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Sirt oslo 1_feb2018
1. Klaus Schmierer, MB BS PhD FRCP
Reader in Clinical Neurology & Consultant Neurologist
Selective immune reconstitution therapy
SIRT
@KlausSchmierer
Oslo, 1 Feb 2018
2. Disclosures (~acknowledgements)
PI of trials 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 London Hospital
St Bartholomew's Hospital
Mile End Hospital
The London Chest Hospital
Newham University Hospital
Whipps Cross University Hospital
5. Two lessons about MS 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
9. Doctor, please can I 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
15. New MS
lesions
en-
hance
Miller et al, 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
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)
3 6 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 T cell 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 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
30. SIRT is also highly effective
NEDA
p<0.0001
Hauser S, et al. N Engl J Med 2017;376:221-34.
31. Hauser S, et al. 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 – similar efficacy, different adverse effects
Baker D, et al. JAMA Neurol 2017.
33. Baker D, et al. Neurol Neuroimmunol Neuroinflamm 2017.
Cladribine – B cell depletion, no secondary autoimmunity!
34. Effective DMTs deplete memory B cells
Baker D, et al. EBioMed 2017;16:41-50. Schmierer K, et al. ABN 2017, Poster 150.
35. Mitoxantrone
Fingolimod
Beta Interferon Hierarchy of 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, et al. EBioMed 2017;16:41-50. Schmierer K, et al. ABN 2017, Poster 150.
Effective DMTs deplete memory B cells
37. B and T lymphocytes
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, et al. European Charcot Foundation 2017.
DCK expression showing (relative) preference of
Cladribine for B cells
39. Ceronie B, et al. 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
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].
47. 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.
48. Choose therapy
A B C
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
Bryan Ceronie
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
