Prof. Sir Marc Feldmann

Kennedy Institute of Rheumatology Nuffield Department of Orthopaedics, Rheumatology

and Musculoskeletal Sciences, University of Oxford

IMI SYMPOSIUM - MILAN – 26th August 2013

HOW ANTI-TNF THERAPY WAS DISCOVERED

BY A PUBLIC-PRIVATE PARTNERSHIP

Supported by

• Chronic immune inflammatory disease

• Sex : F:M 3:1, ~1%

• Progressive joint damage & disability, reduced quality of life

• Structural damage early & progressive

• 50% severely impaired by 10 yrs (not working)

• Pathology: leucocyte recruitment inflammation, tissue destruction and repair

RHEUMATOID ARTHRITIS (RA)

Pannus

Tissue destruction

Inflammation

PLAN OF TALK

A. IDENTIFYING & VALIDATING TNF

AS A THERAPEUTIC TARGET

B. TRANSLATING INTO CLINICAL PRACTICE

C. HOW WAS ANTI-TNF DISCOVERY A

PUBLIC-PRIVATE PARTNERSHIP?

D. FUTURE OF PUBLIC-PRIVATE PARTNERS

e.g. STRUCTURAL GENOMICS CONSORTIUM

WHY LOOK FOR CYTOKINES IN RHEUMATOID ARTHRITIS?

Upregulation of HLA-DR in rheumatoid synovium

(Klareskog, Wigzell, Panayi, Janossy etc. 1981/82)

Rheumatoid Arthritis Osteoarthritis

Expression of HLA-DR on cells usually negative

indicates presence of inducers = cytokines

Londei et al., 1984, Nature Epithelial cells expressing aberrant

MHC class II determinants can

present antigen to cloned

human T cells.

Pujol-Borrell et al.,

1987, Nature HLA class II induction in human

islet cells by interferon-g

plus TNF or lymphotoxin

1983: A NEW HYPOTHESIS FOR AUTOIMMUNITY

Autoantibodies

and

tissue damage

TISSUE DAMAGE

VIRUSES

CYTOKINES

CYTOKINES

T Upregulation of

HLA class II and

antigen presentation

T

B

APC

Non tolerant

autoantigen

reactive

T cells

CYTOKINES &

INTERFERONS

Londei et al., 1985, Science Human T-cell clones from autoimmune

thyroid glands: specific recognition of

autologous thyroid cells.

Bottazzo et al, 1983, Lancet Hypothesis: Role of aberrant

HLA-DR expression and antigen

presentation in the induction of

endocrine autoimmunity.

Marco Londei

MANY CYTOKINES ARE PRODUCED IN

RHEUMATOID SYNOVIUM

ARE ANY THERAPEUTIC TARGETS?

Pro-inflammatory e.g. IL-1, IL-6, TNFa, IL-12, IL-15, IL-17, IL-18, IFNg, IL-2, OncoM, GM-CSF Anti-inflammatory e.g. IL-10, IL-1Ra, TGFb, IL-11, IL-13 Chemokines e.g. IL-8, MIP-1a, MCP-1, RANTES, ENA-78, GROa Growth Factors e.g. VEGF, PDGF, FGF

PRO-INFLAMMATORY

CHRONICITY

ANTI-INFLAMMATORY

Tiny Maini

ANALYSIS OF CYTOKINE REGULATION REVEALED IMPORTANCE OF TUMOUR NECROSIS FACTOR

APPROACH Operative sample RA synovium, cells

placed in ‘tissue culture’

OBSERVATION Spontaneous production of cytokines etc

EXPERIMENT Antibody to TNF

Brennan et al (1989) Lancet ii 244-247 Days of culture

6 3 1 0

10

20

30

control

anti LT

anti TNFa

IL-1

(U

/ml)

Rheumatoid Arthritis

Days of culture

Osteoarthritis

6 3 1 0.0

0.2

0.4

0.6

0.8

1.0

IL-1

(U

/ml)

Fionula Brennan

TNF DEPENDENT CYTOKINE CASCADE

IN RHEUMATOID ARTHRITIS

Immune system

TNFa

Anti-inflammatory

IL-10, IL-1ra, sTNF-R

Pro-inflammatory

IL-6, IL-8, GM-CSF etc

IL-1

Feldmann, Brennan and Maini (1996) Cell, 85: 307

A USEFUL OVERSIMPLIFICATION….

RATIONALE FOR ANTI-TNFa THERAPY IN

RHEUMATOID ARTHRITIS

1. Disregulated cytokine network in RA

synovium is dependent on TNFa

Tiny Maini

2. TNFa/TNF-Receptor upregulated in

synovium

3. Animal model of RA responds

very well to anti TNFa

administered after disease

onset.

FORMAL PROOF:

RANDOMISED, PLACEBO-CONTROLLED TRIAL

OF INFLIXIMAB IN RHEUMATOID ARTHRITIS

Elliott, Maini, Feldmann et al, Lancet 1994; 344: 1105-10

Design

Placebo

1 mg/kg cA2

10 mg/kg cA2

4 3 2 1 0 0 0

10

20

30

40

50

60

70

80

Week

normal range

p<0.001

p<0.01

CRP

4 3 2 1 0 0 0

10

20

30

Week

Swollen Joint Count

p<0.001 p<0.001

3, 10 or 20 mg/kg 1 or 10 mg/kg

or HSA

Week -4 0 4

washout

cA2:

44%

8%

79%

1 mg/kg

Placebo

10 mg/kg

responders

non-responders

p=0.0083

p<0.0001

Paulus 20% responses at week 4

Ferry Breedveld

Jochen Kalden

Josef Smolen

Results

well-tolerated

good clinical responses

in cA2 groups

dose-response

relationship

Used in >70% patients

ENHANCED EFFICACY OF ANTI-TNF WITH

METHOTREXATE: ACR 50 (50% Paulus response)

% P

atie

nts

re

sp

on

din

g 1 mg/kg cA2 3 mg/kg cA2 10 mg/kg cA2

Week

60

80

40

20

0

20

60

80

40

0

0 4 8 12 16 26 0 4 8 12 16 26 Week 0 4 8 12 16 26

100 100

Placebo MTX+ cA2 MTX- cA2 MTX+

Maini RN et al. (1998) Arthritis Rheum.; 41:1552-1563.

Kennedy Institute gets royalties on USE patent

Charles et al (1999) J Immunol; 163: 1521-28

Day 28 21 7 0 14 1 3

0

100

200

150

50

Se

rum

IL

-6 (

pg

/ml

Placebo

1 mg/kg

10 mg/kg

MECHANISM OF ACTION:

TNFa DEPENDENT CYTOKINE CASCADE

IS OPERATIVE IN VIVO

Also IL-1, GM-CSF, IL-8, VEGF etc

Knees Hands

Pre

-tre

atm

en

t

2 w

ee

ks

post-

treatm

ent

MECHANISM OF ACTION:

REDUCED LEUCOCYTE TRAFFICKING

AFTER INFLIXIMAB THERAPY

Taylor et al (2000)Arthritis Rheum 43:38-47

R knee L Hand R hand L knee

Pe

rce

nta

ge

ch

an

ge

cp

m /p

ixe

l /M

Bq

5

-5

-15

-25

-35

-45

-55

-65

111 Indium labelled polymorphs

Peter Taylor

TNF BLOCKADE IN OTHER DISEASE:

1. CLINICAL STUDIES IN MANY DISEASES

2. APPROVAL ALSO IN: Juvenile RA

Ankylosing spondylitis

Psoriatic arthritis

Psoriasis

Crohn’s disease

Ulcerative colitis

3. ROUTINE USE IN: Behcet’s

Amyloidosis

etc

4. FUTURE USE: Fibrosis-Dupuytren’s

Post-Operative Cognitive Decline

CURRENT PROBLEMS OF

ANTI-TNF THERAPY

1. Not all patients respond

2. Degree of response inadequate

3. Side effect profile ● Infection

4. Cost of therapy ($20-30K)

UNEXPECTED: ACCELERATING A THERAPEUTIC REVOLUTION

1977 Kohler and Milstein:

mouse Mab by fusion

- problem immunogenicity

1980’s Molecular engineering

Chimeric Ab

- Infliximab, Rituximab

approved 1999/2002

1990’s Humanization & Human Antibodies - Adalimumab

Phage Display, Engineered Mice

SALES OF MONOCLONAL ANTIBODIES

2012 5 of top 10 drugs Mabs

anti-TNF biggest drug class

Mab revolution driven by

- anti TNFs - $25bn

- anti cancer - >$20bn

Georges Köhler

Cesar Milstein

Greg Winter

ANTI-TNF THERAPY: PRIME EXAMPLE

OF BENEFIT OF OPEN RESEARCH

1. Hypothesis Rationale Proof of Principle 1983-1992

2. Public Disclosure - Sept 1992

- Publication Dec 1993

● Grant by Centocor did not prevent early

disclosure for common good

● Other companies joined fray post hearing of clinical success

e.g. Celltech, Roche, Immunex, BASF (Abbott)

Public disclosure is a fundamental principle of science:

credit for discovery depends on disclosure

- first to disclose is discoverer (Royal Society 1660’s)

- reproducibility is key to science

TIMELINE: DISCOVERY AND

DEVELOPMENT OF ANTI-TNF THERAPY

1983 Hypothesis

1985-90’s Cytokine analysis in RA and Joints

1989 TNF dependent cytokine cascade (Brennan)

1991 Anti-TNF ameliorates mouse arthritis (Williams)

1992 Proof-of-Principle open trial London }

1992/3 Re-treatment }

SEPT 1992 DISCLOSURE IN ARAD, ISRAEL

DEC 1993 PUBLICATION

1993 Randomized, placebo-controlled

1994-5 Dose ranging and combination

1996 Mechanism Action

1997-8 Phase III

1998/9 Registration Etanercept/Infiliximab

2002 Approval NICE

2003- Safety by patient registers

2002 ONWARDS Commercial and Patent Disputes

ACADEMIC

COMMERCIAL

GRANT

PUBLIC-PRIVATE PARTNERSHIPS example in Toronto/Oxford -

Structural Genomics Consortium

SGC-Oxford: human proteins/ structures to

facilitate therapeutics development

• World leader in human protein structural biology

– Nearly 700 novel structures

– 8% of all structures solved per annum

• Generating freely available novel epigenetic inhibitors

– 10 so far

– 5 more per annum

– In partnership with 8 companies (GSK, Pfizer, Novartis, Lilly,

Abbvie, Boehringer-Ingelheim, Janssen, Takeda)

• Now working closely with Kennedy Institute,

to help discover a cure for RA

FUTURE: EVOLUTION OF SGC

• Working closely with Kennedy Institute to develop new

therapeutics on new targets

e.g. DDR1

CCR4-CAF1

• Use of human disease cells to improve target validation

- increase throughput

• Taking new targets and drugs into proof-of- principle

clinical trials

KEY POINTS

• Academic researchers far outnumber Industrial

• Certain specialized skills only in academia due to

restricted resources e.g. human blood/tissue

• Avoiding needless duplication reduces costs, improves quality

• i.p. on targets difficult to sustain

• Commerical use of targets leads to new drugs with solid i.p.

CONCLUSIONS

• Private-Public partnerships are a very

efficient way of conducting research

with major human impact

Sir Ravinder Maini

FUNDING: ARUK, KTRR, MRC, Wellcome Trust,

Centocor, Inc., Nuffield Foundation, etc

Peter Taylor

Richard Williams

Fionula Brennan

ACKNOWLEDGEMENTS

Claudia Monaco