KD : A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cgvhd) - Pharmacodynamics and Updated Results

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1 KD : A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cgvhd) - Pharmacodynamics and Updated Results Madan Jagasia 1, Amandeep Salhotra 2, Carlos R. Bachier 3, James Essell 4, Daniel J. Weisdorf 5, Behyar Zoghi 6, Aleksandr Lazaryan 5, Laurie S. Green 7, Olivier Schueller 7, Alexandra Zanin-Zhorov 7, Jonathan M. Weiss 7, David Eiznhamer 7, Sanjay K. Aggarwal 7, Bruce R. Blazar 8 and Stephanie J. Lee 9 1 Vanderbilt University, Nashville, TN; 2 City of Hope, Duarte, CA; 3 Sarah Cannon Research Institute, Nashville, TN; 4 Oncology/Hematology Care, Cincinnati; 5 University of Minnesota, Minneapolis, MN; 6 Texas Transplant Institute, Methodist Hospital, San Antonio, TX; 7 Kadmon Corporation, LLC, New York, NY; 8 Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; 9 Fred Hutchinson Cancer Research Center, Seattle, WA ASH Annual Meeting, December 2018 Kadmon Holdings, Inc. 1

2 Pathophysiology of Chronic GVHD (cgvhd) cgvhd is Driven by Immune Cells and Pro-inflammatory Cytokines cgvhd involves both T cells and B cells Characterized by overproduction of pro-inflammatory cytokines IL-21 and IL-17 Over-activation of pro-inflammatory T follicular helper (Tfh) cells and B cells, leading to overproduction of antibodies Simultaneously causes deficiency of regulatory T (Treg) cells, leading to a lack of appropriate regulation of immune response Combination of T cell and B cell dysfunction leads to cgvhd Blood,

3 ROCK2 Plays Key Role in Autoimmunity and Inflammation ROCK2 Inhibition Rebalances Immune Response to Treat Immune Dysfunction Rho-associated coiled-coil kinase (ROCK) mediates a wide range of functions, including cell movement, shape, differentiation and function 1 Two isoforms exist: ROCK1 and ROCK2 1 ROCK2 inhibition: Reduces STAT3 phosphorylation and increases STAT5 phosphorylation 2,3 Downregulates TH17 responses and increases Treg function, helping to resolve immune dysregulation 2,3 ROCK2 Activation ROCK2 Inhibition STAT3 (TH17) Inflammation STAT5 (Treg) STAT3 (TH17) STAT5 (Treg) RORgt IRF4 Resolution Inflammation Resolution 1 Small GTPases, 2014; 2 Proc Natl Acad Sci, 2014; 3 Blood,

4 ROCK is an Intercellular Integrator of Pro-Fibrotic Signals ROCK Regulates Multiple Profibrotic Processes, Including Myofibroblast Activation ROCK is downstream of major pro-fibrotic mediators, including: Matrix stiffness Transforming growth factor beta (TGF-β) Matrix stiffness Myofibroblast Cell Stress fiber formation Lysophosphatidic acid (LPA) ROCK regulates fibroblast differentiation to myofibroblasts, a pathological cell type in fibrosis ROCK ROCK mediates stress fiber formation MKL1 ROCK regulates transcription of profibrotic genes, including: Connective tissue growth factor (CTGF) MKL1 MKL1 CTGF Alpha-smooth muscle actin (α-sma) Am J Pathol Apr;185(4):

5 KD025 Reduced cgvhd Severity in Preclinical Models KD025 Reduced Skin Pathology Scores, Epidermal Hyperplasia and Keratosis Skin GVHD Score Skin Vehicle (Day 51) KD025 (Day 51) Vehicle KD025 KD025 Reduced Pathology Scores, Based on Organ Histology (D60) Flynn, Blazar et al, Blood 2016 BM BM + KD025 BM BM + KD025 BM BM + KD025 T cells T cells T cells cgvhd cgvhd cgvhd KD025-treated Mice Challenged with Murine CMV Mounted an Antiviral Immune Response 5

6 KD : Design and Key Endpoints Key Eligibility Criteria: Adults with steroiddependent or steroidrefractory cgvhd Have persistent active cgvhd after at least 2 months of steroid therapy Receiving glucocorticoid therapy +/- calcineurin inhibitor therapy for cgvhd No more than 3 prior lines of treatment for cgvhd Cohort 1: 200mg QD (n=17) Cohort 2: 200mg BID (n=16) Cohort 3: 400mg QD (n=21) Three cohorts enrolled sequentially, following safety assessment of previous cohort Key Endpoints: ORR, per 2014 NIH criteria Safety and tolerability of KD025 in patients with cgvhd Duration of response (DOR) Response by organ system Changes in corticosteroid and calcineurin inhibitor dose All data as of 13 September,

7 KD : Baseline Characteristics 48% of all patients had 4 organs affected Included both inflammatory and fibrotic manifestations 67% of all patients had received 2 prior lines of cgvhd therapy Baseline Characteristics Cohort 1 (n=17) Cohort 2 (n=16) Cohort 3 (n=21) Median age (years (range)) 50 (20-63) 55 (30-75) 46 (25-75) Male/Female (%/%) 76/24 56/44 57/43 Median time cgvhd diagnosis to study (months) Organ Involvement 4 organs involved 8 (47) 10 (63) 8 (38) Eyes 14 (82) 11 (69) 17 (81) Skin 13 (76) 12 (75) 15 (71) Mouth 13 (76) 11 (69) 11 (52) Joints and fascia 12 (71) 11 (69) 10 (48) Lungs 3 (18) 3 (19) 11 (52) Upper GI 2 (12) 4 (25) 2 (10) Esophagus 2 (12) 0 (0) 5 (24) Lower GI 1 (6) 2 (13) 1 (5) Liver 0 (0) 2 (13) 0 (0) Severe cgvhd 1 12 (71) 14 (88) 16 (76) Prior Therapies 2 Cohort 1 (n=17) Cohort 2 (n=16) Cohort 3 (n=21) Median prednisone dose at BL (mg/kg/day) Prior Lines of Therapy Median prior lines of therapy (n (%)) 15(88) 9(56) 12(57) Prior Therapies Corticosteroids 17(100) 16(100) 21(100) Sirolimus 10(59) 9(56) 7(33) Tacrolimus 8(47) 6(38) 11(52) Rituximab 8(47) 3(19) 5(24) MMF 4(24) 4(25) 4(19) Cyclosporin 3(18) 0(0) 2(10) Methotrexate 1(6) 2(13) 0(0) Ibrutinib 1(6) 0(0) 2(10) Ixazomib 1(6) 1(6) 0(0) Others for 1 patient each: Anti Thymocyte Globulin, Imatinib, Ofatumumab, Ruxolitinib, Ibrutinib/Placebo 1 Defined as at least 1 organ with NIH Activity Assessment score of 3, or lung score of 2 or 3, at baseline 2 ECP was not counted as a prior systemic therapy 7

8 KD : Patient Disposition 20 Patients Continuing Treatment with KD025 Cohort 1 Cohort 2 Cohort 3 17 patients enrolled Median treatment duration: 37 weeks 16 patients enrolled Median treatment duration: 33 weeks 21 patients enrolled Median treatment duration: 27 weeks 5 cgvhd Progression 10 cgvhd Progression 3 cgvhd Progression 6 Withdrawal 3 Withdrawal 7 Withdrawal 2 Relapse underlying cancer 2 AEs (headache, diarrhea) 1 Voluntary withdrawal 1 Noncompliance 2 Voluntary withdrawal 1 Investigator decision 3 Voluntary withdrawal 2 Death 1 Relapse underlying cancer 1 Investigator decision 6 Active Median treatment duration: 89 weeks 3 Active Median treatment duration: 68 weeks 11 Active Median treatment duration: 34 weeks 8

9 KD : Safety and Tolerability No treatment-related SAEs No apparent increased risk of infection AEs were overall consistent with those expected in cgvhd patients receiving corticosteroids Safety Overview, n (%) Median weeks of treatment Cohort 1 (n=17) Cohort 2 (n=16) Cohort 3 (n=21) ITT (n=54) Any Adverse Event (AE) 16 (94) 16 (100) 19 (90) 51 (94) Grade 3 / 4 AE 10 (59) 10 (63) 9 (43) 29 (54) SAE 5 (29) 6 (38) 9 (43) 20 (37) Drug related AE Any related AE 6 (35) 9 (56) 9 (43) 24 (44) Related AE leading to discontinuation 2 (12) (4) Related Grade 3 / 4 event 2 (12) 4 (25) 2 (10) 8 (15) Related SAE On Study Deaths (14) 2 3 (6) 1 Headache; Diarrhea 2 Relapse of Leukemia; Lung infection; Cardiac arrest. All considered not related to KD025 Commonly Reported AEs, n (%) All Grade, in 15% Cohort 1 (n=17) Cohort 2 (n=16) Cohort 3 (n=21) ITT (n=54) Upper respiratory tract infection 5 (29) 6 (38) 3 (14) 14 (26) ALT / AST increased 6 (35) 4 (25) 3 (14) 13 (24) Fatigue 5 (29) 3 (19) 5 (24) 13 (24) Nausea 6 (35) 2 (13) 5 (24) 13 (24) Diarrhea 6 (35) 2 (13) 4 (19) 12 (22) Anemia 5 (29) 4 (25) 1 (5) 10 (19) GGT increased 4 (24) 5 (31) 1 (5) 10 (19) Cough 1 (6) 3 (19) 5 (24) 9 (17) Dyspnea 2 (12) 5 (31) 2 (10) 9 (17) Hypertension 5 (29) 2 (13) 2 (10) 9 (17) Hyperuricemia 3 (18) 1 (6) 5 (24) 9 (17) Grade 3 / 4, in 5% GGT increased 3 (18) 3 (19) 0 6 (11) Hyperglycemia 2 (12) 0 2 (12) 4 (7) Anemia 2 (12) 1 (6) 0 3 (6) Dyspnea 1 (6) 1 (6) 1 (5) 3 (6) Infection, All Grade, in 5% Upper respiratory tract infection 5 ( 29) 6 ( 38) 3 ( 14) 14 (26) Pneumonia 2 ( 12) 2 ( 13) 0 4 (7) Influenza 2 ( 12) 1 ( 6) 0 3 (6) Oral candidiasis 2 ( 12) 1 ( 6) 0 3 (6) Sinusitis 1 ( 6) 1 ( 6) 1 ( 5) 3 (6) 9

10 Overall Response Rate KD : Overall Response Rate (ORR) ORR (ITT Population) Responses Achieved Across Key Patient Subgroups ORR Cohort 1 (n=17) 65% (11/17) Cohort 2 (n=16) 63% (10/16) Cohort 3 (n=21) 52% 1 (11/21) 80% 70% 60% 59% 58% 62% 55% 50% 95% CI (41, 83) (39, 82) (32, 72) 40% 1 Three patients in Cohort 3 did not reach first response assessment. On a response-evaluable basis, Cohort 3 ORR = 61% (11/18) 30% 20% 10% 0% ITT 2 Prior prior lines of of therapy 4 Organs organs Involved involved Severe cgvhd (n=54) (n=36) (n=26) (n=42) 10

11 KD : Responses Across Organ Systems Responses observed across all affected organ systems Complete responses (CRs) in upper GI, lower GI, mouth, joints/fascia, esophagus, eyes, liver and skin 2 Partial responses (PRs) in lung Organ Involved n (%) Responders (n=32) CR n (%) PR n (%) ORR n (%) Upper GI 7(22) 7(100) 0(0) 7(100) Lower GI 3(9) 3(100) 0(0) 3(100) Mouth 21(66) 11(52) 5(24) 16(76) Joints and fascia 20(63) 1(5) 13(65) 14(70) Esophagus 3(9) 2(67) 0(0) 2(67) Eyes 27(84) 6(22) 9(33) 15(56) Liver 2(6) 1(50) 0(0) 1(50) Skin 22(69) 5(23) 5(23) 10(45) Lungs 10(31) 0(0) 2(20) 2(20) 11

12 KD : Duration of Response (DOR) Responses Achieved with KD025 Are Durable Responses were rapid: 75% of responders have achieved a response at the first assessment (8 weeks) Amongst responders: Kaplan-Meier median DOR of 28 weeks in ITT responder population Responders with sustained responses for 20 weeks: Cohort 1: 9/11 (82%) Cohort 2: 5/10 (50%) Cohort 3: 4/11 (36%) Durability data continue to mature Duration of Response ITT Responders (n=32) Weeks Number at risk

13 KD : Lee cgvhd Symptom Scale (LSS) Score 72% of Responders Experienced Clinically Meaningful Improvement in Symptoms 1 Cohort 1 (%) Cohort 2 (%) Cohort 3 (%) Patients with improvement in LSS Score 11/17 (65) 9/16 (56) 11/21 (52) Responders with improvement in LSS Score 9/11 (82) 5/10 (50) 9/11 (82) Non-Responders with improvement in LSS Score 2/6 (33) 4/6 (67) 2/10 (20) 1 Clinically meaningful improvement ( 7 point reduction) in LSS score 13

14 KD : Corticosteroid and Tacrolimus Dose Reductions 7 Patients Have Completely Discontinued Steroids Cohort 1 (%) Cohort 2 (%) Cohort 3 (%) % reduction in median corticosteroid dose 44% 23% 10% Patients with corticosteroid dose reduction 13/17 (76) 9/16 (56) 15/21 (71) Responders with corticosteroid dose reduction 8/11 (73) 5/10 (50) 10/11 (91) Non-Responders with corticosteroid dose reduction 5/6 (83) 4/6 (67) 5/10 (50) Corticosteroid discontinuations 4/17 (24) 1/16 (6) 2/21 (10) Patients with tacrolimus dose reductions 4/6 (67) 5/6 (83) 5/11 (45) 14

15 KD : Pharmacodynamics With KD025 treatment: KD025 May Modulate Immune Homeostasis by Restoring the TH17/Treg Balance Treg cells increased TH17 decreased Consistent with KD025 mechanism of action 15

16 KD : Conclusions KD025 Achieved Clinically Meaningful Responses Exploratory Pharmacodynamic Data Support KD025 Mechanism of Action KD025 was well tolerated: No treatment-related SAEs No apparent increased risk of infection Patients achieved NIH-defined clinical responses with KD025 ORRs of 65%, 63% and 52% in Cohorts 1, 2 and 3 respectively CRs in multiple organs, including in organs with fibrotic disease Responses are clinically meaningful: Durable Patients were able to reduce or discontinue corticosteroids and other immunosuppressants Patients experienced clinically meaningful improvement in symptoms (LSS score) Exploratory PD data show a decrease in TH17 and an increase in Treg cells during treatment with KD025 16

17 KD : Ongoing Pivotal Trial of KD025 in cgvhd Objective: Demonstrate clinically meaningful responses with KD025 in a patient population with significant unmet medical need, with an ORR in excess of 30% Key Eligibility Criteria: Adults who have had HSCT Active cgvhd Received at least two prior lines of systemic therapy for cgvhd R KD mg QD (n=63) KD mg BID (n=63) Treat to progression Primary Endpoint: ORR, per 2014 NIH criteria Key Secondary Endpoints: Safety Duration of response Response by organ system Lee Symptom Score Changes in corticosteroid and calcineurin inhibitor dose 17

18 Backup 18

19 KD : Clinical Trial Sites Fred Hutchinson Cancer Research Center University of Minnesota Ohio Oncology Hematology City of Hope Vanderbilt University SCRI: Sarah Cannon Center for Blood Cancer SCRI: Texas Transplant Institute 19

20 KD : Safety and Tolerability (cont.) AST / ALT Elevations Of 13 patients with AST/ALT elevation AEs, 7/13 (54%) had elevations at baseline Elevations were generally low grade, with max Grade 1 in 11/13 (85%) patients None led to treatment discontinuation Dose modifications were rare (1/13 (8%)) 6/13 (46%) were considered possibly drug related Elevations often considered cgvhd-related GGT Elevations Of 10 patients with GGT elevation AEs, 100% (10/10) had elevations at baseline Four of 10 (40%) had their highest measured GGT level prior to initiating KD025 Eight of 10 (80%) had concomitant alkaline phosphatase elevations, a cholestatic pattern often seen with cgvhd liver involvement None led to treatment discontinuation Elevations remained stable in 46% of patients and trended downward in 54% with continued KD025 dosing A Grade 3 elevation in one patient did not recur after restarting KD025 following a 2-week drug holiday 20