XENOX

1. XENOX Randomized double blind (DB) placebo (Plcb) controlled Phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in 1st line treatment of patients (pts) with metastatic colorectal cancer (MCRC). J. CASSIDY, G.A. BJARNASON, T. HICKISH, C. TOPHAM, M. PROVENCIO, G. BODOKY, L. LANDHERR, P. KORALEWSKI, G.LOPEZ-VIVANCO, G. SAID BEATSON ONCOLOGY CENTER (UK), TORONTO SUNNYBROOK REGIONAL CANCER CENTER, (CANADA), POOLE AND BOURNEMOUTH HOSPITALS (UK), ROYAL SURREY COUNTY HOSPITAL (UK), CLINICA PUERTA DE HIERRO (SPAIN), ST LASZLO HOSPITAL (HUNGARY), UZSOKI STREET HOSPITAL (HUNGARY), RYDYGIER MEMORIAL HOSPITAL (POLAND), HOSPITAL DE CRUCES (SPAIN), HÔPITAL De BICÊTRE (FRANCE).

2. Xaliproden Orally active non-peptide neurotrophic and neuroprotective agent: • Increases the expression of neurotrophins (NGF, BDNF, NT3), endogenous proteins acting on the development and repair of neurons • Increases neuronal survival and differentiation • Minimizes experimentally-induced neuronal lesions, including oxaliplatin-induced lesions • 5HT1A –receptor agonist

3. Study Design FOLFOX4 + Xaliproden 1 mg po qd Patients With MCRC R FOLFOX4 + Placebo 1mg po qd • Stratification factors: number of metastatic organs (1 vs 2), LDH ( vs >1.5 x ULN), WHO PS (2 vs 0-1), study site • Treatment with study drug (xaliproden or placebo) started the day of first oxaliplatin infusion and discontinued 15 days following the last oxaliplatin infusion

4. Main Inclusion Criteria • Patient with proven MCRC • No prior chemotherapy for metastatic disease • No prior treatment with oxaliplatin • Measurable disease (RECIST) • No peripheral neuropathy

5. Primary Endpoints Two co-primary endpoints: • Reduction in the risk of occurrence of Grade 3-4 peripheral sensory neuropathy (PSN) relative to the cumulative dose of oxaliplatin • Specific Neurologic Toxicity Scale for Oxaliplatin Dose Adjustment, administered every 2 weeks • Kaplan Meier analysis • Non-inferiority in Response Rate (RR) • Response Evaluation Criteria in Solid Tumors (RECIST) criteria, performed every 8 weeks

6. Statistical Approach • Powered (80%) to demonstrate a 45% reduction in the probability of experiencing Grade 3-4 PSN relative to the cumulative dose of oxaliplatin • 2-sided logrank test with  = 0.05 • Assumption: 18% Grade 3 PSN for a cumulative dose of 1000 mg/m² in the control arm • Powered (80%) to demonstrate non-inferiority in RR • Non-inferiority: lower bound of the 2-sided 95.2 % CI of the ratio of the RRs is at least 0.80 • Assumption: 49% RR in the control arm 310 patients per treatment group needed

7. Secondary Endpoints • Incidence, dose to onset of PSN, oxaliplatin dose reduction/delays, discontinuation due to PSN • Change in nerve conduction study (NCS) • Change in Modified Norris Scale score • Time to recovery from Grade 3-4 PSN • Progression free survival (PFS), overall survival (OS) • Safety

8. Baseline Characteristics (ITT)

9. Exposure to Oxaliplatin

10. Probability of First Onset of Grade 3 PSN Relative to Cumulative Dose of Oxaliplatin (ITT) Logrank test, p = 0.0203 HR [95% CI] = 0.61 [0.40, 0.93] Placebo Xaliproden

11. Probability of First Onset of Grade 3 PSN Relative to Cumulative Dose of Oxaliplatin (ITT) Probability of grade 3 PSN relative to cumulative dose (CD) of oxaliplatin , % CD: mg/m²

12. Nerve Conduction Studies, Sensory Action Potential Relationship between the sensory action potential (SAP) and PSN Grade at the time of the second NCS

13. Incidence PSN (ITT)

14. Acute Symptoms of PSN (ITT)

15. Grade 2/3 PSN Recovery (ITT)

16. Response Rate (ITT) RR ratio [2-sided 95.2% CI] = 1.055 [0.88;1.26]

17. Overall survival 1.0 Placebo 0.9 Xaliproden 0.8 0.7 0.6 0.5 Probability 0.4 Placebo N=324 Xaliproden N=325 0.3 0.2 Nb of events 198 (61.1%) 192 (59.1%) 0.1 Median OS 18.9 20.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Placebo 324 315 296 270 231 194 129 77 50 28 8 3 0 Xaliproden 325 311 299 280 238 202 140 96 61 34 17 1 0

18. Safety Overview

19. All-Grade Adverse Events with 2% Higher Incidence in Xaliproden vs PlaceboTreated Group

20. Conclusions (I) In patients with MCRC treated with 1st line FOLFOX4: • Xaliproden decreases the risk of occurrence of Grade 3 oxaliplatin-induced PSN by 39% (p = 0.0203). • Absence of negative impact of xaliproden on the FOLFOX4 outcome • non-inferiority in Response Rate: 42.6% vs 44.9 in the xaliproden arm • similar median Overall Survival: 18.9 months vs 20.1 months in the xaliproden arm

21. Conclusions (II) In patients with MCRC treated with 1st line FOLFOX4: • Reported safety figures mostly reflect the 5-HT1A –receptor agonist properties of xaliproden • No effect reported on acute symptoms. • No effect reported on recovery but xaliproden discontinued at the end of treatment with oxaliplatin

22. Next Step, Study EF5505, • Confirm XENOX study • Explore continuing treatment with Xaliproden • after oxaliplatin discontinuation Modified FOLFOX6 + xaliproden 1 mg qd End O X A Xaliproden 1 mg qd R PSN >1 Modified FOLFOX6 + Placebo • Stratification factors: number of metastatic organs involved (1, 2), oxaliplatin (yes, no), bevacizumab (yes, no) Placebo Double blind

23. Acknowledgments Investigators: Australia: Slancar M, Abdi E, Grygiel J, Burns I Belgium: Van Cutsem E, Peeters M, Humblet Y, Bols A, Honhon B Canada: Bjarnason G, Fields A, Latreille J, Panasci L France: Ychou M, François E,Metges JP, Viret F, Legoux JL,Rotarski M, Joly JP Hungary: Bodoky G, Nagykalnai T, Moskovits K, Izso J, Thurzo L, Baki M, Boer K Italy: Bonetti A, Pinotti G, Zaniboni A, Villa E, Siena S Poland: Koralewski P, Filipczyk-Cisarz E, Szczylik C, Utracka-Hutka B, Załuski J South Africa: Ruff P, Rapoport BL, Slabber CF/Lombard J, Hacking D, Geddes C, Robertson BM Spain: Tabernero JM, Salgado M, Lopez G, Provencio M, Benavides M, Oaknin A, Rifa J, Cervantes A, Alvarez S UK: Cassidy J, Corrie P, Valle J, Topham C, Samuel L, Hickish T Sponsored by Sanofi-Aventis