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2.6.1 Introduction Property of Novartis Vaccines and Diagnostics Gmbh FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.1 Introduction August 2009 Confidential Page 1 of 3 2.6.1 Introduction Property of Novartis Vaccines and Diagnostics GmbH & Co KG Confidential May not be used, divulged, published or otherwise disclosed without written consent of Novartis Vaccines and Diagnostics GmbH & Co KG Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.1 Introduction August 2009 Confidential Page 2 of 3 TABLE OF CONTENTS 2.6.1 Introduction.....................................................................................................3 Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.1 Introduction August 2009 Confidential Page 3 of 3 2.6.1 Introduction The candidate vaccine, FCC H1N1sw, is a monovalent influenza virus vaccine, surface antigen, inactivated, with MF59C.1 adjuvant. It is a sterile suspension for injection in either pre-filled syringes or multi-dose vials. The active ingredient of the vaccine is purified hemagglutinin (HA) and neuraminidase (NA) from an H1N1 virus (Reassortant virus X-179A, derived from A/California/07/2009). The antigens contained in FCC H1N1sw are cell culture-derived; they are purified from virus grown in Madin Darby Canine Kidney (MDCK) cells. Pending clinical confirmation, the anticipated 0.25 mL clinical dose of FCC H1N1sw will contain 3.75 µg of H1N1 hemagglutinin and 0.125 mL MF59™C.1 adjuvant (MF59). MF59 adjuvant is an oil-in-water emulsion, composed of squalene as the oil phase, stabilized with the surfactants polysorbate 80 and sorbitan trioleate, in citrate buffer. The composition of the FCC H1N1sw vaccine is shown in the table below. Table 1: Composition of FCC H1N1sw vaccine Quantity Reference to Ingredients Function per dose Standards Active Ingredient Influenza virus surface antigens active (hemagglutinin and neuraminidase), 3.75µg, HA* Ph.Eur. ingredient H1N1 Adjuvant Squalene 4.875 mg oil phase In-house spec. polysorbate 80 0.588 mg Surfactant Ph.Eur. sorbitan trioleate 0.588 mg Surfactant Ph.Eur. sodium citrate dihydrate 0.330 mg Buffer Ph.Eur. citric acid monohydrate 0.020 mg Buffer Ph.Eur. Other Ingredients sodium chloride 2.00 mg isotonic aid Ph.Eur. potassium chloride 0.05 mg Buffer Ph.Eur. potassium dihydrogen phosphate 0.05 mg Buffer Ph.Eur. disodium phosphate dihydrate 0.33 mg Buffer Ph.Eur. magnesium chloride hexahydrate 0.025 mg Stabiliser Ph.Eur. calcium chloride dihydrate 0.035 mg Stabiliser Ph.Eur. water for injections up to 0.25 ml Diluent Ph.Eur. * HA = Hemagglutinin Multidose vials will also contain thiomersal (0.01% w/v) as a preservative. Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.2 Pharmacology Written Summary August 2009 Confidential Page 1 of 24 2.6.2 Pharmacology Written Summary Property of Novartis Vaccines and Diagnostics GmbH & Co KG Confidential May not be used, divulged, published or otherwise disclosed without written consent of Novartis Vaccines and Diagnostics GmbH & Co KG Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.2 Pharmacology Written Summary August 2009 Confidential Page 2 of 24 TABLE OF CONTENTS 2.6.2 Pharmacology Written Summary ....................................................................5 2.6.2.1 Brief Summary...................................................................................................5 2.6.2.2 Primary Pharmacodynamics ............................................................................6 2.6.2.3 Secondary Pharmacodynamics.......................................................................22 2.6.2.4 Safety Pharmacology .......................................................................................22 2.6.2.5 Pharmacodynamic Drug Interactions............................................................23 2.6.2.6 Discussion and Conclusions ............................................................................23 2.6.2.7 Tables and Figures...........................................................................................24 2.6.2.8 References.........................................................................................................24 Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.2 Pharmacology Written Summary August 2009 Confidential Page 3 of 24 LIST OF TABLES Table 1: Related Novartis Influenza Vaccines...............................................................5 Table 2: HI titers (heterologous) in FCC/MF59-H5N1-treated rabbits .........................7 Table 3: Mean HI antibody titers induced by egg-derived and MDCK-derived monovalent bulk antigens ..........................................................................................10 Table 4: Mean HI antibody titers against homologous and heterologous virus following administration of egg-derived and MDCK-derived monovalent bulk antigens ......................................................................................................................11 Table 5: Mean HI antibody titers and ranges against homologous virus following administration of MDCK-derived trivalent antigens .................................................12 Table 6: HI titers in mice following administration of three concentrations of trivalent MDCK cell-derived influenza vaccine ......................................................................13 Table 7: Rabbit HI antibody titers ± standard deviation ..............................................14 Table 8: Rabbit A/New Caledonia HI antibody titers – geometric mean and (range).15 Table 9: A/New Caledonia/20/99 HI titers in ferrets ...................................................18 Table 11: MF59C.1 Adjuvant composition....................................................................22 Table 12: Cardiovascular and neurological evaluations during repeat-dose studies with MF59 in dogs .............................................................................................................23 Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.2 Pharmacology Written Summary August 2009 Confidential Page 4 of 24 LIST OF FIGURES Figure 1: Antibody titers 14 days post second dose (ELISA) .........................................8 Figure 2: Antibody titers 14 days post second dose (HI) ................................................9 Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.2 Pharmacology Written Summary August 2009 Confidential Page 5 of 24 2.6.2 Pharmacology Written Summary 2.6.2.1 Brief Summary The primary pharmacological effect of an influenza vaccine is the induction of antibodies to hemagglutinin (immunogenicity), which can confer protection in challenge models. Nonclinical studies with the candidate vaccine, FCC H1N1sw, have not been completed, but relevant nonclinical data with an equivalent MF59-adjuvanted vaccine, FCC/MF59- H5N1 (made using the same process), and the parent vaccine (Optaflu®; non-adjuvanted trivalent seasonal influenza vaccine) are available. In addition, supportive data are provided by studies with Novartis products that are related to FCC H1N1sw as shown below. Table 1: Related Novartis Influenza Vaccines Vaccine Description* Status Cell culture influenza vaccines Cell culture-derived ‘Parent’ vaccine registered for seasonal use in EU Optaflu® trivalent, interpandemic (EU/1/07/394/001-009). non-adjuvanted Cell culture-derived FCC Investigative H1N1 (swine origin) vaccine. monovalent, A/H1N1 H1N1sw Manufacturing based on Optaflu® process. MF59C.1 adjuvant Cell culture-derived FCC/MF59 Manufacturing based on Optaflu® process. monovalent, A/H5N1 -H5N1 Formulation, fill and packaging based on Fluad® process. MF59C.1 adjuvant Related influenza vaccines (provide additional supportive nonclinical data) Under evaluation for use prior to an H5N1 outbreak by Egg-derived EMEA (CP No. EMEA/H/C/804) and the Swiss Aflunov® monovalent, A/H5N1 regulatory authority. Produced using Fluad® MF59C.1 adjuvant manufacturing processes. Egg-derived Registered for seasonal use in EU (MRP No. Fluad® trivalent, interpandemic IT/H/0104/001) and Germany (PEI.H.01444.01.1), also MF59C.1 adjuvant registered outside EU. *All of these vaccines are surface antigen, inactivated The definitive GLP toxicology study supporting the FCC H1N1sw program was performed with the comparable MF59-adjuvanted vaccine containing HA from an H5N1 strain (FCC/MF59-H5N1 vaccine). This study is directly relevant to the FCC H1N1sw vaccine because the manufacturing process for the antigen, and the adjuvant contained in FCC/MF59-H5N1 vaccine, are the same as those in the FCC H1N1sw vaccine. In this 6- week rabbit toxicology study, local (intramuscular) and systemic toxicities were evaluated following repeated intramuscular dosing (3 doses of 15 µg antigen + 0.25 mL MF59 Novartis Vaccines and Diagnostics August / September 2009 FCC H1N1sw Vaccine Module 2 Novartis Vaccines and Diagnostics 2.6.2 Pharmacology Written Summary August 2009 Confidential Page 6 of 24 separated by 2 weeks). Under the conditions of the study, FCC/MF59-H5N1 vaccine was well tolerated and immunogenic. A study in mice evaluated the immunogenicity of seasonal
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