Incyte Corporation · NASDAQ:INCY
Incyte — ASCO 2012
16 slides from Incyte's conference presentation, Jun 16, 2012
Slide 1: Pharmacodynamic assessment of INCB024360, an inhibitor of IDO1 in advanced cancer patients
Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) in advanced cancer patients Robert C. Newton, Peggy A. Scherle, Kevin Bowman, Xiangdong Liu, Gregory L. Beatty, Peter J O’Dwyer, Thomas Gajewski, Jill Bowman, Lance Leopold PRESENTED BY: Gregory L. Beatty
Slide 2: Disclosure Information
Disclosure Information Relationships Relevant to this Session Beatty, Gregory No relevant relationships to disclose. Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org
Slide 3: Indoleamine Dioxygenase-1 (IDO1)
Indoleamine Dioxygenase-1 (IDO1) • IDO1 is a heme-containing monomeric oxidoreductase that metabolizes tryptophan to kynurenine IDO L‐Tryptophan L‐kynurenine Tryptophan Hydroxylase 5‐hydroxy‐ tryptophan Quinolinic Acid Serotonin (5HT) NAD • IDO1 is expressed by antigen presenting cells as well as tu
Slide 4: Indoleamine Dioxygenase-1 as a Target for Therapy
Indoleamine Dioxygenase-1 as a Target for Therapy • IDO1 is expressed in the tumor microenvironment of many cancers Pt A Pt B Breast Colon • IDO1 expression in human tumors is associated with decreased survival • IDO1 activity can suppress host anti-tumor immunity • Inhibition of IDO1 in preclinical
Slide 5: INCB024360 is a Potent IDO1 Inhibitor
INCB024360 is a Potent IDO1 Inhibitor HeLa cells 100 % Inhibition Day 0 80 + INCB024360 60 INCB024360 IFN- + L-1MT 40 L-1MT D-1MT + D-1MT 20 0 Day 2 0.001 0.01 0.1 1 10 100 1000 Compound conc (M) Kynurenine levels measured INCB024360 IC50 = 7.1 nM L-1MT IC50 = 70 μM D-1MT IC50 > 1 mM PRESENTED BY:
Slide 6: INCB024360 is a Potent and Selective IDO1 Inhibitor
INCB024360 is a Potent and Selective IDO1 Inhibitor Assay Cell type IC50 ± SD (nM) HeLa 7.1 ± 0.6 Tryptophan Human dendritic cells (DCs) 12.7 ± 1.1 to kynurenine HEK293/MSR-human IDO1 15.0 ± 3.3 conversion HEK293/MSR-mouse IDO1 52.4 ± 15.7 HEK293/MSR-mouse IDO2 >5,000 HEK293/MSR-human TDO >10,000 Tr
Slide 7: Phase 1 Study INCB24360-01
Phase 1 Study INCB24360-01 Non-randomized, open-label, single agent dose escalation in advanced cancers (all tumor types) Design: • Standard 3 + 3 dose escalation to IC90 for IDO at trough Primary • Determine the safety and tolerability and, if observed, Endpoint: establish the maximum tolerated dos
Slide 8: Phase 1 Study INCB24360-01
Phase 1 Study INCB24360-01 Non-randomized, open-label, single agent dose escalation in advanced cancers (all tumor types) Design: • Standard 3 + 3 dose escalation to IC90 for IDO at trough Primary • Determine the safety and tolerability and, if observed, Endpoint: establish the maximum tolerated dos
Slide 9: Baseline Patient Demographics and Clinical Characteristics
Baseline Patient Demographics and Clinical Characteristics Characteristic No. % Age years Median 59.9 - Range 38-78 - Sex Male 20 52.6 Female 18 47.4 ECOG PS 0 15 39.5 1 23 60.5 2 0 0.0 Primary Site Colon 25 65.9 Breast 1 2.6 Melanoma 3 7.9 Bladder 2 5.2 Endometrial 1 2.6 Appendiceal 2 5.2 Other 4 1
Slide 10: INCB024360-101: DLTs
INCB024360-101: DLTs The MTD Has Not Been Established Cohort N DLTs 50 mg QD 3 -- 50 mg BID 4 -- 100 mg BID 5 -- 300 mg BID 6 Radiation pneumonitis 400 mg BID 11 Grade 3 fatigue 500 mg BID 5 -- 700 mg BID 4 --
Slide 11: INCB24360 Inhibition of Stimulated IDO Activity on Day 15 in Whole Blood Samples
INCB24360 Inhibition of Stimulated IDO Activity on Day 15 in Whole Blood Samples Whole Blood from Dosed Patients IDO (KYN) Day 15 0 hrs 100 IDO KYN (% of Control) 50 mg BID IFN- 80 100 mg BID + 300 mg BID LPS 60 400 mg BID 500 mg BID 40 700 mg BID 18 hrs 20 0 0 2 4 6 Kynurenine levels measured Time
Slide 12: INCB024360 Whole Blood PK/PD Relationship
INCB024360 Whole Blood PK/PD Relationship Study INCB24360-101 100 90 80 % Inhibition IDO(KYN) 70 60 50 40 30 20 10 0 0 1 2 INCB024360 Plasma Concentration (M) PRESENTED BY: Gregory L. Beatty
Slide 13: Published Plasma Kyn Levels and Kyn/Trp Ratios
Published Plasma Kyn Levels and Kyn/Trp Ratios Tumor Type Sample no. Trp, Kyn, Kyn/Trp ratio, mean nM mean nM nM/M AML 3 67,233 4000 60 Breast 13 43,531 2642 62 Colorectal 15 54,213 3449 65 Head and neck 3 55,867 4977 90 Prostate 8 58,075 3494 60 Lung 1 42,900 3010 70 Healthy 12 65,417 2328 36 pers
Slide 14: INCB024360 Decreases Kynurenine Levels in vivo in Preclinical Models
INCB024360 Decreases Kynurenine Levels in vivo in Preclinical Models • Basal kynurenine levels are influenced by both IDO and TDO (liver enzyme that controls dietary tryptophan catabolism) • Reduced kynurenine levels correlate with IDO1 inhibition in vivo • INCB024360 reduces Kyn levels in plasma, l
Slide 15: Plasma Kynurenine Levels in Patients Treated with INCB024360
Plasma Kynurenine Levels in Patients Treated with INCB024360 Kyn Levels Kyn/Trp Ratios 75 75 Kyn/Trp ratios at Day 15 change from baseline in change from baseline in Kyn levels at Day 15 Average percentage Average percentage 50 50 25 25 0 0 0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600
Slide 16: Conclusions
Conclusions • IDO1 inhibition was observed in all patients receiving INCB024360 and inhibition correlated with drug exposure • Greater than 90% inhibition of IDO1 was achieved throughout the dosing interval at doses above 300 mg bid • INCB24360 has been generally well-tolerated and an MTD has not be