Calithera Biosciences, Inc. · OTC:CALA
Calithera Biosciences — Technical Presentation (December 2019)
19 slides from Calithera Biosciences's technical presentation, December 2019
Slide 1: Interim Analysis of a Phase II Study of Telaglenastat (CB-839) with Azacitidine in Advanced MDS
Interim Analysis of a Phase II Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination with Azacitidine in Advanced Myelodysplastic Syndrome (MDS). Veronica A Guerra, Hagop Kantarjian, Jan Burger, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Tapan Kadia, Kimberley Sheppard, Gu
Slide 2: CB-839 + AZA in MDS: Background
CB-839 + AZA in MDS: Background • Glutaminase (GLS) catalyzes conversion of glutamine to glutamate • Many tumor cells require continuous supply of glutamine and upregulate GLS • GLS highly expressed in AML and high-risk MDS • GLS inhibition = reduced cell growth apoptosis • MDS with HMA failure poor
Slide 3: CB-839 + AZA in MDS: Background
CB-839 + AZA in MDS: Background • CB-839: selective, reversible oral GLS inhibitor • Plasma concentrations >300nM >90% GLS inhibition • In preclinical studies the combination CB-839 + azacitidine was synergistic CB-839 Cai et al. Blood 2016; 128 (22): 4084
Slide 4: Endpoints
CB-839 + AZA in MDS : Endpoints • Primary endpoint – Phase I: Determine the recommended phase 2 dose of CB-839 • Secondary endpoints – Explore the pharmacokinetics and pharmacodynamics of CB-839 in combination with AZA – Determine the clinical activity by overall response rate (ORR) by IWG-MDS, over
Slide 5: CB-839 + AZA in MDS: Eligibility
CB-839 + AZA in MDS: Eligibility • High-Risk MDS or intermediate-1 by IPSS with high-risk molecular features (TP53, ASXL1, EZH2 or RUNX1) • Age ≥18 • ECOG PS 0-2 • Adequate organ function – Bilirubin ≤ 2 mg/dL, AST/ALT ≤ 3x ULN – Clearance creatinine > 30 mL/min
Slide 6: CB-839 + AZA in MDS: Study Design
CB-839 + AZA in MDS : Study Design • Azacitidine 75 mg/m2/d IV/SC on days 1-7 • CB-839 600 mg twice daily orally on days 1-28 Azacitidine CB-839 CB-839 C1 C2 C3 C4 C5 C6 EOT BM BM BM BM BM BM Biomarkers Biomarkers Biomarkers Biomarkers Biomarkers Biomarkers PK analysis PK analysis PK analysis
Slide 7: Patient characteristics
CB-839 + AZA in MDS : Patient characteristics Characteristics N=19 (%) / median [range] Age 68 [47-82] Sex Male 15 (79) Treatment Frontline 14 (74) Prior HMA 5 (26) Diagnosis t-MDS 5 (26) MDS-EB-1 4 (21) MDS-EB-2 3 (16) CMML 5 (26) MDS-MLD 2 (11) Hemoglobin 9.3 [7.1-13.1] Platelets 70 [11-520] ANC 1
Slide 8: Patients Characteristics
CB-839 + AZA in MDS :Patients Characteristics Characteristics N (%) Cytogenetics Diploid 7 (37) Complex 7 (37) Other 5 (26) IPSS Score Intermediate-1 9 (47) Intermediate-2 9 (47) High Risk 1 (5)
Slide 9: CB-839 + AZA in MDS: Somatic Mutations
CB-839 + AZA in MDS: Somatic Mutations Frontline Prior HMA Mutations N (%) ASXL1 10 (53) TET2 7 (37) TP53 6 (32) RUNX1 5 (26) SRSF2 4 (21)
Slide 10: Response Rates
CB-839 + AZA in MDS : Response Rates Response All patients Frontline Prior HMA N=19 (%) N=14 (%) N=5 (%) ORR 12 (63) 8 (57) 4 (80) CR 2 (11) 2 (14) mCR 9 (47) 6 (43) 3 (60) HI 1 (5) 1 (20) Stable Disease 6 (32) 5 (36) 1 (20) No response 1 (5) 1 (7) CG Response 5/12 (42) 5/10 (50) 0/2 (0) • Time to C
Slide 11: Response Rates for key MDS subsets
CB-839 + AZA in MDS: Response Rates for key MDS subsets Response Complex CG ASXL1 TP53 N=7 (%) N=10 (%) N=6 (%) ORR 6 (86) 6 (60) 5 (83) CR 1 (14) 1 (10) 1 (17) mCR 5 (71) 4 (40) 4 (67) HI 1 (10) Stable Disease 1 (14) 4 (40) No response 1 (17) CG response 4/7 (57) 2/4 (50) 3/6 (50)
Slide 12: Metabolic Analysis
CB-839 + AZA in MDS: Metabolic Analysis Glutathione Glutamic acid Glutamine Glutamine/Aspartate utilization Metabolic level (relative to cycle 1) Aspartic acid ATP GTP 2.5 UTP CTP 2 ADP CB-839 inhibits GDP 1.5 UDP Nucleotides Glutamine utilization CDP 1 AMP GMP 0.5 UMP CMP 0 Glucose Fructose 6-phosp
Slide 13: Adverse Events
CB-839 + AZA in MDS : Adverse Events 80 70 60 50 40 30 Grade 1-2 Grade 3-4 20 10 0 Adverse events >10%
Slide 14: Disposition
CB-839 + AZA in MDS : Disposition N= 19 patients Median number cycles: 3 [1-10] Follow-up 10.5 months Time to best response: 1 cycle [1-4] CR/mCR/HI Stable Disease No Response N=11 N=7 N=1 Alive N=7 Alive N=5 Died: N=1 On study: N=3 On study: N=3 Cause of death N=7 • Infection N=2 HSCT N= 4 Died N=
Slide 15: Treatment Discontinuation
CB-839 + AZA in MDS : Treatment Discontinuation Cause of Discontinuation N=13 HSCT 5 (26) Death 3 (16) Disease progression 3 (16) Physician decision 1 (5) No response 1 (5)
Slide 16: OS and EFS
CB-839 + AZA in MDS : OS and EFS Overall Survival Event-Free Survival N Events N Events 100 19 7 100 19 9 Percent survival Percent survival 50 50 Median OS Not Reached; 1-year OS 50% EFS 9.8 months; 1-year EFS 33% 0 0 0 5 10 15 20 25 0 5 10 15 20 25 Months Months
Slide 17: OS and EFS (Frontline)
CB-839 + AZA in MDS : OS and EFS (Frontline) Overall Survival (Frontline) Event-Free Survival (Frontline) N Events N Events 14 4 14 5 100 100 Percent survival Percent survival 50 50 EFS 9.8 months; 1-year EFS 47% Median OS Not Reached; 1-year OS 59% 0 0 0 5 10 15 20 25 0 5 10 15 20 25 Months Months
Slide 18: Conclusions
CB-839 + AZA in MDS : Conclusions • CB-839 + Azacitidine is safe and well tolerated in advanced MDS – ORR 63%; CR 11% and mCR 47% – 1-year OS 50%; 1-year EFS 33% – ORR 80% prior HMA; 83% in TP53 patients, 86% in complex karyotype • Safe regimen – CB-839 600 mg BID orally continuously has acceptable
Slide 19: Acknowledgments
Acknowledgments Department of Leukemia, MDACC Albert Einstein College of Medicine Hagop Kantarjian Amit Verma Guillermo Garcia-Manero Jan Burger Calithera Gautam Borthakur Elias Jabbour Susan Demo Naveen Pemmaraju Sam Whiting Tapan Kadia Marina Gelman Kimberley Sheppard Tianyu Cai Research funding M
Calithera Biosciences — Technical Presentation (December 2019) on 6ix