Baker lisbon peg

Overview on the Current Antibody

Treatments for Multiple Sclerosis

Gavin Giovannoni

Slides available on www.ms-res.orgDavid Baker

([email protected])

UCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen Square PEG MEETING LISBON 2016

Dissecting Out the Mode of Action

of Targeted Monoclonal Antibodies

Over the last 15 years I have received personal compensation for participating in

advisory boards in relation to clinical trial design, trial steering committees, and

data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare,

Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW

Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon

BV, Teva, UCB Pharma and Vertex PharmaceuticalsNone RelevantFounder, consultant and shareholder of Canbex therapeutics. Received research funds from

Sanofi Genzyme

DISCLOSURES

IMMUNE ATTACKS ON THE BRAIN COMMON IN UK .1 IN 350 PEOPLE

& SPINAL CORD WITH 3,000,000 WORLDWIDE

OLIGODENDROCYTE LOSS

& NEURODEGENERATION DISEASE OF YOUNG ADULTS

ACCUMULATING LIFE EXPECTANCY

DISABILITY 8-10 YEARS LESS

FATIGUE POLYGENIC

NUMBNESS Sex + 300-450 genes

BLINDNESS (150 immune genes known)

PAIN

INCONTINENCE ENVIRONMETAL INFLUENCE

IMPOTENCE Latitude Effect (vitamin D)

SPASMS & TREMOR Lifestyle Effect (smoking)

COGNITIVE PROBLEMS Infection Effect

MOVEMENT PROBLEMS (Epstein Barr virus/HERV)

& MANY MORE INCLUDING:

DIVORCE & UNEMPLOYMENT MS IS UNIQUELY HUMAN

BIOLOGY OF MULTIPLE SCLEROSIS

INFLAMMATORY PENUMBRA IN MS

MYELIN = BROWN

DEMYELINATION

PERIVASCULAR

LESION

RELAPSING MS


Myelin=brown stain

1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014

SC IFN beta-1b

1995 (RMS)

IM IFN beta-1a

1997 (RMS)

SC IFN beta-1a

1998 (RMS)

Natalizumab

2006 (RRMS)

Glatiramer acetate

20 mg/mL

2003 (RMS)Fingolimod

2011 (RRMS)

Alemtuzumab

2013 (RRMS)

Teriflunomide

2013 (RRMS)

2016

Dimethyl fumarate

2014 (RRMS)

Peginterferon beta-1a

2014 (RRMS)

Daclizumab

2016 (RMS)

Glatiramer acetate

40 mg/mL

2015 (RMS)

Ocrelizumab

2017 (RMS/PPMS)

Oral Cladribine

2017 (RMS/PPMS)

2018

APPROVED ANTIBODIES FOR MS

Approved disease-modifying therapies for MS

1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014

SC IFN beta-1b

1995 (RMS)

IM IFN beta-1a

1997 (RMS)

SC IFN beta-1a

1998 (RMS)

Natalizumab

2006 (RRMS)

Glatiramer acetate

20 mg/mL

2003 (RMS)Fingolimod

2011 (RRMS)

Alemtuzumab

2013 (RRMS)

Teriflunomide

2013 (RRMS)

2016

Dimethyl fumarate

2014 (RRMS)

Peginterferon beta-1a

2014 (RRMS)

Daclizumab

2016 (RMS)

Glatiramer acetate

40 mg/mL

2015 (RMS)

Ocrelizumab

2017 (RMS/PPMS)

Oral Cladribine

2017 (RMS/PPMS)

2018

Rituximab Ofatumumab

APPROVED ANTIBODIES FOR MS

Approved disease-modifying therapies for MS

MS treatments mostly rely on direct targeting of proinflammatory cells

Alemtuzumab

CD52Lysis of mature

B and T cells

Proposed MoA: Anti-migratory

Fingolimod

Natalizumab

Lymph node BBB

CNS

S1P1

B

Tα4-integrin

Limits pyrimidine

availability for

rapid cell division

Teriflunomide

Beta

Interferons

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 cellsDaclizumab

APPROVED TREATMENTS FOR MS

Beta Interferons

Induce protein kinase R

phosphorylates eukaryotic

translation initiation factor to

block proliferation

Dimethyl fumarate Hyroxycarboxylic aacid

receptor 2 (GPR109)Daclizumab

Block IL-2 receptor block

proliferation

Proposed MoA: Pleiotropic effects

Two compartment model


RELAPSING MS

Systemic

immune

compartment

Intrathecal

immune

compartment

Two compartment modelSystemic

immune

compartment

Intrathecal

immune

compartment


RELAPSING MS

PROGRESSIVE MSActive disease triggers degenerative

changes that do not respond (quickly) to

the DMT inhibiting Relapse

MAGIC BULLET

UNPRESIDENTED

EFFICACY

UNEXPECTED

SIDE-EFFECTS

BALANCING EFFECTS OF ANTIBODIES FOR MS

Brain Gut

Cell Entry into

Tissue

No Cell Entry into Tissue

Mode of Action

NATALIZUMAB

IgG4 Given as Monthly Infusion

MOA

Polman et al. N Eng J Med 2006; 354:899

NATALIZUMAB

Inhibition of

Progression

of Disability

Inhibition of

Annualised

Relapse

Rate 42%

Decrease

Inhibition of Lesion LoadAFFIRM Trial : vs placebo

EFFICACY

Progressive Multifocal Leucoencephalopathy (PML)

Cause: John Cunningham Virus

JC virus infects about 55% pwMS

Disease associated with

Immunosuppression (e.g. AIDS)

Demyelinating Disease.

Viraemia induced lysis of

oligodendrocytes

20-25% Risk of Death from PML

Survivors Disabled

Occurs after dimethyl fumarate & fingolimod associated with persistent

leucopaenia

NATALIZUMAB

Demyelination

(Luxol fast blue)

Natalizumab appears to disrupt bone marrow niche of B cells

which enter circulation and increase chance of CNS infection

SIDE EFFECTS

NATALIZUMAB SIDE EFFECTS

www.ms-res.org

Natalizumab PML risk stratification tool

Biogen Data on File, July 2016

Historical PML Risk

JC Virus Negative 1 in 10,000

JC Virus Positive

Immunosuppressive use

>2 years on Natalizumab 1 in ~90

For JC Virus Positive Individuals

Monitor JC-specific antibody titre

Switch DMT use at 2 Year

Progressive Multifocal Leucoencephalopathy-Risk Management

Current Risk

(a) Reactivation/Rebound Disease

(b) Immune reconstitution

inflammatory syndrome (IRIS)

in subclinical JC infection

Mode of Action of Antibody (Zinbryta)

IL-2

IL-2 intermediate-affinity (βγ) receptor

IL-2 high-affinity (βαγ) receptor

Daclizumab

Activation

CD4+

CD4+

Tact

cell

CD4+

Tact

cell

CD56brightCD56bright

CD56bright


CD56bright

T Cell Activation

Blocked

Natural Killer Cell

Expanded

Daclizumab blocks high-affinity IL-2 receptor signalling, resulting in higher levels

of IL-2 available for signalling through intermediate-affinity IL-2 receptor

DACLIZUMAB MOA

IgG1 Given as Monthly s.c. Injection

Bielekova B, et al. Arch Neurol. 2009;66:483–89.

CD4+ T cells

0

2000

2500

500

Mo

-3

Mo

-1

Mo

2.5

Mo

4.5

Mo

6.5

–8

.6

Mo

10

.5

Mo

12

.5–

14

.5

Ab

solu

te n

um

ber

of ce

lls p

er

ul o

f b

lood

IFN-β IFN-β

+dacliz daclizumab

1500

1000

CD56bright NK cells

0

200

250

50

Mo

-3

Mo

-1

Mo

2.5

Mo

4.5

Mo

6.5

–8

.6

Mo

10

.5

Mo

12

.5–

14

.5

Ab

solu

te n

um

ber

of ce

lls p

er

ul o

f b

lood

IFN-β IFN-β

+dacliz daclizumab

1500

100

CD25 blockade prevented IL-2 binding

but resulted in a moderate reduction

in T-cells and Increase in NK cells

DACLIZUMAB MOA

*Difference first observed; P<0.0001. IQR, interquartile range.

Amaravadi L, et al. Poster presentation at AAN 2015;P1.149;

Zinbryta® (daclizumab) SmPC. July 2016.

Daclizumab induces a sustained increase

in serum IL-2 concentrations

CI, confidence interval.

1. Gold R, et al. Lancet. 2013;381:2167–75; 2. Zinbryta® (daclizumab) SmPC. July 2016; 3. Kappos L, et al. N Engl J Med.

2015;373:1418–28.

SELECT Trial : vs placebo DECIDE Trial : vs IFN beta-1a

The 300 mg dose did not provide additional

benefit over the licensed 150 mg dose

DACLIZUMAB EFFICACY

Primary endpoint: Annualised relapse rate

76% relative risk reduction

HR=0.24 (95% CI: 0.09–0.63)

P=0.0037

27% relative risk reduction

HR=0.73 (95% CI: 0.55–0.98)

P=0.03

Mode of Action of Antibody (Zinbryta)

IL-2

IL-2 intermediate-affinity (βγ) receptor

IL-2 high-affinity (βαγ) receptor

Daclizumab

Activation

CD4+

CD4+

Tact

cell

CD4+

Tact

cell


CD56bright


CD56bright

T Cell Activation

Blocked

Natural Killer Cell

Expanded

Daclizumab blocks high-affinity IL-2 receptor signalling, resulting in higher levels

of IL-2 available for signalling through intermediate-affinity IL-2 receptor

CD4+

TReg

cell

T Regulatory Cell Activity

Blocked & No. Reduced

Control of

Autoimmunity Lost

DACLIZUMAB SIDE EFFECT

Side Effects of Antibody (Zinbryta)

INTEGRATED SAFETY

ANALYSIS

Daclizumab 150 mg

n=1943

Skin reactions, % 32

Serious skin reactions, % 2

Discontinuation due to skin reactions, % 4

Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36: Kappos L, et al. N Engl J Med. 2015;373:1418.

SELECT & DECIDE TRIALS

• Hepatic Events in 15% pwMS

• Elevation of transaminases in daclizumab-treated patients occurred throughout treatment

DACLIZUMAB SIDE EFFECT

Alemtuzumab: mechanism of action

ALEMTUZUMAB MOA

IgG1 given five infusions in Year 1

& three infusions in Year 2 (Induction therapy)

Lycke J et al. EFNS 2012.

ALEMTUZUMAB EFFICACY

Inhibition in Relapse Rate

P<0.0001

(↑44.5%)

P=0.0053

(↑32.2%)

37.950.1

67.5

46.7

61.2 60.2 62.4

39.5

Pe

rce

nta

ge

NE

DA

pe

r Y

ea

r

No-Evidence of Disease Activity

5 year follow-up

1. Compston DA et al. AAN 2015; Platform S4.007; 2. Arnold D et al. ECTRIMS

2015; 3. Havrdova E et al. AAN 2015; Poster P7.276; 4. Traboulsee A et al.

ECTRIMS 2015.

(No relapse, MRI activity, No Progression)

____________________________________

Treatment cycle Frequency used

____________________________________

Year 0 & 1 52%

Year 2 36%

Year 3 8%

Year 4 1%

___________________________________

Drug use in Long-term Follow up

Tuohy et al. 2015. J Neurol neurosurg pschyiatry 2015; 86:208

ALEMTUZUMAB SIDE EFFECTS

1. INFUSION REACTIONS: 90%.Reactions & Reactivation of Existing lesions

2. INFECTONS: 67%/77% CARE MS- I/II (Most Mild-Moderate)

16% Herpes Infections

3. SECONDARY 16-18% in Two Years

AUTOIMMUNITIES (Cohen et al. 2012, Coles et al. 2012

About 50% in Five Years (Tuohy et al. 2015)

INCIDENCE OF THYROID DISEASE IN CAREI/II EXTENSION

______________________________________________________________

Year 1 Year 2 Year 3 Year 4 Year 5

______________________________________________________________

Proportion with

Thyroid event 5.7% 10.7% 20.9% 12.6% 10%

______________________________________________________________

Thyroid events in 39%. Senior et al. 2016 Neurol P.2086

INCIDENCE OF THYROID DISEASE IN CAMBRIDGE (CAMMS223) 7 Year Data

_______________________________________________________________

48% Secondary Autoimmunity

41% Thyroid Autoimmunity (63% Hyperthyroidism Grave’s)

(34% Hypothyroidism) Tuohy et al. 2015

_______________________________________________________________


1. CD52 DEPLETES CD4 T CELLS & INHIBITS DISEASE

2. CD19 B CELL DEPLETION LESS EFFICIENT IN LYMPHOID TISSUE

THAN BLOOD (Hu et al. 2009, von Kutzleben et al. 2017).

3. CD52 DEPLETION BLOCKS TOLERANCE INDUCTION

IN CD8 DEPENDENT MECHANISM (von Kutzleben et al. 2017)

mAb

Myelin

Tolerance

Attempt Break

Tolerance

Majority

Tolerized

Majority

Not-tolerized

Mouse Model of Multiple Sclerosis

ANIMAL STUDIES: LOSS OF IMMUNE TOLERANCE

SIDE EFFECTSALEMTUZUMAB

LOSS OF TOLERANCE- B CELL AUTOIMMUNITY

Jones et al. 2005, Thompson et al 2010

Tregs Control Silencing of autoreactive Immature B cells as they exit

from Bone Marrow and enter blood (Kinnumen et al. 2013, Brink 2014)

T cells control autoreactivity generated during affinity maturation of antibodies.

Antibodies against gut bacterial affinity mature to cross-react to thyroid hormone

receptor with stimulating antibodies (Hargreaves et al. 2013,Meyer 2016).

Phase III Trials

No Data Shown in

Trial Reports.

B cells reach lower

limit of Normality

in 6 months

(Cohen et al 2012)

(Coles et al 2012)



Jones et al. 2005, Thompson et al 2010

________________________________________________________________

Antibody Type Target Neutralizing Antibodies

_________________________________________________________________

Rituximab Chimeric anti CD20 15-25%

Ocrelizumab Humanized anti-CD20 0.5-1%

Natalizumab Humanized anti-CD49d 6-9%

Alemtuzumab Humanized anti-CD52 78%

__________________________________________________________________

Natalizumab Neutralizing Antibodies Inhibit Activity

Placebo NeutralizedNatalizumab

85.2% (n = 691/811) have binding antibodies and of 92.2% (n=637/691) have inhibitory antibodies

Zeimmessen et al. 2013,

EMA/H/C/003718,

Time (Months)

0 3 6 9 12 15 18 21 24

Me

dia

n T

itre

of

Ale

mtu

zu

ma

b B

ind

ing A

ntib

od

ies

Me

dia

n T

itre

of

Ale

mtu

zu

ma

b N

eu

tra

lizin

g A

ntib

od

ies

0

100

200

300

400

500

600

700

800

Binding Antibodies

Neutralizing Antibodies

101

102

103

104

105

106

mAb mAb

Alemtuzumab-specific antibodies

LOSS OF TOLERANCE- ANTI-DRUG IMMUNITY


Neutralizing antibodies were not associated with loss activity in trial. However

“If persistent, neutralizing antibodies become problematic in patients

who have received multiple alemtuzumab cycles (Coles 2013)”

SECONDARY AUTOIMMUNITIES-HYPOTHESIS



Antigen

presentation

Autoantibody

production

Ectopic lymphoid

follicle-like aggregates

in CNS

Cytokine

production

B cells play key functional roles in MS

OCRELIZUMAB MOA

Ocreliziumab Selectively Targets B Cells While Sparing Other Immune Cells

Cytotoxic T cells

T helper cellsNatural Killer cells

CD19 B cells

OCRELIZUMAB MOA

Crossover

To ocrelizumab

Hauser et al. 2013

OCRELIZUMAB EFFICACY

74%NEDA improvement

vs IFN β-1ap<0.0001

NEDALesion Load Inhibited by 97%/98%

Relapses Inhibited

98%

Hauser et al 2015

ECTRIMS

OCRELIZUMAB SIDE EFFECTS

Adverse eventsElevated numbers of infusion

reactions.

In trials infections issues were

unremarkable however

Development of Ocrelizumab

halted in Rheumatoid Arthritis

and SLE, due to infectious

issues. MS considered a

worse disease that justifies

the risk.

No Secondary Autoimmunities

No PML….yet

Hauser et al 2015

ECTRIMS

OCRELIZUMAB EFFICACY

Trial 25% active at enrolment, usually only 15% active

Significant Benefit

in Primary Progressive MS

Younger more active people with MS

respond to rituximab

Montelban et al 2015 ECTRIMS

EXPLAINING THE BIOLOGY OF THERAPY

___________________________________________________________________

HIGHLY ACTIVE DMT Target Populations Explanation

___________________________________________________________________

MITOXANTRONE Dividing T, B cells

CYCLOPHOSPHAMIDE Dividing T, B cells

CLADRIBINE T cell B cells

FINGOLIMOD T cell subsets B cells

ALEMTUZUMAB T cell B cells

OCRELUZIMAB - B cells

DACLIZUMAB Dividing T, NK -

WEAK/NON-ACTIVE DMT

CD4 Depleting Antibody T cell -

T CELL CENTRIC

CD20+ T cell subset

Halt Antigen-Presentation

DOGMA INDICATES DISEASE IS CONTROLED BY CD4 TH1/TH17 T CELLS


__________________________________________________________________

Antibody Effect in EAE model Perceived effect in MS

__________________________________________________________________

CD4 mAb Inhibition of CD4 T cell Activity Failed (Marginal Effect)

Inhibition at 85% Depletion Depletion T cells 60-70%

Marginal Inhibition at 60% Depletion Limited to >250 cells/µl

No inhibition at 30% depletion

Ustekinumab Inhibition of IL-12/IL-23 to block Th1 Failed in PhII

Inhibition of EAE Induction

No Inhibition of Relapsing EAE

Secukinumab Inhibition of IL-17A to block Th17 Reduced Lesion Load

Marginal Inhibition of EAE induction by ~50% in PhII

CD20 mAb Inhibition of B Cell Activity Inhibits Relapses

No or Marginal Inhibitory Effect Depletion T cells10-20%

without significant T cell depletion

________________________________________________________

DOGMA INDICATES DISEASE IS CONTROLED BY CD4 TH1/TH17 T CELLS

DISEASE IS CONTROLED BY CD8 T CELLS (major T cell in lesions)

Hartung et al. 2012, Kasper et al. 2013,Thompson et al. 2010, EMA

B Cell Hyper-population

Secondary Autoimmunity

B Cell Mediated

Control of MS

TREATMENT EFFICACY IN MULTIPLE SCLEROSIS

Effective Agents Target memory B cells Alemtuzumab

B Cell Hyper-population

Secondary Autoimmunity

MS +

DAC

Chin

Lin

et a

l. Ann C

linT

ransla

tN

euro

l2015; 2

:445

CD56Brigtht

Natural Killer

Cells

CD4 T cells

CD19 B cells

Absolute Numbers Percentage

MS MS HCHC MS +

DAC

CD25 B cells express CD122, CD132

(alpha, beta and gamma IL-2 receptor)

High levels of IgG but don’t secrete antibody

Peripheral Blood B cells express CD25

32 ± 16% (10-65%)

B Cells Express CD25

Brisslert et al. Immunology

2006; 114:548

Costimulatory molecule Expression (%)

CD25 expression

Brisslert et al. Immunology 2006; 114:548

B Memory Cells Express CD25


Effective Agents Target memory B cells Daclizumab

CD3 T cells CD19 B cells

Memory B cellsNaïve (mature) B Cells

Palanichamy et al. J. Immunol 2014, 193:580

Rituximab Chimeric CD20-specific mAb

Anti-CD20 B Cell Therapy

Rituximab infusion every 6 months (patent expires soon)

Ocrelizumab Infusion in phase III trials every 6 months

Ofatumumab development of Infusion

switched to subcutaneous route repeated dosing


Effective Agents Target memory B cells CD20-specific mAb

Week 144

Ad

just

ed

An

nu

aliz

ed

Re

lap

se R

ate

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo 0-24 week

Beta Interferon 0-24 week

Ocrelizumab 0-24 week, 24-96 week

Placebo switch to Ocrelizumab 24-96 week

Beta Interferon switch to 24-96week

Week 96Week 24 Drug Free

for 18 month

All on 600mgOcrelizumab

Placebo Control600mg Ocrelizumab

Extension Study

Inhibition of relapses with ocrelizumab

Hughes 2013. Ocrelizumab in MS: encouraging long term data

Hauser et al. Neurology 2013, 80:7 Supplement S31.004


Is it an

Induction

Therapy?

Effective Agents Target memory B cells CD20-specific mAb

Atacicept TACI-human IgG fusion protein to block BAFF/APRIL

ATON: Phase II randomized trial of B cell targeting agent atacicept in

Patients with Optic Neuritis (Sergott R.C. et al. J. Neurol Sci 351:174-178)

___________________________________________________

Treatment Conversion to Multiple sclerosis

___________________________________________________

Placebo 3/17 (17.6%)

Atacicept (150mg) 6/17 (35.3%) Worsening

___________________________________________________

Dose-related increase of memory B cells then a decrease in naïve mature B

in RA(Tak et al. Arth Rheumatism 58:61-72).

Blockade of BAFF with BR3-Ig (Briobacept) increases memory CD19+, CD27+

cells


Effective Agents Target memory B cells-AtaciceptIn


___________________________________________________________________

HIGHLY ACTIVE DMT Target Populations Explanation

___________________________________________________________________

MITOXANTRONE Dividing T, B cells

CYCLOPHOSPHAMIDE Dividing T, B cells

CLADRIBINE T cell B cells

FINGOLIMOD T cell subsets B cells

ALEMTUZUMAB T cell B cells

OCRELUZIMAB T cell B cells

DACLIZUMAB Dividing T, NK B cells

WEAK/NON-ACTIVE DMT

CD4 Depleting Antibody T cell -

T CELL CENTRIC

CD20+ T cell subset


B CELL CENTRIC


Inhibit Pathogenic B cells

INFECTION CENTRIC

B cells and the reservoir

for Epstein Barr Virus

Memory B cells have

CD21= EBV receptor

anti-infections

• Revolutionised the treatment of MS

CONCLUSIONS

Induction vs Maintenance therapy

Increased monitoring requirements

De-Risking Testing/Switching strategies e.g. JC virus

Long-term Remission of Relapsing MS

Progressive MS Influenced by DMT,but needs CNS targeting

• Targeted therapies to have better outcomes

Peripheral Immunity Drives Relapsing MS

• Better Outcomes, but more Risk

• New challenges, New Targets

• New Insights into a Complex Biology

Challenging Dogma (T cells vs. B cells)

HOPE FULLY FOOD FOR THOUGHT

THANK YOU FOR LISTENING

HOPE FULLY FOOD FOR THOUGHT

BASIC

SCIENTIST PHARMA & CLINICANS

& ANTIBODY EXPERTS

CLINICIANSDavid Baker

Clinical Studies

Gavin Giovannoni

Klaus Schmierer

Animal Studies

Stephanie von Kutzleben

Gareth Pryce

([email protected])

www.ms-res.org

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