KD025 in Chronic Graft-Versus-Host Disease (cgvhd)

Transcription

1 KD025 in Chronic Graft-Versus-Host Disease (cgvhd) July 11, Kadmon Holdings, Inc.

2 Forward-looking Statement This presentation contains forward looking statements that are based on the beliefs and assumptions and on information currently available to management of Kadmon Holdings, Inc. (the Company ). All statements other than statements of historical fact contained in this presentation are forward-looking statements. Forward looking statements include information concerning the initiation, timing, progress and results of clinical trials of the Company s product candidates, the timing or likelihood of regulatory filings and approvals for any of its product candidates, and estimates regarding the Company s expenses, future revenues and future capital requirements. In some cases, you can identify forward-looking statements by terminology such as may, will, should, expects, plans, anticipates, believes, estimates, predicts, potential or continue or the negative of these terms or other comparable terminology. There are important factors that could cause the Company s actual results to differ materially from those expressed or implied by the forward-looking statements, including those factors discussed under the caption entitled Risk Factors in the Company s Quarterly Report on Form 10-Q for the three months ended March 31, Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the Company s actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Forward-looking statements represent the Company s beliefs and assumptions only as of the date of this presentation. Although the Company believes that the expectations reflected in the forwardlooking statements are reasonable, it cannot guarantee future results, levels of activity, performance or achievements. Except as required by law, the Company assumes no obligation to publicly update any forward looking statements for any reason after the date of this presentation to conform any of the forward-looking statements to actual results or to changes in its expectations. 2

3 Introduction Harlan W. Waksal, M.D. President and Chief Executive Officer Kadmon

4 Agenda: cgvhd Analyst and Investor R&D Day Time Topic Presenter 8:45 9:00am Introduction Harlan W. Waksal, M.D. President and CEO, Kadmon 9:00 9:40am Preclinical ROCK inhibition research 1. ROCK inhibitor platform overview 2. ROCK inhibition in cgvhd models Lawrence K. Cohen, Ph.D. EVP, Research and Business Development, Kadmon Bruce Blazar, M.D. Regents Professor, University of Minnesota 9:40 10:30am Clinical data on KD025 in cgvhd 1. cgvhd overview 2. KD trial design 3. KD initial data 4. Regulatory strategy Harlan W. Waksal, M.D. President and CEO, Kadmon John. L. Ryan, M.D., Ph.D. EVP, Chief Medical Officer, Kadmon Amandeep Salhotra, M.D. Assistant Clinical Professor, City of Hope John. L. Ryan, M.D., Ph.D. EVP, Chief Medical Officer, Kadmon 10:30 11:00am Q&A All 4

5 Kadmon Overview Publicly traded biopharmaceutical company (NYSE: KDMN) Founded in 2009; approximately 100 employees Headquartered in New York City Clinical pipeline addressing significant unmet medical needs in autoimmune and fibrotic diseases, oncology and genetic diseases Two lead product candidates (KD025 and tesevatinib) currently in Phase 2 clinical development Generic trientine hydrochloride formulations (KD034) for Wilson s disease currently under FDA review 5

6 Kadmon s Focus: ROCK Inhibitor Platform Kadmon is Exploring the Potential of the ROCK Signaling Pathway to Treat Multiple Diseases Kadmon has developed a portfolio of oral small molecule ROCK inhibitors: ROCK2-selective inhibitors for autoimmune diseases Pan-ROCK (ROCK1/ROCK2) inhibitors for fibrotic diseases Blood-brain barrier-penetrant ROCK2-selective and pan-rock inhibitors for neurodegenerative diseases Lead compound, KD025, is a ROCK2 inhibitor in Phase 2 clinical development for autoimmune and fibrotic diseases Demonstrated safety and efficacy in 8 clinical trials at doses up to 1,000 mg QD Over 300 subjects have been dosed with KD025 to date KD025 is being studied in three ongoing Phase 2 clinical trials: Moderate to severe psoriasis Idiopathic pulmonary fibrosis (IPF) Chronic graft-versus-host disease (cgvhd) 6

7 Today s Focus: Data on KD025 in cgvhd Preclinical and Clinical Data of KD025 in cgvhd Kadmon ROCK inhibitor platform and science overview Preclinical research of KD025 in cgvhd models Clinical safety and activity data from KD mg QD cohort Initial clinical safety and activity data from KD mg BID cohort 7

8 Kadmon ROCK Inhibitor Platform Lawrence K. Cohen, Ph.D. Executive Vice President, Research and Business Development Kadmon

9 ROCK Signaling: Key Therapeutic Target ROCK Pathway Plays a Key Role in Cell Function ROCK (Rho associated coiled-coil containing protein kinase) is an on switch in cells Two ROCK isoforms: ROCK1 and ROCK2 ROCK signaling plays a key role in many cellular functions: Regulates cell movement, shape and differentiation Dysregulation of these ROCK-driven cellular functions are implicated in many chronic diseases Kadmon research has demonstrated that ROCK inhibition can regulate aberrant immune responses and fibrotic processes ROCK Signaling Mediates a Wide Range of Functions, Depending on Cell Type ROCK Inhibition Potential Indications Autoimmune Diseases Re-establishes immune homeostasis Psoriasis, systemic lupus erythematosus Fibrotic Diseases Neurodegenerative Diseases Reduces collagen deposition and fibroblast activation Reduces neuroinflammation and results in neurite growth and remyelination Idiopathic pulmonary fibrosis, kidney fibrosis, liver fibrosis Multiple Sclerosis, Parkinson s disease, Alzheimer s disease 9

10 Kadmon ROCK Inhibitor Platform Kadmon has developed a comprehensive portfolio of oral small molecule ROCK inhibitors ROCK Inhibitor Platform: Lead Candidates Target Status Includes a distinct series of ROCK2 and pan-rock (ROCK1/ROCK2) inhibitors in preclinical and clinical development, including: KD025 Selective ROCK2 inhibitor Ongoing Phase 2 clinical trials in autoimmune and fibrotic diseases ROCK2 inhibitors for autoimmune diseases Pan-ROCK inhibitors for fibrotic diseases Blood-brain barrier-penetrant pan-rock inhibitors for neurodegenerative diseases KL Pan-ROCK inhibitor for fibrosis Entering GLP toxicology; IND studies anticipated Q Kadmon and other institutions have conducted preclinical research on Kadmon ROCK inhibitors in a variety of autoimmune and fibrotic disease models All preclinical research in GVHD has been conducted with KD025 KL Blood-brain barrier-penetrant pan-rock inhibitor for neurodegenerative diseases In lead optimization (half-life, potency, bioavailability, specificity, etc.) 10

11 ROCK Signaling in cgvhd ROCK Inhibition with KD025 Targets Both the Immune and Fibrotic Components of cgvhd cgvhd is a multi-organ and complex disorder in which transplanted allogeneic hematopoietic stem cell transplantation (HSCT) immune cells attack and damage host body tissues cgvhd demonstrates common features of both autoimmune and fibrotic diseases: Immune system over-activation Fibrotic response Preclinical research has demonstrated that ROCK2 inhibition with KD025 targets both the immune and fibrotic components of cgvhd KD025 down-regulates Th17 and up-regulates Tregs KD025 decreases collagen deposition and myofibroblast formation and proliferation 11

12 KD025 Rebalances Immune Response to Treat Immune Dysfunction Imbalance of Th17 and Treg activity leads to uncontrolled inflammation STAT3 (Th17: IL-17, IL-21, IL-22) Inflammation Immune Dysfunction STAT5 (Treg) ROCK2 inhibition reestablishes immunologic homeostasis: Reduces Th17 activity Increases number and function of Tregs STAT3 (Th17: IL-17, IL-21, IL-22) KD025 Treatment STAT5 (Treg) Resolution Inflammation Resolution KD025 down-regulates pro-inflammatory Th17 responses and increases Treg function, helping to resolve immune dysregulation Reduces STAT3 phosphorylation and increases STAT5 phosphorylation KD025 rebalances immune response instead of suppressing entire immune system 12

13 KD025 Inhibits Th17 Secretion in Healthy Human Cells (in vitro) KD025 Down-Regulates Secretion of Th17 Pro-Inflammatory Cytokines IL-17 IL-21 IL ng/ml 3 2 ng/ml 0.4 ng/ml * KD025 ( M) KD025 ( M) KD025 ( M) No Deleterious Impact on Other T Cell Functions IL-2 IFN- IL-10 Proliferation ng/ml ng/ml ng/ml % Proliferation KD025 ( M) KD025 ( M) KD025 ( M) KD025 ( M) *10 M correlates to 500mg 13

14 ROCK Mediates Multiple Fibrotic Processes ROCK Signaling is a Key Therapeutic Target for Fibrosis Fibrosis is a consequence of aberrant wound-healing Caused by unregulated myofibroblast proliferation, leading to uncontrolled collagen and antibody deposition Results in permanent scarring, potentially leading to organ malfunction and death Key common fibrotic pathway, regardless of the organ involved or initiating events ROCK signaling is part of this key common pathway and is a therapeutic target for pathologic fibrosis ROCK inhibition can interfere with several initiating events of fibrosis Reduces collagen deposition and fibroblast activation, improving organ function Fibroblast Myofibroblast 1. Collagen deposition 2. Alpha smooth muscle actin (αsma) 3. Extracellular matrix (ECM) 14

15 KD025 Downregulates and Impairs α-smooth Muscle Actin (α-sma) KD025 Downregulates α-sma mrna Expression KD025 Impairs Stress Fiber Formation 1.5 Control DMSO KD025, 3.3 M KD025, 10 M KD025 (10 μm) Rat myofibroblasts Hinz B et al., AJP

16 KD025 Decreases mrna Expression and Collagen I Secretion KD025 Decreases Collagen 1 mrna Expression in Fibroblasts KD025 Decreases Collagen 1 Protein Expression in Fibroblasts DMSO KD µM KD µM KD µM KD µM KD µM KD025 5µM KD025 10µM normalize to DMSO (%) DMSO KD025, 1.1 M KD025, 3.3 M KD025, 10 M Col1A fold change 16

17 Kadmon ROCK Research Published in Peer-Reviewed Journals Kadmon Research on ROCK Inhibitor Platform Featured in Multiple Publications, including: Zanin-Zhorov A. et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proceedings of the National Academy of Sciences Nov 25; : Flynn R et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a STAT3-dependent mechanism. Blood Apr 28;127(17): Weiss J. M. et al. ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings. Science Signaling Jul19; 9.437: 73. Zanin-Zhorov A. et al. Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10. The Journal of Immunology Apr 7;

18 Bruce Blazar, MD Regents Professor, Division of Pediatric Blood and Marrow Transplantation, University of Minnesota Director, Clinical and Translational Science Institute, University of Minnesota Director, Center for Translational Medicine, University of Minnesota Vice Dean for Clinical Investigation, University of Minnesota Medical School Author, ~700 publications Investigator, preclinical research on KD025 in GVHD animal models Awards: Bruce Blazar, MD NIH MERIT Award CCRF Chair in Pediatric Oncology, recognizing his work in the development of novel immune-based therapies American Society of Hematology (ASH) Ernest Beutler prize and lectureship Till and McCulloch Lecture Award from the Canadian Blood and Marrow Transplant Group Education and training: Medical degree, Albany Medical College Resident, Pediatrics, University of Minnesota Fellow, Hematology/Oncology and Bone Marrow Transplantation, University of Minnesota 18

19 KD025 in cgvhd: Preclinical Research Bruce Blazar, M.D. Regents Professor, Division of Pediatric Blood and Marrow Transplantation University of Minnesota

20 Pathophysiology of cgvhd cgvhd is Driven by Involvement of Pro-inflammatory Cytokines and Immune Cells cgvhd involves both T cells and B cells Characterized by overproduction of pro-inflammatory cytokines IL-21 and IL-17 Allogeneic HSCT Over-activation of pro-inflammatory T follicular helper (Tfh) cells and B cells, leading to over-production of antibodies IL-21 Treg IL-17 Simultaneously causes deficiency of regulatory T cells, leading to a lack of appropriate regulation of immune response Combination of T cell and B cell dysfunction leads to cgvhd Tfh B-Cell Inflammation/tissue injury 20

21 KD025 in cgvhd: Preclinical Models Summary ROCK2 Inhibition with KD025 Effectively Decreased cgvhd Manifestation KD025 reversed clinical and immunological symptoms of cgvhd in murine models: Improved lung function and blocked progression of skin fibrosis Significantly decreased cgvhd pathology in lung, liver, colon and spleen Maintained the immune system s ability to fight infections Defined the molecular mechanism of targeted ROCK2 inhibition in cgvhd: Decreased the number of pro-inflammatory T cells and B cells and up-regulated the number of regulatory T cells Reduced collagen and antibody deposition in lung Flynn R et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a STAT3-dependent mechanism. Blood Apr 28;127(17):

22 KD025 Significantly Improved Lung Function Tests cgvhd Mouse Model, Induced by a Mismatched Bone Marrow (BM) Transplant Chemotherapy (Cytoxan 120mg/kg) Radiation (TBI 8.5Gy) B10.BR mouse strain (H-2 k ) Transplanted with BM + splenocytes (T cells) from C57Bl/6 mouse strain (H-2 b ) KD025 Days: -3& KD025 Improved Lung Function via Concurrent Modulation of STAT3/STAT5 in Immune Cells Resistance 1.5 * * Resistance Elastance Compliance 80 Elastance ** * 0.08 Compliance ** * BM + T cells (cgvhd) KD025 STAT3 cmh2o.s/ml BM t BM + T cells (cgvhd) 5 KD025 ml/cmh2o BM BM + KD025 T cells (cgvhd) t 5 cmh2o/ml y BM BM + KD025 T cells (cgvhd) t 5 BM + T cells (cgvhd) KD025 Control STAT5 Control 22

23 KD025 Decreased Collagen and Antibody Deposition in Lungs KD025 Normalized Collagen Deposition to Levels Observed in Mice Without cgvhd Collagen Deposition Collagen BM BM + T cells (cgvhd) KD025 Collagen Deposition Collagen deposition shown in red BM BM + T cells (cgvhd) KD025 KD025 Decreased the Amount of Antibodies in Lungs Antibodies BM BM + T cells (cgvhd) KD025 Antibody Deposition Antibodies shown in green BM BM + T cells (cgvhd) KD025 23

24 KD025 Blocks Progression of Sclerodermatous cgvhd KD025 Shows Decrease in Fibrosis in Sclerodermatous Mouse Model TBI (775 cgy) BALB/c mice strain (H-2 d ) BM + T cells from B10.D2 mice strain (H-2 d ) KD025 Days: cgvhd thins skin and causes fibrosis (shown in red) and immune cell infiltration (purple dots) KD025 reduces epidermal hyperplasia (thickening of top layer of skin) and keratosis (abnormal skin growth) while reducing overall skin pathology score Skin Vehicle (Day 51) KD025 (Day 51) Vehicle KD025 In collaboration with Dr. Leo Luznik at The Johns Hopkins University School of Medicine 24

25 KD025 Decreased Antibody-Producing Tfh and B Cells KD025 Decreased Antibody Production, Down-regulating Overall Immune Response KD025 decreased the size of germinal centers (place in spleen where antibodies are produced) KD025 decreased the number of antibody-producing T follicular helper (Tfh) cells and B cells KD025 up-regulated the number of T regulatory cells (Tregs), helping to resolve inflammation Spleen size Spleen size T follicular helper (Tfh) T follicular helper (Tfh) cells cells Germinal center Germinal center B cells B cells T follicular regulatory T follicular regulatory (Treg) (Treg) cells cells BM BM + T cells (cgvhd) KD025 BM BM + T cells (cgvhd) KD025 BM BM + T cells (cgvhd) KD025 BM BM + T cells (cgvhd) KD025 25

26 Genetic Ablation of ROCK2 Reverses cgvhd Pathology Mice Implanted with ROCK2-Deficient T Cells Showed Reversal in cgvhd Pathology Chemotherapy (Cytoxan 120mg/kg) Radiation (TBI 8.5Gy) B10.BR mice (H-2 k ) BM + ROCK2-deficient cells from C57Bl/6 mice (H-2 b ) Lung function tests and tissue analysis Days: -3& ROCK2-Deficient Mice Showed Improved Lung Function Tests via Modulation of Tfh and Treg Cells Lung function tests Resistance Resistance Compliance Compliance Elastance Elastance Cellular analysis in spleen T T % CD4+ PD1Hi CXCR5+FoxP3- BM BM + BM + BM BM + BM + BM BM + BM + W.T. ROCK2- W.T. ROCK2- W.T. ROCK2- p g y 8 Tfh cells 15 Treg cells BM BM + BM + BM BM + BM + W.T. ROCK2- W.T. ROCK2-2 % CD4+ PD1Hi CXCR5+FoxP T 2 26

27 KD025 Reduced cgvhd Severity in Multiple Organs Radiation (TBI 775 cgy) BALB/c mice strain (H-2 d ) BM + T cells from B10.D2 mice strain (H-2 d ) KD025 Days: KD025 Reduced Pathology Scores, Based on Organ Histology Lung Liver Colon Spleen BM BM + T cells (cgvhd) KD025 BM BM + T cells (cgvhd) KD025 BM BM + T cells (cgvhd) KD025 BM BM + T cells (cgvhd) KD025 27

28 KD025 Did Not Affect Anti-CMV Infection Response In Mice KD025-treated Mice Challenged with Murine CMV can Still Mount an Antiviral Immune Response C57BL/6 mice strain Infected with 1X10 4 PFU of murine cytomegalovirus (mcmv) KD025 Days: With KD025, Protective Immune Response is Preserved NK cells Liver Day 5 CD8 T cells Liver Day 10 Viral Titers (Liver) Vehicle KD025 Vehicle KD025 Non-infect. Infected with 1X10 4 PFU Vehicle KD025 Non-infect. Infected with 1X10 4 PFU 28

29 Summary: Demonstrated Activity of KD025 in cgvhd Models Data Highlight the Potential of KD025 for Clinical cgvhd Therapy KD025 targets both the immunologic and fibrotic components of cgvhd Immunologic component: Down-regulated pro-inflammatory Tfh and B cells and up-regulated antiinflammatory Treg cells Fibrotic component: Decreased collagen deposition and improved skin pathology KD025 has a profound effect on decreasing cgvhd pathology Demonstrated improvement across multiple organs affected by cgvhd KD025 treatment preserved the immune system s ability to fight viral pathogens 29

30 cgvhd Overview Harlan W. Waksal, M.D. President and CEO, Kadmon

31 Chronic Graft-Versus-Host-Disease (cgvhd) Overview cgvhd: Complication Following Bone Marrow and Stem Cell Transplantation cgvhd is a common and often fatal complication following allogeneic bone marrow transplantation (BMT) and hematopoietic stem cell transplantation (HSCT) Allogeneic BMT and HSCT are often used to treat patients with cancer of the blood or bone marrow, such as myeloma or leukemia cgvhd has autoimmune and fibrotic disease pathophysiologies Transplanted immune cells (graft) attack recipient tissue (host), leading to inflammation and fibrosis in multiple tissues Two forms: acute GVHD (agvhd) and chronic GVHD (cgvhd) Etiology, pathophysiology and management differ for agvhd and cgvhd agvhd occurs up to 100 days post-stem cell transplantation cgvhd diagnosis hinges on clinical manifestations rather than time of onset 31

32 cgvhd Overview (Cont d) cgvhd Typically Affects Multiple Organ Systems Simultaneously Organ or Tissue Skin 75% Presentation % in Patients Diagnostic Features Three-dimensional discolored skin rashes, skin tightening, skin thickening, scaling Mouth 51%-63% Dry mouth, abscesses, dysphagia Liver 29%-51% Jaundice, hepatomegaly, fatigue Eye 22%-33% GI tract and esophagus Dry, irritated eyes, inflamed eyes, vision changes, sticky secretions, ocular pruritus 7%-45% Anorexia, diarrhea, weight loss Lung 4%-19% Shortness of breath Muscles, fascia and joints 6% Fatigue, muscle weakness, joint pain and stiffness, chronic pain Genitalia 1% Vaginal dryness, scaling and erythema 32

33 Definitions of NIH cgvhd Response Criteria NIH Consensus Criteria Remain the Standard for cgvhd Assessment NIH Overall Response Criteria are based on clinician assessments of 10 organs/tissues Each organ or site is scored on a numeric scale, with increasing score reflective of more severe disease NIH scoring system is the only FDA-accepted disease assessment scale Response Criteria Complete response (CR) Partial response (PR) Overall response rate (ORR) Definition Complete resolution of all reversible manifestations of cgvhd Clinically meaningful improvement in 1 or more organs without clinically meaningful progression in any other organ The proportion of patients who achieved an NIH-defined CR or PR Stable disease (SD) Progressive disease (PD) No clinically meaningful worsening in baseline cgvhd manifestations Clinically meaningful worsening in 1 or more organs, regardless of improvement in other organs 33

34 Other cgvhd Assessment Scales Lee cgvhd Symptom Scale is Considered for Informational Purposes Lee cgvhd Symptom Scale 30-item symptom scale that captures cgvhd-specific symptom burden Questionnaire that asks patients to indicate the degree of bother they experienced during the past four weeks due to cgvhd symptoms 34

35 cgvhd Treatment Landscape Steroids are Currently the Only Standard cgvhd Therapy Steroids are currently the gold standard treatment for cgvhd There are no approved therapies for patients with cgvhd who fail steroids Severe side effects associated with long-term steroid use include increased risk of infection, osteoporosis, muscle weakness, weight gain, blurred vision and high blood pressure Two other drugs, ruxolitinib and ibrutinib, are in development for cgvhd: Ruxolitinib: JAK 1/2 inhibitor currently FDA approved for myelofibrosis and for polycythemia vera Developed by Incyte (Novartis has ex-u.s. rights for GVHD); brand name Jakafi Ibrutinib: BTK inhibitor currently FDA approved for several B-cell cancers Co-developed by Janssen and AbbVie; brand name Imbruvica 35

36 Ibrutinib: Targeted Therapy in Development for cgvhd Ibrutinib Overview in cgvhd Submission Status Supplemental New Drug Application (snda) currently under FDA review for cgvhd after failure of 1 or more systemic therapies snda based on single-arm Phase 2 study in 42 cgvhd patients Granted FDA Breakthrough Therapy Designation for second-line therapy of cgvhd Summary Efficacy Results Overall response rate (ORR) was 67% (28/42) Of the 28 clinical responders, 71% (21/28) sustained response at 20 weeks, and 48% (12/25) sustained response at 32 weeks Overall, 62% of patients achieved steroid dose reduction 36

37 Ibrutinib and Ruxolitinib: Summary Safety Results in cgvhd Notable Treatment-Emergent Adverse Events (AEs) Ibrutinib Summary Serious AEs (SAEs) in 52% of treated patients, including pneumonia (n=6), septic shock (n=2) and pyrexia (n=2) Two fatal events occurred: multilobular pneumonia and bronchopulmonary aspergillosis Ruxolitinib Summary Cytomegalovirus (CMV) reactivation in 15% of patients 37

38 KD : Study Design John L. Ryan, M.D., Ph.D. Executive Vice President, Chief Medical Officer, Kadmon

39 KD : Ongoing Ph2 Trial of KD025 in cgvhd Open-label, dose-finding Phase 2 study to evaluate the safety, tolerability and activity of KD025 in adults with steroid-dependent or steroid-refractory cgvhd and active disease 24-week study, with option to continue for up to 48 weeks Enrolling 48 patients into three cohorts, enrolling sequentially following safety assessment of previous cohort: KD mg QD KD mg BID KD mg QD Open-label, Dose-finding Study of KD025 in cgvhd Cohort KD mg QD KD mg BID KD mg QD Enrollment Status Fully enrolled (17 patients) 15 of 16 patients enrolled Pending completion of enrollment in 200 mg BID cohort 39

40 KD : Enrollment Criteria Key Inclusion Criteria Adults with steroid-dependent or steroid-refractory cgvhd Patients must have had allogeneic BMT or HSCT Patients must have evidence of persistent cgvhd manifestations after at least 2 months of steroid therapy prior to enrollment Patients must be receiving steroid therapy at time of enrollment Patients may or may not be receiving calcineurin inhibitor therapy (e.g., tacrolimus) at time of enrollment Key Exclusion Criteria Patients receiving other immunosuppressive therapies, including mtor inhibitors (e.g., sirolimus), during participation in the study 40

41 KD Key Study Endpoints Endpoint Primary Description KD025 activity in patients with steroid-dependent or steroid refractory cgvhd and active disease at 24 weeks in terms of ORR, as defined by 2014 NIH Criteria for overall response Safety and tolerability of KD025 in patients with cgvhd Secondary Changes in corticosteroid and calcineurin inhibitor dose Changes in cgvhd severity using the Physician-Reported Global Chronic GVHD Activity Assessment Changes in symptom activity as based on cgvhd Activity Assessment Patient Self-Report Exploratory Change in symptom burden/bother using the Lee cgvhd Symptom Scale Changes in the expression of several cytokines (including IL-17α, IL-21, and IL-2) in plasma after KD025 administration Changes in percentage of immune-cell subtypes (including Th17 and Treg cells) in whole blood after KD025 administration 41

42 KD : Seven Trial Sites Site Name Location Principal Investigator City of Hope Duarte, CA Amandeep Salhotra Assistant Clinical Professor, Division of Hematology and Hematopoietic Cell Transplantation, City of Hope Fred Hutchinson Cancer Center University of Minnesota Vanderbilt University SCRI: Tristar Bone Marrow SCRI: Texas Transplant Institute Ohio Oncology Hematology Seattle, WA Minneapolis, MN Nashville, TN Nashville, TN San Antonio, TX Cincinnati, OH Stephanie Lee Professor, University of Washington Aleksandr Lazaryan Assistant Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Madan Jagasia Professor of Medicine, Division of Hematology/Oncology, Vanderbilt University School of Medicine Carlos Bachier Medical Oncologist Behyar Zoghi Transplant Physician James Essell Medical Oncologist 42

43 Amandeep Salhotra, M.D. Assistant Clinical Professor, Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 2013-present Education and training: Fellow, Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, Fellow, Hematology-Oncology, University of Virginia Medical Center, Charlottesville, VA, Fellow, Hematology-Oncology, St. Elizabeth's Medical Center, Boston, MA, Post Doctoral Fellow, Neuro-Oncology, Johns Hopkins University, Baltimore, MD, Resident Physician, Internal Medicine, St. Elizabeth's Medical Center, Boston, MA, Senior Resident, Pediatrics, All India Institute of Medical Sciences, New Delhi, India, Doctor of Medicine degree, Maulana Azad Medical College, University of Delhi, India, 2004 Clinical investigator of ongoing Phase 2 clinical trial of KD025 in cgvhd Amandeep Salhotra, MD 43

44 KD : 200 mg QD Interim Data Amandeep Salhotra, M.D. Assistant Professor, Hematology and Hematopoietic Cell Transplantation City of Hope, Duarte, CA

45 KD : Ongoing Ph2 Trial of KD025 in cgvhd Open-label, dose-finding Phase 2 study to evaluate the safety, tolerability and activity of KD025 in adults with steroid-dependent or steroid-refractory cgvhd and active disease 24-week study, with option to continue for up to 48 weeks Enrolling 48 patients into three cohorts, enrolling sequentially following safety assessment of previous cohort: KD mg QD KD mg BID KD mg QD Open-label, Dose-finding Study of KD025 in cgvhd Today s discussion: Data from 200 mg QD and initial data from the 200 mg BID cohort 45

46 KD : Enrollment Criteria Key Inclusion Criteria Adults with steroid-dependent or steroid-refractory cgvhd Patients must have had allogeneic BMT or HSCT Patients must have evidence of persistent cgvhd manifestations after at least 2 months of steroid therapy prior to enrollment Patients must be receiving steroid therapy at time of enrollment Patients may or may not be receiving calcineurin inhibitor therapy (e.g., tacrolimus) at time of enrollment Key Exclusion Criteria Patients receiving other immunosuppressive therapies, including mtor inhibitors (e.g., sirolimus), during participation in the study 46

47 KD Baseline Characteristics and Transplant History Characteristic N=17 Median age (years) 50 Male / Female 76% / 24% Median time (range) from transplant to cgvhd diagnosis (months) 9.1 ( ) Median time (range) from initial cgvhd diagnosis to KD025 (months) 25.9 ( ) cgvhd organ involvement, % Eyes 94% Liver 65% Skin 82% Lung 53% Mouth 76% GI 18% Joints 65% Esophagus 12% Indication for transplant Acute lymphoblastic leukemia (n=3) Chronic lymphocytic leukemia (n=1) Non-Hodgkin s lymphoma (n=1) Acute myelogenous leukemia (n=3) Chronic myelogenous leukemia (n=1) Primary immune deficiency (n=1) Hodgkin s lymphoma (n=2) Mantle cell lymphoma (n=1) T-cell lymphoblastic lymphoma (n=1) Myelodysplastic syndrome (n=2) Myelofibrosis (n=1) 47

48 Preliminary Activity Data Summary: Cohort 1 Cohort 1: KD mg QD Overall response rate ( ORR ), which includes partial and complete responders, is 12 of 17 (71%) patients Of responders remaining on KD025 through week 24, 7 of 8 (88%) sustained responses 1 additional responder remains on KD025 and is pending week 24 assessment The remaining 3 of 12 responders discontinued study In addition to the 12 responders, 2 patients have stable disease and remain on KD025 through week 24 Overall clinical benefit (response and stable disease) in 14 of 17 patients (82%) 10 of 17 (59%) patients had steroid dose reductions while on KD025 8 of 12 (67%) responders had steroid dose reductions while on KD025 Of the 6 patients on tacrolimus during study, 4 (67%) had dose reductions 8 of 12 (67%) responders saw improvement in the Lee cgvhd symptom score while on KD025 48

49 KD025 Safety Results: Cohort 1 Cohort 1: KD mg QD No drug-related SAEs to date Liver function tests (LFTs): No drug-related LFT elevations have been observed to date 49

50 Preliminary Data Summary: Cohort 2 Cohort 2: KD mg BID 15 of 16 patients have been enrolled Of the 15 patients, 9 patients have reached 8 weeks of KD025 (first clinical assessment) All 9 of these patients remain on study 6 of the 9 patients have achieved a response at 8 weeks No drug-related SAEs to date 50

51 KD025 Conclusions KD025 Shows Clinically Meaningful Responses KD025 shows clinically meaningful responses in patients with steroid-dependent cgvhd at 200 mg QD ORR while on study drug is 12 of 17 (71%) patients In addition to the 12 responders, 2 patients have stable disease and remain on KD025 through week 24 Overall clinical benefit (response and stable disease) in 14 of 17 patients (82%) 10 of 17 (59%) patients in 200 mg QD cohort had steroid dose reductions while on KD025 In the 200 mg BID cohort, 6 of the 9 patients have achieved a response at 8 weeks Additional patients have not yet reached clinical evaluation No drug-related SAEs to date in either cohort (200 mg QD and 200 mg BID) 51

52 KD025 in cgvhd: Regulatory Strategy John L. Ryan, M.D., Ph.D. Executive Vice President, Chief Medical Officer, Kadmon

53 KD Regulatory Strategy Data Readout Plan Submit additional data from all cohorts for presentation at scientific conferences Regulatory Strategy Plan to meet with FDA in 2H 2017 to obtain guidance on Breakthrough Therapy Designation application and regulatory path for approval Path for approval in steroid dependent or refractory cgvhd patient population: Conduct a single-arm study (optimal dose) following completion of enrollment in the ongoing KD study Path for approval in newly diagnosed cgvhd patient population: Conduct a two-arm, placebo controlled study (KD025 + corticosteroid vs. placebo + corticosteroid) Parallel interaction with EMA and FDA to identify and execute appropriate global registration strategy 53

54 Q&A