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Biologicals for Global Health: The
Case for Lower Cost Drugs
Stephen W. Hadley, Ph.D.
Senior Program Officer, Vaccine Development – CMC
ECI Conference on Integrated Continuous Biomanufacturing
Castelldefels, Spain
21 October 2013
Discussion
 Introduction to the Bill & Melinda Gates Foundation
 CMC Technology Innovation Initiatives at the
Foundation
 Case Study for Lower COGS: bNAbs for HIV
January 18, 2014
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OUR HISTORY
1994
1997
2000
2006
2008
2011
Bill Gates Sr. starts
a small philanthropic
foundation at his
son’s request.
Bill and Melinda
read an article
about rotavirus and
are inspired to act.
The Bill & Melinda
Gates Foundation is
created, with a focus
on health, education,
and libraries.
Warren Buffett
pledges Berkshire
Hathaway stock
valued at $31 billion.
Bill joins Melinda
full-time at the
foundation.
The foundation
moves to its new
permanent home
in Seattle.
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OUR VALUES
OPTIMISM
COLLABORATION
RIGOR
INNOVATION
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OUR GLOBAL Reach and Presence
1,200
2012 active grantees
Europe Office
Seattle
China
Washington, D.C.
India
$3.4B
2012 grant payments
Nigeria
Ethiopia
South Africa
1,100
2012 employees worldwide
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WHAT WE DO
GLOBAL HEALTH
GLOBAL DEVELOPMENT
GLOBAL POLICY & ADVOCACY
UNITED STATES PROGRAM
COMMUNICATIONS
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GLOBAL HEALTH
Discovering and developing
affordable vaccines, drugs, and
diagnostics for people in the
developing world.
Strategies:
Enteric and Diarrheal Diseases
HIV
Malaria
Neglected Infectious Diseases
Pneumonia
Tuberculosis
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Global Health
TREVOR MUNDEL,
MUNDEL President
TREVOR
President
Office of the President
Enteric and
Diarrheal Diseases
Neglected Infectious
Diseases
Discovery and
Translational Sciences
HIV
Pneumonia
Integrated Development
Malaria
Tuberculosis
Life Sciences
Partnerships
Strategy, Planning &
Management
President’s Office
Strategies
Vaccine Development
Functions
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Global Health: HIV Strategy Overview
Vaccines
Efficiency and
Effectiveness
TB/HIV
ARV Based
Prevention
Diagnostics
Global Policy &
Advocacy
Prevention
Implementation
Male Circumcision
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CMC Technology Innovation:
Foundation Initiatives
1) High Throughput mAb Development and
Manufacturing Platform
 Challenge: low cost access to 20 – 30 mAbs for
malaria experimental medicine challenge studies.
2) Low Cost Manufacturing of mAbs for Treatment of
Infectious Diseases in the Developing World
 Challenge: mAb COGS at ≈$10/g (or lower)
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Broadly Neutralizing Antibodies (bNAbs)
HIV Program
Background

To date, no candidate HIV vaccines have elicited any significant levels of
bNAbs.

Current estimates indicate that a safe, durable and highly effective HIV
vaccine is at least a decade away.

Rare “Elite” HIV-infected individuals make broadly neutralizing antibodies
against HIV.

Discovery of new highly potent bNAbs in the last 2-3 years has raised the
enthusiasm for using mAb’s for passive immunization/prevention in HIV.

Passive immunization using bNAbs is considered a potential
prevention/treatment modality and a bridge to bring patients closer to a
vaccine.
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Passive administration of bNAbs for HIV
prevention, treatment & cure
bNAb applications in terms of immunobiology...
1
Immunogen
...and fit within the HIV agenda at the Foundation
Active immunization to induce bNAbs
Immunogens to generate adaptive protection
Active
immunization
B cells
2
2
HIV RNA
Passive
immunization
using bNAbs
Direct admin of
exogenous bNAbs
or viral vectors to
provide
(temporary)
protection
Mature
HIV
3
1
bNAbs
4
CD4+ lymphocyte
Use of bNAbs with ARVs
to help control viraemia
and prevent disease
progression
1b
Active
immunization
Active immunization for
treatment & cure
3
Passive
immunization
Immature
HIV
bNAbs as adjunctive
therapy to ARV for
treatment (Tx)
1a
Cure
Passive
immunization
Nucleus
AAV
Treatment
2
7
3
Prevention
5
6
ADCC
Use of bNAbs in
treatment regimens
(e.g. complement to
ARV)
4
NK cells, etc.
4 bNAbs as adjunctive therapy
Use of bNAbs in
Cure regimens (e.g.
complement to ARV,
other approaches TBD)
in functional cure approaches
Use of bNAbs to drive to sustained low
viral load in the absence of continued
treatment
AAV – Adeno associated virus; ADCC – Antibody-dependent,
cell-mediated cytotoxicity
bNAbs
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Passive administration of bNAbs for HIV
prevention, treatment & cure
Relevant
population
Impact on HIV progression
Viral load
bNAbs
W/o intervention
W/ intervention
...
No infection
(incoming virions
are neutralized
immediately)
Prevention
Prevention
A. bNAbs neutralize virions at the site of entry (e.g., mucosal surface)
...
Viral load
W/ intervention
Suppressed
viraemia
(viral load
rebound likely if
bNAbs
discontinued
Treatment
Treatment
infection
B. bNAbs continuously neutralize new virions produced in the host
W/o intervention
bNAbs
ART
Uninfected
individual at
risk
~300-500M
WW
HIV infected
patients
Viral load
C. bNAbs help clear pro-viral DNA and/or latent reservoir
W/o intervention
ART
W/ intervention
bNAbs w/ other Tx
Functional cure
Time limited
treatment + no
viral rebound
(neutralization of
new virions may
or may not
impact reservoir)
Fx Cure
Functional cure
infection
~35M
patients
WW
infection
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Passive immunization (mechanism): Passively administered bNAbs are
active in the host and prevent infection
Theory: Passively administered bNAbs prevent HIV virions from infecting host cells at
the site of entry
HIV-
bNAbs block transmission at site of HIV entry
E.g., Mucosal surface
Different bNAbs block transmission by binding to different sites
of HIV-1 Env spike
Transmembrane
spanning region
gp41 MPER
10E8
(MPER-directed)
3 gp41
subunits
gp120 core
HIV-1 Env spike
ectodomain
E.g., Blood
PGT 128
(glycan
v3-directed)
3 gp120
subunits
Needle
HIV+
VRC01
(CD4-binding
site-directed)
V1/V2
domain
PG9 (V1/V2-directed)
bNAbs administered either via direct administration or gene
transfer block transmitted / founder virus at the site of entry
Option 1 – direct
administration of
manufactured Ab
Option 2 – viral
vectors with bNAb
genes
Source: Klein, Nature, 2012; Corti, Annual Rev. Immunol., 2013; Kwong, Nature Rev. Immunol., 2013; McMichael, Nature Immunol., 2012; Burton, Cell Host and Microbe, 2012; Mascola, Nature, 2007
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Active vs. Passive Immunization
Active Immunization
Passive Immunization
"Classical" vaccine induces
long-lived protection
Temporary protection with
infused antibodies
• An immune response is induced after
exposure to antigens from a pathogen.
• Broad cellular and humoral immune
responses are elicited.
• Immune memory provides long-lasting
protection.
• Antiviral vaccines often protect via
neutralizing antibodies.
• Population receiving antibodies is
"immunized" as long as antibodies
remain.
• No immune response is elicited.
• No immune memory is established.
• Infused mAbs must be supplied
continuously to individuals to maintain
protection.
• Monthly to quarterly injection dosing
regimens.
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Passive immunization for HIV prevention
 Pre-exposure prophylaxis (PrEP) has shown protection against HIV infection in
several clinical trials administering antiviral drugs (ARVs) over the past couple of
years.
•
Daily use of drugs poses a significant adherence problem, which limits its effectiveness,
•
Drug resistance is a significant issue if compliance is low.
 Passive immunization with a broadly neutralizing monoclonal antibody
(bNAb) to HIV on an infrequent basis could provide an alternative or
complementary approach to ARVs.
•
Administered prophylactically to populations in monthly to quarterly injections.
•
Supplied continuously to individuals to maintain protection.
•
A combination of 2-3 mAbs is likely to be required to provide broad protection.
•
A monthly dose of on the order of 1 mg/kg/mAb is believed to be desirable.
If prophylaxis proves possible with mAbs, could a mAb be
delivered at a cost competitive with PrEP? If not, what advances
are required in the field to become cost competitive?
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COGS PPY ($US)
At what cost would mAbs for HIV
prophylaxis be competitive with PrEP?
$90
$80
$70
$60
$50
$40
$30
$20
$10
$0
Avg
Oral Truvada
TMC278
Dipivirine Ring
Injectable
PrEP Intervention
Tenofovir Gel
Assumption: For passive immunization with mAbs to gain traction as a viable
public health intervention, cost of mAb treatment PPY would need to be
competitive with PrEP. This results in a COGS PPY target of ~$50.
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Commercial development, production
and use of therapeutic mAbs is well
established...
Platformed optimization
 Humanized mAb—improve safety
 Optimized efficacy—improve affinity, half-life, effector function
Industrialized capabilities
 Numerous facilities in developed world
 Tens of millions of doses produced annually
Rapid adoption as therapy
 Decades of use
 High efficacy and safety
 Numerous products:
• Autoimmune disease: Humira, Cimzia, Simponi, Remicade, Enbrel,
• Oncology: Rituxan, Avastin and Herceptin
• Infectious diseases: Synagis
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But current mAb COGS are a significant
barrier to HIV Prophylaxis
 There have been few drivers for industry to reduce COGS over time since
margins are typically 60-85%.
•
Average sales prices range from $2,000 to $20,000 per gram for the top 15
mAbs and Fc-fusion products*
 However, recently COGS have been driven down to <$100/g through a
combination of large scale (>10,000L) production capacity and improved
titers in the production bioreactor (>1-2 g/L).
*
2008 figures, Kelley, B. (2009) mAbs, 1(5), 443–52.
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mAb COGS required to enable monthly
administration of 3 HIV mAbs at 1 mg/kg
per mAb
3 - mAb COGS PPY
mAb COGS PPY ($US)
(Assume monthly dosing at
75 mg / 75 kg / mAb)
90
80
70
60
50
40
30
20
10
0
Average cost of PrEP
Target COGs
0
5
10
15
20
mAb COGS ($US/gram)
At the proposed dosing levels for HIV mAbs of 1 mg/kg, COGS must be ~$13/g for
combination therapy with 3 mAbs to be competitive with PrEP.
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Can current CHO-based mAb
manufacturing processes be sufficiently
optimized to reduced COGS to ≈$10/g?
 Current CHO-based mAb production is already highly
optimized, but further refinements and technology
improvements are feasible to achieve greater cost
savings.
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Refinement of existing CHO
manufacturing technologies will enable
COGS to decrease to $10-$30/g
Optimizing current
state-of-the-art CHO
technology allows for
COGS ~$30/g
• By further improving titers (titers of 5 g/L achievable currently)
• By implementing downstream process improvements to better integrate with
high titers
• By using large production facilities (>15,000L scale bioreactor)
Reducing
consumable costs
can lower COGS
• By extending validated ranges for high cost resins and filters (e.g., Protein A
reused for ~ 250-300 cycles)
• By using new disposable materials
Increasing utilization
of plant resources
facilitates economies
of scale
• By designing Greenfield plant optimized for single mAb, which can
significantly lower CapEx and depreciation
• By increasing plant utilization, which has a significant impact on COGS
• Effective seed train timing increases bioreactor utilization
• Multiple, smaller trains keep downstream process utilized
“Incremental” evolution of technology
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Effective use of new and innovative
technologies can reduce COGS below
$10/g
Mitigating bottlenecks
in the downstream
purification process
• Continuous manufacturing using periodic, countercurrent chromatography
• Alternatives to chromatography steps such as precipitation/crystallization
Distributed flexible,
mobile, compact
manufacturing
• Continuous manufacturing will allow for smaller facilities
• Self-contained systems will lower CapEx (no need to maintain HVAC system)
• Options for local manufacturing - distribution and management of cold-chain
will be easier
• Single Use Systems
Development of
inexpensive, highly
productive non-CHO
systems
• The most promising of these alternatives is yeast, but current challenges with
obtaining consistently high titers present a major technological hurdle.
• Models for microbial-based mAb manufacture have shown potential to
reduce COGS to $1-$5/g
“leap” in technology
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Cost of mAbs PPY: COGS, dose, and
frequency of administration all need to
be optimized
Correlation between COGs, dose, and
frequency of administration
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COGS for mAbs: The path to feasibility
Currently achievable COGS ≈ $30/g
Decreasing COGS
Greenfield plant
designed for single
mAb
Increasing
Titers
Use of reusable
technologies
Very high
utilization
COGS ≈ $10/g
Continuous manufacturing
Alternative production systems
Other disruptive innovation
Ex. Precipitation
COGS ≈ $3.5/g
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Drug supply cost is a large component of
the GAVI budget
2016-2020 GAVI Estimate
COGS ≈ $10/g
Drug Supply Costs
74%
Other Costs
COGS ≈ $3.5/g











Penta
Pneumo
Rota
HPV
MR
Measles 2nd Dose
Measles SIA
MenA
YF
JE
Typhoid
Initiatives are ongoing at the Foundation to drive costs lower across the portfolio of
vaccines currently in use in the developing world.
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In 2009
rotavirus
vaccines were
$7.50
per dose.
In 2012
rotavirus vaccines
dropped to
$2.50
per dose.
In 2015
rotavirus vaccines
will drop to
$1.00
per dose.
PROGRESS IN GLOBAL HEALTH
Under-Five Child Deaths Worldwide
1960-2011 (in millions)
20 Million
20
15
10
6.9 Million
5
1960
1965
1970
1975
1980
1985
1990
1995
2000
2005
2010
2011
Source: UNICEF
OUR VALUES
OPTIMISM
COLLABORATION
RIGOR
INNOVATION
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OUR CHALLENGE TO YOU…
How low can you drive COGS for mAbs?
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Thank You
© 2013 Bill & Melinda Gates Foundation. All Rights Reserved.
Bill & Melinda Gates Foundation is a registered trademark in the United States and other countries.