Catania, 9 Marzo 2005 Prospettive della Ricerca Clinica 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, Pomezia Pomezia, Berlin, Pisa, Lomagna Florence, Berlin, Barcelona Florence, Berlin, Barcelona Kinetics & Metabolism Toxicology Chemical Development Galenics Biotechnological Development Molecol. Biol Drug Design Chemistry Pharmacology Phase I Phase II Phase III

Menarini R&D Sites 11 employees in year 1978 736 employees in year 2003 Berlin Milano Florence Pisa Barcelona Rome

Clinical Research Mission INTERNAZIONALIZZAZIONE INNOVATIVITA’

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

Menarini Clinical Research Barcelona Florence Berlin

Normative EU, ICH guidelines La ricerca clinica italiana deve mirare ad uno sviluppo clinico non solo europeo ma mondiale Normative EU, ICH guidelines Scientific Advice Nazionali, EMEA, FDA Advisory Board Accademici

Medical and Social Need Innovatività Medical and Social Need Risk benefit ratio SELEZIONE Prodotti Aree terapeutiche

INNOVATIVITA’  Nuovi prodotti e nuove strategie terapeutiche  Nuove indicazioni  Nuove popolazioni target

strategie terapeutiche 1. Nuovi prodotti e nuove strategie terapeutiche

Status: Clinical Phase III MEN 2234 Project 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 Status: Clinical Phase III

MEN 2234 Survival Benefit Phase I-II Results : Immunization induced by MEN 2234 toward ovarian TAA favours survival in 3rd line therapy of ovarian cancer

Watch-full Waiting Period Epithelial Ovarian Cancer Medical Need + Debulking Surgery Chemotherapy Tumor Response or Stabilisation Progressive disease (85%) Manteinance of Response Second Line Therapy Watch-full Waiting Period Progressive disease

MEN 2234 Phase III study 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

2. Nuove indicazioni

SABARUBICIN Preclinical Evidence potential better risk/benefit ratio than conventional anthracyclines O H N 2 C l . broader antitumoral activity favourable pharmacokinetics lower cardiotoxicity potential

Sabarubicin Small Cell Lung Cancer 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 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

SENIORS Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure

SENIORS Age and Sex of Patients in Major Placebo- Controlled Trials of ß-Blockers in CHF Trial ß-blocker N Mean age % Males US Carvedilol Carvedilol 1094 58 78 MERIT-HF Metoprolol CR/XL 3991 64 77 CIBIS-II Bisoprolol 2647 61 80 2708 BEST Bucindolol 60 78 COPERNICUS Carvedilol 2289 63 79 Mean 61 79

Prevalence of Congestive Heart Failure by Age and Sex in NHANES SENIORS Prevalence of Congestive Heart Failure by Age and Sex in NHANES 1 2 3 4 5 6 7 8 9 10 20-24 25-34 35-44 45-54 55-64 65-74 >74 Men Women Percentage (%) Study population in BB trials Source: CDC/NCHS.

SENIORS Ejection Fraction (%) of Patients in Major Placebo- Controlled Trials of ß-Blockers in CHF Trial ß-blocker N EF% US Carvedilol Carvedilol 1094 22.6 MERIT-HF Metoprolol CR/XL 3991 28.0 CIBIS-II Bisoprolol 2647 27.5 BEST Bucindolol 2708 23.0 COPERNICUS Carvedilol 2289 19.8 Mean 24.9

SENIORS Inclusion Criteria 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 Study Protocol

Baseline Characteristics - Age SENIORS Baseline Characteristics - Age 225 200 175 150 125 Number of patients 100 75 50 25 70 75 80 85 90 95 Age (years) Median age = 75.2 years

Baseline characteristics - LVEF SENIORS Baseline characteristics - LVEF 600 500 400 Number of patients 300 200 100 10 - 14 15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 45 - 49 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 80 Left ventricular ejection fraction (%) LVEF < 35%: mean value = 28.7% LVEF > 35%: mean value = 49.2%

Benefit of Nebivolol vs other beta-blockers SENIORS Benefit of Nebivolol vs other beta-blockers Favours Nebivolol Favours Placebo Primary outcome SENIORS- Overall population - Age < 75 y & LVEF < 35% All cause mortality SENIORS - Overall population - Age < 75 y & LVEF < 35% CIBIS II MERIT COPERNICUS 0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 Hazard ratio and 95% CI

SENIORS Fast Track

> 25.000 Expected Patients in Clinical Trials in 2006 24000 20000 16000 12000 8000 4000 1992 1995 2000 2006