Preclinical Assessment of JTX-2011, An Agonist Antibody Targeting ICOS, Supports Evaluation In ICONIC Clinical Trial

Transcription

1 Preclinical Assessment of JTX-211, An Agonist Antibody Targeting ICOS, Supports Evaluation In ICONIC Clinical Trial Jennifer Michaelson, Ph.D. AACR Annual Meeting April 2, 217 Major Symposium Emerging Targets in Immunotherapy

2 Translational Science Platform Comprehensive Interrogation of the TME to Develop a Sustainable Innovative Pipeline Patient enrichment strategies using predictive biomarkers Comprehensive interrogation of the TME Sustainable immunotherapy pipeline Identifying optimal immune cell targets and developing new immunotherapies 2 217

3 Many Potential Targets: Why Choose ICOS? Jounce Approach Adapted from Mellman et al. Nature 48, (211) Data from Founders labs demonstrated clinical correlate and outcome data that supported activation of ICOS Subsequent laboratory evidence in animal tumor reduction studies ICOS ICOS 3 Jounce Therapeutics 217

4 Many Potential Targets: Why Choose ICOS? Human clinical and mouse preclinical data support activating ICOS receptor for anti-tumor benefit Impaired Tumor Rejection In ICOS / and ICOSL / Mice Treated with Anti CTLA-4 Therapy Chen et al, PNAS (29);; Carthon et al, Clin Can Res (21);; Ng Tang et al, Canc Immunol Res (213) Fu et al. Cancer Res 211;;71: Jounce Therapeutics 217

5 JTX-211: ICOS Agonist Antibody JTX-211: Key Features Specificity for ICOS Species cross-reactive Agonist activity Humanized rodent antibody higg1 Fc backbone 5 Jounce Therapeutics 217

6 JTX-211 Dual Mechanism Shifts Balance of T Cells Towards Anti-Tumor Activity APC 1 st signal JTX-211 NK cell JTX-211 is designed to TCR ICOS Non-Primed T effector cell TCR ICOS ICOS Primed T effector cell IFN-γ IFN-γ X T regulatory cell Stimulate T effector cells in tumor Selectively reduce T regulatory cells in tumor Activation of T eff Reduction of T regs 6 Jounce Therapeutics 217

7 JTX-211 Stimulates Primed Human T Cells No Indiscriminate Activation of T cells Activation of primed CD4+ T effector cells No activation of unprimed CD4+ T effector cells 8 % Proliferation CD3 +CD3 % Divided Cells U n s tim u la te d + c o n tr o l a n tib o d y - c o n tr o l a n tib o d y JTX-211 (nm) No Antibody Anti-CD28 Super JTX-211 agonist anti-cd28 Control Antibody CD3 in all wells except unstimulated 7 Jounce Therapeutics 217

8 JTX-211 Induces Signaling Through AKT Pathway JTX-211 ICOS p85 p11 PI(3)K AKT Control Antibody Control Antibody + Cross-Linker JTX-211 JTX Cross-Linker ICOS antibody re-capitulates signaling activity of ICOS ligand Induces pakt signal in CD4+ T cells when cross-linked 8 Jounce Therapeutics 217

9 JTX-211 Dual Mechanism Shifts Balance of T Cells Towards Anti-Tumor Activity APC 1 st signal JTX-211 NK cell JTX-211 is designed to TCR ICOS Non-Primed T effector cell TCR ICOS ICOS Primed T effector cell IFN-γ IFN-γ X T regulatory cell Stimulate T effector cells in tumor Selectively reduce T regulatory cells in tumor Activation of T eff Reduction of T regs 9 Jounce Therapeutics 217

10 Selective Reduction in Tumor but Not Peripheral T Regulatory Cells Mouse JTX-211 selectively reduces tumor T regulatory cells in vivo Mouse JTX-211 does not reduce spleen T regulatory cells in vivo Implant Tumor Treatment (.2mg/kg) Implant Tumor Treatment (.2mg/kg) TIL analysis Day: Day: Spleen Analysis % S u b s e t in C D C D 4 T e ff C D 4 T re g C D 8 % S u b s e t in C D C D 4 T e ff C D 4 T re g C D 8 Control Antibody m Ig G 2 a Parent mjtx-211 JTX A 1 -m G 2 a J T X m G 2 a Control Antibody m Ig G 2 a Parent mjtx-211 JTX A 1 -m G 2 a Reduction in tumor T regulatory but not tumor T effector cells J T X m G 2 a No change in T cell subsets in spleen, lymph nodes or periphery 1 Jounce Therapeutics 217

11 ICOS Expression is Highest on Mouse and Human Intratumoral Tregs Flow cytometry Multiplexed IF 11 Jounce Therapeutics 217 DO NOT POST

12 Selective Reduction of Tregs vs Teffs in vitro % Change in population nm CD4+ T effector cells CD4+ T regulatory cells ICOS antibody selectively depletes Tregs from IL-2 activated PMBC Under these in vitro activation conditions, Tregs and Teffs express similar levels of ICOS 12 Jounce Therapeutics 217

13 Single Agent Development of JTX-211 Supported by Long-Lasting Response in Preclinical Tumor Models Control ICOS Antibody Animals cured of tumors are immune to tumor re-challenge Tumor volume (mm 3 ) / / Days post-inoculation of tumor cells T u m o r v o lu m e (m m 3 ) 1 5 N o p rio r tre a tm e n t 1 5 A n im a ls p re v io u s ly c u re d b y a n ti-ic O S D a y s a fte r tu m o r r e -c h a lle n g e Sa1/N Tumors Tumor free / animals treated 13 Jounce Therapeutics 217

14 Fc Effector Function is Required for Optimal Anti-Tumor Activity Loss of Activity with Fc Deficient Version of Antibody Control ICOS Antibody Fc-Deficient ICOS Antibody 2 2 1/1 6/1 2 1/1 Tumor volume (mm 3 ) Sa1/N Tumors Tumor free / animals treated 14 Jounce Therapeutics 217

15 Combination Development of JTX-211 with Anti-PD-1 Supported by Enhanced Anti-tumor Activity in Preclinical Models Control antibody Anti-PD /1 6/1 1 5 Tumor volume (mm 3 ) D a y s P o s t-in o c u la tio n D a y s P o s t-in o c u la tio n ICOS Antibody ICOS Antibody + Anti-PD-1 2 1/1 8/1 CT26 Tumors Tumor free / animals treated D a y s P o s t-in o c u la tio n D a y s P o s t-in o c u la tio n 15 Jounce Therapeutics 217

16 Preclinical Safety Features of JTX-211 JTX-211-induced T Cell Activation Requires Initial T Cell Priming Preclinical Toxicity Studies Predict Safety Margin 8 % Proliferation CD3 +CD3 NOAEL = 5 mg/kg;; highest dose tested in cynomolgus monkey IND-enabling GLP toxicology study U n s tim u la te d + control antibody - control antibody JTX-211 (nm).5.3 Activity of ICOS Antibody is Tumor-centric: No Depletion of Tregs in the Periphery Cytokine Storm Not Predicted from in vitro and in vivo Studies % S u b s e t in C D Tumor C D 4 T e ff C D 4 T re g C D 8 % S u b s e t in C D Spleen C D 4 T e ff C D 4 T re g C D 8 No cytokine storm in GLP toxicology studies No cytokine induction by JTX-211 alone or in combination with Opdivo in human whole blood assays Control Antibody m Ig G 2 a 3 7 A 1 -m G 2 a 16 Jounce Therapeutics 217 Parent JTX-211 J T X m G 2 a mjtx-211 Control Antibody m Ig G 2 a Parent mjtx-211 JTX A 1 -m G 2 a J T X m G 2 a

17 Pharmacodynamic Biomarker: Target Engagement in Mouse Efficacy in Syngeneic Mouse Tumor Model Correlates with Duration of ICOS Target Engagement 1 5 Average Tumor Growth Curves 2 ICOS Engagement on Peripheral Blood CD4 T Cells 1 Induction of JTXP T u m o r V o lu m e (m m 3 ) D a y s P o s t-in o c u la tio n o f T u m o r C e lls * % R e c e p to r A v a ilb a le T im e p o s t-d o s e (H o u r s ) J T X P M F I T im e p o s t-d o s e (H o u r s ) Is o ty p e 2.5 m g /k g.2 5 m g /k g. 5 m g /k g 2.5 m g /k g.2 5 m g /k g. 5 m g /k g Is o ty p e 2.5 m g /k g.2 5 m g /k g. 5 m g /k g * s ig n ific a n t b y o n e -w a y A N O V A.5mg/kg.25mg/kg 2.5mg/kg Tumor Free Mice 1/1 5/1 5/1 17 Jounce Therapeutics 217

18 Preclinical Pharmacokinetics and Pharmacodynamics PK and PD in Cynomolgus Monkey Preclinical Studies Pharmacokinetics: T1/2 = 5-12 days in ADA-negative monkeys Pharmacodynamic readouts Target engagement: ICOS is fully engaged for the duration of the dosing interval at all doses JTXP induction: JTXP is induced on monkey cells in peripheral blood % R e c e p to r A v a ila b le ICOS Engagement on Peripheral Blood CD4 T Cells D a y 1 P r e -d o s e D a y 3 D a y 8 V e h ic le P r e -d o s e 5 m g /k g D a y 1 J T X P (fo ld -c h a n g e ) Induction of JTXP D a y 1 D a y 3 D a y 8 P r e -d o s e P r e -d o s e V e h ic le 5 m g /k g D a y 1.5 m g /k g 7 5 m g /k g Non-GLP tox study dosed up to 75 mg/kg with no toxicity observed 18 Jounce Therapeutics 217

19 Preclinical QSP Modeling of JTX-211 Predictions for PK and Target Engagement in First-in-Human Study highest dose starting dose starting dose highest dose 19 Jounce Therapeutics 217

20 Patient Selection Strategy Supported by Mouse Models Better Single-Agent Efficacy in Tumors Expressing Higher Levels of Intra-Tumoral ICOS T B16/SIY Tumor ICOS IHC Score Single Agent Efficacy Combination Efficacy (+ anti-pd-1) Sa1/N ND 2+ B16-SIY LLC1 MC * CT EMT6 1+ +/++ +/- LLC indicates 61-1% tumor regression +++ indicates 41-6% tumor regression ++ indicates 21-4% tumor regression + indicates 1-2% tumor regression - indicates no tumor regressions *Intra-tumoral levels of ICOS+ T cells increases post PD-1 treatment 2 Jounce Therapeutics 217

21 Indication Selection & Patient Enrichment ICOS Immunohistochemistry (IHC) 1 ICOS protein levels vary across indications 2 ICOS protein levels within high ICOS indications vary across individual patients 1 None (n=94) % Tumors 5 Renal Breast Bladder Ovarian Prostate Stomach Colon Melanoma TNBC Lung HNSCC (n=24) None () Low (1+) Medium (2+) High (3+) 21 Jounce Therapeutics 217

22 Integrated Approach to Understanding ICOS in the Context of Immune Oncology Landscape Collaborations with premier Institutions 1s of human tumors interrogated Integrated TCGA and Internal Data Analysis Patient enrichment for our clinical trials 22 Jounce Therapeutics 217

23 Translational Science Platform Informs Biomarker Strategy Example from NSCLC ICOS expression levels across subtypes of NSCLC tumors 23 Jounce Therapeutics 217 ICOS levels are not associated with smoker status DO NOT POST A subset of PD- L1 low tumors have high levels of ICOS expression

24 Biomarker-Driven Strategy for Patient Enrichment Potential for Establishing Complementary and/or Companion Diagnostics Biomarker-Driven Enrichment Strategy Patient Enrollment Study Enrollment All Tumors Indication Selection Patient Enrichment 24 Jounce Therapeutics 217

25 ICONIC: Adaptive, Biomarker-Driven Clinical Study Phase 1/2 Preliminary Efficacy Proof-of-Concept Phase 1 Safety, PK and PD Phase 2 Preliminary Efficacy All-comers, no enrichment for ICOS expression Dose escalate to anticipated clinically effective dose Enriched for patients with high ICOS expression A Single Agent Dose Escalation C NSCLC HNSCC PK/PD Expansions Single Agent Any solid tumor type New indications based on emerging science* B Combo with nivolumab Dose Escalation D NSCLC HNSCC PK/PD Expansions Combo with Nivolumab TNBC Melanoma Gastric New indications based on emerging science* Poster: CT35 * Additional indications, including niche indications, identified through Jounce Translational Science Platform 25 Jounce Therapeutics 217

26 JTX-211: Agonist Monoclonal Antibody that Targets ICOS ICOS: T cell Surface Protein Receptor with Strong Target Rationale Member of family of immune modulators that includes PD-1 and CTLA-4 Potential importance of ICOS supported by key clinical observations Pharmacological activity is focused in the tumor JTX-211: Agonist Antibody Targeting ICOS Significant anti-tumor activity seen in preclinical studies Preclinical data supports use as both a single agent and in combination Safety, PK, and pharmacodynamic features in the monkey inform human FIH study Potential predictive biomarkers identified for patient enrichment strategies ICONIC: JTX-211 Phase 1/2 Clinical Trial JTX-211 being evaluated as monotherapy and in combination with nivolumab Phase 1 to assess safety, PK and PD ongoing Phase 2 will incorporate patient enrichment strategy 26 Jounce Therapeutics 217

27 Thank You Jounce Therapeutics Debbie Law Elizabeth Trehu Christopher Harvey Jim Allison Pam Sharma Tanguy Seiwart Heather Hirsch Jason Reeves Tyler Simpson Lindsey Shallberg Matt Wallace Sriram Sathy Applied Biomath Joshua Apgar ToxStrategies Barbara Mounho-Zamora David Rimm Robert Mabry Amit Deshpande Steve Sazinsky Kutlu Elpek Ellen Duong Jenny Shu Tong Zi