Curis, Inc. · NASDAQ:CRIS
Curis — 4th Waldenstrom Roadmap Symposium 2019
26 slides from Curis's conference presentation, Apr 7, 2019
Slide 1: Development of IRAK4 Kinase Inhibitor CA-4948 for NHL
Development of IRAK4 Kinase Inhibitor CA-4948 for NHL Robert Booher, PhD, Translational Sciences Dena Grayson, MD, PhD, Clinical Development 4th Waldenstrom Roadmap Symposium April 07, 2019
Slide 2: Disclosures
Disclosures Robert Booher, Ph.D. Receives direct remuneration from Curis Dena Grayson, M.D., Ph.D. Receives direct remuneration from Curis 2
Slide 3: Interleukin-1 Receptor-Associated Kinase-4 (IRAK4)
Interleukin-1 Receptor-Associated Kinase-4 (IRAK4) IRAK Kinase Family TLR and IL-1R Signaling Dimerization, TRAF6 MYD88 interaction interaction IRAK1 Death N domain ProST domain Kinase domain C-terminus domain C ProST Pseudokinase C-terminus IRAK2 N Death domain domain domain domain C P MYD88 P Mydd
Slide 4: Activating Mutations in TLR/IL-1R and BCR Signaling Pathways Resulting in NF-kB Induction
Activating Mutations in TLR/IL-1R and BCR Signaling Pathways Resulting in NF-kB Induction BCR Signaling TLR/IL-1R Signaling MYD88 activating CD79B /A mutations ITAM PI3K ITAM CD79A ITAM CD79A mutations P P MYD88 P Cytosol P BTK BTK P P SYK P IRAK4 IRAK1 P PKCβ TRAF6Ub CARD11 Ub activating P NF-κB mu
Slide 5: CA-4948, A Selective Oral Inhibitor of IRAK4 for the Treatment of NHL
CA-4948, A Selective Oral Inhibitor of IRAK4 for the Treatment of NHL IRAK4/CA-4948 Co-crystal Structure CA-4948: Selective, small molecule inhibitor of IRAK4 ATP-competitive, type 1 inhibitor, reversible Excellent drug-like properties: • Orally bioavailable (>100% dog/mouse) • Moderate plasma
Slide 6: CA-4948 Kinase Selectivity Profile
CA-4948 Kinase Selectivity Profile Active-site binding CA-4948 Binding (DiscoverX, 378 kinases) 90-100% Affinity Activity % Inhibition at 0.1 µM 80-89% 60-79% DiscoverX FLT3 40-59% Kinase Kd (nM) 20-39% 0-19% IRAK4 23 IRAK1 12,000 IRAK4 IRAK2 >20,000 IRAK3 8,500 CLK1,2,4 Other top hits: Haspin CLK1
Slide 7: IRAK4 Kinase Inhibitor Blocks the TLR/IL-1R Induced Canonical NF-kB Signaling Pathway
CA-4948 IRAK4 Kinase Inhibitor Blocks the TLR/ IL-1R Induced Canonical NF-kB Signaling Pathway 100 N F - κ B /c - R e l r e p o r t e r a s s a y TLR/IL-1R Signaling In vitro THP1 monocytic cell assays + TLR agonist % In h ib itio n 75 Unstimulated 50 CA-4948 P MYD88 Cytoplasm 25 DMSO 0 CA-4948 IRAK
Slide 8: CA-4948 Selectively Inhibits NF-κB Signaling Pathways that are MYD88-Dependent
CA-4948 Selectively Inhibits NF-κB Signaling Pathways that are MYD88-Dependent M Y D 8 8 -d e p e n d e n t (T L R ) v e rs u s M Y D 8 8 - in d e p e n d e n t ( T N F R 1 ) N F - κ B P a t h w a y S t im u la t io n ( T H P - 1 c e lls ) 100 N F - κ B /c - R e l r e p o r t e r TLR ( % In h ib it
Slide 9: CA-4948 Inhibits Constitutive Cytokine Production in MYD88mut ABC-DLBCL Cell Lines
CA-4948 Inhibits Constitutive Cytokine Production in MYD88mut ABC-DLBCL Cell Lines Cytokine level after 21 hr treatment 150 100 IL - 1 0 (p g /m l) 50 0 300 IL -6 200 (p g /m l) 100 0 C A -4 9 4 8 ( µ M ): - 1 5 10 - 1 5 10 - 1 5 10 O C I-L Y 3 O C I-L y 1 0 S U -D H L -2 M YD 88- M YD 88- M YD 88-
Slide 10: CA-4948 Inhibits Cytokine RNA and Protein Production in DLBCL PDX Tumors
CA-4948 Inhibits Cytokine RNA and Protein Production in DLBCL PDX Tumors CA-4948 Inhibition of Cytokine RNA CA-4948 Inhibition of Tumor-Derived Cytokines in Expression in DLBCL PDX Tumors Plasma From DLBCL PDX-Tumor Bearing Mouse A B C -D L B C L A B C -D L B C L ABC-DLBCL M Y D 8 8 -L 2 6 5 P M Y D
Slide 11: CA-4948 Shows Enhanced Efficacy in ABC vs. GCB DLBCL Tumors
CA-4948 Shows Enhanced Efficacy in ABC vs. GCB DLBCL Tumors ABC DLBCL GCB DLBCL O C I- L Y 3 O C I- L y 1 0 S U -D H L -4 O C I- L y 1 9 (M Y D 8 8 -L 2 6 5 P ) (M Y D 8 8 -L 2 6 5 P ) V e h ic le V e h ic le M e a n T u m o r V o lu m e (m m ) + S E M M e a n T u m o r V o lu m e (m m ) + S E M V e
Slide 12: CA-4948 Efficacy in 6 DLBCL PDX Models
CA-4948 Efficacy in 6 DLBCL PDX Models CA-4948 Mutations/Expression Efficacy BCL6 100 mg/kg, QD DLBCL PDX Cell of MYD88 B-Cell Receptor Expression Model Origin Mutation Mutation %TGI (IHC) CARD11, LY2345 ABC WT 2% 71** TNFAIP3 LY2264 ABC L265P CD79B 60% 70** LY2298 ABC L265P CD79B 20% 54* LY2214 GCB
Slide 13: CA-4948 BID Dosing Exhibits Improved/Equivalent Efficacy Compared to QD Dosing
CA-4948 BID Dosing Exhibits Improved/ Equivalent Efficacy Compared to QD Dosing LY2345 PDX: ABC DLBCL LY2298 PDX: ABC DLBCL MYD88-wt, TNFIAP3-mt MYD88-L265P, CD79B-mut ± SEM ) ± SEM ) T u m o r G ro w th T u m o r G ro w th V e h ic le , Q D 2500 3000 C A - 4 9 4 8 , 7 5 m g /k g , B ID 3 3 2500 M e
Slide 14: CA-4948 Exhibits Combination Effects with Ibrutinib or Venetoclax in an ABC-DLBCL Xenograft Model
CA-4948 Exhibits Combination Effects with Ibrutinib or Venetoclax in an ABC-DLBCL Xenograft Model C A -4 9 4 8 + Ib r u t in ib C A - 4 9 4 8 + V e n e t o c la x O C I- L y 1 0 ( a p 1 ) O C I- L y 1 0 ( a p 1 ) M e a n T u m o r V o lu m e (m m ) + S E M T u m o r G ro w th T u m o r G ro w th M e
Slide 15: CA-4948 In Vitro Effect on TLR Signaling Pathway in Mantle Cell Lymphoma Lines
CA-4948 In Vitro Effect on TLR Signaling Pathway in Mantle Cell Lymphoma Lines Classical NF-κB pathway R E C -1 M IN O J e K o -1 1 .0 1 .0 1 .0 P - IK K α / β / t o t a l IK K α P - IK K α / β / t o t a l IK K α P - IK K α / β / t o t a l IK K α 0 .5 0 .5 0 .5 0 .0 0 .0 0 .0 .5 .0 .5 .5 .0 .0 0 1 0
Slide 16: CA-4948 ± Ibrutinib Exhibits Efficacy in MCL Xenograft Models with Canonical NF-κB Signaling
CA-4948 ± Ibrutinib Exhibits Efficacy in MCL Xenograft Models with Canonical NF-κB Signaling Classical NF-κB pathway Alternative NF-κB pathway R E C -1 M IN O G ra n ta -5 1 9 Z -1 3 8 T u m o r G r o w th T u m o r G r o w th T u m o r G r o w th T u m o r G r o w th D o s in g : Q D , P O 2000 200
Slide 17: CA-4948-101 Phase 1 First-in-Human Trial (NCT03328078)
CA-4948-101 Phase 1 First-in-Human Trial (NCT03328078) 17
Slide 18: IRAK4 Pathway Alterations in Hematologic Malignancies
IRAK4 Pathway Alterations in Hematologic Malignancies Targeting IRAK4 in NHL: Rationale Targeting IRAK4 in AML/MDS: Rationale Prevalence of Oncogenic MYD88-L265P Mutations Prevalence of TLR/IL-R1/MYD88 Alterations Diffuse Large B-cell Lymphoma (ABC-DLBCL) 29% • TLR or IL1R alterations − TLR1, 2 and
Slide 19: CA-4948-101 Phase 1 First-in-Human Trial
CA-4948-101 Phase 1 First-in-Human Trial (NCT03328078) Phase 1a: Phase 1b: Dose Single Agent Dose Escalation Expansion • 3 + 3 Design MTD or RP2D • N = 45 ~ 50 • Dose escalation guided by safety • WM • Starting dose = 50 mg QD • ABC DLBCL MYD88mut • ABC DLBCL MYD88wt • N = ~ 30 • R/R NHL, including
Slide 20: Dose Escalation
CA-4948-101 Study Design and Cohort Accrual tbd tbd Current cohort 200 mg BID Dose Escalation 100 mg BID 50 mg BID 100 mg QD 50 mg QD 20
Slide 21: CA-4948 Plasma Concentration vs. Time Profile (Cycle 1)
CA-4948 Plasma Concentration (ng/mL) vs. Time Profile (Cycle 1) 50 m g Dose 1250 M ean 5 0 m g , Q D (D 1 /2 , n = 6 ) 1000 5 0 m g , Q D ( D 1 5 /1 6 , n = 6 ) C A -4 9 4 8 ( n g /m L ) 5 0 m g , B ID (D 1 /2 , n = 4 ) 750 5 0 m g , B ID (D 1 5 /1 6 , n = 2 ) 500 250 0 0 2 4 6 8 0 2 4 6 8 0 2 4 6 1
Slide 22: CA-4948 PK/PD Relationship Determined Using an Ex-Vivo Whole Blood Assay (Human)
CA-4948 PK/PD Relationship Determined Using an Ex-Vivo Whole Blood Assay (Human) In whole blood from healthy volunteers, cytokine In whole blood from patients treated with CA-4948 production dropped when incubated with CA-4948 cytokine production dropped, mirroring drug exposure IL-6 Production in T
Slide 23: CA-4948 Development Plan
CA-4948 Development Plan Expansion in patients with MYD88 or TLR/IL-1R pathway altered lymphomas 2019 2020 2021 Select Regimen for Dose Escalation Dose Expansion Randomized Pivotal Trial CA-4948 Monotherapy NHL DLBCL, WM, MCL MYD88/TLR-altered Lymphoma CA-4948 Combo Therapy + BTK inhibitor MYD88/TLR
Slide 24: Conclusions
Conclusions CA-4948 is a potent, oral inhibitor of IRAK4 Ser/Thr kinase with >500-fold selectivity vs. IRAK1 CA-4948 inhibited constitutive or TLR-induced signaling in ABC-DLBCL and MCL cell lines and xenograft tumor models CA-4948 exhibited in vivo anti-tumor activity in NHL models with intac
Slide 25: Acknowledgments
Acknowledgments • Participating patients and their families • Investigators, research coordinators, and site personnel − Iris Isufi, Yale School of Medicine, New Haven, CT − Daniel Landsburg, Perelman School of Medicine, Univ. of Penn, Philadelphia, PA − Lori Leslie, Hackensack University Medical Ce
Slide 26: CUS
rm CUS NASDAQ: CRIS