SWITCHING THERAPIES

CONSIDERATIONS REGARDING ALEMTUZUMAB

Professor Gavin Giovannoni

Blizard Institute, Barts 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-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis,

Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Genzyme for making

available data slides on alemtuzumab for this presentation.

No evident disease activity: NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

Treating-2-target

Choosing therapy

X Y Z

Define the

Individual’s MS

No

Treatment failure? Yes

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

• MS prognosis

• Life style and goals

• Shared goals for therapy

Rebaseline

Rebaseline:

• IFNβ, natalizumab, fingolimod,

teriflunomide, DMF=3-6 months

• Glatiramer acetate=9 months

• Alemtuzumab=24 months

DMF=dimethyl fumarate.

Alemtuzumab for the treatment of RRMS

• Alemtuzumab is indicated for adult patients with

relapsing remitting multiple sclerosis (RRMS) with

active disease defined by clinical or imaging

features1.

• Alemtuzumab is a humanized monoclonal antibody

that selectively targets CD52, a protein abundant

on the surface of B and T lymphocytes2

• A phase 2 & 3 clinical trial program was

implemented to establish efficacy and safety in MS

patients

• Completed 3 head-to-head trials vs. high-dose

subcutaneous interferon beta-1a (SC IFNB-1a)

in patients with active relapsing-remitting

multiple sclerosis (RRMS) 3-6

1. SMPC – EMA label; 2. Hu Y et al. Immunology 2009;128:260-70; 3. Coles AJ et al. N Engl J Med 2008;359:1786-801; 4. Coles AJ et al. Lancet

2012;380:1819-1828; 5. Coles AJ et al. Lancet 2012;380(1829-1839); 6. Brinar V et al. Presented at 21st Meeting of the European Neurological

Society, 2011.

CARE-MS II: Subgroup analysis by previous DMT use

• CARE-MS II study enrolled patients with relapsing-remitting MS

(RRMS) who had experienced continued disease activity on

disease-modifying therapies (DMTs)

Patient Subgroups According to DMT Type, or Number of Courses

Freedman MS, et al. Presented at ECTRIMS; 2012; France; P483.

Efficacy outcomes - Relapses Relapse Rate in Patients Stratified by Prior DMT Usage

• Alemtuzumab was superior to SC IFNB-1a at reducing relapse rate

regardless of the type of prior therapy

• The patient group who received SC IFNB-1a prior to study entry had

a higher relapse rate, if treated with SC IFNB-1a, than those who

had no prior SC IFNB-1a use

Freedman MS, et al. Presented at ECTRIMS; 2012; France; P483.

Efficacy outcomes - Relapses Relapse Rate in Patients Stratified by (A) Median Duration of Prior DMT Use and (B)

Number of Prior DMT Courses

• Alemtuzumab was superior to SC IFNB-1a at reducing relapse rate

regardless of the duration of the previous treatment or the number of prior

DMT courses (1 or ≥2)

• The patient group who received more than 1 DMT course prior to study

entry had a higher relapse rate, if treated with SC IFNB-1a, than those who

had just 1 prior DMT course

Freedman MS, et al. Presented at ECTRIMS; 2012; France; P483.

Efficacy outcomes - Sustained Accumulation of Disability

Freedman MS, et al. Presented at ECTRIMS; 2012; France; P483.

SAD in Patients Stratified by Prior DMT Usage

• Alemtuzumab showed a consistent trend toward greater efficacy than SC

IFNB-1a in reducing the risk of SAD regardless of the type of previous

treatment

Freedman MS, et al. Presented at ECTRIMS; 2012; France; P483.

Sustained Accumulation of Disability in Patients Stratified by (A) Median Duration of Prior

DMT Use and (B) Number of Prior DMT Courses

• Alemtuzumab showed a consistent trend toward greater efficacy than SC

IFNB-1a in reducing the risk of SAD regardless of the the duration of prior

DMT use or number of prior DMTs

Efficacy outcomes - Sustained Accumulation of Disability

Previous treatment with Natalizumab

• The number of adverse events among patients who received

natalizumab prior to study entry is too small to draw any

meaningful conclusions

• In patients with prior natalizumab use:

• Relapses occurred in 4 of 7 SC IFNB-1a and 5 of 15

alemtuzumab 12 mg patients

• SAD occurred in 0 of 7 SC IFNB-1a and 1 of 15

alemtuzumab 12 mg patients

Freedman MS, et al. Presented at ECTRIMS; 2012; France; P483.

Important considerations

• Switching from natalizumab

• Carry-over PML

• Rebound post-alemtuzumab

• Switching from fingolimod

• Persistent lymphopaenia

• Rebound post-fingolimod

• Switching from other agents

• Persistent lymphopaenia

BARTS-MS www.ms-res.org

Switching from Nz to Az

Natalizumab

Natalizumab

Alemtuzumab

Asymptomatic PML? LP-JCV DNA & MRI

Alemtuzumab

Natalizumab Alemtuzumab Oral bridging agent (Teriflunomide, DMF or Fingolimod)

Rebaseline MRI **

Asymptomatic PML? LP-JCV DNA & MRI

3-6 MONTH WASHOUT

Asymptomatic PML?* LP-JCV DNA & MRI

Rebaseline MRI

Option 1: Immediate switch (high risk if carry-over PML develops)

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity)

Option 3: Bridging (low risk; mainly related to using a low efficacy bridging agent and using alemtuzumab after the bridging agent)

6-12 MONTHS

* For this option the shorter the washout the more important the screen for asymptomatic PML becomes. ** PML screening and baseline MRI studies are don’t use the same types of scans hence the need for both.

Temporal profile of lymphocyte counts with fingolimod therapy

Francis et al. MSJ 2013

Switching from Fingo to Az

Fingolimod

Fingolimod

Alemtuzumab

Alemtuzumab

Fingolimod Alemtuzumab Bridging agent (IFN-beta, GA, Teriflunomide or DMF)

Only treat with alemtuzumab once lymphocyte counts normalize*

2 to 6 12 MONTH WASHOUT

Only treat with alemtuzumab once lymphocyte counts normalize*

Option 1: Immediate switch (high-risk if persistent lymphopaenia occurs)

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity)

Option 3: Bridging (low risk; mainly related to MS rebound as a result of using a low efficacy bridging agent after fingolimod)

3-12 MONTHS

* What constitutes a normal level post-fingolimod needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below 1.0x109 .

Treat with alemtuzumab before lymphocyte counts normalize

* What constitutes a normal level in this situation needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below 1.0x109 .

Questions