Post on 14-Apr-2017
How close are we to a cure in multiple sclerosis?
Prof. Gavin GiovannoniBarts and The London School of Medicine and Dentistry
Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Professor Giovannoni would like to acknowledge and thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.
3
Window of therapeutic efficacy
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
David Baker’s Animal Model
Jackson et al. J Neuropathol Exp Neurol. 2009;68(6):616-25.
Day 7Day 0
ctrl Day 29 Day 58
Day 105 Early-tolerisation Late-tolerisation
Hampton et al. J Neuroimmunol. 2008;201-202:200-11.Pryce et al. J Neuroimmunol. 2005;165(1-2):41-52.
Prevention of relapsing CREAE after three paralytic episodesdoes not inhibit secondary progression and deterioration of mobility
Pryce et al. J Neuroimmunol 2005.
Durable Efficacy in RRMS Patients Receiving Two Annual Courses of Alemtuzumab and
No Additional Treatment for 4 Years: Pooled Analysis of CARE-MS I and II
Edward J Fox,1 Douglas L Arnold,2,3 Jeffrey A Cohen,4 Gavin Giovannoni,5 Hans-Peter Hartung,6 Eva Havrdova,7 Krzysztof W Selmaj,8 Volker Limmroth,9
David H Margolin,10 Karthinathan Thangavelu,10 Alasdair J Coles11; on behalf of the CARE-MS Investigators
1Central Texas Neurology Consultants, Round Rock, TX, USA; 2NeuroRx Research, Montréal, Québec, Canada; 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 4Cleveland Clinic, Cleveland, OH, USA; 5Queen Mary University of London, Barts and The London School of Medicine, London, UK; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Medical University of Łódź, Łódź, Poland; 9Klinik für
Neurologie und Palliativmedizin, Köln, Germany; 10Sanofi Genzyme, Cambridge, MA, USA; 11University of Cambridge School of Clinical Medicine, Cambridge, UK
AAN 2016Presentation S51.005
Hypothesis: Alemtuzumab Mechanism of Action May Explain Durability of Effect
7
3. Repopulation
BT
T-cellprecursor
Pre/Pro B cell
Lymphocyteprecursor
Stem cell
BT
Lymphocytes repopulate over time3,4
1. Selection
Alemtuzumab binds to CD52, a cell surface antigen present on T and B lymphocytes1,2
Plasma cells
Neutrophils
Lymphocyte precursor
CD52
Macrophages
CD52Monocytes
CD
52
CD52
CD52
CD52
CD52
T
CD
52
CD52
CD52
CD52
CD52B
2. Depletion
CD52 BCD52T
LymphocyteprecursorDepletes circulating T and B lymphocytes1,2
T B
• Following depletion, a distinctive pattern of T- and B-cell repopulation and a shift in cytokines toward a less inflammatory pattern may both contribute to durable efficacy in the absence of continuous treatment
1. Hu Y et al. Immunology 2009;128:260-70; 2. Rao SP et al. PLoS One 2012;7:e39416; 3. Cox AL et al. Eur J Immunol 2005;35:3332-42;4. Hill-Cawthorne GA et al. J Neurol Neurosurg Psychiatry 2012;83:298-304.
AAN 2016
Durable Efficacy on Disability Outcomes Through 5 Years in Patients Receiving Only the Initial 2 Courses of Alemtuzumab
Through Year 5:• 84% had no evidence of 6-month confirmed disability worsening• 43% achieved 6-month confirmed disability improvement
– Of these, 96% were free from 6-month confirmed disability worsening
8
AAN 2016
aEDSS score improvement (≥1.0-point decrease), or stability (≤0.5-point change) compared with baseline EDSS.Confirmed disability worsening: ≥1-point EDSS increase over 6 months.Confirmed disability improvement: ≥1-point EDSS decrease over 6 months for patients with EDSS ≥2.0 at core study baseline.
Mean EDSS Score Over 5 Years
No. ofPatients
445 440 444 440 444 418 417 409 403 395 381
0
Patients With Improved/Stable EDSS Scorea
No. ofPatients 444 417 403 381
89.9 89.4 87.187.3
Years 0–2
Years 0–3
Years 0–4
Years 0–5
≥1-Point improvementStable (≤0.5-point change)
Prop
ortio
n of
Pat
ient
s, %
Most Patients Receiving Only the Initial 2 Courses of Alemtuzumab Achieved NEDA Through 5 Years
9
AAN 2016
No. of Patients
254/370278/384297/407316/427
• 51% of patients achieved sustained NEDA over Years 3–5
NEDA (no evidence of disease activity): no evidence of clinical disease activity (relapse and 6-month disability worsening) and MRI disease activity (new Gd-enhancing T1 on current MRI and new/enlarging T2 hyperintense lesions since last MRI).
Prop
ortio
n of
Pat
ient
s, %
(95%
CI)
Proportion of Patients With NEDA Over 5 Years
Core Studies Extension Study
Alemtuzumab 12 mg (no retreatment or other DMT)
Slowing of Brain Volume Loss Through 5 Years in Patients Receiving Only the Initial 2 Courses of Alemtuzumab
• Median yearly BVL progressively decreased over 3 years and remained low in Years 4 and 5
10
Percentage BVL From Baseline
AAN 2016
Year
Med
ian
Cha
nge
From
B
asel
ine,
% (9
5% C
I)
No. of Patients 43
8432
430
407
384
373
Extension StudyCore Studies
Alemtuzumab 12 mg (no retreatment or other DMT)
Median Annual Brain Volume Change
Extension StudyCore StudiesNo. of Patients 432 429 407 378 358
Alemtuzumab 12 mg (no retreatment or other DMT)
Year
BPF=brain parenchymal fraction; BVL=brain volume loss
Tuohy t al. J Neurol Neurosurg Psychiatry 2014;0:1–8.
Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy
“Four alemtuzumab-treated patients (5%) fulfilled the definition of secondary progression of two consecutive SAD events.”
Autoreactive T Cell
Non-autoreactive T Cell
Autologous hemopoeitic stem cell (HSCT) or bone marrow transplantation (BMT)
Association of non-myeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis
Burt et al. JAMA. 2015 Jan 20;313(3):275-84
Please note that this was an open-label study and there were no treatment related deaths.
High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report
Nash et al. JAMA Neurol. 2015 Feb;72(2):159-69.
Atkins et al. Lancet. 2016 Jun 8. Pii: S0140-6736(16)30169-6. doi: 10.1016/S0140-6736(16)30169-6.
100
90
80
70
60
50
40
30
20
10
0
M3 M6 M9 M12 M15 M18 M21 M24
Time to McDonald MS conversion from randomization date (Months)
203 (0) 165 (37) 119 (82) 113 (87) 108 (88) 87 (95) 71 (96) 39 (98) 1 (99)Cladribine 5.25 mg/kg
204 (0) 167 (36) 114 (88) 108 (92) 92 (102) 82 (104) 71 (107) 39 (110) 3 (110)Cladribine 3.5 mg/kg
201 (0) 143 (58) 71 (128) 58 (141) 43 (154) 32 (162) 23 (165) 13 (169) 2 (169)Placebo
Patients at risk (conversions):
87.1%
51.4%
56.1%
Hazard ratio vs placebob
5.25 mg/kg: 0.425, p<0.00013.5 mg/kg: 0.496, p<0.0001
Cu
mu
lati
ve in
cid
ence
(%
)
Risk reduction5.25 mg/kg: 57.5%3.5 mg/kg: 50.4%
Cladribine reduces the risk of conversion to MS in treatment-naïve patients with a first clinical demyelinating event (FCDE)
– Cladribine 5.25 mg/kg
– Cladribine 3.5 mg/kg
– Placebo
ORACLE-MS
M0
aPatients enrolled in ORACLE-MS were treatment-naïve with an FCDE at high risk of converting to MS. bCox proportional hazards model controlling for the randomization stratification factor (region). FCDE, first clinical demyelinating event; M, Month. Leist TP et al. Lancet Neurol 2014;13:257-67
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100%Benign MS
Proportioned of treated MSers are cured
Naturalhistory
Unrealisticexpectation
Delayed onset of SPMS
CUREREMISSION
survival analysis
“moderately effective maintenance treatments”
“ pulsed immune reconstitution therapy or PIRT”
Secondary Progression
MS is a neurodegenerative
disease hypothesis
No Secondary ProgressionMS is an autoimmune
disease hypothesis
15-20 yearexperiment
Multiple Sclerosis
Environ-ment
Genes
Defining an MS cure?
Hill-Cawthorne et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304.
Treating-2-Target
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
OCB-ve
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
NED
A
END
-ORG
AN
DA
MA
GE
Where to from here?
1. Safer & more cost-effective PIRTs (pulsed immune reconstitution therapies)a. Cladribine
i. EMA (oral cladribine, Merck)ii. Investigator-led studies (sc cladribine, PI - Dr Klaus Schmierer)
b. Anti-CD20i. Ocrelizumab (Roche)ii. Ofatumumab (Novartis)iii. Ublituximab (TG Therapeutics)iv. Rituximab (Investigator-led study, COR-NIH/Kaiser, PI Anette Langer-Gould)
c. HSCT
i. Non-myeloablative HSCT vs. current best care (alemtuzumab (CD52), natalizumab (VLA-4), ocrelizumab (CD20) (PI: Paulo Muraro, Imperial)
ii. Non-myeloablative vs. myeloablative (PI: Basil Sharrack, Sheffield)
2. Follow the biologya. Long-lived plasma cells
i. Proteasome inhibitors (Takeda, Dr Sharmilee Gnanpavan)ii. Teriflunomide (Genzyme-Sanofi, Giovannoni)iii. Cladribine (Merck / Klaus Schmierer)iv. BTK inhibitors (Merck)
delayed worsening1 stabilised2
improved function3 recovered function4
Managing expectations: what does a cure mean?
✓
Does the biology of MS change with time?
Intrathecal Antibody Response
local OCBs
local & systemic OCBs
systemic OCBs
normal / polyclonal
CSFSerum
Intrathecal or central compartment
Systemic or peripheral compartment
C
S
C
S
C
S
C
S
Meningeal Perivascular
Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology
Magliozzi et al. Brain 2007; 130:1089-1104.
Cortical and white matter demyelinationFemale
Age 47 years
MS for 30 years
MS 463 007
Proportion of cortex demyelinated= 59%
Schmierer-Lab, Blizard Institute
BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity
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
• MS prognosis based on clinical and MRI indices
• Life style and goals • Shared goals for therapy
Rebaseline
Rebaselining:• IFNβ, natalizumab, fingolimod,
teriflunomide, Dimethyl-Fumarate=3-6 months
• Glatiramer acetate=9 months• Alemtuzumab=24 months
Choose a therapeutic strategy
Maintenance-escalation Pulsed immune reconstitution therapy
Choose therapy
X Z
Rebaseline
Monitoring
Initiate or Switch or Escalate Rx Complete course / Re-treat
Breakthrough disease
Y
• Patient’s preferences?• Your choice?
NoYes Yes
• Only one licensed induction therapy at present
IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment
Sept-20021st attack
July-20032nd attack
June 2004Alemtuzumab 2005 - 2014
NEDA
June 2005Alemtuzumab
EDSS 3.5 EDSS 0.0
VZVEDSS 6.0
20041st attack
20052nd attack
Nov 2006Alemtuzumab
2008 - 2014NEDA
Nov 2007Alemtuzumab
EDSS 1.5 EDSS 3.5
Feb 2006IFNbeta
EDSS 7.0 EDSS 3.5 Grave’s
Jun 2006 Oct 2006
20 month vs. 32 month delay or 2 relapses
EDSS = 3.5: unable to run, play tennis or walk down stairs quickly without the use of a handrail
EDSS = 0.0: fully functional
The cost of delayed access to highly active treatment