EMA EFPIA workshop Break-out session no. 3 Case Study Title: - PowerPoint PPT Presentation

EMA EFPIA workshop Break-out session no. 3 Case Study Title: Revatio in Paediatric Pulmonary Arterial Hypertension (PAH), an Orphan Indication Lutz Harnisch, MD Pfizer, UK

The Sildenafil Case � Orphan Indication Pulmonary Arterial Hypertension (PAH) ◦ Progressive life-threatening, prevalence 2-20:1M � Aim: Assessment of Sildenafil efficacy and dose selection in children with PAH ◦ Adult PAH program ran in parallel to single pediatric pivotal trial ◦ Labelled adult oral dose regimen 20 mg TID � Pediatric trial ◦ Dose ranging (3 wt based treatment cohorts), plc controlled, in PAH patients, 1-17 years old ◦ Primary PD EP (VO 2peak at week 16) only available in 7 -17 years No widely accepted clinical effect size (~10-15% improvement on CFB), and � different clinical EP (6MWD) compared to adults ◦ Secondary PD EP in 1 -17 years (hemodynamics: PVRI) Clinical relevance under debate, but allows scaling of PD from adults to children � ◦ Population PK scales adult to pediatric exposure from 1-17 years 2

Factors Predicting Treatment Response ... ADME Disease (Progression) / Safety Biomarker Biosphere Dose PK Early Cl EP Late Cl EP Absorption Expression Formulation Expression Expression RO Onset Onset Distribution GT/PH Compliance Adults Distribution Heterogeneity Heterogeneity Metabolism to target Pathway Time-course Time-course Excretion Disease association Translatability Biomarker Biosphere Dose PK Early Cl EP Late Cl EP Absorption Expression Formulation Expression Expression Children RO Onset Onset Distribution GT/PH Compliance Distribution Heterogeneity Heterogeneity Metabolism to target Pathway Time-course Time-course Excretion Disease association 3

... Translated to a Pediatric PAH Population ADME Disease (Progression) / Safety Biomarker Biosphere Dose PK Early Cl EP Late Cl EP Absorption Expression Formulation Expression Expression HD EP predicts 6MWD EP predicts RO Onset Onset Distribution clinical EP (6MWD) GT/PH Compliance Adults M&M EP Distribution Heterogeneity Heterogeneity Metabolism Allometric to target Pathway Time-course Translate Time-course scaling to Excretion Translate Disease association 6MWD define dose HD EP (CPX) in ranging in from adults to children adults to Translatability VO 2peak children (CPX) in Biomarker children Biosphere Dose PK Early Cl EP Late Cl EP Absorption Expression Formulation Expression Expression Children RO Onset Onset Distribution GT/PH Compliance Derive evidence for clinical efficacy in target population Distribution Heterogeneity Heterogeneity Metabolism to target Pathway Time-course Time-course Excretion Disease association 4

M&S Assumptions � Minor assumptions on PK, since measured in pediatric population ◦ fewer patients at lower weight/age range ◦ maturation model on CYP3A4 and IV data in neonates to justify modelled CL intercept at low weight/age � At design stage allometric PK/dose scaling used to project doses predicted to have similar exposure/PDE5 inhibition as 3 tested dose levels in adults ◦ Population PK model of integrated adult/pediatric data discarded the “allometric” relationship Assumption of equal exposure across weight range violated � → weight adjusted dose group comparison inconsistent in statistical analysis � � PD endpoint translation from adult to children ◦ Bridging “hemodynamic” biomarker connects adults and children in response measure ◦ But similarity of HD treatment response between adults and children not undisputed 5

Allometric Scaling Assumption Challenged Exposure distribution across dose and weight groups in pediatric trial Adult Children Cav,ss (ng/mL) 6

Primary EP Analysis for VO 2peak Treatment Difference in Percentage Change from Baseline for VO 2peak at Week 16 VPC of Population PKPD Model Population PKPD Parameter Estimates Parameter Mean CV (%) SD (%) 95%CI Baseline-VO 2peak , 17.6 2.4 23.8 16.8 18.4 mL/kg/min E max , % 8.8 24.3 4.6 12.9 EC 50 , ng/mL 31.1 19.5 19.2 43 HILL 8 Fixed Res-error, % 11.9 EC 90 , ng/mL 40.9 19.5 26.2 56.6 7

Sildenafil Data from Children are Consistent with Adult Data and the FDA Model Univariate Regression of % Δ 6MWD FDA based prediction interval + vs. % Δ PVRI for Pooled Analysis Sildenafil adult and children data 30 % change from baseline in 20 • exercise capacity • Change 6MWD (%) • • 10 • • • • • 0 • -10 Value CV 95%CI Slope -0.148 14.2 -0.189 -0.107 -20 Intercept 7.87 10.0 6.33 9.41 -60 -40 -20 0 20 40 60 Change PVRI (%) % Change from baseline PVRI n=30/bin (dark grey) n=24/bin (light grey) Source: FDA-CDER-CDRAC, 29 th July 2010, Satjit Brar, Pharm.D., Ph.D., Division of Pharmacometrics, 8 "Use of Change in PVRI for Dosing Recommendations of Adult-Approved Drugs in Pediatric PAH Patients"

Target %Change PVRI Effect Size FDA: Δ %6MWD ‐ Δ %PVRI Relationship Minimally Important Effect Target Δ % change in Value CV 95%CI Δ % PVRI Slope -0.436 24.2 -0.64 -0.23 change in Intercept Intcpt -2.23 116.6 -7.33 2.87 CPX no yes 5 17 11 10 28 23 Source: FDA-CDER-CDRAC, 29 th July 2010, Satjit Brar, Pharm.D., Ph.D., Division of Pharmacometrics, 15 40 34 9 "Use of Change in PVRI for Dosing Recommendations of Adult-Approved Drugs in Pediatric PAH Patients" 20 51 46

Sildenafil Data Appear Consistent with ΔΔ - Model and Achieve Target PVRI Response Adults Pediatrics Placebo corrected %CFB Exercise Capacity 20 10 0 -60 -50 -40 -30 -20 -10 0 10 -10 20mg (A1481140) 40mg 80mg -20 80mg (A1481141) Placebo corrected %CFB PVRI Closed symbols: IPAH/SurgRep subpopulation Open symbols: all (+CTD) adult patients 10

Assumption & Modelling vs “ Missing ” Evidence ADME Disease (Progression) / Safety Biomarker Biosphere Dose PK Early Cl EP Late Cl EP Absorption Expression Formulation Expression Expression 6MWD EP predicts RO HD EP predicts Onset Onset Distribution GT/PH Compliance Adults M&M EP clinical EP (6MWD) Distribution Heterogeneity Heterogeneity Metabolism Allometric to target Pathway Time-course Translate Time-course scaling to Excretion Translate Disease association 6MWD define dose HD EP (CPX) in ranging in from adults to children adults to Translatability VO 2peak children (CPX) in Biomarker children Biosphere Dose PK Early Cl EP Late Cl EP Absorption Expression Formulation Expression Expression HD EP predicts Children RO Onset Onset Distribution clinical EP GT/PH Compliance Dose/exposure predicts HD EP response Distribution Heterogeneity Heterogeneity (VO 2peak ) Metabolism to target Pathway Time-course Time-course Excretion ... also in children not able to exercise Disease association 11

Assumption Impact & Consequence Assumption Probability to Consequence Potential M&S impact violate (uncertainty) Based on biological/ Needs to adjust for Generally depends on density of pharmacological/clinical environmental condition available data prior understanding AUC ped = AUC adult likely major ... allows regrouping (assuming allometric scaling) (at design stage) (equal exposure ... PKPD ‐ model to define assumption in stats EC90 analysis) AUC ped ~ AUC adult unlikely moderate ... quantifies confounding (post readout) factors CPX ped ~ CPX adult moderate moderate ... allows bridging only in (clinic. meaningful effect size) conjunction with HDs (CPX~HD) ped = (CPX~HD) adult unlikely major ... qualifies bridging of CPX~HD EPs between populations DP ped = Dp adults unlikely moderate ... justifies design in SP HD ‐ ER ped = HD ‐ ER adults unlikely major ... justifies dose in children HD ‐ ER <7y/non ‐ able = HD ‐ ER >7y/able unlikely major ... justifies dose in younger/non ‐ able children HD ‐ ER strata = HD ‐ ER major ‐ group moderate moderate ... quantifies dose for strata CPX ‐ ER <7y/non ‐ able = CPX ‐ ER >7y/able very likely major No existing data, → future research 12

Conclusions � Model based approach addressed efficacy evaluation of sildenafil in pediatric PAH ◦ including dose selection and evaluation of sub-group performance (backups) � Labelled dose is model based ◦ but input at design stage could have strengthen analyses, especially could have accounted a priori against violating assumptions in the design and primary analyses � M&S could alleviate the risk to violate some assumptions on translational EPs, but not all ◦ might lead to further investigations (development of alternative EPs in very young patients) ◦ led to discussion on label restrictions 13

BACKUPS 14

Cardiopulmonary Exercise Testing in PAH Hemodynamic measures (HD) CPET Measures 6MWD/TTCW - Approved phase II/III EP measures 15

PK Prior and Exploratory Dosing Regimen Predicted Exposure Measures of Sildenafil in Paediatrics across weight groups at each dose level | Applied Dosing Regimen Body Weight (kg) Dose Dose Dose Low Medium High ≥ 8 - 20 10 mg 20 mg >20 - 45 10 mg 20 mg 40 mg >45 10 mg 40 mg 80 mg 16