Curis, Inc. · NASDAQ:CRIS
Curis — Technical Presentation (2021)
22 slides from Curis's technical presentation, 2021
Slide 1: Spliceosome Mutations, IRAK4 and CA-4948 in MDS and AML
Spliceosome Mutations, IRAK4 and CA-4948 in MDS and AML Guillermo Garcia-Manero, MD Department of Leukemia, UT M. D. Anderson Cancer Center, Houston, TX
Slide 2: Background Spliceosome Mutations
Background Spliceosome Mutations SF3B1 mutation >80% of patients with MDS with ring sideroblasts (MDS-RS)1 11.5% of patients with MDS refractory anemia (MDS-RA) U2AF1 mutation Mutations: S34F, R156H, and Q157P/R2 6.3% RA/RARS 9.3% RAEB/RAEBT 5.6% CMML Retention of mutation at progression of disease2
Slide 3: SF3B1 and U2AF1 Mutations are Among the Commonest Mutations in MDS
SF3B1 and U2AF1 Mutations are Among the Commonest Mutations in MDS1 1) Li Genes Chrom 2017 3
Slide 4: SF3B1 and U2AF1 among earliest genes mutated
SF3B1 and U2AF1 among earliest genes mutated1 1) Bersanelli et al. J Clin Oncol 2021 4
Slide 5: RNA isoforms define a subset of AML associated with innate immune pathway activation
RNA isoforms define a subset of AML associated with innate immune pathway activation1 Scatterplot of cumulative and isoform variances Hierarchical clustering analysis and relative expression of Pathway analysis of genes in Group 2 associated of genes in AML samples from TCGA (n = 160). mRNA isoforms
Slide 6: IRAK4 emerged as the leading candidate that drives innate immune signaling
IRAK4 emerged as the leading candidate that drives innate immune signaling in MDS or AML1 The magnitude of IRAK4 isoform switching was highly significant among AML samples and the inclusion of exon 4 alone correlated with worse outcome Kaplan-meier analysis of AML patients Exon architecture of IRAK4
Slide 7: Significant proportion of AML patients primarily express longer IRAK4 isoforms
Significant proportion of AML patients primarily express the longer IRAK4 RNA and protein isoforms1 RT-PCR of IRAK4-L/S using primers flanking exon 4 (CB=cord blood; BM=bone marrow; MNC=mononuclear cells) Relative expression of IRAK4-L to IRAK4-S Immunoblot of IRAK4 using an in normal BM (n = 4) and
Slide 8: IRAK4-L results in maximal activation of innate immune signaling
IRAK4-L results in maximal activation of innate immune signaling1 IRAK4-L AML enriched in inflammatory and TLR signatures IRAK4-S IRAK4-L MAPK NF-κB Signaling Signaling Pathway analysis of enriched genes in AML patients IRAK4-L is necessary and sufficient for NF-κB activation in AML preferentially e
Slide 9: IRAK4-L is Required for Leukemic Cell Function
IRAK4-L is Required for Leukemic Cell Function1 IRAK4-L is the dominant isoform in leukemic cells Similar findings when IRAK4 isoforms deleted Reduced IRAK4-L did not impair progenitor function using CRISPR/Cas9 gene editing of normal cord-blood CD34+ cells, rather increased myeloid and erythroid di
Slide 10: IRAK4-L is Required for Leukemic Cell Function
IRAK4-L is Required for Leukemic Cell Function1 IRAK4 KO ablates progenitor activity IRAK4-L is sufficient to reconstitute progenitor function Parental and IRAK4-KO THP1 cells examined for leukemic progenitor function in methylcellulose. IRAK4-L, but not IRAK4-S, is required for leukemia-propagating
Slide 11: CA-4948 Background
CA-4948 Background IRAK4/CA-4948 Co-crystal Structure • CA-4948 is a novel small molecule oral inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4) • IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways; these pathways are
Slide 12: CA-4948 or IRAK4-L Knockdown is Sufficient to Reduce Leukemic Colonies and Blasts
CA-4948 or IRAK4-L Knockdown is Sufficient to Reduce Leukemic Colonies and Blasts IRAK4-L is Oncogenic CA-4948 Directly Targets IRAK4 IRAK4-L provides a genetic link Direct inhibition of IRAK4 to oncogenic immune signaling in AML/MDS is associated with disease Blocking IRAK4-L reduces the formation
Slide 13: CA-4948 Increases Cell Differentiation from Primary MDS/AML HSPCs
CA-4948 Increases Cell Differentiation from Primary MDS/AML HSPCs Decreases Disease Burden in THP-1 Xenografts 13
Slide 14: IRAK4 Inhibition May Inhibit Adaptive Malignancy Resistance
IRAK4 Inhibition May Inhibit Adaptive Malignancy Resistance DNA damage induces TLR9-IRAK4-NF-κB survival mechanism1 1) Li et al. JCI Insight 2019 14
Slide 15: Landscape of Disease Targets in AML/MDS
Landscape of Disease Targets in AML/MDS % of Patient • Non-targeted therapies administered in monotherapy have historically Disease Driver Population provided limited clinical benefit, especially in relapsed/refractory patients IRAK4-L > 50%1 FLT3 25-30%2 • Targeted therapies (e.g., FLT3, IDH) have
Slide 16: Study Design and Methods
Study Design and Methods • This is a multicenter, open-label, single arm Phase 1 dose escalation study of orally administered CA-4948 monotherapy in adult patients with AML or high risk MDS (NCT04278768) • Each treatment cycle of CA-4948 will be 28 days in length and repeated in the absence of unacc
Slide 17: Inclusion and Exclusion Criteria
Inclusion and Exclusion Criteria Inclusion: • Males and females ≥18 years of age • Cytomorphology based confirmed diagnosis of MDS or AML per the World Health Organization 2016 classification: a) Relapsed or refractory AML (primary or secondary, including treatment-related); OR b) High/very high ris
Slide 18: Patient Characteristics
Patient Characteristics Overall Baseline Characteristics of Ph1 Patients (N=6) Male (%) 5 (83%) Female (%) 1 (17%) Median Age (range) 72 (32-84) Median Prior Therapies (range) 3 (1-4) Histology Acute Myelogenous Leukemia (AML) 4 (67%) Myelodysplastic Syndrome (MDS) 2 (33%) Data cut-off: 23Nov2020 18
Slide 19: Bone Marrow Blast Percentage
Monotherapy Anti-Cancer Activity Observed in Early Ph1 Data 40% AML 35% hrMDS • 1st patient dosed in Q3 2020 30% • Consistent reduction of Marrow Blasts across population (6 patients) Bone Marrow Blast Percentage 300mg 25% 300mg • 2 patients have achieved Marrow CR 20% Blasts Blasts 15% Baseline Bes
Slide 20: CA-4948-102 Trial in Progress: Monotherapy in R/R High-Risk MDS and AML
CA-4948-102 Trial in Progress: Monotherapy in R/R High-Risk MDS and AML UPDATED Cohort 1: 200 mg BID 3 patients (2 hrMDS and 1 AML) No DLT in first 3 patients during DLT period (1st four-week cycle) Cohort 2: 300 mg BID 4 patients (1 hrMDS and 3 AML) No DLT in first 3 patients during DLT period Coho
Slide 21: Conclusion and References
Conclusion and References • All initial patients in the first two cohorts completing cycle 1 had marrow blast reduction, including several Marrow CRs, clinical updates to be later reported • Dose escalation cohorts have subsequently included 200, 300, 400 and 500mg twice daily • After the RP2D has b
Slide 22: Thank You
Thank You Thank you to the participating trial investigators, clinical staff, patients and their families Correspondence: , Inc. 128 Spring St. Suite 500, Bldg. C Lexington, MA 024221 Contact Information: Reinhard von Roemeling, MD. [email protected] 22