Regeneron Pharmaceuticals – Its history, science and technology - Northeast Regional Biomanufacturing Collaborative

mutebabiesBiotechnology

Dec 6, 2012 (4 years and 6 months ago)

426 views

1

Regeneron
Pharmaceuticals


Its history, science and
technology

BIOMAN Conference

July 30, 2009

2

Regeneron at the start



Founded in 1988 by Len Schelifer, MD, PhD, Professor of
Neurology, Cornell Medical School


Four original employees


Expertise in neuroscience


Cutting edge research in neurotropins (CNTF, BDNF, NGF,
NT
-
3)


Commited to the discovery, development and commercialization
of drug products for the treatment on unmet medical conditions


Initial therapeutic target was treatment of neurodegenerative
disease (ALS or Lou Gehrig’s disease)




3

Regeneron Historical

Ups and Downs 1989
-

1999

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

New
HQ in
Tarryt
own

BOD

formed

REGN goes
public


Rens
Mfg site
acquired
for CNTF


CNTF
fails in
PIII

BDNF
collab.
w/

Sumitomo


Axokine
collab.
w/

P&G


Merck
toll mfg
agree

ment


4

Regeneron Historical

Milestones 2000
-

present

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

IL
-
1 Trap collab.
w/

Novartis begins


VEGF Trap collab.
w/

Aventis begins


BDNF
dropped

Sanofi
collab.
expanded

to mAbs


VEGF
Trap

Eye
collab
w/ Bayer


Axokine
poor PIII
outcome

Trap
molecules
begin to
emerge


Merck
contract
ends

IL
-
1 Trap
RA PII

released

Novartis

withdraws

First

2 x 10 kL
mfg suite
on line


IL
-
1 Trap
appoved
in US for
CAPS

Second
2x10 kL
mfg suite
on line


5

Regeneron Evolution and Growth

Historical

Current

Therapeutic
Areas

Neurogenerative disease

VelocImmune turn
-
key approach:



CAPS



Cancer



Gout



Eye disease



Arthritis



Pain

Drug
Candidates

Neurotrophic factors

Cytokine traps


Monoclonal Antibodies & Fusion Proteins

Production
Systems

Bacterial fermentation



misfolded proteins



inclusion bodies

Mammalian cell culture (CHO)



fully folded, functional proteins



post
-
translational modifications



secreted into cell culture fluid

Production
Scale



300 L bioreactor



0.3 m diameter columns



10,000 L bioreactor



1.4 m diameter column

IND filings



3 in 10 years



2


3 per year

6

Therapeutic Proteins Today


Arcalyst, Rilonacept (IL
-
1 Trap)


Approved


Aflibercept (VEGF Trap)



Phase III


REGN88 (IL
-
6R antibody)


Phase II


REGN421 (DLL4 antibody)


Phase I


REGN475 (NGF antibody)


Phase I


REGN668 (IL
-
4R antibody)


IND Sept


REGN727/728 (PCSK9 antibody)

IND Oct

7

Regeneron Today


Broad clinical development portfolio across all
development stages provides multiple “shots on
goal”


Three Phase 3 programs to yield initial data in 2010


Potential multiple product launches in next few years


Nearly 1,000 employees working in a science
-
driven,
entrepreneurial culture


Rensselaer facility among the leaders in antibody
production capacity



8

Regeneron Keys to Success



Commitment to cutting edge science and enabling technologies


Neurotrophins, cytokines, angiogenesis, receptor chemistry
and signaling


Cytokine and growth factor Traps


VelociSuite technologies


Fully integrated biopharmaceutical enterprise


World reknown Board of Directors members
-

3 nobel laureates
as well as seasoned pharmaceutical professionals


Attract and secure investment and favorable corporate
collaborations






9

Collaboration Agreements

sanofi
-
aventis

Bayer
HealthCare

sanofi
-
aventis



Upfront/milestone payments

$130MM

$95MM

$85MM



Development costs paid by
partner *

100%

~
50%

~
100%**



Profit split


Regeneron
share

US

50%

100%

50%

100%

Japan

~
35% royalty

50%

35
-
45%

100%

ROW

50%

50%

35
-
45%

100%

Milestones remaining

Regulatory

$400MM

$90MM





Sales



$135MM

$250MM





Oncology

Eye Disease

Antibodies

Inflammation

* 50% repayment from profits ** plus $475MM of research funding over 5 years

10

Trap Technology

11

Traps: Based on Discovery that Some Receptors
Must “Heterodimerize” for High
-
affinity

Ectodomain

Cytodomain

Factor

Conventional Receptor: Receptors “Homo
-
Dimerize”

+

Many Receptors: Require “Heterodimerization”

Kd = 5 nM

Kd ~ pM

R1

R2

Ectodomain

Cytodomain

Factor

+

Conventional “Homodimeric”
Soluble Decoy Receptor

(e.g. Enbrel for TNF)

Receptor

Ectodomains

Fc Constant
(Dimerization &
Half
-
life)

First Generation Heterodimeric
TRAP

(subpicomolar affinity)

R2

Ectodomain

Fc Constant
(Dimerization &
Half
-
life)

R1

Ectodomain

12

Conventional

“Homodimeric” Soluble
Decoy Receptor (e.g. Enbrel for TNF)

Fc Constant
(Dimerization &
Half
-
life)

Antibody Structure

Light Chain

Heavy Chain

Variable
Regions
(Binding)

Cytokine/Interleukin

Receptor

Ectodomains

Fc Constant
(Dimerization &
Half
-
life)

First Generation Heterodimeric
Interleukin
-
1 Trap

(subpicomolar affinity)

Receptor 2

(IL1 R1)

Ectodomain

Fc Constant
(Dimerization & Half
-
life)

Receptor 1

(IL1 AcP)

Ectodomain

“Single
-
Chain” Interleukin
-
1 Trap

(sub
-
picomolar affinity)

Receptor 2

(IL1 R1)

Ectodomain

Fc Constant
(Dimerization & Half
-
life)

Receptor 1

(IL1 AcP)

Ectodomain

Cytokine/Interleukin

13

Regeneron’s Traps: Proprietary & Turnkey Solutions

for Blocking Well
-
Validated Cytokine & Growth
Factor Targets

Advantages


Allow targeting of extremely well
-
validated cytokines & growth factors


Can target multiple ligands for same
receptor (e.g., IL1
a

&
b
, VEGF &
PLGF)


All human components


Long circulating half
-
life in humans


In each case, Traps are most potent
blockers described for their targets
(often by 100
-
1000 fold)


Prior to development of
VelocImmune

technology, much
more efficient and higher affinity
than conventional human antibody
approaches

Regeneron Traps

2 Receptor’s

Binding Regions

… fused to…

IgG Fc region

14

ARCALYST
®

(rilonacept)

Approved and Launched in 2008


ARCALYST
®

(rilonacept) is approved for treatment of
Cryopyrin
-
Associated Periodic Syndromes (CAPS)*


Rare, inherited, auto
-
inflammatory diseases


Approved for adults and children age 12 and older


Patients with CAPS experience ongoing lifelong symptoms


Intermittent, debilitating exacerbations or flares

can be triggered at any time by

exposure to cooling
temperatures


Symptoms include rash, fever/chills, joint pain, eye
redness/pain and fatigue


Patients often adopt a compromised lifestyle



*

15

Aflibercept (VEGF Trap)

16

Aflibercept Differentiation


Aflibercept


All human amino acid
sequences

~110,000 MW

Kd = 0.5 pM (tighter than
natural receptors)

Blocks all mammalian
VEGF
-
A, as well as PlGF
and VEGF
-
B

Binds VEGF isoforms as
monomer without Immune
Complex formation

Bevacizumab


Humanized MAb

~160,000 MW

Kd = 400
-
1000 pM

Only blocks primate
VEGF
-
A

Forms Immune
Complex with VEGF
-
A

Figure 1. Structure of VEGF Trap

16

17

VEGF Trap
-
Eye

18



0
2
4
6
8
10
12
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
VEGF Trap


Eye Extension Study:

Durable Responses in Visual Acuity to 18 Months

(all 5 dose groups combined, n=117)

*P < 0.0001
vs. baseline

+7.1 letters
*


PRN
-
dosing phase

PRN dosing

2mg

Fixed
-
dosing

+7.3 letters*

+8.4 letters*

Change in Visual Acuity (letters)

3

12

18

Month

18

Results Announced May 2009

19

Nine Phase 3 Trials Currently
Underway


9 Phase 3 Trials








Initial Phase 3 data coming in 2010

20

VelociSuite

of Technologies

21

VelociSuite

of Technologies:

Target Identification and Validation

Together, used to identify and validate drug targets:



Rapidly replaces gene with reporter to see where gene is active


Shows the result of deleting or adding extra copies of genes


Allows direct testing in mammalian models of whether the gene product is an
important target in a disease setting and for therapeutic intervention


Selected to play major role in NIH Knockout Mouse Project

VelociGene
®


VelociMouse


High
-
throughput generation

of almost any desired genetic
alteration in mouse embryonic
stem cells

High
-
throughput generation

of mouse models directly from
embryonic stem cells containing
genetically altered target genes

22

VelociSuite

of Technologies: Human Antibody
Generation and Manufacturing


G
enetically humanized over 6
megabases of mouse immune
genome


VelocImmune

mice mount a robust
immune response and generate
antibodies as efficiently as normal
mice


Antibodies with most desirable
characteristics selected and extracted
from B cells


Antibodies cloned into high
-
expression
manufacturing cell lines, suitable for
clinical and commercial use


VelocImmune
®


Rapid generation

of high
-
quality, fully human
antibodies

VelociMab


High
-
throughput antibody screening and
selection and high
-
expression,
manufacturing cell line development

human heavy chain Vs

Ds

Js

mouse constants and controlling regions

human kappa chain Vs

Js

mouse constant and controlling regions

23

Immunogenicity

Human Antibody Platforms


Phage
-
Display


AstraZeneca (Cambridge Antibody Technology)


Several companies using technology


Transgenic Mouse


Amgen Inc. (Abgenics, Inc.)


Medarex Inc. / Kirin Pharma, Ltd.


Regeneron
VelocImmune


Mouse


Broad
-
based collaboration with Sanofi
-
aventis


Licensed to AstraZeneca and Astellas Pharma

Why Fully Human Antibodies?
Evolution of Technologies

Murine

(0% Human)

Chimeric

(66% Human)

Humanized

(90
-

95% Human)

Fully Human

(100% Human)

24

Selection of Antibody Candidates

Early screening steps focus on:


binding affinity


blocking


diversity


Final screening steps focus on:


protein expression/purification


protein characterization/quality


in vivo

properties

25

Regeneron Cell Line
Technologies


FASTR

System
(
F
low cytometry based
A
utologous
S
ecretion
Tr
ap)


High
-
copy system for high
-
level expression


Inducible Fc capture protein on cell surface to utilize FACS
-
based sorting (96
-
well format)


Perfect for commercial cell lines



EESYR System
(
E
nhanced
E
xpression and
S
tabilit
Y

R
egion)


Provides a common site of integration


High efficiency integration of single copy heavy & light chain


Perfect for head
-
to
-
head comparisons


Perfect for providing a speed
-
to
-
clinic cell line

26

Selecting High Producing Cells
Using Fluorescence Associated Cell
Sorting (FACS)

Key Advantages

-

Speed and Throughput


Individually examines 20,000 cells per
second


Up to 100 million transfected cells examined


Can directly single
-
cell sort
-

eliminates
subcloning step

Droplet Generator

Detector






Electrical Wire

Computer

+

+

-

-

+

+

+

+

+

-

-

-

-

-

+

-

-

-

+

+

Laser

Empty Droplet

Cells In

27

27

Value of

VelocImmune
™ Mouse

Validated By Multiple Relationships









Corporate

Licenses

AstraZeneca/Cambridge
Antibody Technology
(February 2007)

Astellas Pharma

(March 2007)

Columbia University

(September 2008)

The University of Texas
Southwestern

Medical Center

(March 2009)

Academic

Licenses

sanofi
-
aventis

Collaboration

Broad profit
-
sharing

program to

discover, develop and

commercialize

human antibodies

(November 2007)

3 antibodies now in

clinical trials


28

Regeneron is a Fully
-
integrated
Biopharmaceutical
Company

29

Regeneron
Manufacturing

30

State
-
of
-
the
-
Art Manufacturing
Facility

31

Process Area 3


1 x 1600 L
Bioreactor


Primarily for PI/II Supply


Ten years of operating experience


3 Traps


7 mAbs


Flexible Process Design

32

Process Area 1


2 x 3000 L
Bioreactor


Primarily for PII/III Supply


New facility realized in 14
months (!)


Focus on characterizing and
understanding the process

33

Red Mill Process Area

34

Currently Doubling
Manufacturing Capacity

35

IL
-
6R Antibody Formulated Drug Substance Manufacturing

Upstream Operations, 3,000L Production Scale

Thaw of

the MCB

2L Wavebag

20L Wavebag

200L Wavebag

1,000L Bioreactor

3,000L Bioreactor

Centrifugation

Depth and Polish Filtration

Harvest Pool

Protein A

Low pH Hold

500ml Flask

36

Anion Exchange

Chromatography

Hydrophobic Interaction

Chromatography

Viral Clearance Filtration

Concentration and

Diafiltration

Transfer to Formulation Tank

Filling of

1 L bottles

Freezing of

Formulated

Drug Substance

<

-
20C

Addition of concentrated

excipient buffer

IL
-
6R Antibody Formulated Drug Substance Manufacturing

Downstream Operations, 3,000L Production Scale

37

Regeneron Human
Resources

38

Group

Personnel

Quality (QA, QC, Audit)

88

Facilities Operations
(Maintenance, EH&S,
Engineering)

44

Manufacturing (Internal and
External)

70

Business Operations (Finance,
Supply Chain, Warehouse)

35

Process & Analytical Sciences

21

Human Resources and Training

10

Administrative

3

Total

271

Years of
Service

10+ Years
5-9 Years
< 5 Years
43%

18%

39%

8%

4%

25%

61%

Headcount Totals

IOPS Personnel

39

Employee Profile

Title

Degree

Major

Yrs of
Service

Biotech Prod

Associate

AAS/BA/BS

Biology

4

Process

Specialist

BA/BS

Chemical

Engineering

2.3

QA

Specialist

BA/BS

Biology

4.6

QC

Analyst

BA/BS

Chemistry;

Biology

5.8

Process

Scientist

BA/BS

Biology;

Chemical Eng

3.6

Analytical

Scientist

MA/PhD

Chemistry

6.9

40


BACK
-
UP SLIDES



BIOMAN 2009


41

A Look at the U.S. Biotech
Industry


The biotech industry is a major growth area in the global healthcare
market and due to developments in monoclonal antibodies, genomics
and proteomics the biotech market has experienced great expansion
since its emergence in the 1970s



To date, biotechnology has created more than 200 new therapies and
vaccines, including products to treat cancer, diabetes, HIV/AIDS and
autoimmune disorders



There are more than 400 biotech drug products and vaccines currently
in clinical trials targeting more than 200 diseases



As of Dec. 31, 2006, there were 1,452 biotechnology companies in the
United States, of which 336 were publicly held


Source: Biotechnology Industry Organization Guide, “Beyond Borders,“ Ernst & Young Biotechnology Report 2008




42

U.S. Biotech Industry
Statistics


According to BioWorld, biotechnology attracted more than
$24.8 billion in financing in 2007 and raised more than $100
billion in the five
-
year span of 2003

2007



The biosciences employed 1.2 million people in the U.S. in 2004
and generated an additional 5.8 million related jobs



Revenues of publicly traded biotechs grew 12% to $89.7 billion
in 2008. The global industry’s net loss improved 53%, from
US$3 billion in 2007 to US$1.4 billion in 2008



In 2008, the US publicly traded industry posted an aggregate net
profit for the first time
-

US$0.4B


Source: Biotechnology Industry Organization Guide, “Beyond Borders,“ Ernst & Young Biotechnology Report 2008



43

U.S. Biotechnology Regions

There are 10 thriving clusters of life science industry in the U.S., helping to attract
investment, talent and additional resources to specific geographic areas


Ranking of Clusters

by total number of companies


Biotech Bay

Genetown

Biotech Beach

Pharm Country

BIO NC

BIOMidwest

BIOCapital

BIO Forest

BIOCanada

SouthernPharm

US Device

The U.S. Biotechnology Regions map can be found on Biospace.com (
http://www.biospace.com/biotechhotbeds.aspx
).

44

A Look at the Pharm Country
Cluster

Regeneron belongs to “Pharm Country”


The U.S. Biotechnology Regions map can be found on Biospace.com (http://www.biospace.com/biotechhotbeds.aspx).

45

New York State Biotechnology

In its 2009 annual report, the New York Biotechnology Association
(NYBA) reported that:


In New York State, biopharmaceutical companies directly
employed 55,446 workers and were responsible for a total of
130,464 jobs.


The industry
generated $29.1 billion in total economic output
in 2006

and New York State is responsible for nearly seven
percent of all direct biopharmaceutical output nationally


New York last year was
second in the nation with 5,053
clinical testing sites

for potential new medicines


46

Growth of New York Biotechs
Continues

47

Opt
-
in Rights to Novartis IL
-
1 Antibody
Converted to Royalty


Regeneron had opt
-
in rights to canakinumab (Ilaris®, ACZ885) since 2003


Option to share in development, commercialization, and profits


Regeneron would pay upfront, milestones, and 45% of N. American
development costs


Royalty agreement (June 2009)


Opt
-
in rights cancelled


Stepped royalty on worldwide sales in all indications


Initial 4% royalty, reaches 15% of total sales if sales
>
$1.5B


No Regeneron financial obligation


Canakinumab status


Approved in U.S. for CAPS treatment


In clinical trials for gout, COPD, type 2 diabetes, SJIA