Vaccines and Related Biological Products Advisory Committee Meeting November 16, 2011 Prevnar 13 for Adult Use Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) Applicant: Wyeth Pharmaceuticals, Inc Nicolette deVore, Ph.D. Regulatory Reviewer FDA / CBER / OVRR / DVRPA

Outline Approved Pneumococcal Vaccines and Indications Accelerated Approval Regulations Prevnar 13 Regulatory History and use of Accelerated Approval Pathway

Currently Licensed Pneumococcal Vaccines Prevnar 13 (PCV13) Manufactured by Wyeth Licensed in 2010 13-valent conjugate vaccine Prevnar (PCV7) Licensed in 2000 7-valent conjugate vaccine PNEUMOVAX 23 (23vPS) Manufactured by Merck Licensed in 1983 23-valent polysaccharide vaccine

Prevnar 13 (PCV 13) PNEUMOVAX 23 (23vPS) Current Indications Approved for use in children 6 weeks through 5 years of age for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F 23F and 6A. for the prevention of otitis media caused by S.pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. PNEUMOVAX 23 (23vPS) Approved for use in persons 50 years of age or older and persons aged ≥ 2 years who are at increased risk for pneumococcal disease. for active immunization for the prevention of pneumococcal disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, and 2, 8, 9N,10A, 11A, 12F, 15B, 17F, 20, 22F, 33F.

Prevnar 13: Proposed Indication and Usage Active immunization for prevention of pneumococcal disease (including pneumonia and invasive disease) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. Administered as a single intramuscular injection to adults aged ≥ 50 years. Includes those previously vaccinated with pneumococcal polysaccharide vaccine, Pneumovax 23 (23vPS). Note: The adult formulation of PCV13 is identical to the formulation currently licensed for use in children 6 weeks through 5 years of age.

Accelerated Approval 21 CFR 601 Subpart E Applies to biological products that have been studied for safety & effectiveness in treating serious or life-threatening illnesses Provides meaningful therapeutic benefit over existing treatments Approval based on a surrogate endpoint Reasonably likely to predict clinical benefit Effect is established via adequate & well-controlled trials Approval is subject to required confirmatory study, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit Confirmatory study: Verifies & describes clinical benefit Is adequate & well-controlled Usually underway at approval

Surrogate Endpoint Surrogate endpoints are generally defined as endpoints that predict clinical outcome. In the case of accelerated approval pathway the surrogate should be “reasonably likely to predict” clinical benefit.

Vaccines Approved using the Accelerated Approval Pathway Surrogate Confirmatory trial AFLURIA® (inactivated influenza vaccine) HAI Pending Agriflu® Complete FluLaval® Fluarix® Hiberix® (Haemophilus b conjugate vaccine) ELISA and RABA

Status of Pneumococcal Disease in Adults Invasive Pneumococcal Disease (IPD) Defined by isolation of S. pneumoniae from a normally sterile site (i.e. blood, cerebrospinal, pleural or peritoneal fluid). Rates in 2002 – 2003 were 29.4 / 100,000 for those 50 to 64 and 41.7 / 100,000 for those 65 years and older.2 Pneumococcal Pneumonia Community acquired pneumonia is the most common infectious cause of death in the US.5 Streptococcus pneumoniae is the leading cause of community acquired pneumonia in adults. Rates of pneumococcal pneumonia (including invasive) during 2001-2004 were estimated to be 14.8/ 100,000 for 40-64 years of age and 59.3/ 100,000 for those 65 years and older.3 Effectiveness of Pneumovax (23vPS) Protects against invasive disease.1 Effect on pneumococcal pneumonia is not clear.1,4 1. Int J of Antimicrob Agents, 2002; 19(2) 85–93 2. JAMA. 2005; 284 (16) 2043-2051 3. Lancet. 2007;369:1179-86. 4. Eur J Epidemiol. 2004;19(4) 353-63. 5. Am J Med. 2011 Feb;124(2):171-178

Basis for Use of Accelerated Approval Pathway A comparative clinical endpoint study with Pneumovax 23 would be impractical. There is a significant burden of pneumococcal disease in adults ≥50. Protection of adults against pneumococcal pneumonia or pneumococcal pneumonia combined with IPD is the “meaningful therapeutic benefit over existing treatment” required by the accelerated approval pathway regulations.

November 17, 2005 VRBPAC - Licensure Pathways for New Pneumococcal Vaccines in Adults Presentations Changing epidemiology since PCV7 Use of opsonophagocytic assay (OPA) Proposed development plans from manufacturers Committee discussion on licensure pathways Immunogenicity vs clinical endpoint studies VRBPAC considerations Emphasized the need for clinical endpoint studies while acknowledging the challenges Accelerated Approval is a reasonable path to follow

Regulatory History of Prevnar 13 for Adults June & November 2006; November 2007 - meetings held with sponsor on adult program Phase 3 clinical development program Use of Accelerated Approval for licensure Design of Phase 4 Confirmatory Trial September 2008 - Recruitment for phase 4 confirmatory study (CAPITA) began February 2010 - U.S. licensure of Prevnar 13 for infants and children (6 weeks - 5 years of age) December 2010 – submission of efficacy supplement for use of Prevnar 13 in adults ≥50 of age under accelerated approval

Prevnar 13 Phase 3 Studies Study N Age Range Immunization history Primary endpoints -004 1235 50-64 yrs 23vPS-naïve Compare PCV13 and 23vPS immunogenicity by OPA titers -3005 936 ≥ 70 yrs, 23vPS- preimmunized -3010 650 60-64 yrs Compare sequential use of PCV13 and 23vPS immunogenicity by OPA titers -3001 1081 50-59 yrs Compare immunogenicity of PCV13 administered alone or with TIV using IgG ELISA -3008 1152 ≥ 65 yrs -3000 1049 ≥ 68 yrs Safety study

Opsonophagocytic Assay (OPA) Opsonophagocytosis is an important mechanism of protection against pneumococcal disease. Opsonophagocytosis can be measured using the functional antibody assay (OPA) which is reasonably likely to predict clinical benefit. During Prevnar 13 studies in children OPA titers were used as exploratory endpoints. For Prevnar 13 studies in adults: a high through-put version of the assay was validated – microcolony OPA. comparison of OPA titers between the approved Pneumovax 23 vaccine and Prevnar 13 is a primary endpoint for phase 3 studies.

Prevnar 13 Confirmatory Study Community Acquired Pneumonia Immunization Trial in Adults (CAPITA) Conducted in the Netherlands Fully enrolled 84,503 subjects ≥65 years old Randomized 1:1 Prevnar 13 or placebo Many vaccinated on a background of a Trivalent Influenza Vaccine

Prevnar 13 Confirmatory (CAPITA) Study Primary Efficacy Objective Demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed vaccine-type (VT) pneumococcal pneumonia (including bacteremic and non-bacteremic pneumonia) Secondary Efficacy Objectives Demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed non-bacteremic VT pneumococcal pneumonia Demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of VT-IPD Expect results to be submitted in 2013

Summary Prevnar 13 is currently approved for use in infants and toddlers for prevention of otitis media and invasive disease. Proposed Prevnar 13 indication is active immunization for prevention of pneumococcal disease (including pneumonia and invasive disease) in adults ≥ 50 years of age. Wyeth is seeking accelerated approval of adult indication for Prevnar 13. Protection of adults against pneumococcal pneumonia or pneumococcal pneumonia combined with IPD is the “meaningful therapeutic benefit over existing treatment” required by the accelerated approval pathway regulations. OPA is surrogate endpoint “reasonably likely to predict clinical benefit” and is used in all Phase 3 trials in which immunogenicity of Prevnar 13 is compared to Pneumovax 23. CAPITA trial is the ongoing Phase 4 trial to verify clinical benefit.

Today’s Presentations Epidemiology Matthew Moore, M.D., M.P.H (CDC) Wyeth William C. Gruber, M.D. Daniel A. Scott, M.D. OPA Mustafa Akkoyunlu, M.D., Ph.D. (FDA) Immunogenicity Tina Khoie, M.D., M.P.H. (FDA) Safety Rosemary Tiernan, M.D., M.P.H (FDA)

Questions for the Committee 1. Are the immunogenicity data adequate to support the effectiveness of Prevnar 13 under the accelerated approval regulations for the prevention of pneumococcal disease caused by serotypes in the vaccine in adults ≥50 years of age? Please vote yes or no.

Questions for the Committee 2. Are the available data adequate to support the safety of Prevnar 13 when administered to adults ≥ 50 years of age? Please vote yes or no.

Questions for the Committee Given that a confirmatory clinical endpoint study is ongoing, are there any additional studies needed to further evaluate the safety or effectiveness of PCV13? Please discuss.

Thank you