A Phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Clostridium difficile

Transcription

1 A Phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Clostridium difficile vaccine administered with or without Aluminum Hydroxide, in a 3-Dose Regimen in Healthy Adults Aged 50 to 85 Years Louise Pedneault, Eric Sheldon, Nicholas Kitchin, Yahong Peng, Joseph Eiden, William Gruber, Erik Johnson, Kathrin U. Jansen, Michael Pride 5 th ICDS, Bled Slovenia, 20 May 2015

2 Clostridium difficile-associated disease represents a significant unmet medical need Anaerobic spore-forming Grampositive bacillus Main cause of nosocomial infections 1 Increase in CDAD incidence and disease severity 2-5 C.difficile associated disease (CDAD) is directly attributable to production of Toxins A and B by C. difficile 6,7 No prophylactic vaccine is currently available for prevention of primary or recurrent CDAD Estimated US Burden of C.difficile Infection, CO-HCA = community onset health care-associated; NHO = nursing home onset; HO = hospital onset 1 Magill SS et al, NEJM 2014;370: ; 2 Gerding & Lessa, Infect Dis Clin N Am 2015;29:37-50; 3 Lessa FC et al, NEJM 2015;372:825-34; 4 Bauer et al, Lancet 2011;377:63-73; 5 Davies et al, Lancet Infect Dis 2014;14: ; 6 Giannasca et al (1999) Infect Immun; 7 Torres et al. (1995) Infect Immun Pfizer Confidential 2

3 Proof of Concept for a Toxoid Vaccine Toxin-based diseases like diphtheria, cholera and tetanus have been prevented by antitoxin antibodies or toxoid vaccines Clinical data indicate that antitoxin antibodies provide protection from CDAD: 72% reduction of CDAD recurrence Lowy I et al. N Engl J Med 2010;362: Pfizer Confidential 3

4 Pfizer s bivalent toxoid vaccine preserves important antigenic epitopes and neutralizes toxins from circulating clinical strains TOXIN STRUCTURE GENETIC TOXOID EXPRESSION PLASMID EXPRESSION IN C.difficile (Cytotoxic Function) RECIPIENT VPI SPO-A AND TOXIN MINUS Neutralization of B Toxins from C.difficile Strains Chemical Treatment of Genetically Modified Toxins Preserves Neutralizing Epitopes Sample EC 50 (ug/ml) Reduction in Cytotoxtoicity (log) Max Binding (Rmax) Neut mab Genetic txd A Formalin-txdA >1000 > Pfizer-txd A >1000 > Genetic txd B Formalin-txd B > Pfizer-txd B > Pfizer Confidential 4

5 Percent survival Bleed / Vax Bleed / Vax Bleed / Vax Clindamycin Bleed / Challenge (5,000 CFU Strain 630) Day 11/ Termination C. difficile Toxoid Vaccine Candidate Protects Hamsters (n=15/group) from C. difficile Challenge Post challenge W0 W2 W4 W5, 9, W6, 10, or 13 or 14 Challenge Post Last Vaccination Weeks 6 Weeks 10 Weeks Formulation Adjuvant 1 1 Formulation Adjuvant 2 2 Placebo (Matrix/NaCl) Days post-infection Formulation 1 = 93% (14/15) Formulation 2 = 93% (14/15) Days post-infection Formulation 1 = 93% (14/15) Formulation 2 = 80% (12/15) Days post-infection Formulation 1 = 100% (15/15) Formulation 2 = 80% (12/15) 5 Jansen K. 4 th International Clostridium difficile Symposium, 2012, Bled, Slovenia, Abstract O2

6 Phase 1 Study - Methods Design Phase 1, randomized, placebo-controlled, observer-blind Two age cohorts: yo and yo healthy adults Three doses administered on Day 1, Months 1 and 6 4 US sites Study Group* Formulation Subjects receiving Vaccine Placebo 1 50 mcg C. diff mcg C. diff mcg C. diff mcg C. diff mcg C. diff mcg C. diff * Six study groups replicated for each of the two age cohorts Pfizer Confidential 6

7 Phase 1 Study Methods Safety Evaluations Prompted e-diary events (both local reactions and systemic events that occurred in the 7 days after investigational product administration) Acute reactions within the first 30 minutes after investigational product administration Adverse events (AEs), serious AEs (SAEs) Hematologic and blood chemistry assessments Safety-driven stopping rules were in effect throughout the trial Unblinded safety data were reviewed by the internal Pfizer safety review team (PSRT) and external data monitoring committee (DMC) throughout the study Pfizer Confidential 7

8 Phase 1 Study Methods Immunogenicity Assessment Toxin A- and toxin B-specific neutralizing antibody levels measured at multiple time points Pfizer Confidential 8

9 Toxin Neutralization Assay (TNA): A Brief Overview R L U TOXIN REFERENCE STANDARD Neut U/mL R e f S td A (U /m L ) Automated and sensitive assay based on luminescence readout Neutralization titers of test samples are calculated based on Reference standard Assay LLOQ: Txd A = U/ml; Txd B = U/ml

10 Phase 1 Study Statistical Considerations All analyses descriptive Each age cohort analyzed separately Safety analysis population All subjects who received at least one dose of investigational product Primary immunogenicity population: Evaluable population All subjects who received the investigational product to which they were randomized, had blood drawn within specified time frames, had valid and determinate assay results for the proposed analysis, and no major protocol violations Immunogenicity endpoint Geometric mean concentrations (GMCs) of C. difficile toxin A- and toxin B-specific neutralizing antibody levels Pfizer Confidential 10

11 Baseline characteristics year olds Placebo Randomized, n Received dose 1, n Received dose 2, n Received dose 3, n Total Age in years, mean Sex, n Female Male Pfizer Confidential 11

12 Baseline characteristics year olds Placebo Randomized, n Received dose 1, n Received dose 2, n Received dose 3, n Total Age in years, mean Sex, n Female Male Pfizer Confidential 12

13 Any local reaction 1 within 7 days yrs 100% 80% 60% 40% 20% 0% Placebo N=22 + N= Placebo N= N=11 + Placebo N=11 N=20 N=8 + N=11 N=11 + N=10 + N=8 Dose 1 Dose 2 Dose 3 Mild Moderate Severe 1 Injection site pain, swelling, redness Pfizer Confidential 13

14 Any local reaction 1 within 7 days yrs 100% 80% 60% 40% * 20% 0% Placebo N= Placebo N=21 + N= Placebo N=11 N=17 N=10 + N=9 N=8 + N=11 N=10 + N=9 Dose 1 Dose 2 Dose 3 Mild Moderate Severe * One subject reported severe redness and swelling on Day 2 after Dose 2 this was an e-diary entry error (the true diameters were mild). 1 Injection site pain, swelling, redness Pfizer Confidential 14

15 Any systemic event 1 within 7 days yrs 100% 80% 60% 40% 20% ** * 0% Placebo N=22 + N= Placebo N= N=11 + Placebo N=11 N=20 N=8 + N=11 N=11 + N=10 + N=8 Dose 1 Dose 2 Dose 3 Mild Moderate Severe * One subject reported severe fever on Days 2&3 after Dose 1 this was an e-diary entry error (the subject actually had no reactions). ** One subject reported severe fever (39.2ºC) and headache (as well as moderate diarrhea and joint pain) on Day 2 after Dose 1; both headache and diarrhea were mild on Day 3 and then resolved. One subject reported severe fever (up to 39.3ºC) on Days 1&2 after Dose 2, accompanied by moderate headache and muscle pain. 1 Vomiting, diarrhea, headache, fatigue, new or worsening muscle or joint pain Pfizer Confidential 15

16 Any systemic event 1 within 7 days yrs 100% 80% 60% 40% 20% * ** 0% Placebo N= Placebo N=21 + N= Placebo N=11 N=17 N=10 + N=9 N=8 + N=11 N=10 + N=9 Dose 1 Dose 2 Dose 3 Mild Moderate Severe Grade 4 * One subject reported Grade 4 fever (41.1ºC) on Day 4 after Dose 1 this was an e-diary entry error (the subject actually had no fever or other reactions on that day). ** One subject reported severe joint pain on Day 4 after Dose 2. The investigator confirmed that this reaction was not vaccine related, but that the subject had broken his finger a month earlier and developed a soft tissue infection secondary to a local laceration. 1 Vomiting, diarrhea, headache, fatigue, new or worsening muscle or joint pain Pfizer Confidential 16

17 Any adverse event up to 28 days post-dose 3 100% 80% 60% 40% 20% yrs 0% Placebo N=22 + N= yrs 100% 80% 60% 40% 20% 0% Placebo N= Five subjects reported SAEs all considered unrelated + Pfizer Confidential 17

18 Safety summary All dose levels and both formulations were generally safe and well tolerated Majority of local reactogenicity reported was injection site pain and majority of systemic events reported were headache and fatigue Median duration of local reactions and systemic events was generally 1 to 2 days and 1 to 3 days, respectively Within dose levels: Tendency for more frequent local reactions in recipients of the toxoidalone formulations in both age cohorts Tendency for more frequent systemic events in recipients of the toxoid-alone formulations in the younger age cohort Adverse events more frequent amongst older age cohort No worsening of safety laboratory parameters in relation to vaccination Pfizer Confidential 18

19 Robust Anti-Toxin A Immune Response in Both Age Cohorts (Geometric Mean Concentrations, Evaluable Immunogenicity Population) Toxin A-Specific Neutralizing Antibody GMC (50- to 64-Year Age Cohort) Pfizer Confidential 19

20 Robust Anti-Toxin A Immune Response in Both Age Cohorts (Geometric Mean Concentrations, Evaluable Immunogenicity Population) Toxin A-Specific Neutralizing Antibody GMC (65- to 85-Year Age Cohort) Pfizer Confidential 20

21 Robust Anti-Toxin B Immune Response in Both Age Cohorts (Geometric Mean Concentrations, Evaluable Immunogenicity Population) Toxin B-Specific Neutralizing Antibody GMC (50- to 64-Year Age Cohort) Pfizer Confidential 21

22 Robust Anti-Toxin B Immune Response in Both Age Cohorts (Geometric Mean Concentrations, Evaluable Immunogenicity Population) Toxin B-Specific Neutralizing Antibody GMC (65- to 85-Year Age Cohort) Pfizer Confidential 22

23 Phase 1 Study Conclusions Pfizer s Clostridium difficile vaccine at 3 toxoid dose levels, administered at Months 0, 1, 6, with or without Alhydrogel is generally safe and well tolerated in healthy adults aged 50 to 85 years No clear dose response was observed, due to limited sample size and 95% confidence intervals often overlapping Toxin-neutralizing antibody titers increased with each dose Increased GMC s sustained up to at least 6 months postdose 3 The encouraging early immune response and favorable safety profile reported in this FIH study warrant further investigation of Pfizer s Clostridium difficile vaccine Pfizer Confidential 23