AAPS NBC 2016 IBD Symposium

Transcription

1 AAPS NBC 2016 IBD Symposium Steven W Martin, PhD Group,, Pfizer, Cambridge, MA

2 MAdCAM plays a central role in lymphocyte homing to the gut Adapted from Cheroutre and Madakamutil 2004

3 Anti-MAdCAM Mechanistic Rationale MAdCAM (mucosal addressin cell adhesion molecule) Predominantly expressed on high endothelial venules of organized intestinal lymphoid tissue Binds 4 7 integrin on lymphocytes Facilitates lymphocyte homing & extravasation expression at sites of GI inflammation PF-00547,659 Fully human IgG2 monoclonal antibody Binds with high affinity & specificity to MAdCAM Blocks MAdCAM/ 4 7 dependent lymphocyte recruitment to gut Designed to reduce inflammation caused by excessive lymphocyte infiltration in GI disease Underdevelopment for Ulcerative colitis and Crohn s Disease

4 Points of differentiation between PF , vedolizumab, Natalizumab, Etrolizumab and other emerging agents targeting T cell migration Aliment Pharmacol Ther 2014; 39:

5 PF Clinical Program Ulcerative Colitis A : Phase 1 FIH SAD/MAD in moderate to severe ulcerative colitis patients A : Phase 2 Dose Ranging Proof of Concept Study (Turandot) A : Phase 2 Open Label Extension Study (Turandot II) Crohn s Disease A : Phase 2 Dose Ranging Proof of Concept Study (Opera) A : Phase 2 Open Label Extension Study (Opera II) A : Phase 2 Cerebrospinal Fluid Study (Tosca) OLE study

6 Inclusion CriteriaStudy population Male or female (WONCBP) subjects aged 18 to 70 years inclusive Active UC as defined by a score of 6 on the Mayo score An endoscopic sub-score of 2 on the Mayo score Stable medication history including at least one of the below therapies Oral 5-ASA Oral steroids Azathioprine or 6-mercaptopurine (6-MP) Exclusion Criteria Subjects with UC, which is confined to a proctitis Subjects receiving the following therapy Within 3 months: Biological, Methotrexate, Mycophenolate, Cyclosporine Within 1 month prior: Intravenous steroid Within 1 week prior: Any therapy delivered via the rectal route except bowel preparation immediately prior to the sigmoidoscopy Subjects with history of steroid dependence Long term steroid usage

7 Patient Criteria FIH Study (A ) Moderate to Severe UC Patients (Mayo Score 6) Efficacy Evaluation Single Dose Total Mayo Score, Wk 0, 4. Multiple Dose Total Mayo Score, Wk 0, 4 and 12. PD Evaluations Soluble hscrp, Fecal Calprotectin, α4β7 cells Single Dose Groups Dose (n=4 active, 1 Placebo) 0.03 mg/kg or placebo iv 0.1 mg/kg or placebo iv 0.3 mg/kg or placebo iv 1.0 mg/kg or placebo iv 3.0 mg/kg or placebo sc 10 mg/kg or placebo iv Multiple Dose Groups Dose week 0, 4 & 8. (n= 4 active, 1 Placebo) 0.1 mg/kg or placebo iv 0.3 mg/kg or placebo iv 3.0 mg/kg or placebo iv (n= 20 active, 10 Placebo) 0.3 mg/kg or placebo sc 1 mg/kg or placebo sc

8 Serum concentration PF (ng/ml) Serum concentration PF (ng/ml) Pharmacokinetics of PF Intravenous 10 mg/kg IV 3mg/kg IV 1 mg/kg IV 0.3 mg/kg IV 0.1 mg/kg IV 0.03 mg/kg IV Mean (SD) serum concentration time profiles of PF Subcutaneous following single dose subcutaneous administration of 0.1 to 3 mg/kg 1 mg/kg SC 3 mg/kg SC 0.1 mg/kg SC Time (Weeks) PF Peripheral Compartment Time (Weeks) Target Mediated Disposition Model Assuming Pseudo Steady State Binding IV Dose V2 R 0 Q MAdCAM synthesis RL PF Subcutaneous Absorption Site F SC Dose Ka PF Central Compartment V1 CLD free MAdCAM Central Compartment CLL free V1 K D Complex Central Compartment V1 CLDL

9 d. red. 24 Antibody conc. (n Target Mediated Disposition Model Visual Predictive Check TIME (w eeks) 90% Pred. Median Pred. Data Antibody conc. (ng TIME (w eeks) 90% Pred. Median Pred. Data Phase 1 FIH; PK of PF Antibody conc. (ng d. red. 24 Antibody conc. (ng/ml) mg/kg SC MD TIME (w eeks) 90% Pred. Median Pred. Data Antibody conc. (ng/ml) mg/kg SC MD Antibody conc. (ng/ml) mg/kg IV MD TIME (w eeks) 90% Pred. Median Pred. Data TIME (w eeks) 90% Pred. Median Pred. Data Antibody conc. (ng/ml) d. red. g/ml) mg/kg 0.1 mg/kg IV MDIV MD TIME (wtime eeks) (w eeks) 90% Pred. 90% Pred. Median Median Pred. Pred. Data Data Antibody conc. (ng/ml) Antibody conc. (ng/ml) mg/kg 0.3 mg/kg IV MDIV MD Antibody conc. (ng/ml) mg/kg IV MD TIME (wtime eeks) (w eeks) 90% Pred. 90% Pred. Median Median Pred. Pred. Data Data 3.0 mg/kg 3.0 mg/kg IV MDIV MD 0.3 mg/kg 0.3 mg/kg SC MD SC MD g/ml) 0000 g/ml) 0000 TIME (w eeks) 1 mg/kg SC MD g/ml) 90% Pred. Median Pred. Data

10 PK Model Predicts Target Engagement and MAdCAM Suppression 0.1 mg/kg 0.3 mg/kg 3.0 mg/kg Antigen (nmole) Antigen (nmole) TIME (w eeks) 0.1 mg/kg SC TIME (w eeks) Antigen (nmole) Antigen (nmole) TIME (w eeks) 0.3 mg/kg SC TIME (w eeks) Antigen (nmole) TIME (w eeks) RunNA.R Wed Aug 13 13:51: Solid Black Line = Median abundance Grey Area = 80% Prediction interval

11 FIH Study: Understanding Treatment Effect in UC FIH Efficacy data Total Mayo score responder and remission rates Drug effect Clinical Response evident by week 4, but no clear dose-response Drug effect Clinical Remission evident by week 4, but no clear dose-response Clinical (total score) response p= p= Clinical (total score) remission Placebo PF-00547,659 (all doses) p= p= Week 4 Week 12 Week 4 Week Endoscopic response p= p= Endoscopic remission

12 40 40 (all doses) 32 p= FIH Study: Understanding Treatment Effect in UC p= FIH Efficacy data (Endoscopic score; responder and remission rates) Drug effect Endoscopic Response evident by week 4, but no clear dose-response Drug Week effect 4 Endoscopic Week Remission 12 evident by week Week 4, but no clear Week dose-response Endoscopic response p= p= Endoscopic remission p=0.074 p= Week 4 Week 12 Week 4 Week 12 0

13 FIH Study: Understanding Dose Response in UC Serum hscrp WK 4 - Minor decreases at in all groups WK 12 - Placebo increased (7%) Possible dose-response L 39% & H 62% decrease. Fecal Calprotectin Minor drug effect evident by week 4, potential dose-response with ED50 << 1 mg/kg Faecal Calprotectin WK Ratio change Placebo (n=10) Low (n=6) High (n=15) Baseline Placebo Low Doses (<0.3mg/kg) High Doses (>1mg/kg) 12 Placebo P=0.369 P=0.043 Unable to adequately characterize treatment effect due to high variability

14 FIH Study: Understanding Dose Response in UC Dose-Response of Daily Diary Data Blood in Stools Diary Stool Count Low ED50 ( mg/kg) Low ED50 not adequately quantified. Treatment Effect but no dose response

15 FIH Study: Understanding Dose Response in UC PD Effects on α4β7 Expression T Cells in Blood. CD4+ A4B7+ve T cells (Percent change from baseline) Muliple dose cohorts + single dose cohorts up to day 28. CD4+ve A4B7 cells Dose 3 mg/kg IV Dose 1 mg/kg IV Dose 0.3 mg/kg IV Dose 0.1 mg/kg IV Placebo Group Time (days)

16 Summary of FIH Trial in UC patients Limitations of small N Most cohorts 5 subjects ( 4 active, 1 placebo) PF : Performs better than placebo in clinical endpoints Total Mayo score Endoscopic sub score Rectal bleeding Demonstrates an effect on fecal calprotectin, and CRP Was well tolerated & AE Profile similar to placebo No difference between IV and SC

17 FIH Study What do we know about the dose response Theoretical ligand saturation curve ED50 ~ 7.5 mg, >97% suppression at 22.5 mg Efficacy data Mayo score Drug effect evident by week 4, but no clear dose-response Endoscopic sub-score Drug effect evident by week 4, but no clear dose-response Biomarker data Fecal calprotectin Drug effect evident by week 4, potential dose-response with ED50 << 1 mg/kg Daily diary data Stool count: evident drug effect, but no apparent dose response Blood in stools: Emax model reasonable for severity, ED mg/kg (95% CI 0.036, mg/kg) Where dose-response can be determined, mean ED50 is low mg/kg 3 35 mg AND effects are seen early

18 Phase 2 Dose Selection Considerations Target Mediated Disposition Model Predicted MAdCAM Suppression MAdCAM Suppression* (0-12wks) % Suppression % Pred Median Pred Dose (mg) Low Mid High % 56.6% 78.8% % 83.9% 93.3% % 92.7% 96.4% % 93.9% 96.9% % 95.5% 97.5% % 98.7% 99.2% % 99.4% 99.6% % 99.6% 99.8% *Suppression = 100*(1-(AUC MAdCAM,T /AUC MAdCAM,BL )) Dose (mg)

19 Phase 2 Study Design Methodology for Simulations Objective: Maximize probability of selecting a phase 3 dose by determining optimal doses and sample size given the uncertainty in underlying dose-response 1. Construct range of scenarios 4, 5 or 6 arms, including placebo Doses ranging from 7.5 to 225 mg Sample size ranging from n=35, 50, 60, 70, infinity per arm 2. Define dose-response attributes and associated variability (random sampling) Emax 45% difference from placebo effect Placebo assumed at 15% ED50 range from 0.75 to 75 mg 3. Establish performance metrics for comparison across scenarios The ability of 225 mg dose to achieve criteria (based on modeled response) The ability to correctly determine the lowest dose that meets criteria Depends on model convergence, attainment of efficacy and accurate determination of the dose 4. Conduct 1000 trial simulations for each scenario and summarize results Summarized as the probability of that design to correctly determine lowest dose upon 1000 simulations

20 Phase 2 Dose selection Simulations Remission Rate ED50=0.75 ED50=7.5 ED50=15 ED50=30 ED50=45 ED50=60 ED50= Dose Dependent on ED50, the lowest dose to meet criteria could be: 3.2, 32, 64, 128, 193, 257 or 321 mg

21 Phase 2 Dose Selection Range of Scenarios Case Number of treatment Groups Dose Groups Used for Simulation (Doses given in mg) (Benchmark)

22 Phase 2 Dose-Selection PK Model Predicted MAdCAM Suppression at Selected Doses 63.4% Average Suppression 93.4% Average Suppression 98.6% Average Suppression 99.6% Average Suppression

23 A Phase 2 UC Study Design Study designed as a dose-response study with E max model (four-parameter) planned to be the primary analysis method. A lower dose (7.5 mg Q4W) was included based on M&S of the available efficacy and BM data from the FIH Phase 1b study in UC. Week 0 Dosing Week 4 Dosing Week 8 Dosing 6 weeks Screening Dose 1 (7.5 mg SC, n = 60) Dose 2 (22.5 mg SC, n = 60) Dose 3 (75 mg SC, n = 60) Dose 4 (225 mg SC, n = 60) Placebo (n = 60) F/U 24 months OR OL Extension Study 12 Weeks

24 A Phase 2 UC Study Primary endpoint Proportion of subjects in Clinical Remission (0 or 1) at Week 12 Total Mayo score of 2 with no individual subscore (SC) >1 and rectal bleed SC of 0 or 1. Key secondary endpoints: Proportion of subjects with a Clinical Response (0 or 1) at Week 12 Decrease from baseline of at least 3 points in TM score with at least a 30% change, accompanied by at least 1 pt decrease or absolute score of 0 or 1 in rectal bleeding SC. Proportion of subjects with Mucosal Healing (0 or 1) at Week 12 Absolute Mayo SC for endoscopy of 0 or 1. Proportion of subjects with decrease from baseline in Partial Mayo score of 2 with no individual SC >1 at Wks 4, 8, 12. CFB in Total Mayo scores and individual subscores at 4, 8 and 12 wks CFB in fecal calprotectin and hscrp Safety and PK

25 Pop PK Model predicted the observed exposure in UC Patients

26 Remission Rate Turandot A (Phase 2) Study Efficacy: Most Dose Arms Had Significant Clinical Remission at Week 12 vs placebo 25.0% 20.0% 15.0% 11.3%* 16.7%* 15.5%* 35.0% 30.0% 25.0% 20.0% Naïve Experienced Anti-TNFalpha treated Populations 14.1%* 16.7% 25.8% 18.3%* 23.3% 12.9% 10.0% 15.0% 5.0% 2.7% 5.7% 10.0% 5.5% 6.5% 5.0% 7.3% 9.8% 9.8% 10.0% 2.5% 0.0% 0.0% 0.0% 0 mg 7.5 mg 22.5 mg 75 mg 225 mg 0 mg mg mg mg mg mg 75 mg 75 mg 225 mg 225 mg Dose Dose mitt Population

27 Clinical Response and Mucosal Healing Rates at Week % 50.0% Mucosal Healing Response 54.2% 50.0% 45.1% 40.0% 38.0% 30.0% 28.8% 27.8% 25.4% 20.0% 15.5% 14.3% 10.0% 8.2% 0.0% 0 mg 7.5 mg 22.5 mg 75 mg 225 mg Central Read (mitt) Dose

28 Analysis Results of Placebo Corrected Clinical Remission Rate, Clinical Response Rate and Mucosal Healing Rate Based on Total Mayo score at Week 12

29 Exposure-Response: E max Model Predicted Clinical Remission at week 12 Base Model (M0) Estimate (%RSE) EC50 * Emax E Model predicted median and the 90% CI. Observed mean and the 90% CI (red symbols and vertical lines) Distribution of C trough values at various doses examined in the Phase 2 study.

30 Exposure-Response: E max Model Predicted Mucosal Healing and Clinical Response Rates at Week 12 Mucosal Healing # Clinical Response MH Base Model (M0) Estimate (%RSE) EC50 * Emax E Clin Response Base Model (M0) Estimate (%RSE) EC50* Emax E # Central reading Model predicted 90% confidence intervals (CI)

31 Higher Efficacy Across All Endpoints in Anti-TNF naive & lower Baseline Endoscopic Score

32 Conclusions For ER analysis, it was assumed that the lower response at 225 mg dose of PF was due to inherent variability in binary data and thus included in the exposure-response Emax model. The E max models for C trough linked to logit transformation of probability of the binary response data well described relationships between C trough and each efficacy endpoint. Lower baseline endoscopic scores and anti-tnf naïve patients were associated with higher clinical efficacy across all endpoints. Clinical trial simulations from the ER model suggested that the clinical efficacy against placebo reached plateau between around 25 mg to 75 mg for most of the endpoints.

33 Acknowledgements Alaa Ahmed PhD, Clin Pharm, PTx, Cambridge, MA. Anasuya Hazra PhD, Clin Pharm, Global Product Develop, Collegeville PA. Satoshi Shoji PhD, Global, Tokyo, Japan Yoshiro Tomono PhD, Global, Tokyo, Japan Arnab Mukherjee PhD, Clin Pharm, Global Product Develop, Groton, CT Rujia Xie PhD, Global, Global Product Develop, China. Anne Heatherington, PhD, Clin Pharm, PTx, Cambridge, MA. Robert Clare, Project lead, Clinical R&D, PTx, Collegeville PA Fabio Cataldi MD, Clinician, Clinical R&D, PTx, Cambridge PA

34 Data Pharmacokinetics of PF in UC Population PK based on 363 moderate to sever UC Patients enrolled in 3 clinical trials. Phase 1/2a (A ) single or multiple (MD) intravenous (IV) or subcutaneous (SC) dosing every 4 weeks up to 8 weeks with doses ranging from 0.03 to 10 mg/kg. Phase 2 (A ;) SC doses of 7.5, 22.5, 75 and 225 mg PF every 4 weeks up to week 12 (Dosing at weeks 0, 4, 8). A Phase 2, (A ) for subjects completed 12-week treatment in A with response, two dose levels of 75 mg and 225 mg, SC, MD, dosing every 4 weeks, a 19 month treatment period. Analysis Method NONMEM, version 7.2 and PsN v Analyses were conducted using first order conditional estimation (FOCE) with interaction (FOCEI). 34

35 Pharmacokinetics of PF in Results UC Patients Typical patient (73 kg, Albumin = 3.9 g/dl, CRP = 0.52 mg/dl) CL (linear) = 8.43 ml/h Vc and Vperipheral = 3.34 L and 2.2 L respectively. SC bioavailability 86.6% Covariates Identified Bwt on CL and Vc. 10% increase or decrease in Bwt = increase or decrease in CL of 3.92% or 4.15%, respectively; 10% increase or decrease in Bwt = increase or decrease in V1 was 6.89%. Albumin on CL 10% increase or 10% decrease from median Albumin of 3.9 g/dl, change in CL was 8.19% lower or 9.96% higher, respectively. CRP on CL 10% increase or 10% decrease in baseline CRP from 0.52 mg/dl, CL increased or decreased by 0.83%.