The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations

Dr. Thomas Schreitmueller, Regulatory Policy, BiologicsF. Hoffmann – La Roche Ltd., Basel, Switzerland

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Table of content

Disease Challenges, Strategies and Developments

Biotech History, Process and Products

Biotech Regulations

Biosimilars

Pre-1950s 1950/60’s 1970/80’s 1990/00’s

Cells/Organisms

Understanding Disease MechanismsWhere did we come from, where are we going?

Today

DNA Structure Genetic Code Human Genome

Disease Mechanisms

# P

lau

sib

le T

arg

ets1000’s

10’s

100

Pathways

Basic Biological Mechanisms

Observational Biology

Understanding the disease is one thing -Fitting treatments to patients another

Effectiveness of treatment can be improved . . .

• 20-75% of patients do not receive effective treatment1

• Thousands of deaths/yr from adverse drug reactions (e.g. US2)

. . . by tailoring treatments to selected patient groups defined by biomarkers

1 Spears et al., Trends Mol Med, 20012 Lazarou et al., JAMA, 1998

Personalised Healthcare is becoming a reality Molecular insights allow better treatment decisions

Identifying those patients optimizes care

MoleculardiagnosisPatients with breast

cancer: only the portion of patients that show over-expression of the HER2 gene and will benefit from Trastuzumab

Trastuzumab Changed the Natural History of HER2+mBCHER2-positive status has become a favorable prognostic factor

Pro

babili

ty o

f su

rviv

al (%

)

Time from

diagnosis

(months)

100

80

60

40

20

00 12 24 36 48 60

HER2-positive

Herceptin n=191

HER2-positive

No Herceptin

n=118

HER2-positive

Herceptin n=191

HER2-positive

No Herceptin

n=118

HER2-negative

n=1,782

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Table of content

Disease Challenges, Strategies and Developments

Biotech History, Process and Products

Biotech Regulations

Biosimilars

Serum Therapy 1893

E. Bäumler, Auf der Suche nach der Zauberkugel, Econ-Verlag 1971

•first Nobel prize for medical research in history for the discovery of “antibodies” 1901

Emil von Behring immunizing a“serum-horse”

Biotech Manufacturing Historical Perspectives

1978

The first biotech drug using recombinant technology was developed. Herbert Boyer and others succeeded at genetically manipulating plasmids of E. coli bacteria to produce insulin with the same amino sequence as seen in humans. (Insulin - Genentech)

Herbert W Boyer and Robert A Swanson the founders of Genentech talking about recombinant DNA.

Image: Courtesy of Genentech Inc

BioTechnology Developments

Biotech products manufacturing

DNA Vector

ATG

Stop

Working Cell Bank

AmplificationMaster Cell Bank

Biological product complexity: Examples of modifications: inherent or due to the manufacturing process

11Adapted from: Steven Kozlowski; FDA

K

pyro-E

G

D

O

D

G

OD

pyro-E • Pyroglutamyl peptides

K

• C-terminal Lysine

D

D

D • Deamidation

O

O• Methionine oxidation

G

G

• Glycation

• High mannose, G0, G1, G1, G2

• Sialylation

Modifications may result in approximately 108 potential variants

Protein Microheterogeneity

Small Molecule Drug

ProteinDrug

Carter, P.J. (2006) Nature Revs. Immunol. 6, 343-357

Glycosylation: important modification on MAbs

Enhancing antibody performance

NK

or MØ

Bi-specific antibodybinds to two different targetsand enhances specificity

Antibody inhibits or activates signaling

Naked Antibodiesbi-specific Antibodies

Bi-specific antibodybinds to two different targets in different cells

bi-specific Antibodiesdrugdrug

drugdrug

Antibody recruits immune effectorcell and induces cytotoxicity

ADCC enhanced Antibody

Antibody specifiesdelivery of drug

Armed Antibodies

Trastuzumab emtansine ADC 14 CT performed/ongoing

Emtansine release

Inhibition of microtubule

polymerization

15

Internalization

HER2

Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

T-DM1

Lysosome

Nucleus

PP

P

• Increased direct cell-death induction

• Enhanced antibody-dependentcell-mediated cytotoxicity (ADCC)

• Lower complement-dependent cytotoxicity (CDC) activity

In collaboration with Biogen IdecUmaña et al, Blood 2006; 108, abstract 229, Umaña et al, Ann Oncology 2008, 19 (suppl 4), abstract 098

CD20 peptide

Type II recognition

& elbow-hinge residues

Carbohydrate glycoengineered (GlycoMabTM technology):Overexpression of GnTIII and ManII glycosylation genes in Ab production cell lines leads to Ab glycoforms bearing bisected, complex afucosylated oligosaccharides in Fc region

Obinutuzumab: glycoengineered, anti-CD20 mAb10 CT performed/ongoing

More than 500 clinical trials in over 50 cancers investigating the use of Bevacizumab*Bevazizumab has the largest clinical trial program ever initiated in oncology

*www.clinicaltrials.gov April 2010

Valuable and Vulnerable Industry • Developing a new medicine is lengthy, risky, and costly.

• New drug development takes an average of 10–15 years, and costs approx. € 1.2 billion

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INDEFINITE

Drug Discovery Preclinical Clinical Trials FDA/EMA Review

Scale-Up to Mfg. Post-MarketingSurveillance

ONE FDA/EMA-

APPROVED DRUG

0.5 – 2 YEARS6 – 7 YEARS3 – 6 YEARS

NUMBER OF VOLUNTEERS

PHASE 1

PHASE 2

PHASE 3

5250~ 5,000 – 10,000

COMPOUNDS

PR

E-D

ISC

OV

ER

Y

20–100 100–500 1,000–5,000

IND

SU

BM

ITT

ED

ND

A S

UB

MIT

TE

D

Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org

Biotech Pharmaceuticals – Where do we stand today?

• Biotechnology has produced medical treatment for hitherto serious incurable diseases.

• Hundreds of biologics drugs approved.

• Biotech drugs accounting approx. 17% of the world pharma market.

• Approx. 50% new drugs are biotech drugs.

19 Source: IMS 2010

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Table of content

Disease Challenges, Strategies and Developments

Biotech History, Process and Products

Biotech Regulations

Biosimilars

How regulatory systems should evolve globally ?

• Greater regulatory convergence of pharmaceutical regulations is necessary facilitating R&D investment and to increase and expedite patient access to new and innovative medicines

– Remove duplicative/different requirements between agencies, which hinder global drug development and supply

– Develop a more innovative evaluation framework

• adaptive licensing

• inter agency reviews

– Mutually recognize GMP inspections

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Table of content

Disease Challenges, Strategies and Developments

Biotech History, Process and Products

Biotech Regulations

Biosimilars

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Biosimilars Global Regulations

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Thomas Palmberger, Pharmaceutical Development, Sandoz Bioharmaceuticals, 7-8 June 2011, Basel, Switzerland, 4th PDA Europe Workshop on Monoclonal Antibodies

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Biosimilar pathways – EMA biosimilar antibody guideline

• The guideline is setting the stage for the overall stepwise development approach having the goal “…ensuring that the previously proven safety and efficacy of the drug is conserved.”.

• The stepwise approach at the clinical side is outlined more clearly focusing on the main principles to be considered when establishing clinical similarity: “The guiding principle is to demonstrate similar clinical efficacy and safety compared to the reference medicinal product, not patient benefit per se, which has already been shown for the reference medicinal product.”.

• This has to be achieved by planning all studies “…with the intention to detect any potential differences between biosimilar and reference medicinal product and to determine the relevance of such differences, should they occur.”

Biosimilar vs. innovator clinical studies (oncology) Differences in requirements and study designs

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Aspects of Development

Biosimilar Innovator

Patient Population Sensitive and homogeneous (patients are models)

Any

Clinical Design Comparative versus innovator, normally equivalence

Superiority vs standard of care (SoC*)

Study Endpoints Sensitive

Clinically validated PD markers

Clinical outcomes data or accepted/established surrogates (e.g. OS and PFS)

Safety Similar safety profile to innovator; no new findings

Acceptable benefit/risk profile versus SoC*

Immunogenicity Similar immunogenicity profile to innovator

Acceptable risk/benefit profile versus SoC*

Extrapolation Possible if justified Not allowed

* In some cases SoC may not exist

Demonstration of Clinical Similarity and Extrapolation of Indications - A Challenge for Biosimilar Antibodies• Comparative safety and efficacy trials in sensitive

populations are required to demonstrate clinical equivalence to the reference product within pre-defined margins.

• The sensitive patient population/indication for the required similarity assessments with respect to PK, PK/PD, Efficacy, Safety or Immunogenicity

may be a different one for each assessment.

• Extrapolation across indication will require extensive scientific justification, additional efficacy, safety and immunogenicity data may be needed as well as specific risk mitigation strategies.

EMA: In support of the EU biosimilar framework

“Considering the complexity of biomolecules, the limitations at present in analytical characterization and in clinical trials (like defining sensitive and feasible endpoints to detect differences), it is necessary that the biosimilar concept relies on demonstrating comparability at all three levels (that is, quality, preclinical and clinical to ensure as complete a picture as possible on the features of such complex molecules). A relaxation of these requirements is not justified.”

Christian K Schneider1,2, John J Borg3, FalkEhmann4, Niklas Ekman5, Esa Heinonen5,6,Kowid Ho7, Marcel H Hoefnagel8, RoelandMartijn van der Plas8, Sol Ruiz9, AntoniusJ van der Stappen8, Robin Thorpe10, KlaraTiitso4, Asterios S Tsiftsoglou11, CamilleVleminckx4, Guenter Waxenecker12, MatsWelin13, Martina Weise14 & Jean-HuguesTrouvin7,15on behalf of the Working Partyon Similar Biological (Biosimilar) MedicinalProducts (BMWP) and the Biologicals WorkingParty (BWP) of the Committee for MedicinalProducts for Human Use (CHMP)

Based on science, the Concept of Biosimilarity is built on five indispensible pillars:

The use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.

S c i e n c e

An

alyt

ical

Sim

ilar

ity

Pre

-cli

nic

al S

imil

arit

y

Cli

nic

al S

imil

arit

y

Ph

arm

aco

vig

ilan

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B i o s i m i l a r i t y

Pro

per

Qu

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Thank You !