Le Biotecnologie e le Scienze della Vita per la Promozione della Salute

22 maggio 2007

I Farmaci Innovativi

Stefano VellaDirettore, Dipartimento del Farmaco

Istituto Superiore di Sanità

What does innovation mean?

1. the commercial concept: any newly marketed me-tooproduct, new substances, new indications, new formulations, and new treatment methods

2. the technology concept: any industrial innovation, such as use of biotechnology, or the introduction of a new substance delivery system (patch, spray, etc.), selection of an isomer or a metabolite

3. the concept of therapeutic innovation: a new treatment that benefits the patient when compared topreviously existing options

ISDB “Declaration on therapeutic advance in the use of medicines” - Paris, November 2001

0 5 10 15 20 25 30 35 40

A

B

C

D

G

H

J

L

M

N

P

R

S

V

ATC

cod

e

Number of drugs

Distribution of approved drugs according to ATC classification

alimentary tract and metabolism

bloodcardiovascular system

dermatologicalsgenitourinary system and sex organs

systemic hormones

antiinfectives

antineoplastics

musculo-skeletal system

nervous system

antiparasitics

respiratory systemsensory organs

various

*SEE ANNEX “PART A” - EEC 2309/93

*Non-biotechnological

Biotechnological

According to the International Society of Drug Bulletins (ISDB), about 80% of new products or new clinical uses approvedeach year in developed countries provideno advantage over existing treatments. About 2% of drug treatments offer a realadvance to patients, and 5% provide minor benefits

diseaseseriousness

therapeuticeffect

availabletreatments

THERAPEUTIC INNOVATION

Therapeutic innovation: further refinement of the concept

Therapeutic innovation: a proposal by Montanaro & Martini at CPT 2000

Results (3): therapeutic innovation of drugs fornon-serious diseases

A = important

B = moderate

C = modest

PharPhar = = pharmacologicalpharmacological innovationinnovation

TechTech = = technologicaltechnological innovationinnovation

02

01

0011 3

11

0

2

4

6

8

10

12

14

A B C Phar Tech

Non-biotechnological

Biotechnological

A11% B

5% C0%

Phar11%

Tech73%

Results (2): therapeutic innovation of drugs for risk factors

A = important

B = moderate

C = modest

PharPhar = = pharmacologicalpharmacological innovationinnovation

TechTech = = technologicaltechnological innovationinnovation

00 0

2

00

2

2

0

5

0

1

2

3

4

5

A B C Phar Tech

Non-biotechnological

Biotechnological

A0%

B18% C

0%

Phar36%

Tech46%

Results (1): therapeutic innovation of drugs for serious diseases

A = important

B = moderate

C = modest

PharPhar = = pharmacologicalpharmacological innovationinnovation

TechTech = = technologicaltechnological innovationinnovation

A38%

B17%

C3%

Phar18%

Tech24%

13

33

6

15

13

10

12

19

11

0

5

10

15

20

25

30

35

40

45

50

A B C Phar Tech

Non-biotechnological

Biotechnological

most (80%) of the EMEA-approved therapeuticallyactive substances target serious diseases

the degree of important/moderate therapeutic innovation among EMEA-approved active substances is significant (> 50%) only if we consider drugs approved for serious diseases

non-therapeutic (technological or pharmacological) innovation prevails (> 80%) among drugs targeted to risk factors for serious diseases or non-serious diseases

biotechnological and pharmacological innovation should not be confused with therapeutic innovation, because only the latter is an important public health goal

Innovation areas

• New drugs• New therapies• New combinations• New delivery systems

New drugs and therapiesA new treatment is really innovative when offers to patients

greater benefits with respect to previous treatments in terms of efficacy, safety and convenience.

Three factors contribute to determine the level of innovationof a drug:

• Its potential to reduce mortality, morbility and/or disabilityof a certain diesease;

• Its capability to reduce the social costs of a disease; • Its contribution to economic and social development.

HIV / AIDS

The International AIDS Society–USAIn: Gulick RM, Topics HIV Med, 2002;10(4).

Stages of HIV-1 Life CycleTargeted by Anti-HIV Drugs

1989: X-ray crystallographicstructure of HIV-1 protease

Translational products of the HIV gag-pol gene and the sites at which the gene product is cleaved by the virus-encoded protease.

p17 capsid protein,

p24 matrix protein,

p7 nucleocapsid.

The arrows denote cleavageevents catalyzed by the HIV-specific protease.

December 1995: FDA approves Invirase(Saquinavir), the first PI by Hoffman-LaRoche

March 1996: Norvir (Ritonavir) fromAbbott and Crixivan (Indinavir) fromMerck are approved

Mortality in patients with CD4<100 of antiretroviral (ARV) therapy including a protease inhibitor among those

patients, USA, 1994–1997

0

10

20

30

40

1994 1995 1996 1997

Dea

ths

per 1

00 p

erso

n ye

ars

0

20

40

60

80

100 AR

V therapy including protease

inhibitors (% of patient days)

DeathsARV

Source: Palella et al., New England Journal of Medicine, 1998 Mar, 26:338–6098036-E-35 – 15 July 1998

Percentage of Patient-days on HAART

Deaths per 100 Person-Years

0

5

10

15

20

25

30

35

40

1995 1996 1997 1998 1999 2000 2001

Dea

ths

per 1

00 P

erso

n-Ye

ars

0

25

50

75

100Percentage of Patient D

ays on HAAR

T

DEATHS

USE OF HAART

Mortality vs. HAART Utilization

Palella F et al, HOPS Study

05

10152025303540

82 84 86 88 90 92 94 96 98*Year

Dea

ths

per 1

00,0

00 P

opul

atio

n UnintentionalinjuryCancer

Heart disease

Suicide

HIV infection

Homicide

Chronic liverdiseaseStroke

Diabetes*Preliminary 1998 dataNational Center for Health StatisticsNational Vital Statistics System

Trends in Annual Rates of Death from Leading Causes of DeathAmong Persons 25-44 Years Old, USA, 1982-1998

CANCER

Example of innovative drugs(oncology)

• Docetaxel(Taxotere®, Sanofi Aventis)• Paclitaxel (Taxol®, Anzatax®, Paxene®)• Oxaliplatino (Eloxatin®,SanofiAventis)• Irinotecan (Camptò®, Pfizer)• Pemetrexed (Alimta®, Lilly)• Bortezomib (Velcade®, Janssen Cilag)• Rituximab (Mabthera®, Roche)• Trastuzumab (Herceptin®, Roche)• Bevacizumab (Avastin®, Roche)• Ibritumomab Tiuxetano (Zevalin®, Schering) • Capecitabina (Xeloda®, Roche)• Temozolamide (Temodal®, Schering Ploug)• Doxo liposomiale peg (Caelyx®, Schering Ploug)• Doxo liposomiale non peg (Myocet®, Zeneus Ph)• Raltitrexed (Topotecan ®, GlaxoSmithKline)• Topotecan (Hycamptin®, Astrazeneca)

Murine mAb to ErbB2

About 25-30% of women who have metastatic breast cancer overexpress HerB2(EGF) receptor

Reactivity on tumour samples

Humanization of the murinemAb to ErbB2 for immunotherapyof metastatic breast cancer (1996)

1995

ErbB2 expressionis associatedwith metastatic breastcancer!

The humanization of the murine mAb to HerbB2has been accomplished in 1996 using a recombinant -DNA based approach developed by Winter et al., (1990)

Herceptin (TrastuzuMAb) anti-HER MAbs

1999:Approved

EMEA think-tank group• The EMEA created the “think-tank group on innovative drug

development” in order to form a view both on the current and emerging scientific approaches in the development of medicinalproducts and on the related standards in Europe to identify what isneeded in terms of science uptake for their scientific evaluationpurposes.

• The approach was to identify bottlenecks in the development of medicinal products and possible redundant scientific requirements, as well as to discuss the application of new methods and procedures to support the sound scientific development and approval of medicinal products.

• In this context preliminary consideration was given also on how tobenefit from and provide support to the European Commission in its7th Framework Programme, especially for the Innovative MedicinesInitiative (IMI) technology platform and its Strategic ResearchAgenda (SRA).

R&D intensity as % of GDP, 2003Source: European Commission - DG Research, Key Figures 2005

1,12

1,16

1,26

1,31

1,54

1,71

1,89

1,93

2,15

2,37

2,37

2,51

2,59

2,62

3,15

3,49

4,27

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5

Ireland

Italy

Ccech Republic

China

Slovenia

Luxembourg

UK

EU-25

France

Belgium

Austria

Germany

US

Denmark

Japan

Finland

Sweden

The proposed EC contribution to the IMI JTI will be 1 billion € for the period of FP7 (2007-2013). The annual contribution from the EC will start in the range of 100 million € and gradually increase to reach 300 million € at the end of the period.

The biopharmaceutical industry partner(s) will match the funds from the European Union’s 7th Research Framework Programme with R&D resources such as staff, laboratories, materials and clinical research capabilities.

The Strategic Research Agenda focuses on bottlenecks in biomedical R&D

Discoveryresearch

Preclinicaldevelop.

Translationalmedicine

Clinicaldevelop.

Pharmaco-vigilance

Predictive pharmacology

Predictive toxicology

Efficacy Safety

Identification of

biomarkers

Validation of biomarkers

Patient recruitment

Risk assessmentwith regulatory

authorities

SAFETYGoal: improve the predictability of toxicological observations using:

In silico toolsToxicogenomicsToxicoproteomicsMetabonomics

How can these technologies be used in an integrated approach?How can the in silico and in vitro data be validated by safety data in human? Main recommendations:

Create a European Center of Drug SafetyEstablish a framework for biomarker development to study human relevance and regulatory utility, Develop in silico methods for predicting toxicity

EFFICACYGoal: improve clinical performance and early access to innovative medicine:

Patient databasesBiomarkers validationTissue banksImagingDevelop a better common understanding of the trade-off between risk and reward that comes with innovation

Main recommendations:Stimulate translational medicine in an integrated fashionCreate disease specific imaging networksDevelop partnership with regulators for innovative clinical trial design and acceptance of biomarkers

Integrated Project:- Toxicogenomics- Biomarkers in AD

Activities across Framework Programmes 6 and 7

FP62002 2006

SubmissionNov 2004

FP720132007

Development of theStrategic Research

Agenda

FundsOct 2005

The Innovative Medicines InitiativeImplementation of the Strategic Research Agenda

Funds

The Strategic Research Agenda

A unique achievementA European Joint Technology

Initiative is a bold and imaginative way of realising the IMI’s goals

Provides a means of gaining competitive advantage for Europe if we act fast

Will encourage inward investment to help meet the Lisbon goal

Will produce profound benefits for healthcare

Needs the support of the Member States

http://www.imi-europe.org

Identifying Therapeutic Gaps in the North and the South of the World

• Needs (burden of disease / efficacy of existing medicines)

• Likelihood of public health trends• Resource requirements• Underlying values / social solidarity

Therapeutic Gaps in the North and the South of the World (1)

• Infections due to resistant microrganisms• Pandemic Influenza• Secondary Prevention of Cardiovascular Diseases• Diabetes• Cancer Therapeutics• Acute Stroke• HIV/AIDS• Tuberculosis• Neglected Diseases (e.g. sleeping sickness, Chagas

disease, etc)• Malaria

Therapeutic Gaps in the North and the South of the World (2)

• Alzheimer Disease• Osteoarthritis• Chronic Obstructive Pulmonary Disease• Alcohol Use Disorders• Depression• Postpartum Haemorrage and Maternal Mortality• Orphan Diseases (5,000-8,000 conditions….)

• Cross cutting Themes:

– New delivery mechanisms– Pharmaceuticals and the Elderly– Pharmaceuticals and Children– Women and Pharmaceuticals

What is needed to fill the gaps• Gaps prevalently of the North

– Basic Research (pathogenesis !!)– Fight bottlenecks in drug development

• Gaps prevalently of the South– Expanding access to proven interventions– Building infrastructure– Operational Research– Drug/vaccine research

• AIDS vaccine, microbicides• Heat stable insulin and oxitocin• Drug resistance…• …..