biologicals for global health: the case for lower cost drugs · biologicals for global health: the...

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

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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 © 2013 Bill & Melinda Gates Foundation | 2

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© 2013 Bill & Melinda Gates Foundation | 3

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OUR HISTORY


4 © 2013 Bill & Melinda Gates Foundation |

2006 Warren Buffett pledges Berkshire Hathaway stock valued at $31 billion.

2008 Bill joins Melinda full-time at the foundation.

1997 Bill and Melinda read an article about rotavirus and are inspired to act.

2000 The Bill & Melinda Gates Foundation is created, with a focus on health, education, and libraries.

1994 Bill Gates Sr. starts a small philanthropic foundation at his son’s request.

2011 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

1,100 2012 employees worldwide

$3.4B 2012 grant payments

Ethiopia

Europe Office

China Washington, D.C.

India

Nigeria

South Africa

Seattle

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WHAT WE DO



GLOBAL HEALTH GLOBAL DEVELOPMENT UNITED STATES PROGRAM

GLOBAL POLICY & ADVOCACY 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 President

Office of the President Enteric and Diarrheal Diseases

HIV

Malaria

Neglected Infectious Diseases

Pneumonia

Tuberculosis

Discovery and Translational Sciences

Integrated Development

Life Sciences Partnerships

Strategy, Planning & Management

Vaccine Development

President’s Office

Strategies

Functions

TREVOR MUNDEL, President

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Global Health: HIV Strategy Overview


Vaccines Efficiency and Effectiveness

Prevention Implementation

ARV Based Prevention

Diagnostics Global Policy & Advocacy

TB/HIV

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

© 2013 Bill & Melinda Gates Foundation | 13 AAV – Adeno associated virus; ADCC – Antibody-dependent, cell-mediated cytotoxicity

bNAbs as adjunctive therapy to ARV for treatment (Tx) Use of bNAbs with ARVs to help control viraemia and prevent disease progression

bNAb applications in terms of immunobiology... ...and fit within the HIV agenda at the Foundation

Prevention Treatment Cure

Active immuni-

zation

Passive immuni-

zation

Active immunization

Passive immunization

Use of bNAbs in treatment regimens (e.g. complement to

ARV)

Use of bNAbs in Cure regimens (e.g. complement to ARV,

other approaches TBD)

1a

2

3

4

Active immunization for treatment & cure

1b

ADCC

Mature HIV

Immature HIV

2

CD4+ lymphocyte

Nucleus

1 3

4

5

6

7

bNAbs

AAV NK cells, etc.

B cells

Immunogen Active immunization to induce bNAbs Immunogens to generate adaptive protection

1

Passive immunization using bNAbs Direct admin of exogenous bNAbs or viral vectors to provide (temporary) protection

bNAbs as adjunctive therapy in functional cure approaches Use of bNAbs to drive to sustained low viral load in the absence of continued treatment

4

HIV RNA

bNAbs

2

3

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Passive administration of bNAbs for HIV prevention, treatment & cure


A. bNAbs neutralize virions at the site of entry (e.g., mucosal surface)

B. bNAbs continuously neutralize new virions produced in the host

C. bNAbs help clear pro-viral DNA and/or latent reservoir

Impact on HIV progression

Vira

l loa

d W/o intervention W/ intervention

Vira

l loa

d

W/o intervention W/ intervention

Vira

l loa

d

W/o intervention W/ intervention

infection

infection

infection

Suppressed viraemia (viral load

rebound likely if bNAbs

discontinued

Functional cure Time limited

treatment + no viral rebound

(neutralization of new virions may or may not impact reservoir)

bNAbs

bNAbs ART

bNAbs w/ other Tx ART

...

...

No infection (incoming virions are neutralized immediately) Pr

even

tion

Trea

tmen

t Fu

nctio

nal c

ure

Prevention Treatm

ent Fx Cure

Uninfected individual at risk

HIV infected patients

~35M patients WW

~300-500M WW

Relevant population

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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

Theory: Passively administered bNAbs prevent HIV virions from infecting host cells at the site of entry

Passive immunization (mechanism): Passively administered bNAbs are active in the host and prevent infection

HIV+

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

Different bNAbs block transmission by binding to different sites of HIV-1 Env spike

Transmembrane spanning region

HIV-1 Env spike ectodomain

3 gp41 subunits

3 gp120 subunits

VRC01 (CD4-binding site-directed)

V1/V2 domain

PG9 (V1/V2-directed)

PGT 128 (glycan v3-directed)

10E8 (MPER-directed)

gp41 MPER

gp120 core

bNAbs block transmission at site of HIV entry

Needle

HIV- E.g., Mucosal surface

E.g., Blood


Active vs. Passive Immunization


Active Immunization "Classical" vaccine induces

long-lived protection

• 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.

Passive Immunization Temporary protection with

infused 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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At what cost would mAbs for HIV prophylaxis be competitive with PrEP?


$0$10$20$30$40$50$60$70$80$90

Oral Truvada TMC278Injectable

Dipivirine Ring Tenofovir Gel

CO

GS

PPY

($U

S)

PrEP Intervention

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.

Avg

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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).

© 2013 Bill & Melinda Gates Foundation | 20 * 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


0102030405060708090

0 5 10 15 20mAb

CO

GS

PPY

($U

S)

mAb COGS ($US/gram)

3 - mAb COGS PPY (Assume monthly dosing at

75 mg / 75 kg / mAb)

Average cost of PrEP

Target COGs

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


• 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)

Optimizing current state-of-the-art CHO technology allows for

COGS ~$30/g

Reducing consumable costs can lower COGS

Increasing utilization of plant resources

facilitates economies of scale

“Incremental” evolution of technology

• By extending validated ranges for high cost resins and filters (e.g., Protein A

reused for ~ 250-300 cycles) • By using new disposable materials

• 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

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Effective use of new and innovative technologies can reduce COGS below $10/g


• Continuous manufacturing using periodic, countercurrent chromatography • Alternatives to chromatography steps such as precipitation/crystallization

Mitigating bottlenecks in the downstream purification process

Distributed flexible,

mobile, compact manufacturing

Development of inexpensive, highly

productive non-CHO systems

• 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

• 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


Continuous manufacturing Alternative production systems Other disruptive innovation

Ex. Precipitation

Greenfield plant designed for single

mAb

Increasing Titers

Use of reusable technologies

Very high utilization

Currently achievable COGS ≈ $30/g

COGS ≈ $10/g

COGS ≈ $3.5/g

Decreasing C

OG

S

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Drug supply cost is a large component of the GAVI budget


COGS ≈ $10/g

COGS ≈ $3.5/g

2016-2020 GAVI Estimate

Drug Supply Costs

Other Costs

Penta Pneumo Rota HPV MR Measles 2nd Dose Measles SIA MenA YF JE Typhoid

74%

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

per dose. $7.50

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Source of chart: GAVI Alliance 2012 progress report. Page 46

In 2012 rotavirus vaccines

dropped to

per dose. $2.50

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In 2015 rotavirus vaccines

will drop to

per dose. $1.00

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Under-Five Child Deaths Worldwide 1960-2011 (in millions)

5

10

15

20

2011 1960 1965 1970 1980 1985 1990 1995 2000 2010 1975 2005

6.9 Million

PROGRESS IN GLOBAL HEALTH

20 Million

Source: UNICEF

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Most of this burden is infectious diseases. As 2015 approaches, the world is taking a hard look at how it is doing on the MDG goals. Although we won't achieve them all, we've made amazing progress, and the goals have become a report card for how the world is performing against major problems affecting the poor. The MDG target of reducing extreme poverty by half has been reached ahead of the deadline, as has the goal of halving the proportion of people who lack access to safe drinking water. Living conditions for more than 200 million slum dwellers have also improved-double the target. Some goals, however, were set at such an ambitious level that they will be missed. For instance, while we have reduced the number of mothers who die during childbirth by almost 50 percent-which is incredible-we will, however, fall short of the goa We're also not on track to meet one of the most critical goals-reducing the number of children who die under the age of five by two-thirds. We've made substantial progress. The number of children who die has declined from nearly 12 million in 1990 to 6.9 million in 2011. While that means 14,000 fewer children around the world are dying every day than in 1990, we won't reach the two-thirds target by 2015. Still, many individual countries are on track to achieve this target of a 75 percent reduction.

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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biologicals for global health: the case for lower cost drugs · biologicals for global health: the...

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