Phase III ARISER trial data ASCO 2013 RENCAREX - Unique targeted antibody therapy for adjuvant treatment of non-metastatic clear cell renal cell carcinoma patients June 2013
Carbonic Anhydrase IX (CAIX): A novel, highly specific tumour target Carbonic Anhydrase IX: a transmembrane glycoprotein (cell surface receptor) Functional role in acid/base metabolism Constitutively upregulated in clear cell RCC (ccrcc) CAIX is not expressed in normal tissue (except low-level expression in the GI tract) Upregulated by hypoxia in other solid tumours CAIX is considered to be one of the best cellular biomarkers of hypoxia Antibody Girentuximab binds to CAIX 2
Mode of Action ADCC: Antibody Dependent Cellular Cytotoxicity Girentuximab binds to CAIX expressed on tumour cells The constant region of Girentuximab binds to the Fc receptor of natural killer cells (NK cells) NK cells act as effector cells which destroy the tumour cells Cell growth inhibition Direct Girentuximab effects on tumour cells Additional mechanism of Girentuximab action independent of ADCC 3
Excellent targeting of Girentuximab to primary tumour and metastasis Primary tumour left kidney Rib metastasis Clavicula metastasis Courtesy of Michael Yu, Fox Chase Cancer Center Images of PET/CT of Iodine-124 labeled Girentuximab (REDECTANE ) 4
Adjuvant RENCAREX Immunotherapy Phase III Trial to Study Efficacy in Non-metastatic Renal Cell Carcinoma A prospective randomized double-blind phase III study to evaluate adjuvant Girentuximab treatment versus placebo in patients with ccrcc and risk factors for relapse Central randomisation Independent central radiology review Central pathology review Independent Data Monitoring Committee (IDMC) Objectives Primary objectives Disease-free survival (DFS) Overall survival (OS) Secondary objectives Quality of life (QLQ-C30; EORTC) Safety Risk group 1 Risk group 2 Risk group 3 Risk Factors Any T3 or T4 and N0/NX M0 Any T stage and N+ disease and M0 T1b N0/NX M0 or T2 N0/NX M0 grading G* 3 *Fuhrman or any other nuclear grading system with at least 3 grades TNM stages according to 6 th edition UICC, 2002 5
ARISER: Well balanced, controlled and conducted Confirmed high risk population 97% of all patients express CAIX in their tumour tissues Good patient compliance Low number of major protocol deviations and discontinuations Balanced distribution in both treatment arms for all parameters e.g. High risk groups Tumour status at baseline Age, gender and ethnicity Protocol deviations, compliance and reasons for discontinuation Global Health Status maintained during study Professor Seppo Pyrhoenen, Chairman of the ARISER IDMC: I have over 30 years experience in treating patients with kidney cancer and applaud this study for being well balanced, controlled and very well conducted. This is probably the most comprehensive study in the adjuvant setting conducted in the past 20 years! 6
Data published in October 2012 Disease Free Survival: ITT cohort Placebo RENCAREX Intent to treat (ITT) approach includes all patients of the trial Placebo RENCAREX Median DFS Never Reached 71.4 months 5-year DFS 51.6% 53.9% p-value (Log-rank test) 0.74 Hazard Ratio (95% CI) 0.97 (0.79 1.18) RENCAREX did not meet the primary endpoint Median DFS: No difference between RENCAREX and placebo Unexpected long disease free survival of 72 months 7
Further biomarker analyses Efficacy of Girentuximab is dependent on CAIX expression AND density CAIX density is determined by a CAIX score Proportion (%) of CAIX positive cells High CAIX score Low CAIX score Staining intensity of CAIX positive cells No or Faint/Weak staining Intensity = 1 Moderate staining Intensity = 2 Strong staining Intensity = 3 CAIX score Hazard Ratio (HR) Calculation of CAIX score % positive * staining intensity 85% positive with Moderate Intensity (2): = CAIX Score 1.7 Increasing CAIX density determined by CAIX score leads to increased efficacy of RENCAREX >0.4 0.96 >0.8 0.92 >1.2 0.87 >1.6 0.91 >2.0 0.78 >2.4 0.77 >2.6 0.54 8
Companion Diagnostics to stratify patients who may benefit from RENCAREX adjuvant therapy Diagnosis: nonmetastatic ccrcc Non-Responders: low to medium CAIX levels Nephrectomy + CAIX Companion Diagnostic Adjuvant Therapy: RENCAREX Responders: high CAIX levels Companion Diagnostic to identify ccrcc patients with high CAIX levels WILEX proprietary CAIX IHC diagnostic kit to be developed for patient selection and reimbursement RENCAREX adjuvant treatment in ccrcc patients with high CAIX levels RENCAREX significantly improved DFS of patients with high CAIX score in non-metastatic ccrcc patients after nephrectomy 9
RENCAREX significantly improved DFS in patients with high CAIX score 2.6 (ITT) Placebo RENCAREX Intent to treat (ITT) approach includes all patients of the trial Placebo RENCAREX Median DFS 51.2 months 73.6 months 5-year DFS 48.4% 70.6% p-value (Log-rank test) 0.02 Hazard Ratio (95% CI) 0.54 (0.32 0.93) RENCAREX improves median Disease Free Survival (DFS) by over 22 months (= 44%) Statistically significant treatment effect (p=0.02) Very impressive clinical effect (HR=0.54) in 151 patients 10
Per protocol population: high CAIX score ( 2.6) Placebo RENCAREX Per protocol population includes all patients from the ITT population who had: received at least eight consecutive administrations of study medication (week 1 to 8) and a final diagnostic assessment no major protocol deviation CAIX score - High Placebo RENCAREX Median DFS [months] 51.2 73.6 5y DFS [%] 47.8 73.1 p-value (Log-rank test) 0.007 Hazard Ratio 0.51 RENCAREX improved 5 year DFS by over 50% p-value and Hazard Ratio further improved HR=0.51, p=0.007, 139 patients 11
Patients < 65 years and with high CAIX score of 2.0 (ITT) Placebo RENCAREX Placebo RENCAREX Median DFS Never Reached Never Reached 5-year DFS 55.2% 70.9% p-value (Log-rank test) 0.01 Hazard Ratio (95% CI) 0.60 (0.40 0.89) RENCAREX showed a clinically and statistically significant DFS with a CAIX score 2.0 HR=0.60, p=0.01, 286 patients Median DFS not reached 12
Conclusions Patients treated with RENCAREX had ~40% lower risk of recurrence if they: had a high CAIX score ( 2.6) or had a CAIX Score ( 2.0) and < 65 years of age Patients who may benefit from RENCAREX adjuvant therapy may be stratified by CAIX scores Confirmatory prospective study to confirm predictive value in high CAIX scores patients Professor Arie Belldegrun, Principal Investigator of the ARISER trial, Director of the UCLA Institute of Urologic Oncology, Los Angeles The ARISER trial, which is one of the most important prospective trials in kidney cancer in the past decade, has demonstrated a surprisingly long Disease Free Survival. This might pose a challenge for adjuvant ccrcc drug development without appropriate patient stratification. The finding that a subgroup of patients had a 40% lower risk of recurrence if treated with RENCAREX is important and should be confirmed in a future prospective trial now that we know that CAIX density can serve as a predictive companion diagnostic for RENCAREX. 13
Commercial potential Adjuvant treatment of non-metastatic ccrcc: no drugs approved by FDA or EMA Market assumptions North America EU-27 NA + EU-27 Kidney Cancer Incidence 2018 (Globocan 08, 2,5% growth rate p.a.) 100% 78,200 92,900 171,100 Renal Cell Carcinoma (RCC) a 85% 66,500 79,000 145,400 Clear cell RCC (ccrcc) a 77% 51,200 60,800 112,000 Non-metastatic ccrcc a 75% 38,400 45,600 84,000 Patients with CAIX score 2.0 and < 65 years 31% 11,900 14,100 26,000 Revised peak sales potential of RENCAREX : > USD 300 million Adjuvant setting of ccrcc High CAIX scores a - SEER 2013 IP protection beyond 2026 Orphan Drug status: USA 7 years, Europe 10 years Stratification by biomarker CAIX also applicable to other indications with CAIX expression colon, non-small cell lung, head and neck and oesophageal cancer 14
Outlook Discussions with regulatory authorities (FDA and European Authorities) H2/2013 planned on a confirmatory prospective Phase III trial with RENCAREX in the adjuvant therapy of ccrcc in the defined subgroup using a CAIX companion diagnostic for stratification Next steps in partnering strategy to conduct a confirmatory prospective trial WILEX and Prometheus are currently in discussion on the formalities and timing regarding the termination of the existing licensing agreement for the US marketing rights of RENCAREX Enter into partnership for financing, development and commercialisation of RENCAREX 15
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