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??