Alemtuzumab in Multiple Sclerosis

1
Dr. Pramod Krishnan,
Consultant Neurologist, Manipal Hospital, Bengaluru.
Alemtuzumab:
Patient selection, efficacy and safety

2
Alemtuzumab: Dosage and Administration
Initial treatment course:
12 mg/day for 5 consecutive days (60 mg total dose)
Second treatment course (after 12 months): 12 mg/day for
3 consecutive days (36 mg total dose).
Retreatment: 12 mg/day for 3 consecutive days.
After 24 months of last dose, if indicated.

3
Alemtuzumab Proposed Mechanism of Action:
Targeting of T and B Cells
1. Selection1,2 2. Depletion1,2 3. Repopulation1,2
BT
T cell
precursor
Pre/Pro
B cell
Lymphocyte
precursor
Stem cell
BT
Plasma
Cells
Monocytes
Macrophages
Neutrophils
Lymphocyte
precursor
Lymphocyte
precursor
CD52
CD52
B
T
CD52
CD52
B
T
• Alemtuzumab is a monoclonal antibody directed at the CD52 surface
antigen expressed highly on T and B lymphocytes1,3
• Innate immune cells that express lower levels of CD52 are minimally or
transiently impacted by alemtuzumab treatment1,3
MOA
EfficacySafety
CD52

4
Durability of Effect
Efficacy Implications of Alemtuzumab action
The distinctive pattern of T- and B-cell repopulation likely explains the
durable efficacy and safety in the absence of continuous treatment?
1. Coles AJ et al. ECTRIMS 2016, Presentation 213; 2. Fox EJ et al. ECTRIMS 2016, P1150.
• Reduction in clinical disease activity1,2
― Relapse rate
― Disability worsening
• Improvement in preexisting disability1,2
MoA
Safety
Efficacy

5
Alemtuzumab: Indications
• Treatment of adult patients with RRMS with active disease defined
by clinical or imaging features.
• Active Disease:
1. ≥2 clinical episodes in the prior 2 years,
2. ≥1 relapse occurring during prior treatment and
3. ≥1 Gd- enhancing lesion
Other possible indications:
1. Treatment naïve patients with highly active disease.
2. JC virus positive patients with active disease.
3. Those not tolerating other agents.

6
Alemtuzumab Clinical Program
Core Studies (vs High-Dose SC IFNB-1a) and Open-Label Extension
aExploratory arm, discontinued enrolment early; bEnrolled patients from all 3 studies; cFor each patient, study ends 4 years after enrolment; dFor each patient, study ends 5.5
years after enrolment. CDW=confirmed disability worsening.
Phase 2 Core Study:
CAMMS2231
(Completed)
n=334
Phase 3 Core Study:
CARE-MS I2
(Completed)
n=581
Phase 3 Core Study:
CARE-MS II3
(Completed)
n=840
Phase 2/3 Extension4,b
Study
(Completed)
N=1322
TOPAZ5
(Ongoing)
Patient
population
Active RRMS,
treatment-naïve
Active RRMS,
treatment-naïve
Active RRMS,
relapsing on prior
therapy
RRMS patients enrolled
into phase 2 and 3
studies
into extension phase
‘Active’ definition
≥2 relapses in prior 2 years
and
≥1 Gd-enhancing lesion at
baseline
and
≥1 relapse in prior year
and
NA NA
Study duration, y 3 2 2 4c 5.5d
Inclusion criteria
EDSS ≤3
Onset ≤3 years
Enhancing lesion
EDSS ≤3
Onset ≤5 years
EDSS ≤5
Onset ≤10 years
CAMMS223,
CARE-MS I and II patients
Completion of ≥48 months
of extension study
Treatment arms
Alemtuzumab 12 mg IV
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
—
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Alemtuzumab 24 mga
SC IFNB-1a 44 µg
NA
(Either re-treatment with
alemtuzumab 12 mg or
other DMT)
NA
other DMT)
Alemtuzumab
dosing and
administration
Up to 3 annual courses at
Months 0, 12 and 24 (5 or
3 consecutive days)
2 annual courses at Months
0 and 12 (5 or 3
consecutive days)
0 and 12 (5 or 3
consecutive days)
As needed As needed
Co-primary
outcomes
Relapse rate, CDW Relapse rate, CDW Relapse rate, CDW
Long-term safety and
efficacy outcomes
efficacy outcomes

7
0.39
0.18
0
0.1
0.2
0.3
0.4
0.5
0.6
Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28.
Alemtuzumab Significantly Reduced Annualised
Relapse Rate vs SC IFNB-1a in Treatment-naïve
Patients
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
55% reduction vs
SC IFNB-1a
P<0.0001
Annualisedrelapserate
N=187 N=376
CARE-MS I
(co-primary endpoint at 2 yrs)2
0.36
0.11
0
0.1
0.2
0.3
0.4
0.5
0.6
CAMMS223
(co-primary endpoint at 3 yrs)1
Annualisedrelapserate
69% reduction vs
SC IFNB-1a
P<0.0001
N=111 N=112

8
Alemtuzumab Significantly Reduced the Risk of 6-
month SAD vs. SC IFNB-1a in Patients Who
Relapsed on Prior Therapy
8a
Risk of Sustained Accumulation of Disability
(CARE-MS II: co-primary endpoint)1
21.1%
12.7%
42% reduction
vs SC IFNB-1a
P=0.0084
Alemtuzumab 12 mg
SC IFNB-1a 44 μg
30
25
20
15
10
0 3 6 9 12 15 18 21 24
5
0
Follow-up month
PatientswithSAD(%)
• Alemtuzumab significantly reduced the risk of 6-month sustained
accumulation of disabilitya by 42% vs SC IFNB-1a.
• Six-month SAD is defined as EDSS score increase ≥1.0 point for
≥6 months (or ≥1.5 points when baseline EDSS = 0).

9
Alemtuzumab improved pre-existing disability in
patients who relapsed on prior therapy
9
Mean EDSS Change From Baseline1,2
• At 2 years, mean EDSS scores improved from baseline with
Alemtuzumab treatment and worsened with SC IFNB-1a
treatment2
-0.17
P=0.004
P<0.0001
0.24
P=0.0064
MeanEDSSscore
3.25
3.00
2.75
2.50
2.25
Follow-up Month
Alemtuzumab 12 mg
SC IFNB-1a 44 μg
0 3 6 9 12 15 18 21 240 3 6 9 12 15 18 21 24
Follow-up month

10
Durable Reduction in Relapse Rate With
Alemtuzumab vs SC IFNB-1a
Phase 2 Core Study and Extension Period
Coles AJ et al. Neurology 2012;78:1069-78.
Safety Efficacy
MoA
CAMMS223
SC IFNB-1a
Alemtuzumab 12 mg
Annualizedrelapserate
0.5
0.4
0.3
0.2
0.1
0.0
Year 3 to Year 5Baseline to Year 5
66% reduction vs SC IFNB-1a
P<0.0001
Reduction in Relapse Rate Through 5 Years
P=0.090

11
Durable Reduction in Risk of Confirmed Disability
Worsening With Alemtuzumab vs SC IFNB-1a
Phase 2 Core Study and Extension Period
Coles AJ et al. Neurology 2012;78:1069-78.
Alemtuzumab 12 mg 112 106 105 100 98 96 90
SC IFNB-1a 111 93 83 76 69 65 56
No. at Risk
Months
0
5
10
15
20
25
30
35
40
0 6 18 36 42 7
2
%ofPatientsWithCDW
8
4
12 24 30 48 54 60 7
8
54
29
54
27
51
25 25
48 15
6
4
1
4
0
0
0
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Safety Efficacy
MoA
CAMMS223
Reduction in Risk of 6-Month CDW Through 5 Years
P=0.0005

12
0.08 0.07 0.07 0.08 0.07 0.07 0.08 0.07 0.08
0
0.1
0.2
0.3
0.4
0.5
Y0-2 Y0-3 Y0-4 Y0-5 Y0-6 Y0-7 Y0-8 Y0-9 Y0-10
CumulativeARR(95%CI)
Follow-up Year (N=60)
Durable Effect of Alemtuzumab on Relapse Rate
Through 10 Years
Phase 2 Study
1. Coles AJ et al. AAN 2016, Poster P3.053; 2. Selmaj KW et al. ECTRIMS 2016, P679.
Y0-2 Y0-3 Y0-4 Y0-5 Y0-6 Y0-7 Y0-8 Y0-9 Y0-10
CAMMS223
CORE STUDY
EXTENDED FOLLOW-UP
PERIOD
CARE-MS EXTENSION STUDY
Annualised Relapse Rates Through Year 10 (Alemtuzumab 12 mg)1,2

13
0.08 0.07 0.07 0.08 0.07 0.07 0.08 0.07 0.08
0
0.1
0.2
0.3
0.4
0.5
Y0-2 Y0-3 Y0-4 Y0-5 Y0-6 Y0-7 Y0-8 Y0-9 Y0-10
CumulativeARR(95%CI)
Follow-up Year (N=60)
Durable Effect of Alemtuzumab on Relapse Rate Through
10 Years
Phase 2 Study
1. Coles AJ et al. AAN 2016, Poster P3.053; 2. Selmaj KW et al. ECTRIMS 2016, P679.
Y0-2 Y0-3 Y0-4 Y0-5 Y0-6 Y0-7 Y0-8 Y0-9 Y0-10
CAMMS2
23
CORE STUDY
EXTENDED
FOLLOW-UP
PERIOD
CARE-MS EXTENSION STUDY
Annualised Relapse Rates Through Year 10
(Alemtuzumab 12 mg)1,2

14
0.16
0.19
0.14 0.16 0.12
0.0
0.2
0.4
0.6
0.8
1.0
Years 0–2 Year 3 Year 4 Year 5 Year 6
ARR(95%CI)
CARE-MS I: Reduction in ARR1
0.28 0.22 0.23
0.19
0.15
0.0
0.2
0.4
0.6
0.8
1.0
ARR(95%CI)
Durable Reduction in ARR Through Year 6
Phase 3 Core and Extension Studies
1. Coles AJ et al. ECTRIMS 2016, Presentation 213; 2. Fox E et al. ECTRIMS 2016, P1150.
No. of
Patients 376 349 342 340
Core
Study
Extension Study
CARE-MS II: Reduction in ARR2
Safety Efficacy
MoA
335
No. of
Patients 435 393 387 367 357
Core
Study
Extension Study
• Durable efficacy was maintained through 6 years with low
retreatment rates
• 84%, 87%, 88%, and 89% of patients were free from relapses in
Years 3, 4, 5, and 6, respectively
• Durable efficacy was maintained through 6 years with low
retreatment rates
• 81%, 80%, 84%, and 88% of patients were free from relapses in
Years 3, 4, 5, and 6, respectively
63% of patients received no alemtuzumab
re-treatment and no other DMTs since Month 12
CARE-MS EXTENSION

15
Proportion of Patients Free From 6-Month
Confirmed Disability Worsening Through Year 6
ProportionofPatients,%
92
88
83
79 77
0
10
20
30
40
50
60
70
80
90
100
Years 0-2 Years 0-3 Years 0-4 Years 0-5 Years 0-6
ProportionofPatients,%
89
82
77 75 72
0
10
20
30
40
50
60
70
80
90
100
Years 0-2 Years 0-3 Years 0-4 Years 0-5 Years 0-6
CARE-MS I: Free From 6-month CDW1 CARE-MS II: Free From 6-month CDW2
No. of
Patients 322 303 283 248270 No. of
Patients 348 321 285 270 219
Core
Study
Extension Study
Core
Study
Extension Study
CARE-MS EXTENSION
Safety Efficacy
MoA

16
51%
27%
22%
Relapse
Only
MRI
Only
Relapse
and
MRI
Over 6 Years, the Majority of Patients Were
Not Re-treated With Alemtuzumab
Reasons for
Alemtuzumab
Re-treatment
CARE-MS I1
Number of
Alemtuzumab
Re-treatments
Over Years 2–6
64
24
8 3 <1
0
20
40
60
80
100
0 1 2 3 4
Patients,%
CARE-MS II2
55
30
12
2 1
0
20
40
60
80
100
0 1 2 3 4
Patients,%
• 64% of patients received no alemtuzumab
re-treatment since Month 12
re-treatment since Month 12
Safety Efficacy
MoA
60%
15%
23%
Relapse
Only
MRI
Only
Relapse
and
MRI
CARE-MS EXTENSION

17
Durable Effect on ARR With Alemtuzumab
Phase 3 Extension Study: Patients Who Received 2
Alemtuzumab Courses Only
CARE-MS I & II: Reduction in ARR
Safety Efficacy
MoA
Fox EJ. AAN 2016, Presentation S51.005.
Extension Study
No. of
Patients
Core Studies
0.13
0.07 0.06 0.06
0.0
0.1
0.2
0.3
0.4
Years 0–2 Year 3 Year 4 Year 5
ARR(95%CI)
445 445 436 419
Alemtuzumab 12 mg (no retreatment and no other DMT)
0
CARE-MS EXTENSION

18
Durable Effect on Disability Outcomes With
Alemtuzumab
Phase 3 Extension Study: Patients Who Received 2 Alemtuzumab Courses Only
• Of patients with CDI, most were also free from 6-month CDW through Year 5
(CARE-MS I: 92%, CARE-MS II: 97%)
CDI=Confirmed disability improvement defined as a decrease from baseline by at least one EDSS point confirmed over 6 months
for patients with baseline EDSS scores of at least 2·0
1. Havrdova E et al. ECTRIMS 2015, Platform 152; 2. Fox EJ. ECTRIMS 2015, P1102.
CARE-MS I1
n=231
CARE-MS II2
n=214
Proportion of patients free from
6-month CDW
87% 81%
Proportion of patients with
6-month CDI
40% 46%
Extension Study: Disability Outcomes Through Year 5
Safety Efficacy
MoA
CARE-MS EXTENSION

19
Alemtuzumab: Overall AE rates in clinical trials
• Rate of AEs with Alemtuzumab 12 mg,
including those leading to treatment
discontinuation, generally similar to
those with IFNB-1a SC
2-year active-controlled experiencea
• AE profiles similar for
treatment-naïve patients and
those who relapsed on prior
therapy
Adverse Events (AEs)
IFNB-1a SC 44 μg
n=496
Alemtuzumab 12 mg
n=919
AEs, n (%) 469 (94.6) 896 (97.5)
Grade 1 (mild) 400 (80.6) 815 (88.7)
Grade 2 (moderate) 402 (81.0) 831 (90.4)
Grade 3 (severe) 106 (21.4) 227 (24.7)
Grade 4 (very severe) 10 (2.0) 27 (2.9)
AEs leading to treatment discontinuation, n
(%)
39 (7.9) 21 (2.3)
Serious AEs, n (%) 91 (18.3) 168 (18.3)
Serious AEs leading to treatment
discontinuation, n (%)
10 (2.0) 7 (0.8)
Deaths 0 2b
Alemtuzumab is not registered in any of the MENA COUNTRIES

20
Risks identified in clinical trials
Identified Risk
Rate in treated
Patients Comments
ITP AutoimmuneEvents ~1%
• Onset generally occurred 14-36 mo after first exposure.
• Most cases responded to first-line medical therapy.
0.3%
• Generally occurred within 39 mo after last administration.
• Responded to timely treatment and did not develop permanent kidney failure.Nephropathies
Thyroid
disorders
(Hypo-/hyper-)
~36%
(serious, 1%)
• Occurred 6-61 mo after first Alemtuzumab exposure; peaked in year 3 and
declined thereafter.
• Most mild to moderate, most managed with conventional medical therapy,
however, some patients required surgical intervention.
• Higher incidence in patients with history of thyroid disorders.
IARs
>90%
(serious, 3%)
• Occurred within 24 h of Alemtuzumab administration
• Most mild to moderate; rarely led to treatment discontinuation.
• May be caused by cytokine release following mAb-mediated cell lysis.
Infections
71%
(serious, 2.7%)
• Incidence highest during first mo after infusion; rate decreased over time.
• Predominately mild to moderate in severity.
• Generally of typical duration; resolved following conventional medical treatment.
Alemtuzumab is not registered in any of the MENA COUNTRIES

21
Incidence of Infusion-Associated Reactions
(IARs) With Alemtuzumab Decrease With
Subsequent Courses
Incidence of IARs by course in patients who
received alemtuzumab 12 mg in CARE-MS I and II
and the extension study
Proportionof
Patients,%
2.0 1.0 0.7 0Serious AE, %
811 791 268 78No. of Patients
0
11
Treatment Course
MOA
EfficacySafety

22
Overall infection rate with Alemtuzumab
decreases over time.
Lymphocyte Counts by Occurrence of Infection in
Alemtuzumab-treated Patients3
Incidence of Infections and Serious Infections by
Year (CARE-MS I and II Pooled)1Patients(%)
Core
 Patients who developed
infections had similar
lymphocyte counts to those
who did not.
Extension
 Most common infections were
nasopharyngitis, UTI, URTI, sinusitis, oral
herpes, influenza, and bronchitis.
 Herpetic infections were reduced with
acyclovir prophylaxis in the core studies.

23
No Increased Risk of Malignancies in
Alemtuzumab-Treated Patients
• Thyroid malignancy was the most frequently occurring malignancy AE
― The rate of thyroid malignancy in the alemtuzumab clinical development program was 0.073 per 100 patient-years
― Trial evidence suggests no increased risk
― Ascertainment bias may have been a factor, due to additional screening for alemtuzumab patients with thyroid AEs
― Risk not significantly different vs retrospective cohort of 32,348 MS patientsb
• Continued assessment of malignancies in long-term follow-up studies and post-marketing experience
a 0.496 events per 100 patient-years; b Standardised incidence ratio (SIR): 0.98, 95% CI: 0.44–2.19. Expected number of events
was 6.10/1000 patient-years.
Lecumberri B et al. ECTRIMS 2015, P117.
All Malignancies
Patients treated, n 1486
Patient years of follow-up 8266
Rate of malignancy 2.4%a
Safety Efficacy
MoA
CARE-MS EXTENSION

24
Pregnancy Outcomes in Alemtuzumab Clinical Program1
Alemtuzumab 12 or 24 mg (n=972)
Number of pregnancies 200 pregnancies
Completed pregnancies 181 pregnancies
Live birth 122 (67.4)
Elective abortion 19 (10.5)
Spontaneous abortion (<20 weeks) 39 (21.5)
Stillbirth (≥20 weeks) 1 (0.6)
Ongoing 11 (5.5)
Unknown 8 (4.0)
Pregnancy Risk
All Available Follow-up as of 31 December 2015a
• The rate of spontaneous abortion in alemtuzumab-treated patients (22%)1 was comparable with rates observed in
MS patients receiving other DMTs and with the general population2-4
• Of the 200 pregnancies, 192 occurred ≥4 months after the last alemtuzumab dose (ie, after the period for
contraception use recommended in the drug label)1
• To date, no congenital abnormalities or birth defects have been observed in delivered infants1
a Includes all available follow-up for CAMMS223, CARE-MS I, and CARE-MS II up Dec 31, 2015.
1. Oh J et al. AAN 2016, S24.008; 2. Vanya M et al. J Matern Fetal Neonatal Med 2014;27:577-81; 3. Weber-Schoendorfer C,
Schaefer C. Mult Scler 2009;15:1037-42. 4. Giannini M et al. BMC Neurol 2012;12:124.
Safety Efficacy
MoA
CARE-MS EXTENSION

25
Patient Selection Criteria in India
• First Line/Second Line/Third Line
• SPMS/PPMS
• Cost
• Safety
• Infections

26
Summary of Alemtuzumab Clinical Efficacy
Phase 2 Core and Extension Study
• Alemtuzumab 12 mg vs SC IFNB-1a demonstrated superior clinical outcomes in the phase 2 core and extension period1,2
• Alemtuzumab demonstrated durable efficacy on relapse rates in the extension study through 10 years3,4
Phase 3 Core Study
• Alemtuzumab demonstrated superior clinical outcomes in both treatment-naïve patients and in patients who had an inadequate
response to prior therapy vs high-dose SC IFNB-1a5,6
• Superior efficacy with alemtuzumab treatment vs high-dose SC IFNb-1a was also demonstrated in7,8:
― Previously treated patients regardless of the type of DMT available at the time of the study and as per the in- and
exclusion criteria7,8
Extension Study
• Alemtuzumab demonstrated durable efficacy on clinical endpoints in the absence of continuous treatment9-10
― Most patients did not receive re-treatment with alemtuzumab or another DMT after the initial 2 courses in the core study
through Year 69,10
― Patients who crossed over to alemtuzumab after receiving SC IFNB-1a in the core study demonstrated significant
improvement after switching11,12
TOPAZ: Will extend safety and efficacy findings through an additional 5 years13
1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Coles AJ et al. Neurology 2012;78:1069-78; 3. Coles AJ et al. AAN 2016, Poster
P3.053; 4. Selmaj KW et al. ECTRIMS 2016, P679, 5. Cohen J et al. Lancet 2012;380:1819-28; 6. Coles A et al. Lancet 2012;380:1829-
39; 7. Freedman MS et al. AAN 2013, Poster P07.111; 8. Twyman C et al. AAN 2013, Poster P07.098; 9. Coles AJ et al. ECTRIMS 2016,
Presentation 213; 10. Fox E et al. ECTRIMS 2016, P1150; 11. Oreja-Guevara C et al. ECTRIMS 2016, Poster 1232; 12. Boyko AN et al.
ECTRIMS 2016, Poster 680; 13. Brinar V et al. AAN 2015, Poster P7.219.
Safety Efficacy
MoA

27
Global Approvals
• Approved in more than 40 countries worldwide
• EU – Sep 2013
• FDA – Nov 2014
• 10 year long term data available on safety and efficacy
• REMS Program in place
• >8,000 patients worldwide

28
Alemtuzumab Dosing Schedule
• In the phase 3 clinical trials, most patients completed their first course of alemtuzumab infusions on 5 consecutive days (95.1%) and
96.6% patients completed Course 2 with 3 infusions on 3 consecutive days2
• A total of 58 (7.2%) patients had a prolonged treatment course over nonconsecutive days (Course 1, n=40; Course 2, n=19; 1 patient
had both courses prolonged)2
― 25 patients completed Course 1 over 6–10 nonconsecutive days, and 15 completed Course 2 over 4–8 nonconsecutive days2
― Infusions are recommended to be given on consecutive days2
1. Oh J et al. AAN 2016. Presentation S24.008; 2. Wray S et al. AAN 2015, Poster P7.277.
Alemtuzumab administration
1500
4000
4500
2500
3500
500
0
2000
3000
1000
Day 0
Concentration(ng/mL)
Day 5 Day 10 Day 15 Day 20 Day 25 Month 1
First Treatment Course
Time
1500
4000
4500
2500
3500
500
0
2000
3000
1000
0 1 3 6 9 12 2415 18 21
Concentration(ng/mL)
13
Months1
Course 1 Course 2
Safety Efficacy
MoA

29
Alemtuzumab Clinical Programme
aExploratory arm, discontinued enrolment early; bEnrolled patients from all 3 studies; cFor each patient, study ends 4 years after enrolment;
dFor each patient, study ends 5.5 years after enrolment. CDW=confirmed disability worsening
1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-
39; 4. www.clinicaltrials.gov. NCT00930553; 5. www.clinicaltrials.gov. NCT02255656
Phase 2 Core Study:
CAMMS2231
(Completed)
n=334
Phase 3 Core Study:
CARE-MS I2
(Completed)
n=581
Phase 3 Core Study:
CARE-MS II3
(Completed)
n=840
Study
(Completed)
N=1322
TOPAZ5
(Ongoing)
Patient
population
Active RRMS,
treatment-naïve
Active RRMS,
treatment-naïve
Active RRMS,
relapsing on prior
therapy
into phase 2 and 3
studies
and
baseline
and
and
NA NA
Inclusion criteria
EDSS ≤3
Onset ≤3 years
Enhancing lesion
EDSS ≤3
Onset ≤5 years
EDSS ≤5
Onset ≤10 years
CAMMS223,
of extension study
Treatment arms
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
—
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Alemtuzumab 24 mga
SC IFNB-1a 44 µg
NA
other DMT)
NA
other DMT)
Alemtuzumab
dosing and
administration
3 consecutive days)
0 and 12 (5 or 3
consecutive days)
0 and 12 (5 or 3
consecutive days)
As needed As needed
Co-primary
outcomes
efficacy outcomes
efficacy outcomes

30
n=92
Treatment Schematic
Phase 2 Core Study, Extension Period, and Extension Study
aRe-treatment criteria were based on evidence of relapse or radiological activity.
1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Coles AJ et al. Neurology 2012;78:1069-78; 3. Coles AJ et al. AAN 2016,
Poster P3.053; 4. Selmaj KW et al. ECTRIMS 2016, Poster P679.
CAMMS223
Treatment Schematic Through 10 Years1-4
M0 M 36M 24
Alemtuzumab
12 mg daily IV
n=112
24
(3rd course)
77
n=102
Alemtuzumab
24 mg daily IV
n=110
22
(3rd course)
82
IFNB-1a
44 µg tiw SC
n=111
n=47
n=104
At Month 60
n=72
n=79
n=60
Alemtuzumab Courses
21 3 (optional)
M 120
CORE STUDY-3y EXT PERIOD-2y EXTENSION STUDY-5y
Possible re-treatment with alemtuzumaba
• 95% remained on study at Year 10
n=66
n=92
n=42
M 36
n=67
n=74
49 no additional treatment
4 alemtuzumab retreatments
17 other DMTs

31
Significant Reduction in Annualised Relapse Rate
(ARR) With Alemtuzumab vs SC IFNB-1a
Phase 2 Core Study
0.36 0.11
0
0.1
0.2
0.3
0.4
0.5
AnnualisedRelapseRate
Coles AJ et al. N Engl J Med 2008;359:1786-801.
N=111 N=112
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
P<0.0001
Safety Efficacy
MoA
CAMMS223
CAMMS223 Through Year 3: Reduction in ARR

32
0
5
10
15
20
30
60 1812 24 3630
25 26.2%
8.5%
PatientsWithCDW(%)
Significant Reduction in Risk of CDWa With
Alemtuzumab vs SC IFNB-1a
Phase 2 Core Study
a Six-month CDW (confirmed disability worsening) defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when
baseline EDSS = 0).
Coles AJ et al. N Engl J Med 2008;359:1786-801. Figure reprinted with permission from Massachusetts Medical Society.
Safety Efficacy
MoA
CAMMS223
CAMMS223 Through Year 3: Reduction in 6-Month CDW
Months
P<0.001
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Alemtuzumab 12 mg 112 106 101 98
SC IFNB-1a 111 91 83 76
No. at Risk
97
68
94
65
88
56

33
Summary of Alemtuzumab Clinical Efficacy
Phase 2 Study
• Alemtuzumab 12mg vs SC IFNB-1a demonstrated superior clinical outcomes in the
phase 2 core and extension period
― Core Study1
• 69% reduction in ARR
• 75% reduction in CDW
― Extension Period2
• 69% reduction in ARR
• 72% reduction in CDW
• Alemtuzumab 12 mg demonstrated durable efficacy on relapse rates in the extension
study3,4
― Through 10 years of follow-up, a low ARR was maintained despite the fact that most patients were
not re-treated with Alemtuzumab
1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Coles AJ et al. Neurology 2012;78:1069-78; 3. Coles AJ et al. AAN 2016,
Poster P3.053; 4. Selmaj KW et al. ECTRIMS 2016, P679.

34
Alemtuzumab Clinical Programme
aExploratory arm, discontinued enrolment early; bEnrolled patients from all 3 studies; cFor each patient, study ends 4 years after enrolment;
dFor each patient, study ends 5.5 years after enrolment. CDW=confirmed disability worsening
1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-
39; 4. www.clinicaltrials.gov. NCT00930553; 5. www.clinicaltrials.gov. NCT02255656
Phase 2 Core Study:
CAMMS2231
(Completed)
n=334
Phase 3 Core Study:
CARE-MS I2
(Completed)
n=581
Phase 3 Core Study:
CARE-MS II3
(Completed)
n=840
Study
(Completed)
N=1322
TOPAZ5
(Ongoing)
Patient
population
Active RRMS,
treatment-naïve
Active RRMS,
treatment-naïve
Active RRMS,
relapsing on prior
therapy
into phase 2 and 3
studies
and
baseline
and
and
NA NA
Inclusion criteria
EDSS ≤3
Onset ≤3 years
Enhancing lesion
EDSS ≤3
Onset ≤5 years
EDSS ≤5
Onset ≤10 years
CAMMS223,
of extension study
Treatment arms
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
—
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Alemtuzumab 24 mga
SC IFNB-1a 44 µg
NA
other DMT)
NA
other DMT)
Alemtuzumab
dosing and
administration
3 consecutive days)
0 and 12 (5 or 3
consecutive days)
0 and 12 (5 or 3
consecutive days)
As needed As needed
Co-primary
outcomes
efficacy outcomes
efficacy outcomes

35
Randomisation and Treatment
Phase 3 CARE-MS I Core Study
 Randomised, rater-blinded, global, multicentre
 Safety-related physician and patient education and monitoring programme
 Both treatment arms received 1 g/day methylprednisolone for 3 days at Months 0 and 12
MSFC=Multiple Sclerosis Functional Composite
Cohen JA et al. Lancet 2012;380:1819-28.
Randomised 2:1
Alemtuzumab:IFNB-1a
3×/week
Alemtuzumab
12 mg IV
SC IFNB-1a
44 μg
1 infusion on 5
consecutive days
Study Duration (months)
0 12 246 183 9 15 21
MRI assessments X X X
MSFC assessments X X X X X
EDSS assessments X X X X XX X X X
1 infusion on 3
consecutive days
CARE-MS I

36
Significant Reduction in Annualised Relapse
Rate With Alemtuzumab vs SC IFNB-1a
Phase 3 Core Study
0.39
0.18
0.0
0.2
0.4
0.6
0.8
P<0.0001
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
(95%CI)
CARE-MS I Through Year 2: Reduction in ARR
CARE-MS I
Safety Efficacy
MoA
(n=187) (n=376)

37
Benefits in Relapse Rate Were Consistent Across
Disease Subgroups With Alemtuzumab vs SC IFNB-1a
Phase 3 Core Study
a Subgroups with numerical cutoffs are split at the sample median of the Full Analysis Set; b Patients who had ≥2 relapses in the 1
year prior to randomisation and ≥1 gadolinium-enhancing lesion at baseline. Fox E et al. AAN 2012, Poster PD5.004.
Relapse rateSubgroupa
Favours Alemtuzumab Favours SC IFNB-1a
Baseline EDSS
<2
≥2
Number of prior relapses
≤2
>2
Baseline BPF
<0.819505
≥0.819505
Baseline MRI T2 lesion volume (cc)
<4.117
≥4.117
Disease duration (y)
<1.6
≥1.6
Gd activity at baseline
No
Yes
Highly activeb
No
Yes
Primary analysis
0.50.25 1 2 4
CARE-MS I
CARE-MS I: Reduction in ARR by Subgroup
Safety Efficacy
MoA

38
Reduction in Risk of Confirmed Disability Worseninga
With Alemtuzumab Vs SC IFNB-1a
Phase 3 Core Study
• Alemtuzumab did not significantly reduce the risk of 6-month CDWa vs high-dose SC IFNB-1a in treatment-naïve patients (CARE-MS I)1
― Fewer high-dose SC IFNB-1a patients had worsened disability than expected based on the phase 2 study, which may have reduced
the ability to detect a significant treatment effect1,2
a Six-month CDW defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when baseline EDSS = 0).
PatientsWithCDW(%)
8.0%
11.1%
25
15
10
5
0
20
0 3 6 9 12 15 18 21 24
Follow-up Month
CARE-MS I
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
CARE-MS I: Risk of 6-Month CDW
Safety Efficacy
MoA
P=0.22
Alemtuzumab 12 mg 376 376 372 368
SC IFNB-1a 187 185 181 177
No. at Risk
363
170
357
164
352
162
345
158
336
149

39
Randomisation and Treatment
Phase 3 CARE-MS II Core Study
 Randomised, open-label, rater-blinded, global, multicentre trial
 Safety-related physician and patient education and monitoring programme
 All treatment arms received 1 g/day methylprednisolone ×3 days at Months 0 and 12
 Randomisation into a third treatment arm (24 mg alemtuzumab) was discontinued early, and it was deemed exploratory for statistical purposes
Coles AJ et al. Lancet 2012;380:1829-39.
Alemtuzumab
12 mg
3 x/week
SC IFNB-1a
44 µg
Study duration (months)
0 12 24
Alemtuzumab
24 mg IV
Randomised 2:1
(Alemtuzumab: SC IFNB-1a)
1 infusion on 5
consecutive days
1 infusion on 3
consecutive days
1 infusion on 5
consecutive days
1 infusion on 3
consecutive days
CARE-MS II
MRI assessments X X X
MSFC assessments X X X X X
EDSS assessments X X X X XX X X X

40
Significant Reduction in ARR With Alemtuzumab
vs SC IFNB-1a
Phase 3 Core Study
0.52
0.26
0.0
0.2
0.4
0.6
0.8
(95%CI)
P<0.0001
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
N=426N=202
CARE-MS II Through Year 2: Reduction in ARR
CARE-MS II
Safety Efficacy
MoA

41
Benefits in Relapse Rate Were Consistent Across
Disease Subgroups With Alemtuzumab vs SC IFNB-1a
Phase 3 Core Study
aData cutoffs are based on median values; b Patients who had ≥2 relapses in the 1 year prior to randomisation and ≥1 gadolinium-
enhancing lesion at baseline. Twyman C et al. AAN 2013, Poster P07.098.
Relapse rateSubgroupa
Favours Alemtuzumab Favours SC IFNB-1a
Baseline EDSS
<4
≥4
Number of prior relapses
≤2
>2
Baseline BPF
<0.816105
≥0.816105
Baseline MRI T2 lesion volume (cc)
<5.7135
≥5.7135
Disease duration (y)
<3.8
≥3.8
Gd activity at baseline
No
Yes
Highly activeb
No
Yes
Primary analysis
0.50.25 1 2 4
CARE-MS II
CARE-MS II: Reduction in ARR by Subgroup
Safety Efficacy
MoA

42
Durable Effect on Risk of Confirmed Disability
Worseninga With Alemtuzumab vs SC IFNB-1a
Phase 3 Core Study
a 6-month CDW defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when baseline EDSS = 0).
21.1%
12.7%
PatientsWithCDW(%)
30
25
20
15
10
0 3 6 9 12 15 18 21 24
5
0
Follow-up Month
CARE-MS II
CARE-MS II: Reduction in Risk of 6-Month CDW
Safety Efficacy
MoA
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
P=0.0084
• 42% risk reduction vs SC IFNB-1a
Alemtuzumab 12 mg 426 426 412 404
SC IFNB-1a 202 200 184 175
No. at Risk
392
167
384
162
380
155
375
145
154
131

43
0.65
0.33
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0.41
0.20
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
SC IFNB-1a Alem 12 mg/day
Significant Reduction in Annualised Relapse Rates in Patients
With Highly Active Disease With Alemtuzumab vs SC IFNB-1a
Phase 3 Core Study
Highly Active subset includes patients with 2 or more relapses in the prior year and 1 or more gadolinium-enhancing lesions at
baseline.
1. Krieger S et al. ACTRIMS-ECTRIMS 2014, P088; 2. Singer B et al. AAN 2015. P7.269.
Years0–2(95%CI)
P=0.0068
(n=61) (n=105)
CARE-MS I & II
CARE-MS I Through Year 2:1
Reduction in ARR
P<0.0044
(n=101)(n=42)
CARE-MS II Through Year 2:2
Reduction in ARR
Years0–2(95%CI)
SC IFNB-1a 44 µg
Alemtuzumab 12 mg

44
Reduced Risk of 6-month CDW With Alemtuzumab
vs SC IFNB-1a, Regardless of Prior DMT Use
Phase 3 Core Study
Freedman MS et al. AAN 2013, Poster P07.111.
17.8
21.9
20.1
23.0
20.7
21.9
10.5
13.2
12.5
13.0 12.5 13.0
0
5
10
15
20
25
30
35
40
No
(n=110)
Yes
(n=518)
No
(n=409)
Yes
(n=219)
No
(n=413)
Yes
(n=215)
KMEstimateofEvent
41%
reduction
44%
reduction
46%
reduction
39%
reduction
42%
reduction
43%
reduction
Any prior IFN use Prior SC IFNB-1a use Prior GA use
SC IFNB-1a 44 µg Alemtuzumab 12 mg
CARE-MS II
CARE-MS II: Reduction in Risk of 6-Month CDW by Prior DMT Use
Safety Efficacy
MoA

45
Alemtuzumab
12 mg IV
(n=376)
Follow-up Year
Follow-up Month
Course 1 As-needed re-treatmentb with alemtuzumab
or other DMT
Course 2
48120 36 60
Year 1 Year 2 Year 3 Year 4 Year 5
CORE EXTENSIONa
24
Randomised2:1
(Alemtuzumab:SCIFNB-1a)
3×/week
SC IFNB-1a 44 µg
Course 1 Course 2
Alemtuzumab
12 mg IV
Evaluating Durability of Effect With Alemtuzumab
CARE-MS Extension Study
• 95% and 93% of 12 mg alemtuzumab-treated patients completing CARE-MS I and CARE-MS II, respectively, enrolled
in the extension study1,2
• Of those entering the extension, 93% and 88% remained on study from Month 24 through Month 72 (end of Year 6)1,2
aPatients who had received 24mg in CARE-MS II could also participate in the extension study
b≥1 protocol-defined relapse, or ≥2 new/enlarging T2 hyperintense and/or new Gd-enhancing T1 lesions at the discretion of the
treating investigator, or other DMTs, at the investigator’s discretion.
Study Design
72
Year 6
CARE-MS EXTENSION

46
CARE-MS Extension
Study Populations
• Alemtuzumab 12 mg group full cohort
• Alemtuzumab 12 mg 2-course cohort
• SC-IFNB-1a patients in core study who switched to alemtuzumab
12 mg during the extension
CARE-MS EXTENSION

47
Patients Who Received 2 Alemtuzumab Courses
Only
Phase 3 Extension Study
• Cohort comprises alemtuzumab patients who only received the initial 2 courses (excludes patients who received
re-treatment or another DMT in the extension study)
1. Havrdova E et al. ECTRIMS 2015, Platform; 2. Fox EJ et al. ECTRIMS 2015, P1102.
Study duration
48120 36 60
Follow-up Month
Follow-up Year
Initial
2 courses and
no DMT
No re-treatment or DMT since Month 12 (4 Years)
Course 1 Course 2
Alemtuzumab
12 mg IV
CORE EXTENSION
Study Design: Patients Treated With Alemtuzumab 12 mg in Core Study1,2
24 72
Year 6
CARE-MS EXTENSION

48
CARE-MS Extension Study
• 83% (n=290) of SC IFNB-1a–treated patients completing CARE-MS I (144/173) and CARE-MS II (146/175) enrolled in the
extension study2,3
― 87% of patients enrolled in CARE-MS I and 86% of patients enrolled in CARE-MS II completed the first 4 years of the extension study
1. Barkhof F et al. AAN 2016, P6.183; 2. Oreja-Guevara C et al. ECTRIMS 2016, Poster 1232; 3. Boyko AN et al. ECTRIMS 2016,
Poster 680.
Alemtuzumab
12 mg IV
(n=376)
Follow-up Year
Follow-up Month
Course 1 As-needed re-treatmenta with alemtuzumab
or other DMT
Course 2
48120 36 60
CORE EXTENSION
24
Randomised2:1
(Alemtuzumab:SCIFNB-1a)
3×/week
SC IFNB-1a 44 µg
Course 1 Course 2
Alemtuzumab
12 mg IV
Study Design1
72
Year 6
CARE-MS EXTENSION

49
0.39
0.10 0.12 0.11
0.15
0.0
0.2
0.4
0.6
0.8
1.0
Durable Effect of Alemtuzumab on Relapse (1/2)
Phase 3 Core and Extension Studies (SC-IFNB-1a crossover)
*P<0.0001 vs core study SC IFNB-1a treatment; statistical comparisons not performed for Years 3 and 4.
†Compared with 2 years on SC IFNB-1a.
1. Oreja-Guevara C et al. ECTRIMS 2016, Poster 1232; 2. Boyko AN et al. ECTRIMS 2016, Poster 680.
SC IFNB-1a 44 μg (core study: before switch)
Alemtuzumab 12 mg (extension study: after switch)
CARE-MS I1 CARE-MS II2
Safety Efficacy
MoA
Extension Study
ARR(95%CI)
Core Study
No. of
Patients 187 139 138 138 128
*
*
69%†74%†
0.52
0.13
0.17
0.12
0.17
0.0
0.2
0.4
0.6
0.8
1.0
Extension Study
ARR(95%CI)
Core Study
No. of
Patients 202 143 140 137 131
*
*
67%†75%†
75% of patients did not receive
alemtuzumab treatment since
M12 after switching
71% of patients did not receive
alemtuzumab treatment since
M12 after switching
CARE-MS EXTENSION

50
0.82
0.17 0.18
0.23
0.19
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Durable Effect of Alemtuzumab on Relapse (2/2)
Phase 3 Core and Extension Studies: Patients Who Relapsed on SC IFNB-1a
(SC-IFNB-1a crossover)
*P<0.0001 vs core study SC IFNB-1a treatment; statistical comparisons not performed for Years 3 and 4.
†Compared with 2 years on SC IFNB-1a.
SC IFNB-1a 44 μg (core study: before switch)
Alemtuzumab 12 mg (extension study: after switch)
CARE-MS I1 CARE-MS II2
Safety Efficacy
MoA
Extension Study
ARR(95%CI)
Core Study
No. of
Patients 60 60 60 60 54
*
*
78%†79%†
1.07
0.22
0.26
0.17
0.26
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Extension Study
ARR(95%CI)
Core Study
No. of
Patients 73 73 72 72 67
*
*
75%†79%†
CARE-MS EXTENSION

51
EDSS-Based Disability Outcomes After Discontinuing
SC IFNB-1a and Switching to Alemtuzumab
KM Estimate,
%
Extension Y2
After Switching
Extension Y3
After Switching
Extension Y4
After Switching
No evidence of
6-month CDW
(n=128) (n=114) (n=94)
93 87 81
Achieving 6-
month CDI
(n=55) (n=50) (n=40)
17 18 27
CDI=confirmed disability improvement; CDW=confirmed disability worsening
aChange from extension study baseline.
KM Estimate,
%
Extension Y2
After Switching
Extension Y3
After Switching
Extension Y4
After Switching
No evidence of
6-month CDW
(n=120) (n=106) (n=74)
88 82 80
Achieving 6-
month CDI
(n=82) (n=74) (n=47)
14 20 22
CARE-MS I1,a CARE-MS II2,a
Safety Efficacy
MoA
CARE-MS EXTENSION

52
Overview of TOPAZ Study: 10-Year Follow-up1,2
*Monthly laboratory safety variables were collected for 48 months after the last infusion of alemtuzumab.
Brinar V et al. AAN 2015, Poster P7.219
Scheduled visits*
TOPAZ
CAMMS223
CARE-MS I
CARE-MS II
CARE-MS Extension
4 years
(at least 48 months)
42 M 48 M 54 M6 M
Day 1
End of study
60 M
18 M12 M 24 M 36 M
Imaging
30 M
• An open-label, single-group, multicenter phase 3b/4 study to provide long-term care for patients who
have completed the CARE-MS extension study
• TOPAZ is being conducted at ~180 sites in North America, Europe, Australia, and Latin America
• The primary objective is to evaluate long-term safety of alemtuzumab
• Secondary objectives are to assess the following:
― Long-term efficacy of alemtuzumab
― The safety of receiving other DMTs after alemtuzumab treatment
― Patient-reported quality-of-life outcomes and health resource utilization of patients who received alemtuzumab
― As-needed retreatment with alemtuzumab or other DMTs

53
Mechanism of IARs After Alemtuzumab Treatment
Pathogenesis and Aetiology of Cytokine-Release Syndrome
• The interaction between Alemtuzumab-bound lymphocytes and CD16+ NK cells initiates a cascade of
events that results in the release of cytokines
• Cytokine release then generates clinical signs and symptoms described as IARs
IFNɣ=interferon gamma; IL-6=interleukin 6; NK=natural killer; TNFɑ=tumour necrosis factor alpha
Wing GM et al. J Clin Invest 1996;98:2819-26.
Safety Efficacy
MoA
Lymphocyte
IARs
Nitric oxide
Cytokine
release
Alemtuzumab
CD16+ NK Cells TNFα, IFNγ
and IL-6

54
IAR AEs Incidence by Treatment Course
Phase 3 Core and Extension
• IAR AEs were most frequent during the first treatment course1,2
― 2% had a serious IAR AE1,2
― There were no serious IARs reported from Course 4 to 6
• <4% of Alemtuzumab patients from CARE-MS I and II who enrolled into the extension went on to receive a fifth and/or sixth course of
Alemtuzumab1,3
― 40%–50% of them experienced IARs
a Serious adverse events were defined as those that were fatal, life-threatening, required or prolonged hospitalisation, caused
persistent or significant disability/incapacity, congenital anomaly or required intervention to prevent permanent impairment or
damage; b Includes all patients who entered the extension study from CARE-MS I, and CARE-MS II.
Any IAR
Serious IAR Adverse Event
Safety
Efficacy
MoA
Infusion-associated Reaction (IAR) AE and Serious AE Incidence With Alemtuzumab 12 mg1-3a,b
84.7%
68.7%
62.3% 62.5%
42.4%
48.0%
2.0% 1.0% 0.6% 0.0% 0.0% 0.0%
0%
20%
40%
60%
80%
100%
Course 1
(n=811)
Course 2
(n=791)
Course 3
(n=302)
Course 4
(n=104)
Course 5
(n=26)
Course 6
(n=5)
Patients,%
Core Study Extension Study
CARE-MS EXTENSION

55
Alemtuzumab Infusion Management
a Pretreatment with antihistamines and/or antipyretics prior to Alemtuzumab administration may also be considered; b If an IAR
occurs, provide the appropriate symptomatic treatment, as needed. If the infusion is not well tolerated, the infusion duration may
be extended. If severe infusion reactions occur, immediate discontinuation of the intravenous infusion should be considered.
1. Casady L et al. CMSC 2014, DX42; 2. Alemtuzumab [Summary of product characteristics] Genzyme Therapeutics Ltd, United
Kingdom; June 2016.
Pre-infusion patient
education
Premedication
(methylprednisolone
1 g IV)a
Generally infusion over
4 hours; infusion rate
adjustment and/or
symptomatic treatmentb
2-hour post-infusion
observation, and as-needed
symptomatic treatmentb
IAR
Management2
Before
Infusion1,2
During/After
Infusion1,2
Adapted from Casady L et al. CMSC 2014.

56
Rate of Infection by Year in Alemtuzumab-
Treated Patients
56.1
47.3 46.1
41.0 40.0
35.5
0
10
20
30
40
50
60
70
Year 1
(n=376)
Year 2
(n=376)
Year 3
(n=360)
Year 4
(n=344)
Year 5
(n=340)
Year 6
(n=335)
Any infection
Incidence,%
Rate of Infections in CARE-MS I1 Rate of Infections in CARE-MS II2
Safety Efficacy
MoA
63.2 61.8
50.0 50.6
44.7 43.4
0
10
20
30
40
50
60
70
Year 1
(n=435)
Year 2
(n=434)
Year 3
(n=412)
Year 4
(n=387)
Year 5
(n=367)
Year 6
(n=357)
Any infection
Incidence,%
Core Study Extension Study Core Study Extension Study
CARE-MS EXTENSION

57
Immune Competence After Alemtuzumab
Treatment (1/2)
• All patients given the diphtheria, tetanus, and poliomyelitis vaccine had seroprotective levels of antibodies to diphtheria and tetanus
before and after vaccination
― The percentage of patients seroprotected against polio increased after the vaccination
• Post Alemtuzumab treatment, responses to diphtheria, tetanus and polio were comparable with that of controls based on GMTR
(geometric mean of individual post-/pre-vaccination titres) values
• Participants had received alemtuzumab between 1.5 and 86 months previously
• Antibodies to common viruses were measured before alemtuzumab treatment, then at 1 and 9–11 months after treatment
a Derived from published data. b Tetanus GMTR could not be calculated because the majority of patients had antibody levels above
the upper detection limits of the assay. GMTR = geometric mean of individual post-/pre-vaccination titers.
McCarthy CL et al. Neurology 2013;81:872-76.
Response to T-cell–dependent recall antigens
Diphtheria, tetanus, and poliomyelitis vaccine (n=22)
Seroprotected
pre-vaccine n (%)
Seroprotected
post-vaccine n (%)
GMTR
(±90% CI)
GMTR from literature
controls
Diphtheria 22 (100) 22 (100) 2.6 (±1.2) 2.2a (2.0–2.5)
Tetanus 22 (100) 22 (100) Not doneb
Polio 1 21 (95) 22 (100) 3.5 (±22) 7.3a (5.9–9.0)
Polio 2 21 (95) 21 (95) 5.0 (±7.5) 10.0a (8.4–11.9)
Polio 3 17 (77) 21 (95) 16.5 (±15.6) 17.1a (13.6–21.4)
Safety Efficacy
MoA

58
Immune Competence After Alemtuzumab
Treatment (2/2)
• The proportion of seroprotected patients increased post- vs. pre-vaccination for both Hib and Men C, with seroconversion rates of 83
and 95%, respectively
• These seroconversion rates were similar to historical controls
a Serotype 3 and 8 seroconversion rates calculated from 15 and 20 patients, respectively, as the remaining patients had antibody
titres above the upper detection limit of the assays. b From published data. c Hib seroconversion rate calculated from 19 patients
because the remaining patients had antibodies above the upper detection limit of the assay. GMTR = geometric mean of individual
post-/pre-vaccination titers.
McCarthy CL et al. Neurology 2013;81:872-6.
Response to T-cell–independent antigen
Pneumococcal polysaccharide vaccine (n=21)
Seroconversion
2-fold antibody rise, n/N (%)
Seroconversion
from literature controls, %
GMTR GMTR from literature controls
Serotype 3 11/15 (73)a 35–47b 2.6 (1.7–4.0) 1.8–2.0b
Serotype 8 19/20 (95)a 81–85b 11.6 (6.0–17.3) 5.86–6.66b
Response to T-cell–dependent novel antigen
Haemophilus influenzae type b (Hib) and meningococcal group C (Men C) conjugate vaccine (n=23)
Seroprotected
pre-vaccine, n (%)
Seroprotected
post-vaccine, n (%)
Seroconversion
4-fold antibody increase, n (%)
Seroconversion
from literature controls, n%
Men C 3 (13) 21 (91) 19 (83) 97.6–100b
Hib 17 (74) 23 (100) 18/19 (95)c 82–90b
• 18/21 patients mounted a normal pneumococcal polysaccharide vaccine response based on an expert consensus definition
Safety Efficacy
MoA

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