1. Optimal Antifungal Prophylaxis The Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases – Intensive Care Center for Clinical Trials BMBF 01KN0706 University of Cologne

2. Sources of information 2 RCT Institutional data

3. Leukemia Treatment Path Newly diagnosed = Uncontrolled leukemia Induce remission by induction chemotherapy Remission achieved ? Yes No Consolidate remission by consolidation chemotherapy

4. Posaconazole 3x 200 mg Fluconazole 1x 400 mg or Itraconazole 2x 200 mg

5. Number of Induction Chemotherapies POS (n = 304) FLU/ITZ (n = 298) n (%) 1174 (57)182 (61) 296 (32)89 (30) 334 (11)27 (9)

6. Time to Systemic Antifungal Use Kaplan-Meier analysis of the time to empiric systemic antifungal use within the 100-day phase showed a significant difference in favor of POS (P =.0235) 100 75 50 0 25 020406080100 % with systemic antifungal Time From Randomization Posaconazole Other azole Posaconazole – censored Other azole – censored Censoring time is the minimum of the last contact date and day 100

7. Posaconazole Prophylaxis Effectively Prevented Invasive Fungal Infections P =.0009 7/30425/298 2% 8% 0% 2% 4% 6% 8% 10% 12% IFI During Prophylaxis Incidence of IFIs (%) Posaconazole FLU/ITZ 725

8. Clinical Response, n (%) Posaconazole (n = 304) Standard Azoles (n = 298)P 95% CI Clinical success195 (64)160 (54) Clinical failure*109 (36)138 (46).009 –18.3% to – 2.6% Proven or probable invasive fungal infection 7 (2)25 (8)<.001–9.7% to – 2.5% Use of systemic antifungal for 4 consecutive days for suspected/probable/proven invasive fungal infection 68 (22)101 (34).002 –18.7% to – 4.3% Related adverse event leading to study drug discontinuation 25 (8) 0.94 Use of IV study drug for 4 consecutive or 10 total days 6 (2)12 (4)0.14 Withdrawal from study for any reason and loss to follow-up 8 (3)1 (<1).02 0% to 4.2% Clinical Success and Reasons for Failure *Patients might have been classified as experiencing clinical failure for more than 1 reason. Clinical failure included patients randomly assigned but not treated (posaconazole, 7 [2%]; standard azoles, 6 [2%]). Chi-square test.

9. Overall Mortality – Time to Death log rank, P =.035 Probability of Survival 1.00 0.75 0.50 0.00 0.25 020406080100 Days after Randomization Posaconazole FLU/ITZ Censoring time is last contact or day 100.

10. Numbers Needed to Treat Primary and Secondary Endpoints in the Neutropenia Trial Cornely OA, Ullmann AJ. Clin Inf Dis 2008. All diagnostic procedures applied – IFI still under diagnosed.

11. Posaconazole 3x 200 mg Fluconazole 1x 400 mg Ullmann AJ et al. NEJM 2007.

12. Incidence of Proven/Probable IFIs 0 5 10 15 20 25 30 PosaconazoleFluconazole Number of IFIs All IFIsInvasive Aspergillosis P =.004 P =.001 While on treatment 7 22 3 17 All IFIsInvasive Aspergillosis P =.074 P =.006 Primary time period 112 days after randomization 27 16 7 21 Ullmann AJ et al. NEJM 2007.

13. Posaconazole Prophylaxis in Real Life The Cologne Institutional Experience 2003-2005No changes in diagnostic and therapeutic strategy 2006-2008Posaconazole Prophylaxis Two time periods for a historic comparison of AML/MDS patients undergoing 1 st induction chemotherapy

14. Current Approach to Febrile Neutropenia Neutropenia >10 Days Fever >72h or Galactomannan positive Posaconazole Prophylaxis Rüping MJGT et al. Drugs. 2008.

15. Neutropenia >10 Days Fever >72h or Galactomannan positive Posaconazole Prophylaxis Empiric Treatment CT BAL Rüping MJGT et al. Drugs. 2008. Current Approach to Febrile Neutropenia Targeted Treatment

16. Characteristics Topical polyene (N= 82) Posaconazole (N= 77) P Age (Years)Mean Median Range 52 14.1 54 18 – 76 54 13.5 55 19 – 75 NS* Female – no. (%)32 (39.0%)42 (54.5%)NS Neutropenic DaysMean Median Range 31.2 12.99 28 5 – 89 32.8 11.54 32 10 – 66 NS* G-CSF (no. [%])43 (52.4%)27 (35.1%)0.037 *P-test for independent samples (two-sided) Fishers exact test (two-sided)Granulocyte colony stimulating factor

17. Endpoints 100 = 6.4 19.5% – 3.9%

18. Other Clinical Endpoints

19. Pharmacokinetic Aspects

20. PK of Posaconazole – AML Induction Patient CharacteristicP Value* Age.4637 Sex.3242 Race.0028 Baseline body weight.1716 Baseline BSA.1157 GGT.0184 Liver enzymes.4077 Mucositis.6409 Neutropenia.4575 Diarrhea<.0001 Vomiting.5561 H 2 receptor antagonist use.5887 PPI use.0010 *t-test. White vs nonwhite. Cornely et al. ICAAC 2006.

21. Posaconazole Plasma Levels Were Similar in Patients With and Without IFIs Krishna G, et al. Pharmacotherapy. 2008;28:1223-1232.

22. Posaconazole Plasma Concentrations in AML/MDS Cologne Cohort

23. Posaconazole Distribution into Pulmonary Components: Steady State Levels in Healthy Volunteers 0.01 0.1 1 10 100 1000 10000 024681012141618202224 Posaconazole Concentration, μ g/mL Hours Following Last Dose Alveolar cells Pulmonary epithelial lining fluid Plasma MIC 90 Aspergillus spp Conte JE et al. Antimicrob Agents Chemother. 2009;53:703-707.

24. Posaconazole Concentrations in Peripheral Blood Compartments Farowski F et al. TIMM-4, Athens, 2009. PBMC (n=23), PMN (n=20), RBC (n=22), plasma (n=23); *p=.01, unpaired t-test; ***p<.001

25. Posaconazole Prophylaxis – Undefined Areas Patient groups outside the RCTs –Remission consolidation chemotherapy –Neutropenic allogeneic SCT –Other neutropenic, e.g. aplastic anemia, CLL, pallative AML or MDS Pharmacokinetics –Is there a cut-off plasma concentration? –Bridging with IV during periods of e.g. nausea Antifungal strategy –Persistent fever –Possible breakthrough IFI