Catania, 9 Marzo 2005

Prospettive della Ricerca Prospettive della Ricerca Clinica in ItaliaClinica in Italia

Angela Capriati, Corporate Clinical Research- Menarini Group

I tempi dello sviluppo clinico

registrativo impongono di

definire oggi le strategie che

condizioneranno le prospettive

a medio-lungo termine della

ricerca clinica

Le prospettive della ricerca

clinica italiana dipendono

strettamente dalla qualità ed

investimenti in ricerca

Research and Development of a new Drug

DISCOVERY PRECLINICAL CLINICAL REGULATORY MARKETING

DEVELOPMENT DEVELOPMENT SUBMISSION AUTHORIZ.

Florence, PomeziaPomezia, Berlin, Pisa, Lomagna

Florence, Berlin, Barcelona

Florence, Berlin, Barcelona

Molecol. Biol

Drug Design

Chemistry

Pharmacology

Kinetics & Metabolism

Toxicology

Chemical Development

Galenics

Biotechnological Development

Phase I

Phase II

Phase III

BerlinBerlin

BarcelonaBarcelona RomeRome

FlorenceFlorencePisaPisa

Menarini R&D Sites 11 employees in year 1978 736 employees in year 2003

MilanoMilano

Clinical Research Mission

INNOVATIVITA’

INTERNAZIONALIZZAZIONE

Internazionalizzazione

La ricerca clinica in Italia è di fatto una ricerca clinica in Europa

Barcelona

Florence

Berlin

Menarini Clinical Research

Nazionali, EMEA, FDA

La ricerca clinica italiana deve mirare ad uno sviluppo clinico non solo europeo ma mondiale

Scientific Advice

Advisory Board Accademici

Normative EU, ICH guidelines

Medical and Social Need Risk benefit ratio

SELEZIONE

Aree terapeutiche

Prodotti

Innovatività

INNOVATIVITA’

Nuovi prodotti e nuove strategie terapeutiche

Nuove indicazioni

Nuove popolazioni target

1. Nuovi prodotti e nuove strategie terapeutiche

MEN 2234 Project

Status: Clinical Phase III

Therapeutic vaccine:

it acts as a murine monoclonal anti-idiotype antibody mimicking the structure of CA 125, the Tumor Associated Antigen (TAA) over-expressed on epithelial ovarian cancer

Phase I-II Results : Immunization induced by MEN 2234 toward ovarian

TAA favours survival in 3rd line therapy of ovarian cancer

MEN 2234 Survival Benefit

Debulking Surgery

Chemotherapy

Progressive disease

Second Line Therapy

Tumor Response or Stabilisation

Watch-full Waiting Period

Progressive disease

+

Manteinance of Response

Epithelial Ovarian Cancer Medical Need

(85%)

Total number of patients to be randomised: 1164 (n=582 per arm)

2 year recruitment + 2 year min follow up

>150 Investigational Sites to be activated in EU and USA

MEN 2234 Phase III study

2. Nuove indicazioni

potential better risk/benefit ratio

than conventional anthracyclines

O

O

O H

O H

O H O

O

O

O

O H

O H

O

H ON H2 H C l.

SABARUBICIN Preclinical Evidence

• broader antitumoral activity

• favourable pharmacokinetics

• lower cardiotoxicity potential

• rare disease (year prevalence < 5 cases / 10,000)

• first line chemotherapy used always as combination regimens (EP, CAV, CEV)1 with limited impact on survival but significant toxicity

• very poor prognosis (median survival <12 months despite of its high chemosensitivity)

High medical need for new chemotherapy with improved efficacy and/or improved safety

1 EP= etoposide-cisplatin; CAV/CEV=Cyclophosphamide+adriamicine/epirubicine+vincristine

Sabarubicin Small Cell Lung Cancer

Sabarubicin Phase II Clinical evidence

• Most promising antitumoral activity (response rate, survival) as single agent in phase II clinical trial recruiting patients with SCLC-ED;

• Incidence and severity of toxicity (including class-related myelotoxicity and cardiotoxicity) in the overall six phase II studies lower than expected for anthracyclines.

Sabarubicin Orphan Medicinal Product Designation

According to Regulation (EC) No 141/2000 of the European Parliament and of the Council of the European Union the designation of orphan medicinal product for the indication of SCLC was sought

• as treatment of a disease affecting not more than 5 in 10,000 persons in the Community [Art. 3 (1) (a)]

and

• as a medicinal product which will be of significant benefit to those affected by that condition [Art. 3 (1) (b)]

Sabarubicin Orphan Medicinal Product Designation

3. Nuove popolazioni target

Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors

with Heart Failure

SENIORSSENIORS

612647BisoprololCIBIS-II

643991Metoprolol CR/XLMERIT-HF

581094CarvedilolUS Carvedilol

61Mean

632289CarvedilolCOPERNICUS

602708BucindololBEST

Mean ageNß-blockerTrial

Age and Sex of Patients in Major Placebo-Controlled Trials of ß-Blockers in CHF

% Males

77

78

80

78

79

79

SENIORS

Prevalence of Congestive Heart Failure by Age and Sex in NHANES

Source: CDC/NCHS.

00

11

22

33

44

55

66

77

88

99

1010

20-2420-24 25-3425-34 35-4435-44 45-5445-54 55-6455-64 65-7465-74 >74>74

MenMen WomenWomen

Per

cen

tag

e (%

)P

erce

nta

ge

(%)

Study populationin BB trials

SENIORS

27.52647BisoprololCIBIS-II

28.03991Metoprolol CR/XLMERIT-HF

22.61094CarvedilolUS Carvedilol

24.9Mean

19.82289CarvedilolCOPERNICUS

23.02708BucindololBEST

EF%Nß-blockerTrial

Ejection Fraction (%) of Patients in Major Placebo-Controlled Trials of ß-Blockers in CHF

SENIORS

• Age >70 years• A clinical diagnosis of chronic heart failure (HF) and either

of:

a) documented LVEF < 35% within previous 6 months

or

b) hospital admission within previous 1 year for congestive HF

• Written consent prior to enrolment into the study

SENIORS Inclusion Criteria

Study ProtocolSENIORS

0

25

50

75

100

125

150

175

200

225

Age (years)

Nu

mb

er o

f p

atie

nts

70 75 80 85 90 95

Median age = 75.2 years

SENIORS Baseline Characteristics - Age

0

100

200

300

400

500

600

10 -

1415

- 19

20 -

2425

- 29

30 -

3435

- 39

40 -

4445

- 49

50 -

5455

- 59

60 -

6465

- 69

70 -

7475

- 80

Left ventricular ejection fraction (%)

Nu

mb

er o

f p

atie

nts

LVEF < 35%: mean value = 28.7% LVEF > 35%: mean value = 49.2%

Baseline characteristics - LVEFSENIORSSENIORS

0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20

Hazard ratio and 95% CI

Benefit of Nebivolol vs other beta-blockersFavours Nebivolol

Favours Placebo

Primary outcomeSENIORS- Overall population

- Age < 75 y & LVEF < 35%

All cause mortalitySENIORS - Overall population

- Age < 75 y & LVEF < 35%

CIBIS II

MERIT

COPERNICUS

SENIORS

Fast TrackSENIORS

> 25.000 Expected Patients in Clinical Trials in 2006

0

4000

8000

12000

16000

20000

24000

1992 1995 2000 2006