Curis, Inc. · NASDAQ:CRIS
Curis — Technical Presentation (2022)
13 slides from Curis's technical presentation, 2022
Slide 1: CA-4948 in combination with BRAF/MEK inhibition in melanoma brain metastases
CA-4948 in combination with BRAF/MEK inhibition in melanoma brain metastases Dr. Bently Doonan, MD, MS Assistant Professor University of Florida Health Cancer Center University of Florida Brain Tumor Immunotherapy Program
Slide 2: Disclosures
Disclosures • Research grant from Curis, Inc for preclinical investigation on CA-4948
Slide 3: Melanoma Brain Metastases Baseline (MBM)
Melanoma Brain Metastases Baseline (MBM) • MBM are detected in 1/3 of newly diagnosed stage IV patients1 • 75% of patients will have MBM at time of death2 2 cycles • Roughly 50% of MBM will carry BRAF V600 mutations3 • DREAMSEQ and SECOMBIT support use of dual checkpoint inhibitor therapy first, fol
Slide 4: BRAF/MEK therapy
BRAF/MEK therapy 4 cycles • 3 approved regimens • Intracranial response rate of 42-50%1 • Resistance usually occurs after 6 months2 • MBM that progress on BRAF/MEK therapy are resistant to dual checkpoint inhibition through Bridge to Ipi/Nivo upregulation of IPRES gene signature2 • Acquired resistan
Slide 5: IRAK-4
IRAK-4 • Upregulation of IRAK-4 in tumors leads to constitutive activation of NF-κB, JNK, and MAPK1,2 • Previous work has shown upregulation of IRAK-4 in cutaneous melanoma, which promotes carcinogenesis regardless of direct mutation or not3 • IRAK-4 upregulation is associated with increased phenoty
Slide 6: CA-4948 (Emavusertib)
CA-4948 (EmavusertibTM) • First-in-class IRAK-4 inhibitor1 • Excellent oral bioavailability • Rapid absorption and crosses the blood-brain barrier readily • No inhibition of CYP450s • T1/2 = 6 hrs, no accumulation with qD dosing1,2 • Excellent safety profile in Phase I/II trials in NHL (NCT03328078)
Slide 7: IRAK-4 expression in MBM
IRAK-4 expression in MBM *Manuscript in review
Slide 8: NF-KB pathway protein expression in MBM
NF-KB pathway protein expression in MBM 80 normal cortex Relative Protein Expression Met. Melanoma 60 40 20 0 IκBε IκBα p53 IL-1 RI c-Rel BCL10 IRAK1 IRF5 IRF8 JNK2 TLR2 ASC CARD6 JNK1/2 IL-17 RA IL-18 Rα MYD88 NFκB1 NFκB2 RelA/p65 STAT2 TRAF2 SOCS6 p53 (pS46) STAT1p91 IKK2/IKKβ SHARPIN cIAP1/BIRC2
Slide 9: CA-4948 decreases NF-KB, MAPK, and pERK
CA-4948 decreases NF-KB, MAPK, and pERK 0.0376 merge pNF-κB P65S536 CD45 GFAP DAPI B16 % pNF-κB P65S536+ 25 merge pERKT202/Y204 CD45 GFAP DAPI 20 vehicle 15 10 vehicle 5 CA-4948 0 8 C icle 94 eh -4 A V merge pP38T180/Y182 CD45 GFAP DAPI 80 0.0005 + T180/Y182 CA-4948 60 vehicle 40 B16 % pP38 0.0481 B
Slide 10: Single-agent effects on human BRAF mutant cells
Percent viability U 0 100 50 nt re at e d 1n m 2n m 3n m 4n m A375 IC50 Encorafenib 6n m 10 n m 12 n m Percent viability U 0 100 50 nt re at ed 10 nm 20 nm 50 nm 10 0n 50 m 0n m Binimetinib A375 IC50 1u m 5u m 10 um Percent viability U 0 100 50 nt re at e d 1u m 3u m 5u m 7u m 9u m CA-4948 A375 IC50
Slide 11: Combination therapy overcomes BRAF therapy resistance
* = p<0.05 **= p<0.01 Percent viability ***= p<0.001 U 0 100 150 50 En c n or tre B in afe ate im n d et ib 3 in ib nm C 1 A -4 00n 94 m 8 10 En um ✱✱✱ En co co / B / C i ni A En Bin -49 co i/C 4 /B A 8 ✱ in -49 i/C 4 Combination treatments A 8 A375 IC50 combinations -4 ✱✱✱✱ 94 ****= p<0.0001, by mu
Slide 12: Conclusions
Conclusions • IRAK-4 is a novel potential target in MBM with high expression and multiple roles in tumorigenesis • Inhibition of IRAK-4 in MBM results in downregulation of shared MAPK pathway targets of BRAF/MEK inhibition • CA-4948 has cytostatic potential in human BRAF-mutant melanoma and could po
Slide 13: UFBTIP and Mayo Jacksonville collaborators
UFBTIP collaborators MAYO Jacksonville collaborators Duane Mitchell Han Tun Christina Von Roemeling Lan Hoang-Minh Rylynn Russell Vrunda Trivedi Mohammed Gbadamosi Vincent Archibald Erica Matich Funding Support Tyler Elliott Kelena Klippel