feb2018-180202071032/75/Sirt-oslo-1_feb2018-47-2048.jpg)
More Related Content
Sirt oslo 1_feb2018
- 1. Klaus Schmierer, MBBS PhD FRCP Reader in Clinical Neurology & Consultant Neurologist Selective immune reconstitution therapy SIRT @KlausSchmierer Oslo, 1 Feb 2018
- 2. Disclosures (~acknowledgements) PI oftrials sponsored by Novartis, Roche, Teva, Medday. Involved in trials sponsored by Biogen, Genzyme, BIAL, Cytokinetics, Canbex. Speaking honoraria from, and/or served in an advisory role for, Biogen, Merck, Merck Inc., Novartis, Roche, Teva Supported for attendance of meetings by Genzyme, Merck, Novartis, and Roche. Research grant support from Biogen, Lipomed, Novartis, MS Society of Great Britain & Northern Ireland, National MS Society (US), Royal College of Radiologists, and Barts Charity.
- 3. The Royal LondonHospital St Bartholomew's Hospital Mile End Hospital The London Chest Hospital Newham University Hospital Whipps Cross University Hospital
- 4. Women Men Prevalence/ethnicit y Mult Scler2017;23:36-42 n east Londoners: 907,151
- 5. Two lessons aboutMS that guide my approach to treatment: 1 MS is “progressive” from day 1 2 People with MS have a better chance of leading a life uncompromised by disease if treated early
- 7.
- 8.
- 9. Doctor, please canI have a drug that … 1 Helps me get on with life as before 2 Hits the disease hard, whilst being gentle to me! 3 I can forget about
- 12. Define personality Worrier vsrisk taker Escalation IRT A treatment algorithm? Patient? Patient? Doctor? Doctor?
- 14. MS/EAE immunology iscomplex Baker D, et al. EBioMed 2017;16:41-50.
- 15. New MS lesions en- hance Miller etal, Brain 1988; McFarland, et al 1992 Barkhof, et al Acta Radiol 1992 Katz, et al Ann Neurol 1992 Bruck, et al Ann Neurol 1997 BBB disruption and perivascular inflammation lead to Gadolinium enhancement
- 16. Acute axonal damage& degeneration Trapp, et al. NEJM 1998
- 17. Switching off adaptiveimmune-response inhibits MS Baker D, et al. EBioMed 2017;16:41-50.
- 18. B, B cell;BBB, blood–brain barrier; CNS, central nervous system; HCAR2, hydroxycarboxylic acid receptor 2; MoA, mechanism of action; nrf 2, nuclear factor (erythroid-derived 2)-like 2; S1P1, sphingosine-1-phosphate receptor 1; T, T cell; Th, T-helper cell. Adapted from: Loleit V, et al. Curr Pharm Biotechnol. 2014;15:276–96; Scannevin R, et al. J Pharmacol Exp Ther. 2012;341:274–84; Chen H, et al. J Clin Invest. 2014;124:2188–92. Alemtuzumab CD52 Lysis of mature B and T cells Proposed MoA: Anti-migratory Fingolimod Natalizumab Lymph node BBB CNS S1P1 B T α4-integrin Proposed MoA: Pleiotropic effects Limits pyrimidine availability for rapid cell division Teriflunomide IFNs Activation of 100+ IFN-response genes Activation of 700+ nrf 2 responsive genes and HC-AR2 Glatiramer acetate Modulation of Th1:Th2 balance Dimethyl fumarate Proposed MoA: Targeted cell lysis Periphery Proposed MoA: Reduced proliferation CD20 Ocrelizumab CladribineIL2 modulator expands CD56-bright NK cells Daclizumab (anti-CD25)
- 20.
- 21.
- 26. 2 6 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0.5 0.4 0.3 0.2 0.1 0.0 Tcells(x109/L) Bcells(x109/L) Pre Post (Day 2) 36 9 12 15 18 Months after alemtuzumab (20 mg x 5) B cells CD8+ T cells CD4+ T cells AUC, area under the curve; EDSS, Expanded Disability Status Scale; GBM, glomerular basement membrane; ITP, immune thrombocytopenic purpura; SRD, sustained reduction in disability. Refer to alemtuzumab EU Summary of Product Characteristics for further information. Coles AJ, et al. Lancet 1999;354:1691–5. Tuohy O, et al. J Neurol Neurosurg Psychiatry 2015;86:208–15. Alemtuzumab EU Summary of Product Characteristics. • 36% autoimmune thyroid disorders3 • 1% serious events of ITP3 • 0.3% nephropathies (including anti-GBM disease)3 Haematological changes after alemtuzumab1 12-month sustained reduction in disability2 Months since first treatment %SRDofat-riskpopulation 60 0 12 24 36 48 60 72 84 96 108 120 50 40 30 20 10 0 EDSS-years 30 20 10 0 -10 -30 -50 -20 -40 Net better n=43 (50%) Net unchanged n=9 (10%) Net worse n=35 (40%) AUC values: EDSS change from baseline vs follow-up2 “NIRT is highly effective!”
- 27. Cladribine: Moderate Tcell effect, yet high efficacy T Baker D, et al. EBioMed 2017;16:41-50. Schmierer K, et al. ABN 2017, Poster 149.
- 28. Subgroup at baselineHR (95% CI) Definition Overall (N=870) 47% RR 0.53 (0.36, 0.79)b HRA Patients with ≥2 relapses during the year prior to study entry, regardless of prior use of DMD HRA (n=261) 82% RR 0.18 (0.08, 0.44)c Non-HRA (n=609) 19% RR 0.81 (0.51, 1.28) HRA+TNR As for HRA plus patients with ≥1 relapse in the year prior to study entry while on DMD and ≥1 T1 Gd+ or ≥9 T2 lesions HRA+TNR (n=289) 82% RR 0.18 (0.07, 0.43)d Non-HRA+TNR (n=581) 18% RR 0.82 (0.51, 1.30) HR (95% CI) 6-month confirmed EDSS progression Favours oral cladribine Favours placebo High relapse activity subgroup of oral cladribine indicated reduced relative risk of disease progression by 82% compared to placebo 28 Oral cladribine had a greater effect in patients in both the HRA and HRA+TNR subgroups on study aAll HDA analyses were post-hoc and not prespecified; no multiplicity adjustments were done to the resulting p-values. All comparisons where the p-value was less than 0.05 by statistical testing should be regarded as nominally significant; bp<0.0001; cP=0.0002; dP=0.0001. RR and associated 95% CIs were estimated using a Poisson regression model with fixed effects for treatment group, the number of relapses in previous year as covariate and with the log of time on study as the offset variable. CI, confidence interval; DMD, disease-modifying drug; EDSS, Expanded Disability Status Scale; HDA, high disease activity; HRA, high relapse activity; HRA+TNR, high relapse activity plus treatment non-response; RR, relative risk. Giovannoni G, et al. EAN 2017 [EP1157]. 10 0.5 1.5 2
- 29. Antigen presentation Autoantibody production Ectopic lymphoid follicle-like clusters inthe CNS Functional role of B cells in MS Cytokine production
- 30. SIRT is alsohighly effective NEDA p<0.0001 Hauser S, et al. N Engl J Med 2017;376:221-34.
- 31. Hauser S, etal. Neurology 2013;80 (suppl) S31.004. Hughes S (2013) http://www.medscape.com/viewarticle/781671. Palanichamy A, et al. J Immunol 2014;193:580-6. Baker D, et al. EBioMed 2017;16:41-50. Unexpected long term effects of B cell depletion
- 32. Alemtuzumab – similarefficacy, different adverse effects Baker D, et al. JAMA Neurol 2017.
- 33. Baker D, etal. Neurol Neuroimmunol Neuroinflamm 2017. Cladribine – B cell depletion, no secondary autoimmunity!
- 34. Effective DMTs depletememory B cells Baker D, et al. EBioMed 2017;16:41-50. Schmierer K, et al. ABN 2017, Poster 150.
- 35. Mitoxantrone Fingolimod Beta Interferon Hierarchyof Responsiveness Dooley J et al. Neurology N2 2016 3 (e240). Baker D et al. EBioMedicine 2017;16:41. Ceronie B, et al. ECTRIMS 2017:P1896. Cladribine Cladribine n=11 Effective DMTs deplete memory B cells
- 36. Baker D, etal. EBioMed 2017;16:41-50. Schmierer K, et al. ABN 2017, Poster 150. Effective DMTs deplete memory B cells
- 37. B and Tlymphocytes MAVENCLAD® selectivity for lymphocytes is due to preferential intracellular activation in B and T cells 37Saven A, Piro LD. Ann Intern Med 1994;120:784–91; Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35. Other cells Slow degradation by ADA MAVENCLAD® HIGH levels of activated MAVENCLAD® High kinase-to-phosphatase ratio MAVENCLAD® kinase activation phosphatase inactivation Slow degradation by ADA MAVENCLAD® Low levels of activated MAVENCLAD® Low kinase-to-phosphatase ratio MAVENCLAD® kinase activation phosphatase inactivation High levels of activated MAVENCLAD® Low levels of activated MAVENCLAD® ADA, adenosine deaminase
- 38. Ceronie B, etal. European Charcot Foundation 2017. DCK expression showing (relative) preference of Cladribine for B cells
- 39. Ceronie B, etal. European Charcot Foundation 2017. Both Cladribine and Alemtuzumab effectively suppress Memory B cells
- 40. 40 Totallymphocytecount3 Median(Q1–Q3)lymphocytecount(109/L)a Grade 1b Grade 2 Grade3 Grade 4 CLARITY CLARITY-EXT c Error bars represent 5–95 percentile range for cell counts at each time point. aPooled data from CLARITY, CLARITY EXT and PREMIERE; figure includes treatment gap. Visits with sample size ≥30 are displayed; +Reductions in absolute lymphocyte counts (lymphopenia) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE): 1, <lower limit of normal– 800/mm3; 2, <800–500/mm3; 3, <500–200/mm3; 4, <200/mm3; cPatients who received placebo in CLARITY and did not enter CLARITY EXT but were registered in PREMIERE; dPlease note that lymphocyte count data were not available for all patients at every observation. CP, Cladribine tablets (3.5 mg/kg) in CLARITY, placebo in CLARITY EXT. Year 1 Year 2 Year 3 Year 4 434 683 415 645 263 437 378 624 358 574 86 298 94 265 69 167 147 131 116 106 66 32 Number of patientsd 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0 24 48 72 96 120 144 168 192 216 240 264 288 312 Weeks Cladribine Tablets Placebo No further treatment CP MAVENCLAD® demonstrated durable efficacy beyond total lymphocyte count recovery Proportion of patients qualifying as relapse free (%)1 77.8 75.6 0 20 40 60 80 100 CLARITY CLARITY EXT MAVENCLAD® (Cladribine tablets 3.5 mg/kg) Years 1 & 2 MAVENCLAD® (Cladribine tablets 3.5 mg/kg Years 1 & 2) Placebo | Years 3 & 4 1. Figure adapted from Giovannoni G, et al. ECTRIMS 2016 [Abstract 553; Poster P636]; 2. Giovannoni G, et al. ECTRIMS 2016 [Abstract 554; Oral 164]; 3. Figure adapted from Soelberg-Sørensen P, et al. ECF 2016 [abstract and poster].
- 41. Antibody Secretion Cytokine Secretion APC Function CD21 C3d Receptor (EBVreceptor) Memory B cell MHC Y EBV Alemtuzumab Effective Anti-Immune Effect Eliminate Viral Reservoir Memory B cells link clinical observation, immune phenotyping and biology of disease
- 42. Oct 2012Oct 2012Jun 2015 Apr 2016Oct 2014Mar 2012 Optic neuritis MRI+ve Jun 2015 JCV+ve (index = 2.7) Apr 2016 Alemtuzumab or cladribine tablets? Copaxone Spinal cord weakness right leg, off balance IV methylprednisolone Mar 2012 Natalizumab MRI: 2 Gd+ve spinal cord lesions MRI: every 3 months Fingolimod MRI: 2 new T2 lesions brain Lumbar puncture to rule out PML EDSS = 4.0 EDSS = 2.5 EDSS = 2.5 EDSS = 2.5 Caroline, 37 years Oct 2014 EDSS, Expended Disability Status Scale; Gd+, gadolinium-enhancing; iv, intravenous; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy.
- 44.
- 45.
- 46.
- 47. LYMPHOPENIA INFECTIONS MALIGNANCY MAVENCLAD® has awell-characterised safety profile, with no cases of PML or autoimmunity over 8 years of follow-up in the PREMIER safety registry1–8 47 • In clinical studies, malignancies were observed more frequently in MAVENCLAD®- treated patients compared to patients who received placebo • In the CLARITY trial, the SIR of malignancy was 0.99 (95% CI 0.25, 2.70) for MS patients treated with MAVENCLAD® vs matched general population8 • In a meta-analysis, the malignancy rate for MAVENCLAD® in the CLARITY trial (0.34%) was similar to that reported with DMTs in other trials (0.6%, p=ns)8 LYMPHOPENIA INFECTIONS MALIGNANCY Transitory, mostly mild-to-moderate1 Overall risk is similar to placebo – except for herpes zoster7 Malignancy incidence is generally similar to other DMTs8 • Grade 4 lymphopenia seen in <1% of patients5 • In clinical studies, 20–25% of patients developed transient Grade 3 or 4 lymphopenia5,6 • Patients generally recover to either normal lymphocyte counts or Grade 1 lymphopenia within 9 months5 • Lymphocyte monitoring is required before and during treatment5 • Herpes zoster infection was more frequent in patients treated with MAVENCLAD® vs placebo (1.9% [8/430] vs 0% [0/435])7 • All cases were dermatomal and only one was rated as serious (the patient was treated in hospital with anti-viral therapy)7 • MAVENCLAD® may increase the likelihood of infections5 1. Giovannoni G, et al. N Engl J Med 2010;362:416–26; 2. Montalban X, et al. AAN 2016 [P3.029]; 3. Leist TP, et al. Lancet Neurol. 2014;13:257–67; 4. PREMIER Clinical trials registry. Available at: https://clinicaltrials.gov/ct2/show/NCT01013350 [Accessed November 2017]; 5. MAVENCLAD® EU Summary of Product Characteristics; 6. Giovannoni G, et al. N Engl J Med 2010;362:416–26 (Supplementary information); 7. Cook S, et al. Mult Scler. 2011;17:578–93; 8. Pakpoor J, et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158. CI, confidence interval; DMTs, disease-modifying therapy; ns, non-significant; PML, progressive multifocal leukoencephalopathy; SIR, standardised incidence ratio.
- 48. Choose therapy A BC Define the individual’s MS Treatment failure? • Patient’s preferences? • Your choice? Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers, e.g. NABs? Monitoring Personalisation: • MS prognosis based on clinical and MRI indices • Lifestyle and goals • Shared goals for therapy Rebaseline Rebaselining: • IFNβ, natalizumab, fingolimod, teriflunomide, Dimethyl- Fumarate= 3-6 months • Glatiramer acetate= 9 months • Induction= (6 and) 24 months Choose a therapeutic strategy Maintenance-escalation Immune reconstitution/selective suppression Choose therapy X Z Rebaseline Monitoring Initiate, switch or escalate Rx Complete course / Re-treat Breakthrough disease NoYes Yes • Two licensed ‘induction’ therapies at present IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment Giovannoni G, et al. Mult Scler Relat Disord 2015;4:329-33. Y Consider changing induction Rx BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity
- 49. @KlausSchmierer www.ms-res.org David Baker BryanCeronie Cristo Albor Cesar Alvarez-Gonzalez Daniele Carassiti Dayo Afolabi Francesco Scaravilli Gareth Pryce Gavin Giovannoni Monica Marta Natalia Petrova Samuel Herrod Sharmilee Gnanapavan Zhifeng Mao