Targeting the PI3K-Akt-mTOR pathway with GDC-0068, a novel selective ATP competitive Akt inhibitor

Transcription

1 Targeting the PI3K-Akt-mTOR pathway with GDC-0068, a novel selective ATP competitive Akt inhibitor Josep Tabernero, Andrés Cervantes, Cristina Saura, Desamparados Roda, Yibing Yan, Kui Lin, Sumati Murli, Jose Baselga, and Premal Patel Vall d'hebron University Hospital (Barcelona, Spain), Hospital Clinico Universitario (Valencia, Spain), and Genentech, Inc. (South San Francisco, USA) March 9, 2011

2 Akt pathway is frequently activated in cancer Compelling evidence for targeting Akt in human malignancies 2

3 GDC-0068: Novel, specific, ATP competitive Akt inhibitor Enzymatic potency and selectivity of GDC-0068 Kinase IC50 (nm) Akt1/2/3 5/18/8 PKG1a/b 98/69 p70s6k 860 PKA 3100 SGK >1000* PDK1 >1000* AMPK >1000* *No inhibition when screened at 1000 nm in a protein kinase panel Cellular potency of GDC-0068 Cell line ppras40 IC50 (nm) LNCaP 157 BT474M

4 GDC-0068: Effectively blocks Akt signaling and induces cell cycle arrest in human cancer cell lines in vitro (PTEN-) 4

5 High Akt activity predicts sensitivity to GDC-0068 Sensitivity in breast cancer cell line panel: Strongest in HER2+ and Luminal subtypes. Driven by PI3K kinase domain mutations, PTEN loss and HER2 amplification. Negative association with KRas/BRaf mutations and EGFR expression. 5

6 GDC-0068 exhibits significant efficacy in PTEN- and PI3K mutant xenograft models 6

7 IHC/IF and RPPA: Complementary platforms to demonstrate PD changes GDC-0068 reduces ps6 and peif4g levels in BT474-Tr xenografts Vehicle GDC-0068 ps6 RPPA ps6 IHC Vehicle peif4g IHC GDC-0068 peif4g RPPA 7

8 IHC/IF: Akt Inhibitor GDC-0068 relocalizes FOXO3a to nucleus Subcellular localization of FOXO3a regulated by phosphorylation by Akt Nuclear FOXO3a controls transcription of pro-apoptotic and cell cycle inhibitory genes Vehicle 18d, 2h FOXO3a P GDC-0068 FOXO3A (H-Score) Cytoplasmic FOXO Nuclear FOXO AKT: ON AKT: OFF FOXO3a P27, FASL cytoplasm nucleus Cell cycle inhibition GDC-0068 (mg/kg) apoptosis GDC-0068 treated BT474-Tr xenografts 8

9 RPPA analyses demonstrate feedback upregulation of HER3 and perk induced by the Akt Inhibitor GDC-0068 HER3 Log 2 Intensity p-erk1/2 Log 2 Zimmermann and Moelling, Science, 1999 # Serra et al., Oncogene, 2011; Makhija, et al., J. Clin. Oncol., 2010; Garrett, et al., Cancer Res., 2009 GDC-0068 treated BT474-Tr xenografts 9

10 GDC-0068 Phase I dosing strategy Single dose PK (days 1 7) DLT assessment (days 1 35) 1 Day 8 Day Dose: oral daily x 21 days on/ 7days off Schema: Single PK dose in week 1, then 21/28 day dosing Dose GDC-0068 in am (post O/N fast) and fast 2 hrs post dose Standard 3+3 design PD: Surrogate tissue: AKT pathway evaluation in platelet-rich plasma pre- and on-treatment skin biopsy of all patients Tumor biopsy when 50% pathway knockdown achieved in surrogate tissue 10

11 Phase I dose escalation Trial overview: FPI 3/2010 Currently, completing 800 mg cohort No DLTs cohort 1-5 At least 3 patients in each cohort 100 mg had pre and ontreatment tumor biopsy 11

12 GDC-0068 preliminary clinical PK summary Preliminary summary of PK properties: Rapidly absorbed with tmax of hours Generally dose proportional increase in Cmax and AUC 2-3 fold accumulation following QD dosing to steady-state Half-life ranges from 20.1 to 34.1 hours; suitable for once-daily dosing Low (~ 20%) inter-patient variability in AUC at steady-state 12

13 Phase Ia safety profile: All AEs related to GDC-0068* Cohort/dose Gr/AE (# patients) 1 25mg Gr 1 Asthenia (1) 2 50mg Gr 1 Hyperglycemia (3) Gr 1 Alopecia (1) Gr 1 Dyspepsia (1) Gr 1 Decreased appetite (1) Gr 2 Asthenia (2) 3 100mg Gr 1 & 2 Asthenia (1 each) Gr 1 Rash (1) Gr 1 Nausea (1) Gr 3 Hypercholosterolemia (1) 4 200mg Gr 1 Hyperglycemia (2) Gr 1 Pneumonia (1) 5 400mg Gr 1 Hyperglycemia (1) Gr 1 Nausea (2) Gr 1 Emesis (1) Gr 1 Abdominal pain (1) Gr 1 Dysguesia (1) * AEs up to start of 800 mg cohort are listed Hyperglycemia: G1 1: >ULN 160; Gr2 > ; Gr 3 > ; Gr 4 >500 mg/dl GDC-0068 was well-tolerated to 400 mg; no DLTs observed 13

14 Typical GDC-0068/insulin/glucose relationship post drug administration GDC-0068 Glucose GDC-0068 Glucose Insulin GDC-0068 PK and glucose/insulin relationship was assessed on D1 and D15 (light meal was given at 2hrs) Representative data from a patient from cohort 4 is plotted Mild elevation in glucose (up to 2-3 fold), and substantial increase in insulin was observed Insulin 14

15 Preliminary evidence of PD modulation in surrogate tissue Platelet Rich Plasma (PRP)assay Day 1 pgsk3β pgsk3β Day 15 Platelet rich plasma collected on D1 and D15 pgsk3β level normalized to total GSK3β protein was determined A dose- and time-dependent pharmacologic response was demonstrated, with a decrease in pgsk3β level of 60% at doses 200 mg 15

16 Preliminary evidence for pathway knockdown in tumors Core Biopsies IHC/IF FFPE OCT RPPA Tumor biopsies were obtained from patients during screening (baseline) and once during Cycle 1 (between Days 15 and 21). Needle core biopsies were snapfrozen and evaluated by reverse phase protein array for epitopes, including ppras40. Decreases of 60% 70% in ppras40 (compared with baseline) were demonstrated in all 3 patients treated at 400 mg once daily 16

17 Conclusions GDC-0068 is a novel, oral, selective ATP-competitive AKT inhibitor Preclinical activity is most pronounced in models driven by PI3K kinase domain mutations, PTEN loss and HER2 amplification GDC-0068 treatment resulted in pronounced PD effects in tumor xenograft models as measured by RPPA and/or IHC, including dose-dependent suppression of P-S6 and P-eIF4G, as well as induction of FOXO nuclear localization In clinic, GDC-0068 has been well tolerated up to cohort 5 (400 mg once daily), with mild, manageable hyperglycemia GDC-0068 has low (~ 20%) inter-patient variability for exposure and half-life (~24 hrs) suitable for once-daily dosing At well-tolerated doses, GDC-0068 results in >60% pathway knockdown in surrogate and tumor tissue 17

18 Acknowledgments Genentech/Array GDC-0068 Akt Team Jose Baselga s Lab: Violeta Serra Ludmila Prudkin Celina Garcia 18