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PMX 2058: Rationale for Recent Preclinical Evaluation

PMX 2058: Rationale for Recent Preclinical Evaluation. Review of existing xenograft data with PMX 290 and PMX 2058 Borderline to modest efficacy in the colon (HCT116), breast (MDA-MB-435) and renal (CAKI-1) xenografts studied. Other models more sensitive to PMX 2058? Mechanism of action

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PMX 2058: Rationale for Recent Preclinical Evaluation

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  1. PMX 2058: Rationale for Recent Preclinical Evaluation Review of existing xenograft data with PMX 290 and PMX 2058 Borderline to modest efficacy in the colon (HCT116), breast (MDA-MB-435) and renal (CAKI-1) xenografts studied. Other models more sensitive to PMX 2058? Mechanism of action Some uncertainty associated with primary target – data not entirely supportive of PMX 290 being a Trx/TrxR inhibitor. Consistent evidence supporting inhibition of HIF-1 signalling. Data available for other agents PX-12 (Trx inhibitor) – Phase I data provides evidence of stable disease in patients with pancreatic carcinoma. PX-478 (selective HIF-1 inhibitor) – preclinical efficacy in broad spectrum of tumour types including small cell lung, prostate, pancreatic and ovarian carcinomas. Strictly confidential

  2. Xenograft studies in HCT116, MDA-MB-435 and CAKI-1 show modest activity. NCI mean LC50 data • ACHN more sensitive than CAKI-1 • Other agents that target Trx-1 (PX-12) and HIF-1 signalling (PX-478) show efficacy in pancreatic models. • Further in vitro studies to select more sensitive cell lines: • Panc-1 IC50: 104nM • BxPC3 IC50: 272nM • MIA PaCa-2 GI50:313nM • ACHN IC50:107nM Colon Renal Breast HCT 116 CAKI-1 MDA-MB-435 LC50 values relative to overall mean (vertical line) Wells et al J Med Chem 46 532-541, 2003 PMX 290: In Vitro Antitumour Activity Strictly confidential

  3. PMX 2058: Target Clinical Indications? Colorectal carcinoma Existing xenograft data demonstrates modest activity. Pancreatic carcinoma Clear unmet clinical need. Existing therapies offer small increase in survival - Low regulatory hurdle but particularly challenging area Approval of erlotinib in combination with gemcitabine based on increase in median survival from 5.9 to 6.4 months when compared to gemcitabine alone. Renal carcinoma A number of drugs approved Sunitinib (Sutent) – median TTP 11 months compared to 5 months with IFN. Sorafenib (Nexavar) – 39% OS improvement compared to placebo at initial review. Temsirolimus (Torisel) – median survival 10.9 months compared to 7.3 months with IFN. Bevacizumab (Avastin) – with IFN increases survival from 5.4 months to 10.2 months. Clinical need remains but crowded landscape Melanoma / Others? – PMX 290 potent in methotrexate, cisplatin and doxorubicin resistant cell lines but not in histotypes that are clinically relevant. Await further data. Strictly confidential

  4. PMX 2058: Pancreatic Cancer as Target Indication? (1) Pancreatic tumours – particularly hypoxic Pancreatic ductal adenocarcinomas – 4 fold increase in Trx Good potency of PMX 290 in Panc-1 and BxPC3 cells PX-12 (Trx Inhibitor) - development deprioritized Sept 08 Ongoing Phase II study in advanced pancreatic cancer 33% patients with elevated plasma Trx-1 (>ULN: 18ng/ml) achieved stable disease. No patients with normal level of plasma Trx-1 achieved stable disease Plasma Trx-1 may be a suitable predictor of response - patient selection Plasma VEGF decreases – may be a biomarker of response Does PMX 2058 inhibit Trx/TrxR? Strictly confidential

  5. PMX 2058: Pancreatic Cancer as Target Indication? (2) PX-478 PMX 290 HIF signalling Decrease Decrease Hypoxia-mediated VEGF Decrease Decrease Normoxic VEGF No change ? HIF-1 protein levels Decrease Increase HIF-2 protein levels Unchanged Increase Cell growth inhibition (differing experimental conditions): MCF-7 25µM3µM HT-29 30µM 5µM PX-478 (selective HIF-1 inhibitor) Ongoing Phase I trial Preclinical studies in Panc-1 xenograft model 20mg/kg x 5 (p.o) affords ~ 60% TGI. Enhanced efficacy in combination with radiation. Pancreatic cancer likely target indication. Strictly confidential

  6. PMX 2058 Efficacy: Panc-1 Xenografts (1) Efficacy data supported by limited PK and PD data. Strictly confidential

  7. PMX 2058 Efficacy: Panc-1 Xenografts (2) Bold type – statistically significant (p<0.05) Strictly confidential

  8. PMX 2058 Efficacy: Panc-1 Xenografts (2) Insert available PK data – awaited Insert available PD data (HIF-1, VEGF, GLUT-1 and CD31) - awaited. Strictly confidential

  9. PMX 2058 Efficacy: BxPC3 Xenografts Insert updated efficacy data – awaited. Efficacy data supported by limited PK and PD data – data to be generated. Strictly confidential

  10. PMX 2058: Rationale for Recent Preclinical Evaluation Back-up slides Strictly confidential

  11. PMX 290: Efficacy • Significant activity i.p. in 3/3 xenograft models: Colon (HCT 116), melanoma (MDA-MB-435) and renal (CAKI-1) HCT 116, MDA-MB-435 CAKI-1 • 150 / 200 mg/kg d 7 100 / 150 mg/kg d 7, 14 • 25 / 50 mg/kg d 7-11 25 / 50 mg/kg d 7-11 Strictly confidential

  12. PMX 290 Efficacy: CAKI-1 Xenografts (s.c) Route of administration: I.P Species: Ncr nu/nu mice 100 / 150 mg/kg d 7, 14 25 / 50 mg/kg d 7-11 • Borderline and transient inhibition of tumour growth except at 50mg/kg/d x 5 • 50mg/kg/d x 5 results in maximal T/C of 52% (day 35). • All doses, except 25mg/kg/d x 5, result in diarrhoea • 50mg/kg/d x 5 causes a body weight loss of 13%. Strictly confidential

  13. PMX 290 Efficacy: HCT116 Xenografts (s.c) Route of administration: I.P Species: NMRI nu/nu mice 150 / 200 mg/kg d 7 25 / 50 mg/kg d 7-11 • Toxic deaths at 150mg/kg and 200mg/kg – after treatment. Prevented planned second dose. • Toxic deaths associated with diarrhoea. Inflamed gut at autopsy. • Maximal T/C of 39% (day 14) at 50mg/kg/d x 5 • 50mg/kg/d x 5 causes a body weight loss of 12%. Strictly confidential

  14. PMX 290 Efficacy: HCT116 Xenografts (s.c) * Efficacy following administration of 40mg/kg/day i.p attained significance: p  0.05 T/C: 36% (Day 21) Strictly confidential

  15. PMX 290 Toxicity: HCT116 Tumour-Bearing Mice Mice: NMRI (nu/nu); HCT116 (colon) xenografts Treatment period: Daily on Days 11 – 15. Inoculation: 107 cells / mouse – Day 0 (Subcutaneous). Vehicle: Saline containing 10%v/v DMSO and 0.05%v/v Tween 80. Blood parameters determined on Day 15 (n = 5). a Day on which maximum response observed in parentheses. T = Size of tumours in treated mice; C = Size of tumours in non-treated, control mice. Responses in bold type attain statistical significance with respect to control group (p < 0.05). b Day(s) on which toxic deaths observed in parentheses. Strictly confidential

  16. PMX 290 Efficacy: MDA-MB-435 Xenografts (s.c) Route of administration: I.P Species: NMRI nu/nu mice 150 / 200 mg/kg d 7 25 / 50 mg/kg d 7-11 • Toxic deaths at 150mg/kg and 200mg/kg – after treatment. Prevented planned second dose. • Toxic deaths associated with diarrhoea. Inflamed gut at autopsy. • Maximal T/C of 35% and 32% (day 14) after 150mg/kg and 200mg/kg respectively • 150mg/kg and 200mg/kg causes body weight loss of 12% and 17% respectively. Strictly confidential

  17. PMX 290 Efficacy: MDA-MB-435 Xenografts (s.c) Efficacy following administration of 40mg/kg/day i.p attained significance: p  0.05 Maximal T/C: 47% (Day 16) Strictly confidential

  18. PMX 290 Toxicity: MDA-MB-435 Tumour-Bearing Mice Mice: NMRI (nu/nu); MDA-MB-435 (breast) xenografts Treatment period: Daily on Days 6 – 10. Inoculation: 107 cells / mouse – Day 0 (Subcutaneous). Vehicle: Saline containing 10%v/v DMSO and 0.05%v/v Tween 80. Blood parameters determined on Day 10 (n = 5). a Day on which maximum response observed in parentheses. T = Size of tumours in treated mice; C = Size of tumours in non-treated, control mice. Responses in bold type attain statistical significance with respect to control group (p < 0.05). b Day(s) on which toxic deaths observed in parentheses. Strictly confidential

  19. PMX 2058: In Vivo Conversion to PMX 290 • Rapid conversion to PMX 290 in vivo (rat) – via mono-adduct (GW002057) • PMX 290 concentrations  0.05µM for entire 8h study period Strictly confidential

  20. PMX 2058 Efficacy: HCT116 Xenografts (s.c) • PMX 2058 efficacy following administration of 100mg/kg/day x 5 i.v - attained borderline significance: p  0.05 • Comparable to PMX 290 at 50mg/kg/day x 5 i.p • PMX 2058 Maximal T/C: 45%; Body weight loss: 5% (Control body weight loss: 2%) • PMX 290 Maximal T/C: 35%; Body weight loss: 15% Strictly confidential

  21. PMX 2058: Consideration of Clinical Space Strictly confidential

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