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J.P. Delord , N. Houédé, A. Awada, A. Taamma, S.J. Faivre,

First-in-Man Phase Ι Safety, Pharmacokinetic and Pharmacodynamic Analysis of the Oral MEK-Inhibitor AS703026 (2 Regimens) in Patients With Advanced Solid Tumors. J.P. Delord , N. Houédé, A. Awada, A. Taamma, S.J. Faivre, T. Besse-Hammer, A. Italiano, C. Vignaud, M. Donica, E. Raymond.

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J.P. Delord , N. Houédé, A. Awada, A. Taamma, S.J. Faivre,

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  1. First-in-Man Phase Ι Safety, Pharmacokinetic and Pharmacodynamic Analysis of the Oral MEK-Inhibitor AS703026 (2 Regimens) in Patients With Advanced Solid Tumors J.P. Delord, N. Houédé, A. Awada, A. Taamma, S.J. Faivre, T. Besse-Hammer, A. Italiano, C. Vignaud, M. Donica, E. Raymond Institut Claudius Regaud, Toulouse, France, Institut Bergonié, Bordeaux, France, Institut Jules Bordet, Brussels, Belgium, Merck Serono SA, Geneva, Switzerland, Hôpital Beaujon, Clichy, France.

  2. MEK Inhibitor AS703026 • A biaryl amine derivative • In vitro and in vivo pharmacology: • High selectivity for MEK1/2 • Anti-proliferative effects in tumor cell lines • Efficacy in xenograft models with activated MAPK signaling • HCl MW: 467.8 KDa (HCl salt)

  3. AS703026 Phase Ι Trial Objectives • Primary objective • To determine the MTD for 2 distinct dosing schedules administered orally once daily • Secondary objectives • To provide preliminary findings on the safety profile • To assess the pharmacokinetics • To assess biological activity and pharmacodynamic markers in blood and in pre/post dosing tumor biopsies in a subset of patients • To assess the antitumor activity in patients with solid tumors

  4. AS703026 Phase ΙTrial Design • 3 + 3 Open-label Phase I trial • Two dosing schedules tested • AS703026 orally once daily (after at least 2 hours fasting) • Dose escalation: separate for each schedule • If no grade 2 toxicity observed a 100% dose increment • If a grade 2 toxicity is observed: Modified Fibonacci

  5. AS703026 Phase Ι Trial Baseline Patient Characteristics Other: breast, esophagus, gall bladder, head & neck, lung, mesothelioma, ovary, pancreas, renal, sarcoma, thyroid, bladder

  6. AS703026 Phase Ι Trial - Dose Escalation Cohort expanded due to occurrence of DLT: * LFT elevation, **retinal vein occlusion

  7. AS703026 Phase Ι TrialTreatment Exposure Number of initiated cycles per patient Schedule 2 Schedule 1 Dose level * * 195 mg/day * 150 mg/day * * 120 mg/day * * 94 mg/day 68 mg/day 45 mg/day 28 mg/day 14 mg/day 7 mg/day 5.0 mg/day 3.5 mg/day 2.5 mg/day 2.0 mg/day 1.5 mg/day 1 mg/day 0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11 *patient ongoing Number of initiated cycles Number of initiated cycles

  8. AS703026 Phase Ι TrialMost Common Adverse Events (≥15% of patients in at least one schedule) All AEs are grade 1-2

  9. AS703026 Phase Ι TrialDose Limiting Toxicity • Schedule 1: • DL 7 (28 mg/day): • 1 / 6 patients: Grade 3 Liver function test elevation (treatment delay more than 2 weeks) • DL 11 (120 mg/day): • 1 / 3 patients: Grade 2 Retinal Vein Occlusion (cycle 3) • Cohort expansion ongoing • Schedule 2: • No DLT up to 195 mg/day • Dose escalation ongoing

  10. AS703026 Phase Ι TrialFocus on Ocular Adverse Events • Most common adverse events were: • abnormal perception of colors • blurred vision • visual field defect • Most reported adverse events were mild to moderate (CTCAE grade 1-2) • Ocular adverse events often occurred early after first dosing (median: 3 days [range 1-105]) • Visual disturbances usually resolved spontaneously while remaining on treatment

  11. Indication for dose-proportional increase in Cmax and AUC Median Tmax is 1 hour (range 0.5 – 4.0 h) Mean Cmax – by dose , Day 1 (n=80) 1200 1000 800 600 Mean Cmax (ng/mL) 400 200 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Dose (mg) AS703026 Phase Ι TrialPK Evaluation – Preliminary Results • Median terminal elimination half-life (t1/2) is 5.1 hours • Exposure at 120 mg Day 1 (n=7): • Median Cmax 670 ng/mL • Median AUC 2270 ng*h/mL

  12. AS703026 Phase Ι Trial p-ERK Inhibition in PBMC – Preliminary Results Chart 160 140 160 120 140 120 100 100 percent_var 80 80 60 60 40 40 20 20 0 0 Pre-dose 2h 8h 24h 1 1.5 2.5 3.5 7 14 28 45 68 94 120 Percentage of pERK inhibition compared with baseline across dose levels (Cycle 1 Day 1) Time course of % of pERK inhibition compared with baseline Pt 3186 (120mg) % of pERKvs baseline % of pERKvs baseline Dose (mg) Time point • Dose dependent inhibition of pERK at 2 hrs post administration leading to ≥ 80% inhibition at 28 mg and above • Sustained inhibition of pERK

  13. Maximum reduction from baseline in tumor size per individual patient 100 Both schedules (DL ≥28 mg/day) 90 80 70 60 28 68 50 68 120 40 68 94 30 45 28 28 28 20 28 45 % tumor change from baseline [sum of target lesions] 94 10 68 45 120 45 28 120 94 120 28 94 68 94 195 0 -10 -20 -30 -40 -50 -60 -70 -80 AS703026 Phase Ι TrialAnti-Tumor Activity – Schedules 1 & 2 Melanoma CRC Other  Patient receiving Schedule 1; Patient receiving Schedule 2 No. of treated patients = 46 No. of treated patients with measurable disease at baseline and ≥ one tumor assessment on-study = 26

  14. AS703026 Phase Ι Trial Patient 2960. Male, 70 years, right inguinal melanoma in 2007 with metachronous lung metastasis that progressed after IFN, dacarbazine and fotemustine AS703026: 68 mg/day Baseline: 03 July 2009 End of Cycle 1: 21 July 2009

  15. AS703026 Phase Ι TrialSummary • AS703026 is a highly selective oral small molecule that inhibits MEK1/2 phosphorylation • AS703026 has been tested in this phase I trial in solid tumor patients using two dosing schedules • In the 5-day on / 2-day off schedule, one DLT retinal vein occlusion occurred at 120 mg/day, cycle 3. Cohort expansion is ongoing • In the 2-week on / 1-week off schedule, dose escalation is ongoing

  16. AS703026 Phase Ι TrialConclusions • Adverse events are usually mild to moderate and reversible during treatment or after dose interruption • Pharmacokinetic parameters seem to be dose-proportional across the dose range investigated • Almost complete and sustained (>8h)pERK inhibition is observed in PBMC at AS703026 doses ≥ 28 mg/day • Three partial responses have been reported in melanoma

  17. Acknowledgements • Merck Serono • Sabrina Bigeard • Franck Brichory • Jerome Chague • Ann Clark • Patricia Digon • Athos Gianella-Borradori • Christian Lüpfert • Marco Minerdo • Giacomo Mordenti • Janet Ogden • Stefano Ongarello • Hôpital Beaujon, Clichy, France • Pr Eric Raymond • Pr Sandrine Faivre • Fateh Cheklat • Institut Claudius Regaud, Toulouse, France • Pr Jean-Pierre Delord • Dr Yann Bergé • Muriel Laumond • Institut Bergonié, Bordeaux, France • Dr Nadine Houédé • Dr Antoine Italiano • Alejandro Gobema • Institut Jules Bordet, Brussels, Belgium • Dr Ahmed Awada • Dr Tatiana Besse-Hammer • Michel Dubuisson

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