Biologics Market: Where Are We Now?

Where Are We Going?

Rakesh Dixit, Ph.D., DABT

Vice President, Research & Development

AstraZeneca-Medimmune Biologics R & D

Scope of Biologics Medicines

Biotechnology Derived Products

(e.g., Products made in live cells)

Hormonese.g., Growth hormone,

insulin

Blood productse.g., albumin,

clotting factors

Cytokinese.g., interferons,

interleukins

mAbs (CDER)e.g., humanized, chimeric, Murine,

single chain/bispecific, naked/conjugated

Vaccinese.g., recombinant

Proteins, DNA plasmid

Anti-idiotype

Gene Transfer Productse.g., Viral and

non-viral vector delivery

Cell therapy products

(CAR-T cells)

Tissue Engineered

Products

Distribution of Biologics Market

56 Approved

Current State of Biologics

Non-Mab Biologics Approvals (Future of Biologics)

Future of Biologics Drugs

Prescription Bio-Pharma Market

2015-2022

~ 6.5 % Increase in

Sales/year of

prescription

Biopharmaceuticals

> 1 trillion $

Oncology

BiologicsMajor share by

Immunotherapy Biologics

(e.g., Immune Checkpoint

Antagonists, CAR-T cells)

Anti-Diabetic

Drugs to

grow over

7%/year

Non-Mab Current status

Future of Biologics Drugs

A Perspective on the Future of Biologics

❖ Biosimilars and Biobetters/Biosuperors

❖ Bispecifics drugs to offset the cost of combination biologics

❖ Antibody Drug Conjugates

❖ CAR-T cells advances

❖ Long-term future is in disrupting biologics model.

❖ Personalized in vivo biologics- using your own cells to make your

biologics drugs- no need for bioreactors

❖ Advancement in delivery technologies

❖ Oral delivery of biologics

❖ Innovations in injectable biologics

❖ Virus to patient

❖ Gene to patients

❖ Cells to patients

Biosimilar BiologicsWhere Are We Now and Where Are We Going

Global Opportunities for Biosimilars

By 2030

> 240 Billion $

Opportunity

Cost

savings

Up to 70 billion $

Drivers and Brakes for Biosimilars

Opportunities to increase

affordability of life-saving

biologics

Advancement in biosimilars

development

– Bioanalytical-CMC capabilities

– Nonclinical and clinical

evaluation

Cost efficiency in

manufacturing of biologics

Increasing world-wide

regulatory approvals,

including US FDA

Better acceptance of

biosimilars by physicians and

patients; increasing market

absorption world-wide

Gaps in knowledge and

understanding of biosimilars

Highly variable and fragmented

biosimilar regulations and

approvals world-wide

– Interchangeability, naming etc.

Patent Infringements (the Major

Brake in Effective Marketing)

– Abbvie claims that Amgen violated > 50 patents

related to humira biosimilarAmjevita

(adalimumab-atto)

Impact of Patent Protections

Example of Humira

• Potentially no marketing of humira biosimilars until 2019 or this

could extend to 2022

• Humira will likely become > 20 billion $ drug by 2022

Biosimilars versus Biosuperiors

Innovator vs.

Biosimilars

Innovator vs.

Biosuperior/Biobetter

• Same MOA/class

• Highly similar CMC

• Similar antibody

protein quality

• Similar PK-PD,

safety,

immunogenicity

• Similar efficacy

❖ Biobetter/Biosuperior

• Same or similar MOA

• Potency improvement

• Enhanced half-life

• Enhanced and convenient

delivery

• Better safety and

immunogenicity

• Better and broader efficacy

• PHC approaches

Scientific and

technological

advances

Concepts in Biobetters or Biosuperiors

(within the similar MOAs)

Second in

Class(slight improvement)

Increasingly

better in class(increasingly

differentiated

products)

Increasing Innovations

Opportunities for Biosimilars and Biobetters

Biosimilars

– Lower prices, saving

hundreds of billion $

to health care

providers

• No negative

impact on safety

and efficacy

– Broader affordability

– Potential for serving

a greater number of

patients in both

developed and

developing world

Biobetters

– Unmet medical needs

– Current therapies:

inadequate to treat

refractory patients

– Highly differentiated

and potent biologics

within the same

general MOA

– Serving patients not

benefited from existing

therapies

– High blockbuster

potential

19

NK

BioSuperiors

Applying Best Science + Antibody Technologies

Agonist/antagonis

t mAbInduction of T Cell Killing

ADC: Ab-drug conjugate

Release of cytotoxic

drug

Internalized Ab

Target cell

BiTE

mAb (+YTE)

Enhanced ADCC

Ab mimetic

Antibody*

Bispecific Ab

Single-chain immunotoxin

Blocks protein

synthesis

T

cell

Major Biosimilars and Biobetters

in Development

Product Biosimilars Biobetters

Humira

(adalimunmab) 20 7

Remicade

(infliximab) 13 8

Epogen (epoetin alfa) 82 25

Neupogen (filgrastim) 56 15

Enbrel (etanercept) 26 11

Rituxan (rituximab) 43 19

Herceptin

(transuzumab) 37 14

Source: Biotechnology Information Institute

Bispecific Biologics

NK

Cell

ADCC

Enhanced

Antibody

Drug Conjugate

Immunotoxins

CD-3 binding arm

Bispecific T-Cell Engagers

Enhanced War on CancerTargeted Weapon Systems of MedImmune

TAA binding arm

Checkpoint

Antagonists

Oncolytic

Viruses

Bispecifics, Combinations and

Mixtures of Antibodies

23

Bispecific CombinationsMixtures

• Single

molecular

biologic entity

• Multiple targets

• Antigens

• Effector

functions

• Not a single

biologic entity

• More than one

antibody

• Combinations

• In a single bag

as a mixture

• Sequenced

• Simultaneous

• Combination of

antibodies (single or

multiple targets) in

mixture

• May be considered a

single entity, if

produced as a single

product

• Typically, a constant

ratio of antibodies

24

Multi-targeted Oncology Biologics Vs.

Combination of Two or More Biologics

Design flexibility with various formats:

able to combine multiple targets in a

single molecule

Highly specific and effective targeting

High avidity/valency like target

interactions may allow better efficacy

– Must provide synergistic benefits >

combinations or mixture of two MOAs

Toxicity can be reduced by

engineering differential potency in one

mAb

Cost of one mAb vs. combining two

separate expensive mAbs could be

less and attractive to payers

Convenience of dosing and

flexibility with dosing schedule

(simultaneous, sequential etc.)

to reduce toxicities

Fixed combinations with

enhanced efficacy and reduced

toxicities are potentially

attainable

Business case for combining

two expensive antibodies can

only be made in terminal

cancers or other debilitating

diseases with very few options

BiS (multi-targeted) mAb Combination of mAbs

Challenges and Opportunities for Oncology Bispecifics

Challenge for industry:

– Costs matter to both payers and providers

• Are the exceptionally high prices of biologics justified by the health

benefits they afford to patients?

• Do biopharmaceuticals provide good “value for money”?

Opportunity for industry:

– High efficacy due to synergism with potential for lower toxicity vs. mixtures

and combinations

– Use of a bispecific molecule could substantially reduce costs associated with

drug development, production, clinical testing, and regulatory approval

compared to single protein-based agents developed in combination therapies

Opportunity for payers / patients:

– Payment for one drug product instead of payment for each of single protein-

based agents in combination

25PMID 22858161, PMID: 22377753

Oncology Bispecifics: Financial Case

Cost-effectiveness of adding bevacizumab to chemotherapy for

patients with untreated metastatic colorectal cancer:

– Adding bevacizumab to Irinotecan+Fluoruacil+Leuvocorin costs approximately

£62,857 ($96,258 USD) per Quality ADJUSTED LIFE YEAR QALY gained

– Adding bevacizumab to 5-FU/LV costs approximately £88,436 ($135,433 USA)

per QALY gained.

Costs for newest biologics (financial toxicity):

– Two courses of the newly approved agent blinatumomab, used to treat relapsed

or refractory B-cell precursor acute lymphoblastic leukemia (ALL), cost a

staggering $178,000

– The cost of using ipilimumab alone is ~ $158,282 (for a median progress-free

survival [PFS] of 2.9 months), the cost of nivolumab alone is ~ $103,220 (for a

PFS of 6.9 months), and the cost of the combination is ~ $295,566 (PFS of 11.4

months, nearly four times that seen with ipilimumab alone, which is currently the

standard of care).

26PMID 22377753, PMID 19193576 , PMID 17910914

If drug-makers want to retain pricing control and have broad

distribution in the world markets, then the drugs in

combination must provide substantial benefit over single

agent therapies

– Cost of two drugs cannot be the sum of individual drug price

Challenges and Opportunities for Bispecifics in Reducing

Financial Toxicity of Combinations and Providing Synergistic

Superior Efficacy

– Identify patient population most likely to respond

– Demonstrate superior synergistic efficacy as measured by gain

in length and quality of life compared to single-target biologics

• Cost of a bispecific antibody should generally be lower than the cost

of combinations in most cases

27

Can bispecifics strike a balance across fiscal sustainability and

innovation, as well as demonstrate substantial benefit to patients?

28

> 30

> 60

BiS In Clinical

Development

ADPE BiS Formats

2 Approved BiS

Bispecific (BiS) Biologics Landscape

Amgen's bispecific antibody Blincyto®

(blinatumomab)

Removab( EpCAM X CD3 trifunctional mab)

Flavors of Bispecific (BiS) Biologics with Desired Properties

29

• Multiple antigen (s)

binding simultaneously

• Maintaining FcGamma

interactions to maximize

the benefits of ADCC and

CDC

• Low Immunogenicity

• FcRn function delivering

desirable PK similar to

parental antibodies Or

use of other

methodologies to

maintain desirable PK

• High quality CMC and

good yield in

manufacturing with

consistency

Bispecific Biologics Landscape

30

Formats in Clinical Trials

Platform

# of

Can

dida

tes

BiTE

TrioMab

DNL

scFv fusio

ns2 in

1

Tandab

CrossMab

Nanobody

DVD-Ig/T

BTI

Other

0

1

2

3

4

5

Source: Roots Analysis

>80% are monovalent bispecific

70% are for oncology

Antibody Drug Conjugate

paylo

ad

antibody

linker

warhead

Designer antibodiesLow off-target binding

Differential epitopes (tumors vs.

normal cells)

Metabolically stable linkersSite selective conjugation

Differential tumor enzymes

cleavable linkers

cancer cell

32

Normal

Cell

Our strategies for redirecting the toxicity of potent warheads exclusively to tumors

Designer warheadsMaximal tumor killing

Abilities to kill all tumor cells,

including cancer stem cells

Synthetic lethality

Better screening technologies

On-target and off-target binding

And internalization

Off-targetTarget selection

Tumor (high)

Normal cells (none or very low)

On-Target

Non-target

mediated

36

Thank you for attention

Questions??