TG Therapeutics, Inc. · NASDAQ:TGTX
TG Therapeutics — 23rd Congress of EHA (June 2018)
22 slides from TG Therapeutics's conference presentation, Jun 15, 2018
Slide 1: Resurrecting response to ruxolitinib: Phase I study of ruxolitinib and umbralisib
Resurrecting response to ruxolitinib: A Phase I study of ruxolitinib and umbralisib (TGR-1202) in ruxolitinib- experienced myelofibrosis Tamara K. Moyo, Jeanne Palmer, Yi Huang, Olalekan Oluwole, Sanjay R. Mohan, Rebekah Caza, Gregory D. Ayers, Lynne Berry, Channing Dudley, Laura Dugger, Hari P. Mis
Slide 2: Background
Background • The JAK1/2 inhibitor ruxolitinib improves symptoms, reduces spleen size, and improves overall survival in Intermediate-2/High risk myelofibrosis. • Depth of response is variable. • Loss of response to ruxolitinib poses a clinical challenge – Alternative therapies are currently limited –
Slide 3: PI3Kδ is overexpressed in myelofibrosis
PI3Kδ is overexpressed in myelofibrosis • PI3Kδ is overexpressed in PMF patient samples irrespective of prior exposure to ruxolitinib. • Inhibition of PI3K/AKT signaling reduces P proliferation and clonogenic potential of hematopoietic progenitors of PMF patients. P PI3K P STAT Meadows SA, et al. Bl
Slide 4: Umbralisib (TGR-1202) is highly selective for PI3Kδ
Umbralisib (TGR-1202) is highly selective for PI3Kδ • Chemically distinct from other inhibitors in its class. • More selective than other PI3K inhibitors for the delta isoform. • Led to apoptosis in AML and ALL cell lines and patient- derived AML, ALL, and CLL cells Friedman DR, et al. Blood 2012 Va
Slide 5: Single-agent umbralisib is well-tolerated
Single-agent umbralisib is well-tolerated Umbralisib Idelalisib Duvelisib Ruxolitinib n = 90 n=125 n=110 n=210 n=155 Adverse Event CLL NHL CLL* LEUK/LYMPH MF Anemia 9% 2% 5% 19% 45% Neutropenia 13% 27% 42% 32% 7% Thrombocytopenia 6% 6% 10% 14% 13% Hepatotoxicity 3-6% 13% 5-9% 19% Colitis 2% 3% 6% 11
Slide 6: Hypothesis
Hypothesis Addition of umbralisib to ruxolitinib could augment or re-sensitize response for patients with suboptimal or lost response to single- agent ruxolitinib.
Slide 7: Study design and patient populations
Study design and patient populations EXPANSION COHORT 1 Ruxolitinib-experienced MF Ruxolitinib-experienced MF Ruxolitinib-experienced MF Ruxolitinib-experienced ESCALATION STAGE 1 ESCALATION STAGE 2 Myelofibrosis (MF) EXPANSION COHORT 2 • PMF, post-PV MF or Treatment-naïve MF post-ET MF • Grade ≥1 f
Slide 8: Patient characteristics
Patient characteristics Baseline Characteristic n = 23 (range) Baseline Characteristic N = 23(range) Median Age 67 (49-83) Median Plt x10−9/L 197 (34-1420) Male 14 Median Hgb g/dL 9.5 (8.5-13.9) Diagnosis Median ANC x10−9/L 6.7 (2.1-57.1) Primary MF 7 Splenomegaly 14 PET MF 10 <5cm below LCM 7 PPV M
Slide 9: Safety
Safety VANDERBILT QJ UNIVERSITY MEDICAL CENTER Lleol wrists network VANDERBILT-INGRAM CANCER CENTER
Slide 10: Dose escalation
E 400mg / 20mg umbralisib / ruxolitinib S (n=3) daily / BID C A L A 800mg / 5mg 800mg / 10mg 800mg / 15mg T (n=1) (n=3) (n=2) I O N 1
Slide 11: Dose escalation and expansion
E 400mg / 20mg umbralisib / ruxolitinib S (n=3) daily / BID C A L A 800mg / 5mg 800mg / 10mg 800mg / 15mg T (n=1) (n=3) (n=2) I O N 600mg / 10mg 600mg / 15mg 600mg / 20mg (n=1) (n=1) (n=1) 1 600mg / 10mg 600mg / 15mg 600mg / 20mg ESCALATION 2 (n=2) (n=1) (n=2) 600mg / 5mg 600mg / 10mg 600mg / 15mg E
Slide 12: Dose limiting toxicity investigation
Dose limiting toxicity investigation 140 390 Amylase (units/L) Lipase (units/L) AE AE Grade 300 Grade 105 III 210 II III 70 II I 120 I 35 NL 30 NL 0 20 40 60 80 0 20 40 60 80 Time (Days) Time (Days) 4000 Umbralisib (ng/mL) 3000 2000 1000 0 0 0.5 1 2 4 6 8 2 8 15 29 Time (hours) Time (days)
Slide 13: Adverse events (all cause)
Adverse events (all cause) • Seventeen subjects experienced at least one adverse event (AE). • Thirteen subjects collectively experienced 17 AEs Grade ≥ 3. Most Common (>5%) AEs and all AEs of Special Interest Grade 1 Grade 2 Grade 3 Grade 4 n (%) n (%) n (%) n (%) Anemia 1 (4%) 6 (26%) 3 (13%) - Ne
Slide 14: Efficacy
Efficacy VANDERBILT §F UNIVERSITY MEDICAL CENTER Lleol wrists network VANDERBILT-INGRAM CANCER CENTER
Slide 15: IWG-MRT & ELN responses to umbralisib + ruxolitinib
IWG-MRT & ELN responses to umbralisib + ruxolitinib DLT Best IWG-MRT & ELN Response* DLT Not Assessed MC Stable Disease Clinical Benefit MC Complete Remission PD Status MC Off-study MC Continues on Treatment MC Off Study Reason PD MC DLT Dose-limiting Toxicity (n=2) PD AE Adverse Event (n=1) AE PD P
Slide 16: Two subjects achieved complete remission
Two subjects achieved complete remission Case 1 Case 2 Baseline Follow-up Baseline Follow-up Marrow Marrow Reticulin
Slide 17: Complete remission case comparison
Complete remission case comparison Case 1 Case 2 Diagnosis Post-ET MF Post-PV MF EHA Fibrosis Score MF-2 MF-1 DIPSS Risk Intermediate-1 Intermediate-1 Driver Mutation MPL 515W JAK2 V617F Stable dose of ruxolitinib 20 mg BID 15 mg BID Measures of insufficient Thrombocytosis, leuko- New MF-related sym
Slide 18: Umbralisib augments rux to reduce spleen volume
Umbralisib augments rux to reduce spleen volume • Spleen volume determined from CT images using synthetic segmentation network n = 17 (incl. 2 s/p splenectomy) • Median decrease in spleen p = 0.025 volume by 13% (mean 18%) – Largest absolute reductions in spleen size with baseline spleen volumes >10
Slide 19: Umbralisib led to increase in hemoglobin levels
Umbralisib led to increase in hemoglobin levels • Five subjects achieved >2 g/dL increase in hemoglobin – Median time to >2 g/dL was 141 days (range 36-197 days) – Response was sustained beyond 100 days in 3/5 subjects 4 Best Hemoglobin Change (g/dL) 3 n = 23 p<0.001 Median ∆Hgb +1.2g/dL 2 1
Slide 20: Umbralisib improved MF-related symptoms
Umbralisib improved MF-related symptoms • Majority of subjects had improvement in MF- related symptoms after addition of umbralisib to ruxolitinib • Seven subjects achieved IWG-MRT and ELN Symptom Response criterion (50% reduction) • Median response was 35% reduction in MPN- n = 22 SAF total symptom
Slide 21: Conclusions
Conclusions • Umbralisib + ruxolitinib was well-tolerated – Dose-limiting toxicities of asymptomatic amylase/lipase elevations of unclear clinical consequence – AST/ALT elevations were mild and transient. – Only one event of colitis (in pt with known mesenteric ischemia) and no pneumonitis • Increas
Slide 22: Acknowledgements
Acknowledgements Ruben Mesa Dan Ayers The Patients and Richard Abramson Bennett Landman their Families Michael Savona Jeanne Palmer TG Therapeutics Peter Sportelli Brandon McMahon Laura Michaelis Hari Miskin Dan Pollyea Amy Cavers Mike Weiss