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A phase I dose-escalation study of LDE225, a Smoothened (Smo) antagonist, in patients with advanced solid tumors. J Rodon 1 , J Baselga, 1 HA Tawbi, 2 Y Shou, 3 C Granvil, 3 J Dey, 3 MM Mita, 4 AL Thomas, 5 DD Amakye, 3 AC Mita 4

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  1. A phase I dose-escalation study of LDE225, a Smoothened (Smo) antagonist, in patients with advanced solid tumors J Rodon1, J Baselga,1 HA Tawbi,2 Y Shou,3C Granvil,3 J Dey,3 MM Mita,4 AL Thomas,5 DD Amakye,3 AC Mita4 1Vall d’Hebron University Hospital, Barcelona, Spain; 2University of Pittsburgh Cancer Institute, Pittsburgh, PA; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ; 4Cancer Therapy & Research Center, San Antonio, TX; 5Leicester Royal Infirmary, Leicester, UK

  2. Scientific rationale: the Hedgehog (Hh) signal transduction pathway AAAAA Ptc1 Ptc1 g g GLI GLI Shh Shh Shh Shh Shh Shh Shh Shh Shh Smo Smo b b PI3K Smo PDK PKB Gli3 Gli1 Gli2 Sufu Sufu MIM MIM Cellular proliferation, differentiation and survival CBP/p300 HIP, PDGFR,Gli, Cyclin D1,N-myc, Wnt mRNAs Gli1/2 Gli3 Gli, glioma-associated oncogene homolog zinc finger protein

  3. Scientific rationale: the Hedgehog (Hh) signal transduction pathway Ptc1 Ptc1 g g GLI GLI Gli3 Gli1 Gli2 Sufu Sufu MIM MIM Shh Shh Shh Shh Shh Shh Shh Shh Shh Smo Smo BCC b b PI3K BCCMedulloblastoma Smo PDK Pancreatic cancer Colon cancer Lymphoma PKB Basal Cell Carcinoma (BCC) Hh activation in 70% of cases SCLC CML Pancreatic cancer Breast cancer • Tumorigenesis of several human cancers caused by different mechanisms: • Genetic: • Inactivating mutations in Patched (Ptch) or Suppressor of Fused (SuFu) protein • Activating mutations in Smo • Autocrine • Paracrine • Aberrant activation of the Hh pathway (tumor or stem cells)

  4. LDE225 – a potent and selective Smo antagonist H C F N 3 O H H O H H H H N N H O O N Cyclopamine O LDE225 • LDE225 is a novel oral inhibitor of Smo • Structurally distinct from steroidal alkaloids such as cyclopamine

  5. LDE225 – preclinical summary LDE225 Gli-1 mRNA (human) Luciferase (mouse) Gli-1 promoter Ptch +/-, p53 -/- MB model 3000 Vehicle 2500 5mg/kg 2000 Tumor volume (mm3) mean ± SEM 1500 1000 10 mg/kg 500 20 mg/kg 0 8 10 12 14 16 18 20 22 Days post-implantation LDE225 is a novel oral inhibitor of Smo that potently inhibits Smo-dependent proliferation in vivo in preclinical studies Gli, glioma-associated oncogene homolog zinc finger protein; Shh, Sonic Hedgehog

  6. Topical LDE225 (0.75%) in Naevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) Germ line mutations in Ptch, leading to subsequent development of multiple BCCs Established proof of concept Orphan drug status granted in EU for BCC in Gorlin Syndrome Complete response Partial response No response 14 12 10 8 Cumulative number of tumors 6 4 2 0 LDE225 Vehicle 8 NBCCS patients 27 BCC patients n=13 LDE225 cream (BID) n=14 Vehicle Baseline After 4 weeks De Rie MA, et al. Society for Investigative Dermatology (SID) 2010

  7. Phase I study design (oral formulation) Primary Determination of MTD and/or optimal biologic dose, characterization of DLTs of oral LDE225 administered on a daily continuous schedule Secondary Safety and tolerability of LDE225 Pharmacokinetic profile 7-day PK run-in period to characterize the PK profile of LDE225 following a single oral dose Days 1, 8, 15 and 28 in Cycle 1 Biomarker and pharmacodynamic assessments: effect on markers of Hh signaling pathway (Gli-1 expression by RT-PCR) 18FDG-PET for metabolic anti-tumor activity Overall response as per RECIST

  8. LDE225 Phase I: study designPhase IA, multicenter, open-label, single-agent, dose-escalation study in patients with advanced solid tumors Dose-escalation phase Bayesian logistic regression model using overdose control MTD expansion phase Oral, daily LDE225, 28-day cycle Declaration of MTD* 100 mg/day 1500 mg/day 200 mg/day 800 mg/day 400 mg/day Ongoing Dose levels • Advanced solid tumor – including locally advanced, multifocal or metastatic basal cell carcinoma (BCC), and recurrent medulloblastoma (MB) • Age 18 years or older, WHO performance status ≤2, and other standard Phase I inclusion criteria Decision to dose escalate based on review of toxicities in Cycle 1 and other clinical, PK, and laboratory data *Defined as the highest drug dosage not causing DLT in >33% of patients during the first treatment cycle

  9. Baseline cohort characteristics

  10. Most common grade 1–2 AEs potentially related to LDE225 treatment AEs with total incidence of ≥2 represented; cut-off date 24 May 2010

  11. Pharmacokinetic profile after a single dose (7-day run-in) Mean effective half-life ~90 h (range: 23–230 h) Median time to reach Cmax was 4 h (range: 1–48 h) Steady state conditions achieved between Days 15–22 10000 1000 LDE225 plasma conc. (nM) 100 100 mg QD (n=6) 200 mg QD (n=6) 400 mg QD (n=5) 800 mg QD (n=11) 1500 mg QD (n=7) 10 1 0 24 48 72 96 120 144 168 Time (h)

  12. PK: relationship between LDE225 dose and plasma exposure (Cmax and AUC) at Day 15 100 200 400 800 1500 • Dose-proportional systemic exposure up to 1500 mg/day (R2=0.6019 P=0.0001) • Two-fold increase in Cmax and five-fold increase in AUC on Day 15 versus Day 1 • Target exposure (AUC) as predicted by preclinical models was achieved by Day 15 at doses ≥400 mg daily • Variability in exposure was moderate–high (CV%) in AUC (43–104%) and Cmax (38–90%) 4000 Cmax Day 15 3000 Plasma Cmax (nM) 2000 1000 0 80000 AUC0-24 Day 15 60000 Plasma AUC0-24 (nM*hr) 40000 Target exposure 20000 0 Dose (mg/day)

  13. Biomarkers: LDE225-induced changes in skin Gli-1 mRNA expression after 28 days 5 0 -5 –10 –15 Fold-change from baseline 100 mg 200 mg 400 mg 800 mg 1500 mg –20 –25 –30 –35 Patients –3.56 –7.36 Mean Fold Change –1.14 –3.17 –19.14 Mean % inhibition 12.3% 68.4% 86.4% 72.0% 94.8%

  14. Reduction in Gli-1 expression observed in skin correlated with plasma exposure . . . . . . . . . . . Cmax (nM) Day 15 . Cmin (nM) Day 15 . AUC24 (nM*h) Day 15 . . . . . . . . . . . . . . . . . . . . . . 0 . . . . . . . . . . . . . . . Skin Gli-1 Reduction (DCt) . . . . . –2 . . . . . . . –4 0 1000 2000 3000 0 1000 2000 3000 0 20000 40000 60000 PK measurement value Cohort 1; 100 mg Cohort 2; 200 mg Cohort 3; 400 mg Cohort 4; 800 mg Cohort 5; 1500 mg CT, threshold cycle by RT-PCR analysis

  15. Summary of anti-tumor activity (n = 31) One patient (medulloblastoma, 200 mg/day) achieved an objective partial response (PR) One partial metabolic response in a second patient with medulloblastoma Six patients (2 NSCLC, basal cell carcinoma, spindle cell carcinoma, osteocarcinoma and breast cancer) have received LDE225 for more than 4 months

  16. LDE225 is active in medulloblastoma Baseline C2D28 FDG-PET, fluorodeoxyglucose-positron emission tomography Patient A (200 mg) Prior surgery, radiation, 4 chemotherapy regimens and autologous BMT Partial response following 2 cycles of therapy A Cycle 2 Day 28 Pre-treatment MRI Patient B (1500 mg) Prior surgery, radiation, 4 chemotherapy regimens and autologous BMT Partial metabolic response following 2 cycles of therapy B

  17. Conclusions • LDE225 is generally well tolerated at doses of 100–1500 mg daily • No DLTs to date • LDE 225 has demonstrated a favorable PK profile, with dose-proportional exposure up to 1500 mg daily • Exposure-dependent target inhibition was observed • Up to 95% Gli-1 reduction in skin • Anti-tumor activity was observed across a wide therapeutic dose range • Dose escalation is ongoing to establish a recommended dose and schedule for future studies

  18. Acknowledgements Patients who took part in this trial and their families All staff at the following study sites: Vall d’Hebron University Hospital: Marta Beltran, Gemma Sala University of Pittsburgh Cancer Institute: Kathleen Kovalik, Andrea Yartin Cancer Therapy & Research Center in San Antonio: Patricia O'Rourke, Hope Moreno, Celina Herrera Leicester Royal Infirmary, UK: Rahima Ibrahim, Samantha Baker, Kate Sorrell University Hospital of Zurich, Switzerland: Prof. Reinhard Dummer, Dr. Sharon Gobbi, Severine Buffoni, Gionata Cavadini Novartis LDE225 Research and Development Team Special acknowledgement to:Kathleen Roberge, Novartis Clinical Trial Leader

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