Society for Immunotherapy of Cancer (SITC) Annual Meeting November 10, 2017

Transcription

1 Society for Immunotherapy of Cancer (SITC) Annual Meeting November 10, 2017

2 Forward-Looking Statements This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of Such forward-looking statements include those regarding the company s expectations about: the therapeutic potential of PI3K-gamma selective inhibition and IPI-549, alone and in combination with immune checkpoint inhibitors, including Opdivo ; clinical trial plans regarding IPI-549, including enrollment projections and timing for trial expansion; the timing and type of plans to report clinical and translational data of IPI-549; patent protection for IPI-549; the market sizes and commercial opportunity for IPI-549; and the company s ability to execute on its strategic plans. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the company s current expectations. For example, there can be no guarantee that IPI-549 will successfully complete necessary preclinical and clinical development phases or that any positive developments with IPI-549 will result in stock price appreciation. Management s expectations and, therefore, any forward-looking statements in this presentation could also be affected by risks and uncertainties relating to a number of other factors, including the following: Infinity s results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; Infinity s ability to obtain, maintain and enforce patent and other intellectual property protection for IPI-549; the content and timing of decisions made by the U.S. FDA and other regulatory authorities; Infinity s ability to obtain and maintain requisite regulatory approvals and to enroll patients in its clinical trials; unplanned cash requirements and expenditures; and development of agents by Infinity's competitors for diseases in which Infinity is currently developing or intends to develop IPI These and other risks which may impact management s expectations are described in greater detail under the caption Risk Factors included in Infinity s quarterly report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 7, 2017, and other filings filed by Infinity with the SEC. Any forward-looking statements contained in this presentation speak only as of the date hereof, and Infinity expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Infinity s website is Infinity regularly uses its website to post information regarding its business, product development programs and governance. Infinity encourages investors to use particularly the information in the section entitled Investors/Media, as a source of information about Infinity. References to in this presentation are not intended to, nor shall they be deemed to, incorporate information on into this presentation by reference. 2

3 Infinity s Team at SITC 2017 Adelene Perkins Chair & CEO Jeffery Kutok, M.D., Ph.D. Chief Scientific Officer Larry Bloch, M.D., J.D. President Claudio Dansky Ullmann, M.D. SVP Clinical Development Les Brail, Ph.D. Sr. Dir. Clinical Development Suresh Mahabhashyam, MD, MPH Sr. Dir. Safety & Risk Mgmt. 3

4 IPI-549: Potential First-in-Class, Transformative Approach within Immuno-Oncology Believed to be the only potent, oral, selective PI3K- inhibitor in development Discovered and developed by Infinity Composition of matter patents into

5 IPI-549: Potential First-in-Class, Transformative Approach within Immuno-Oncology Believed to be the only potent, oral, selective PI3K- inhibitor in development Discovered and developed by Infinity Composition of matter patents into 2034 Targeting macrophages is emerging as a compelling approach to reduce immunosuppression 1 PI3K- inhibition uniquely impacts both M2 (pro-tumor) and M1 (anti-tumor) phenotypes 1 Kaneda et al. Nature, 2016 Nov;539: De Henau et al. Nature, 2016 Nov;539:

6 IPI-549: Potential First-in-Class, Transformative Approach within Immuno-Oncology Believed to be the only potent, oral, selective PI3K- inhibitor in development Discovered and developed by Infinity Composition of matter patents into 2034 Targeting macrophages is emerging as a compelling approach to reduce immunosuppression 1 PI3K- inhibition uniquely impacts both M2 (pro-tumor) and M1 (anti-tumor) phenotypes Phase 1/1b clinical study ongoing Evaluating as monotherapy and in combination with Opdivo Plan to evaluate up to 200 patients with advanced solid tumors 2 1 Kaneda et al. Nature, 2016 Nov;539: De Henau et al. Nature, 2016 Nov;539: NCT

7 IPI-549: Potential First-in-Class, Transformative Approach within Immuno-Oncology Believed to be the only potent, oral, selective PI3K- inhibitor in development Discovered and developed by Infinity Composition of matter patents into 2034 Targeting macrophages is emerging as a compelling approach to reduce immunosuppression 1 PI3K- inhibition uniquely impacts both M2 (pro-tumor) and M1 (anti-tumor) phenotypes Phase 1/1b clinical study ongoing Evaluating as monotherapy and in combination with Opdivo Plan to evaluate up to 200 patients with advanced solid tumors 2 Encouraging clinical and translational data from monotherapy dose-escalation portion of study 3 Favorable safety, pharmacokinetics and pharmacodynamics 44% clinical benefit rate, defined as patients who remained on treatment at 16 weeks, including one partial response Initial translational data demonstrate that IPI-549 treatment results in immune stimulation 1 Kaneda et al. Nature, 2016 Nov;539: De Henau et al. Nature, 2016 Nov;539: NCT Hong et al., SITC

8 IPI-549 Phase 1/1b Trial in ~200 Patients in Advanced Solid Tumors Dose Escalation Peripheral Blood Samples Monotherapy* 10 mg to 60 mg QD 3+3 design Combination IPI-549* + Nivolumab** 6+6 design Expand at RP2D Expand at RP2D Expansion Peripheral Blood Samples Mandatory Pre-Treatment and On-Treatment Biopsies All Solid Tumors (60 mg QD) NSCLC Melanoma SCCHN TNBC Checkpoint inhibitor-resistant** ** Must have de novo or acquired resistance to immediately prior anti-pd-1/anti-pd-l1 therapy Checkpoint inhibitor-naïve Cohort Status Completed Ongoing Pending *28 day cycles, continuous QD dosing, **Flat-dose Nivolumab 240 mg Q2W 8

9 IPI-549 Phase 1/1b Trial in ~200 Patients in Advanced Solid Tumors Dose Escalation Peripheral Blood Samples Monotherapy* 10 mg to 60 mg QD 3+3 design Combination IPI-549* + Nivolumab** 6+6 design Expand at RP2D Expand at RP2D Expansion Peripheral Blood Samples Mandatory Pre-Treatment and On-Treatment Biopsies All Solid Tumors (60 mg QD) NSCLC Melanoma SCCHN TNBC Checkpoint inhibitor-resistant** ** Must have de novo or acquired resistance to immediately prior anti-pd-1/anti-pd-l1 therapy Checkpoint inhibitor-naïve Cohort Status Completed Ongoing Pending *28 day cycles, continuous QD dosing, **Flat-dose Nivolumab 240 mg Q2W 9

10 IPI-549 Phase 1/1b Trial in ~200 Patients in Advanced Solid Tumors Dose Escalation Peripheral Blood Samples Monotherapy* 10 mg to 60 mg QD 3+3 design Combination IPI-549* + Nivolumab** Cohort Status 6+6 design Completed Ongoing Pending Expand at RP2D Expand at RP2D Expansion Peripheral Blood Samples Mandatory Pre-Treatment and On-Treatment Biopsies All Solid Tumors (60 mg QD) NSCLC Melanoma SCCHN TNBC Mesothelioma Adrenocortical Carcinoma Checkpoint inhibitor-resistant** ** Must have de novo or acquired resistance to immediately prior anti-pd-1/anti-pd-l1 therapy Checkpoint inhibitor-naïve *28 day cycles, continuous QD dosing, **Flat-dose Nivolumab 240 mg Q2W Checkpoint inhibitor-independent 10

11 IPI-549 Results from Eight Components of Phase 1/1b Study Anticipated Throughout H2018 Report data from the monotherapy expansion cohort Report data from the combination dose-escalation Report initial data from combination expansion cohorts 2H2018 Report additional data from at least six combination expansion cohorts, with more mature clinical and translational data, including insights from paired tumor biopsies 11

12 Today s Featured Speakers Taha Merghoub, Ph.D. Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering David Hong, M.D. Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 12

13 Today s Agenda Reprogramming Tumor-Associated Macrophages by Targeting PI3K- with IPI-549 Taha Merghoub, Ph.D., Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering Monotherapy Dose Escalation Clinical and Translational Data from the First-in-Human Study in Advanced Solid Tumors of IPI-549, an Oral, Selective PI3K- Inhibitor Targeting Tumor Macrophages David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Panel Discussion and Q&A (Moderator: Mike Huckman) Dr. Taha Merghoub, Dr. David Hong, Dr. Claudio Dansky Ullmann, Dr. Jeffery Kutok Wrap up 13

14 Today s Agenda Reprogramming Tumor-Associated Macrophages by Targeting PI3K- with IPI-549 Taha Merghoub, Ph.D., Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering Monotherapy Dose Escalation Clinical and Translational Data from the First-in-Human Study in Advanced Solid Tumors of IPI-549, an Oral, Selective PI3K- Inhibitor Targeting Tumor Macrophages David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Panel Discussion and Q&A (Moderator: Mike Huckman) Dr. Taha Merghoub, Dr. David Hong, Dr. Claudio Dansky Ullmann, Dr. Jeffery Kutok Wrap up 14

15 Reprogramming Tumor-Associated Macrophages by Targeting PI3K- with IPI-549 Taha Merghoub, Ph.D. Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center 15

16 Disclosures I am one of the IMVAQ therapeutics founders Supported research: Bristol-Myers Squibb Surface Oncology Kyn Therapeutics Infinity Pharmaceuticals, Inc. Peregrine Pharmeceuticals, Inc. Adaptive Biotechnologies Leap Therapeutics, Inc. 16

17 Targeting Macrophages Is Emerging as a Compelling Approach to Reduce Immunosuppression Tumors commandeer regulatory pathways to maintain an immunosuppressive tumor microenvironment Attempting to reverse this immune-suppressive effect solely by directly activating T cells may not fully restore activity M2 (pro-tumor) macrophages maintain immune-suppressive signals, rendering T cells non-functional and allowing tumors to evade immune attack M1 (anti-tumor) macrophages defend against cancer Reprogramming macrophages from M2 to M1 may be a key approach to promoting an anti-tumor response 17

18 PI3K- Has a Unique Pattern of Expression and Biologic Function PI3K- PI3K- PI3K- PI3K- Highly Expressed in TAMs, MDSCs Macrophage polarization Innate immune function Immune cell trafficking and activation vs. Ubiquitous Mutated in solid tumors Insulin signaling Ubiquitous PTEN deleted solid tumors Platelet activation Insulin signaling Highly Expressed in B-cells, T-cells B-cell and T-cell activation and function FC receptor signaling in mast cells 1. Vanhaesebroeck B et al. Nat Rev Mol Cell Biol. 2010;11: Kaneda M et al. Nature, 2016; 539: Reif K et al. J Immunol 2004; 173: Lannutti BJ, et al. Blood. 2011;117(2): Hirsch E. et al. Science. 2000;287: Wee S. et al. PNAS. 2008, 105:

19 IPI-549 Is an Oral Selective Inhibitor of PI3K- Assay PI3K- PI3K- PI3K- PI3K- Binding Affinity Kd (nm) Biochemical IC 50 (nm) >8421 DeHenau et al AACR 2016 #554 Cellular IC 50 (nm) > 100X selectivity in cellular assay Chemical Structure of IPI-549 Evans et al. ACS Med. Chem. Lett. (2016). 19

20 Preclinical Data Demonstrate PI3K- Plays a Key Role in Reprogramming Macrophages Kaneda et al. Nature, 2016 Nov;539:

21 IPI-549 Reprograms Macrophages from Pro-Tumor (M2) to Anti-Tumor (M1), Enabling Anti-Tumor T Cell Response M2 macrophages Suppressed T cells Tumor cells Kaneda et al. Nature, 2016 Nov;539:

22 IPI-549 Reprograms Macrophages from Pro-Tumor (M2) to Anti-Tumor (M1), Enabling Anti-Tumor T Cell Response M1 M2 macrophages Activated T cells Tumor cells IPI-549 Kaneda et al. Nature, 2016 Nov;539:

23 IPI-549 Reprograms Macrophages from Pro-Tumor (M2) to Anti-Tumor (M1), Enabling Anti-Tumor T Cell Response Kaneda et al. Nature, 2016 Nov;539:

24 PI3K- Inhibition Switches Gene Expression Profiles from Pro-Tumor (M2) to Anti-Tumor (M1) PI3K -/- IPI-549 PI3K -/- CD11b+ Increase in anti-tumor gene expression *p<0.01 Decrease in pro-tumor gene expression M2, immunosuppressive genes M1, immunostimulatory genes Kaneda et al. Nature, 2016 Nov;539: Note: Cells isolated from LLC (lung cancer) tumors 24

25 Percent Change Relative to Control IPI-549 Treatment Increases the Ratio of M1 to M2 Macrophages without Depletion and Increases Numbers of Intratumoral T Cells 4T1 (breast) B16-GMCSF (melanoma) Corresponding increase in numbers of activated, proliferating cytotoxic T cells within tumor Note: CD11b+ marker for myeloid cells, F4/80+ marker for tumor-associated macrophages (TAMs), CD206+ marker for M2-like TAMs, MHCII+ marker for M1-like TAMs. De Henau et al. Nature, 2016 Nov;539:

26 Tumor volume (mm 3 ) IPI-549 Monotherapy Demonstrates Tumor Growth Delay in the Lewis Lung Carcinoma Model Vehicle n=13 15 mg/kg QD n= * *p < Treatment start Day post-implant IPI-549 effects are both macrophage-dependent and T cell-dependent Kutok et al., Immune Microenvironment: Transforming the Future of Cancer Therapies Meeting,

27 IPI-549 Monotherapy Demonstrates Tumor Growth Delay in Multiple Syngeneic Solid Tumor Models Cancer Type Cell Line % Tumor Growth Inhibition Range (n experiments) Lung LLC-luc brei 28-52% [10] Colon MC % [3] Breast 4T1-luc 19-38% [6] Colon CT % [12] Melanoma B16-GMCSF 24-56% [6] De Henau et al. Nature, 2016 Nov;539:

28 Potential Combination Targets IPI-549-Mediated Immune Activation Also Upregulates Immune-Regulatory Targets, Providing a Rationale for Combination Approaches 549-Treated Vehicle Co-stimulatory and checkpoint immuno-oncology targets are increased after 9 days of IPI-549 treatment in the CT26 colorectal cancer model, demonstrating immune activation with treatment De Henau et al. AACR Poster 554, Note: RNAseq on whole tumors from vehicle or IPI-549 treated mice. 28

29 Preclinical Data Demonstrate Targeting PI3K- in Macrophages Overcomes Resistance to Checkpoint Blockade De Henau et al. Nature, 2016 Nov;539:

30 IPI-549 in Combination with Anti-PD-1 Improves Survival and Provides Lasting Anti-Tumor Immune Memory in Preclinical Model Survival to 3000 mm 3 Improved survival with IPI-549 Treatment Start Day 4 Stop Treatment Day 56 Days Post-Implant Note: In vivo data in CT26 cell line (colon cancer). De Henau et al. Nature, 2016 Nov;539:

31 Resistance to Checkpoint Blockade Is Associated with Suppressive Myeloid Cell-Rich Tumors Checkpoint Inhibitor Resistant Checkpoint Inhibitor Sensitive 4T1 (breast) B16-GMCSF (melanoma) B16F (melanoma) Within Resistant tumors: Increased M2 macrophage number and function Decreased cytotoxic T cells * p<0.05 De Henau et al. Nature, 2016 Nov;539:

32 T u m o r s iz e (m m 3 ) IPI-549 Treatment Overcomes Resistance to CPI and Augments CPI Benefit; Provides Survival Benefit Compared to Checkpoint Blockade Alone V e h ic le P D -1 Enhanced Survival IP I-54T1 4 9 P D -1 + IP I T * ** (15 mg/kg) * **** P < D a y s p o s t im p la n ts * P <0.05 ** P <0.01 IPI-549 in combination with anti-pd-1 and anti-ctla4 therapies provides the most effective knockdown regarding tumor growth, with significantly increased survival (e.g., 0% vs. 30%) De Henau et al. Nature, 2016 Nov;539:

33 Key Preclinical Takeaways Reprograms macrophages from M2, pro-tumor phenotype, to the M1, anti-tumor phenotype Demonstrated monotherapy activity Improved survival in combination with anti-pd1 antibodies Reverses resistance to checkpoint inhibitors 33

34 Today s Agenda Reprogramming Tumor-Associated Macrophages by Targeting PI3K- with IPI-549 Taha Merghoub, Ph.D., Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering Monotherapy Dose Escalation Clinical and Translational Data from the First-in-Human Study in Advanced Solid Tumors of IPI-549, an Oral, Selective PI3K- Inhibitor Targeting Tumor Macrophages David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Panel Discussion and Q&A (Moderator: Mike Huckman) Dr. Taha Merghoub, Dr. David Hong, Dr. Claudio Dansky Ullmann, Dr. Jeffery Kutok Wrap up 34

35 Monotherapy Dose Escalation Clinical and Translational Data from the First-in-Human Study in Advanced Solid Tumors of IPI-549, an Oral, Selective PI3K- Inhibitor Targeting Tumor Macrophages David Hong, M.D. Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 35

36 IPI-549 Phase 1/1b Trial Design in ~200 Patients DOSE ESCALATION COHORTS Solid Tumors Peripheral Blood Samples EXPANSION COHORTS Peripheral Blood Samples Mandatory Pre-Treatment and On-Treatment Biopsies COMPLETED Monotherapy 10 mg to 60 mg QD ONGOING All Solid Tumors ONGOING 3+3 design Combination IPI Nivolumab* 6+6 design *Flat-dose Nivolumab 240 mg Q2W 28-day cycles PENDING NSCLC SCCHN Melanoma TNBC Checkpoint inhibitor-resistant** ** Must have de novo or acquired resistance to immediately prior anti-pd-1/anti-pd-l1 therapy Checkpoint inhibitor-naïve Hong et al., SITC Mesothelioma Adrenocortical Carcinoma Checkpoint inhibitor-independent 36

37 IPI-549 Phase 1/1b Study: Monotherapy Dose Escalation DOSE ESCALATION COHORTS Solid Tumors Monotherapy 40 mg QD Monotherapy 60 mg QD COMPLETED No DLTs: MTD was not identified Expansion initiated based on PK/PD Monotherapy 30 mg QD Monotherapy 10 mg QD Monotherapy 15 mg QD Monotherapy 20 mg QD Endpoints: PK/PD Safety Activity Peripheral Blood Samples for Translational Analysis 3+3 design N=19 total, 18 evaluable Hong et al., SITC

38 Patient Demographics Baseline Characteristics All Patients N=19 Age (years), median (range) 63 (42-83) Male, n (%) 7 (37) Female, n (%) 12 (63) ECOG Performance Status, n (%) 0 7 (37) 1 11 (58) # of Prior Lines of Therapy, median (range) 4 (0-11) Prior PD-1/PD-L1 Therapy, n (%) 2 (11) Data as of 18 October 2017 Hong et al., SITC

39 Δ Monocyte PI3K- - Induced pakt (T308) Concentration (ng/ml) PK/PD Time Profile Cycle 1 Day 1 Cycle 2 Day 1 PK 60 mg, 3 40 mg, 3 30 mg, 3 20 mg, 3 15 mg, 3 10 mg, 3 60 mg, 3 40 mg, 2 30 mg, 3 20 mg, 3 15 mg, 2 10 mg, 3 PD Hong et al., SITC Time (hrs) Time (hrs) Linear PK, limited accumulation; sustained inhibition of PI3K- at doses 20 mg QD 39

40 Safety Summary (N=19) Data as of 18 October 2017 IPI-549 monotherapy has been well tolerated (doses up to 60 mg QD) No DLTs - MTD was not identified Majority of reported AEs have been Grade 1-2 per NCI CTCAE No treatment-related SAEs or treatment-related deaths 2 patients discontinued study drug due to treatment-related AEs: Grade 2 rash and Grade 2 ALT/AST increase Grade 3 ALT/AST increase Hong et al., SITC

41 TEAEs >15% of Patients (All Causality; All Grades and Grade >3) TEAE All Grades n (%) Grades >3 n (%) Alanine aminotransferase increased 5 (26) 1 (5) Aspartate aminotransferase increased 5 (26) 1 (5) Anaemia 5 (26) 2 (11) Fatigue 4 (21) 0 Diarrhoea 4 (21) 0 Cough 4 (21) 0 White blood cell count decreased 3 (16) 1 (5) Rash maculo-papular 3 (16) 0 Nausea 3 (16) 0 Headache 3 (16) 0 Hypomagnesaemia 3 (16) 0 Pyrexia 3 (16) 0 Hong et al., SITC Data as of 18 October

42 Treatment-Related* TEAEs (All Grades and Grades >3) Hong et al., SITC Treatment-Related* TEAE All Grades n (%) Grades >3 n (%) Alanine aminotransferase increased 3 (16) 1 (5) White blood cell count decreased 2 (11) 0 Rash maculo-papular 2 (11) 0 Aspartate aminotransferase increased 2 (11) 1 (5) Headache 2 (11) 0 Dysaesthesia 1 (5) 0 Gamma-glutamyltransferase increased 1 (5) 0 Hypomagnesaemia 1 (5) 0 Paraesthesia oral 1 (5) 0 Nausea 1 (5) 0 Blepharospasm 1 (5) 0 Dizziness 1 (5) 0 Neuropathy peripheral 1 (5) 0 Eye swelling 1 (5) 0 Hypoalbuminaemia 1 (5) 0 Diarrhoea 1 (5) 0 Blood cholesterol increased 1 (5) 0 Hyponatraemia 1 (5) 0 Ocular hyperaemia 1 (5) 0 Anaemia 1 (5) 0 Fatigue 1 (5) 0 Pruritus 1 (5) 0 Hypercalcaemia 1 (5) 0 *As assessed by Investigator Data as of 18 October

43 Time on Study (N=19) Dose (mg) Tumor Type 15 Adenoid 20 Mesothelioma MSS 20 Colorectal 15 Ovarian Prior PD-1 10 Endometrial 20 Endometrial 40 Head & Neck 60 Breast 30 Neuroendocrine MSS 30 Colorectal 30 Adenoid 10 Ovarian 60 Endometrial 60 Esophageal 40 Merkel Cell 10 Pancreatic 15 Pancreatic 40 Ovarian Prior PD-1 40 Head & Neck Weeks On Study Partial Response Disease Progression Discontinued Drug Related Discontinued Week Partial Response Occurred Data as of 18 October 2017 Hong et al., SITC

44 Time on Study (N=19) Dose (mg) Tumor Type 15 Adenoid 20 Mesothelioma MSS 20 Colorectal 15 Ovarian Prior PD-1 10 Endometrial 20 Endometrial 40 Head & Neck 60 Breast 30 Neuroendocrine MSS 30 Colorectal 30 Adenoid 10 Ovarian 60 Endometrial 60 Esophageal 40 Merkel Cell 10 Pancreatic 15 Pancreatic 40 Ovarian Prior PD-1 40 Head & Neck Partial Response Disease Progression Discontinued Drug Related Discontinued Week Partial Response Occurred Clinical benefit defined as patients who have not progressed at 16 weeks (8/18 evaluable patients) Hong et al., SITC Weeks On Study Data as of 18 October

45 Partial Response in a Patient with Advanced Peritoneal Mesothelioma 50 yo Male with Peritoneal Mesothelioma (epithelioid type) Original Dx Oct/ prior regimens, last regimen pemetrexed/carboplatin (DOT 2.5 months) Started on 20 mg Aug 4/2016 Patient remains on treatment Hong et al., SITC

46 Partial Response in a Patient with Advanced Peritoneal Mesothelioma Original dx: October prior regimens, last regimen pemetrexed/carboplatin (DOT 2.5 months) Patient remains on treatment Hong et al., SITC Baseline End of Cycle 15 46

47 Improvement of Malignant Pleural Effusions and Ascites in Heavily Pre-Treated Patient with KRAS+ MSS CRC Stage IV dx: July 2012 with 8 prior regimens (duration of last prior therapy: ~2 months) Extensive peritoneal carcinoma with ascites; bilateral pleural effusion, as well as liver and lung lesions On Monotherapy Tx for 36 weeks Hong et al., SITC Baseline End of Cycle 2 47

48 Translational Data in Peripheral Blood Monotherapy treatment enables demonstration of IPI-549-specific immunemodulatory activity Monotherapy dose escalation translational studies using peripheral blood include: Serum cytokine/chemokine analysis (Milliplex luminex 61 analyte panel) Immune subset analysis (Flow cytometry) Gene Expression Profiling (RNA seq) Hong et al., SITC

49 Initial Translational Data in Peripheral Blood Support IPI-549 On-Mechanism Immune Stimulation Evidence of immune stimulation Up-regulation of interferon-gamma ( ) responsive factors Reinvigoration (proliferation) of exhausted CD8+ T-cells Clinical benefit associated with markers of increased monocyte/ myeloid cell activation Hong et al., SITC

50 Initial Translational Data in Peripheral Blood Support IPI-549 On-Mechanism Immune Stimulation Evidence of immune stimulation Up-regulation of interferon-gamma ( ) responsive factors Reinvigoration (proliferation) of exhausted CD8+ T-cells Clinical benefit associated with markers of increased monocyte/ myeloid cell activation Hong et al., SITC

51 CXCL9 concentration (pg/ml) CXCL10 concentration (pg/ml) Increase in Interferon- -Responsive Serum M1 Chemokines 1, Consistent with IPI-549-Induced Immuno-Stimulatory State CXCL9 CXCL10 p <0.05 p <0.05 C1D1 C2D1 N Median Avg C1D1 C2D1 N Median Avg Similar increases in CXCL9 and CXCL10 were reported in patients receiving anti-pd-1 therapy 2 Hong et al., SITC Goswami, et al. Cellular Immunology Choueiri, et al. Clin Cancer Res

52 Evidence for Similar Increases in IFN- Inducible Chemokines in Patients Treated with Anti-PD-1 Therapy Chemokines CXCL10 and CXCL9 Are Increased After Anti-PD1 Therapy in Renal Cell Carcinoma Patients Hong et al., SITC Choueiri et al. Clin Cancer Res; (22);

53 Up-Regulation of Interferon- -Responsive Gene Expression, Consistent with IPI-549-Induced Immuno-Stimulatory State IFN- - responsive genes Fold increase at C2D1 P value CD274 (PDL1) x 10-5 FCGR1B x 10-3 GBP x 10-4 GBP x 10-4 GBP x 10-4 GBP x 10-4 C1D1-monotherapy C2D1-monotherapy CD274 (PDL1) FCGR1B GBP2 GBP5 GBP1 GBP4 RNA Seq peripheral blood across all dose levels The above interferon- -responsive genes were among the top 30 most significantly differentially expressed genes Hong et al., SITC

54 Initial Translational Data in Peripheral Blood Support IPI-549 On-Mechanism Immune Stimulation Evidence of immune stimulation Up-regulation of interferon-gamma ( ) responsive factors Reinvigoration (proliferation) of exhausted CD8+ T-cells Clinical benefit associated with markers of increased monocyte/ myeloid cell activation Hong et al., SITC

55 Absolute Percent Change * IPI-549 Monotherapy: Reinvigoration of Exhausted CD8+ Memory T Cells Proliferating PD1+ memory CD8+ T cells Increases in proliferating CD8+ T cells appear specific to PD1+ memory subset. Similar increases in proliferating PD1+ CD8+ memory T cells reported in melanoma patients receiving anti-pd-1 therapy. (Huang et al. Nature. 2017;545:60-65) Hong et al., SITC C=cycle, D=day *Difference in % from C1D1 of Ki-67+ PD1+CD8+ memory T cells of total PD1+ CD8+ memory T cells (CD3+ CD8+ CD45RA-) 55

56 Absolute Percent Change Proliferating PD1+mCD8* mmdscs (cells/μl) mmdscs (cells/μl) Decrease in High Basal Monocytic MDSCs with IPI-549 Treatment is Associated with Reinvigoration of Exhausted Memory CD8+ T Cells C1D1 C1D8 C2D1 C3D1 N= 18 C=cycle, D=day Hong et al., SITC *Difference in % from C1D1 of Ki-67+ PD1+CD8+ memory T cells of total PD1+ CD8+ memory T cells (CD3+ CD8+ CD45RA-) C1D1 C1D8 C2D1 C3D1 56

57 Initial Translational Data in Peripheral Blood Support IPI-549 On-Mechanism Immune Stimulation Evidence of immune stimulation Up-regulation of interferon-gamma ( ) responsive factors Reinvigoration (proliferation) of exhausted CD8+ T-cells Clinical benefit associated with markers of increased monocyte/ myeloid cell activation Hong et al., SITC

58 Fold Change CD86+ monocytes from baseline Fold Change HLA-DR+ monocytes from baseline Patients with Clinical Benefit (>16 Weeks on Study) Show Increased Numbers of Activated Monocytes CD86 HLA-DR <16 weeks on study >16 weeks on study <16 weeks on study >16 weeks on study p <0.05 p = 0.08 Max change Max change N 10 8 Median Avg Max change Max change N 10 8 Median Avg Hong et al., SITC Max change = Maximum change observed among C1D8, C2D1, C3D1. 58

59 Key Clinical Takeaways IPI-549 has been well tolerated at all doses studied (10 mg to 60 mg QD); expansion at 60 mg QD is ongoing No DLTs, treatment-related SAEs, or treatment-related deaths Hong et al., SITC

60 Key Clinical Takeaways IPI-549 has been well tolerated at all doses studied (10 mg to 60 mg QD); expansion at 60 mg QD is ongoing No DLTs, treatment-related SAEs, or treatment-related deaths IPI-549 as monotherapy demonstrates evidence of clinical activity 44% of patients on treatment for at least 16 weeks Partial response in mesothelioma; expansion cohort in combination with nivolumab being initiated Hong et al., SITC

61 Key Clinical Takeaways IPI-549 has been well tolerated at all doses studied (10 mg to 60 mg QD); expansion at 60 mg QD is ongoing No DLTs, treatment-related SAEs, or treatment-related deaths IPI-549 as monotherapy demonstrates evidence of clinical activity 44% of patients on treatment for at least 16 weeks Partial response in mesothelioma; expansion cohort in combination with nivolumab being initiated Encouraging evidence of IPI-549-induced immune activation in peripheral blood across multiple tumor types and dose levels, including evidence of biomarkers that correlate with clinical benefit (>16 weeks on study) Pre- and on-study biopsies in currently enrolling monotherapy expansion patients will enable further characterization of intra-tumoral, immune-activating effects Hong et al., SITC

62 % Change Adrenocortical Carcinoma Partial Response with IPI-549 (30 mg QD) and Nivolumab Combination % % Change In Lesion Size (RECIST) % PR % -60% -70 BL C3 C5 C7 57 year old male diagnosed with adrenocortical carcinoma 7/2013, underwent surgery April 2014, six cycles chemotherapy (Adriamycin, Platinum, Etoposide and Mitotane) with maintenance Mitotane until Feb 2017 No prior anti-pd1/pd-l1 therapy 62

63 Partial Response in an Adrenal Cortical Cancer Patient with IPI-549 and Nivolumab Extensive metastatic disease including liver (typically poor prognosis), lung, retroperitoneum, spleen, lymph nodes Baseline Cycle 3 Day 1 Courtesy of Dr. Ryan Sullivan/Dr. Dejan Juric 63

64 Today s Agenda Reprogramming Tumor-Associated Macrophages by Targeting PI3K- with IPI-549 Taha Merghoub, Ph.D., Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering Monotherapy Dose Escalation Clinical and Translational Data from the First-in-Human Study in Advanced Solid Tumors of IPI-549, an Oral, Selective PI3K- Inhibitor Targeting Tumor Macrophages David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Panel Discussion and Q&A (Moderator: Mike Huckman) Dr. Taha Merghoub, Dr. David Hong, Dr. Claudio Dansky Ullmann, Dr. Jeffery Kutok Wrap up 64

65 Today s Panel Dr. Taha Merghoub MSK Dr. Jeffery Kutok Infinity Pharmaceuticals Dr. David Hong MD Anderson Dr. Claudio Dansky Ullmann Infinity Pharmaceuticals Moderator Mike Huckman W2O Group 65

66 Today s Agenda Reprogramming Tumor-Associated Macrophages by Targeting PI3K- with IPI-549 Taha Merghoub, Ph.D., Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering Monotherapy Dose Escalation Clinical and Translational Data from the First-in-Human Study in Advanced Solid Tumors of IPI-549, an Oral, Selective PI3K- Inhibitor Targeting Tumor Macrophages David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Panel Discussion and Q&A (Moderator: Mike Huckman) Dr. Taha Merghoub, Dr. David Hong, Dr. Claudio Dansky Ullmann, Dr. Jeffery Kutok Wrap up 66

67 Looking Ahead 67

68 2017 IPI-549 Program Goals Present preclinical and clinical data at PI3K Keystone Symposia Conference Complete monotherapy dose-escalation in 1H17 Initiate monotherapy expansion cohort in 2H17 Report additional Phase 1 data in 2H17 (November 10 th at SITC) Complete combination dose-escalation in 2H17 Initiate six combination expansion cohorts patients in 2H17 (non-small cell lung cancer, melanoma, triple negative breast cancer, head and neck cancer, mesothelioma, adrenocortical carcinoma) 68

69 IPI-549 Results from Eight Components of Phase 1/1b Study Anticipated Throughout H2018 Report data from the monotherapy expansion cohort Report data from the combination dose-escalation Report initial data from combination expansion cohorts 2H2018 Report additional data from at least six combination expansion cohorts, with more mature clinical and translational data, including insights from paired tumor biopsies 69

70 IPI-549: Potential First-in-Class, Transformative Approach within Immuno-Oncology Believed to be the only potent, oral, selective PI3K- inhibitor in development Discovered and developed by Infinity Composition of matter patents into 2034 Targeting macrophages is emerging as a compelling approach to reduce immunosuppression 1 PI3K- inhibition uniquely impacts both M2 (pro-tumor) and M1 (anti-tumor) phenotypes Phase 1/1b clinical study ongoing Evaluating as monotherapy and in combination with Opdivo Plan to evaluate up to 200 patients with advanced solid tumors 2 Encouraging clinical and translational data from monotherapy dose-escalation portion of study 3 Favorable safety, pharmacokinetics and pharmacodynamics 44% clinical benefit rate, defined as patients who remained on treatment at 16 weeks, including one partial response Initial translational data demonstrate that IPI-549 treatment results in immune stimulation 1 Kaneda et al. Nature, 2016 Nov;539: De Henau et al. Nature, 2016 Nov;539: NCT Hong et al., SITC

71 Today s Presentations During SITC Title: Monotherapy dose escalation clinical and translational data from first-in-human study in advanced solid tumors of IPI-549, an oral, selective, PI3K-gamma inhibitor targeting tumor macrophages Abstract number: O43 Presenter: Dr. David Hong Oral session: Clinical Trials - New Agents Time: 2:15 p.m. 2:30 p.m. ET IPI-549 poster presentations from 12:30-2:00 p.m. and 6:30-8:00 p.m. ET today will include: Clinical and translational poster corresponding to oral presentation (Hong et. al.) Clinical trials in progress poster (Ribas et al.) 71

72 Society for Immunotherapy of Cancer (SITC) Annual Meeting November 10, 2017