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Fidaxomicin

Fidaxomicin. Slide resource set. Rationale for a new treatment. Clostridium difficile infection (CDI ) remains a disease for which there are significant unmet needs: Therapy to provide sustained clinical cure (defined as clinical cure without recurrence) 1

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Fidaxomicin

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  1. Fidaxomicin Slide resource set

  2. Rationale for a new treatment Clostridium difficile infection (CDI) remains a disease for which there are significant unmet needs: Therapy to provide sustained clinical cure (defined as clinical cure without recurrence)1 Therapy to reduce recurrence (relapse and/or reinfection)1 Better identification of patients at risk of recurrence or those for whom the impact of recurrence would be most dramatic2 New approaches under investigation but data from large-scale randomised controlled trials are lacking3 Management strategies to treat acute episodes of CDI effectively and markedly reduce the risk of recurrence would represent a significant therapeutic advance4 Cornely OA. ClinMicrobiol Infect 2012;18(Suppl 6):28­–35; Kelly CP. ClinMicrobiol Infect 2012;18(Suppl 6):21­–7; Bauer MP, et al. ClinMicrobiol Infect 2009;15:1067–79; Bouza E. ClinMicrobiol Infect 2012;18(Suppl 6):5–12. FDX/12/0076/EUk|MB145

  3. Fidaxomicin (DIFICLIR™) chemical structure Fidaxomicin (C52H74Cl2O18) First in a new class of antibacterials known as macrocycles1 Fermentation product from Dactylosporangium aurantiacum1 Unsaturated 18-membered macrocyclic core with two highly functionalised sugars as side chains2 Main metabolite of fidaxomicin is the hydrolysis product, OP-11183 Miller M. Expert OpinPharmacother 2010;11:1569–78; Swanson RN, et al. Antimicrobial Agents Chemother 1991;35:1108–11; FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699). FDX/12/0076/EUj| OC109

  4. Mechanism of action of fidaxomicin -35 -10 σ subunit Promoter DNA -35 -10 +1 Activesite RNA polymerase holoenzyme Closed complex Core RNA polymerase X Fidaxomicin First intermediate complex Open complex Second intermediate complex +1 +Nucleotide triphosphates X X Myxopyronin +1 Rifamycins Elongation of mRNA Fidaxomicin inhibits bacterial DNA-dependent RNA polymerase Results in inhibition of the initiation of bacterial RNA synthesis Causes cell death Adapted from Artsimovitch I, et al. Clin Infect Dis 2012;55(Suppl 2):S127–31. FDX/13/0034/EU | ACE03

  5. In vitro activity of fidaxomicin against C. difficileisolates • Fidaxomicin shows good in vitro activity against all strains of C. difficile that have been tested MIC, minimum inhibitory concentration required to inhibit 50%/90% of organisms Credito KL, Appelbaum PC. Antimicrob Agents Chemother 2004;48:4430–4; Finegold SM, et al. Antimicrob Agents Chemother 2004;48:4898–902; Ackermann G, et al. Antimicrob Agents Chemother 2004;48:2280–2; Hecht DW, et al. Antimicrob Agents Chemother 2007;51:2716–19; Karlowsky JA, et al. Antimicrob Agents Chemother 2008;52:4163–5. FDX/12/0076/EUj| OC114

  6. In vitro activity against C. difficile from patients in fidaxomicin trials *In pooled analysis of both phase 3 trials MIC, minimum inhibitory concentration required to inhibit 50%/90% of organisms In vitro activity of fidaxomicin against C. difficile isolates from patients in the phase 2 and 3 clinical trials was consistent with earlier in vitro studies:1,2 In the phase 2A proof-of-concept study, the MIC90 for the 38 C. difficile isolates tested was 0.125 μg/mL1 The activity of fidaxomicin against 792 C. difficile isolates from patients enrolled in the phase 3 trials is shown in the table below Citron DM, et al. Anaerobe 2009;15:234–6; Goldstein EJC, et al. Antimicrob Agents Chemother 2011;55:5194–9. FDX/12/0076/EUj|OC115

  7. Activity against other Gram-positive bacteria Fidaxomicin is not significantly active against Streptococcus spp. MICs are typically in the range of 16–128 μg/mL1 Fidaxomicin has MICs in the range of 2–16 μg/mL against Enterococcus spp. Fidaxomicin is 2–4-fold less active against enterococci than vancomycin (MIC range 0.5–4 μg/mL)1 Lower activity of fidaxomicin against enterococcimay prove beneficial in reducing colonisation with vancomycin-resistant enterococci (VRE)2 Finegold SM, et al. Antimicrob Agents Chemother 2004;48:4898–902; Nerandzic MN, et al. Abstract presented at ICAAC 2009; K-1915. FDX/12/0076/EUj| OC116

  8. Activity against Bacteroidesfragilis Colonic levels of B. fragilisbefore (Day 0) and after treatment (Day 10) p=NS p=0.03 Fidaxomicin 200 mg bid (n=12) Vancomycin 125 mg qid (n=8) Day 0 Day 10 Day 0 Day 10 CFU, colony-forming units; bid, twice daily; qid, four-times daily; NS, not significant Louie TJ, et al. Antimicrob Agents Chemother 2009;53:261–3. FDX/12/0076/EUj| OC118

  9. Bactericidal effects against C. difficile strains In vitro activity of fidaxomicin and vancomycin against C. difficile strain ATCC 43255 over time 1 × 108 Control (no drug) Fidaxomicin(4 × MIC; 0.5 µg/mL) Vancomycin(4 × MIC; 4 µg/mL) 1 × 106 CFU/mL 1 × 104 1 × 102 2 6 24 48 Time (hours) CFU, colony-forming units;MIC, minimum inhibitory concentration Bactericidal activity is defined as a 3 log10 reduction in CFU Babakhani F, et al. J Med Microbiol 2011;60:1213–7. FDX/12/0076/EUj| OC119

  10. Post-antibiotic effect Recovery of viable C. difficile after 1-hour exposureto fidaxomicin or vancomycin 1 × 108 1 × 106 Control (no drug) Fidaxomicin (0.5 µg/mL) Fidaxomicin transferred (0.5 µg/mL) Vancomycin (2 µg/mL) CFU/mL 1 × 104 1 × 102 Post-wash 10 20 30 40 Time (hours) Babakhani F, et al. Antimicrob Agents Chemother 2011;55:4427–9. CFU, colony-forming units FDX/12/0076/EUj| OC120

  11. Inhibition of C. difficile sporulation Effect of exposure to fidaxomicin or vancomycin on sporulation by C. difficile strain ATCC 43255 1 × 109 Control (no drug) Fidaxomicin (1/4 × MIC) Vancomycin (1/4 × MIC) 1 × 107 Spore CFU/mL 1 × 105 1 × 103 Detection limit 3 23 48 72 96 120 144 168 192 216 Drug added ATCC, American Type Culture Collection; CFU, colony-forming units;MIC, minimum inhibitory concentration Time (hours) Babakhani F, et al. Clin Infect Dis 2012;55(Suppl 2):S162–9. FDX/12/0076/EUj| OC121

  12. Inhibition of C. difficile toxin production Effect of exposure to fidaxomicin and vancomycin on toxin levels in C. difficilestrain ATCC 43255 Toxin levels(% of no-drug control) Data obtained for at least 2 independent runs, on Day 4, following antibiotic addition in vitro; MIC, minimum inhibitory concentration Babakhani F, et al. J Antimicrob Chemother 2013;68:515–22. EPG06

  13. Low risk of acquisition of VRE Comparative effects of fidaxomicin and vancomycin on acquisition of VRE p<0.001 8/114 41/133 Nerandzic MN, et al. Clin Infect Dis 2012;55(Suppl 2):S121–6. VRE, vancomycin-resistant enterococci FDX/12/0076/EUj| OC117

  14. Emergence of resistance to fidaxomicin Low propensity for resistance development1 Low frequency of spontaneous resistance (FSR)2 FSR for fidaxomicin and vancomycin at 8 × MIC: <1.41 × 10−9–<4.13 × 10−9 No MIC shift seen after 12 serial passages2 No shifts in MIC developed during fidaxomicin therapy in either of the phase 3 trials2–4 No cross-resistance with existing classes of antibacterial agents2 Babakhani F, et al. Abstract presented at ICAAC 2004; E-2047; FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699); Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. FDX/12/0076/EUj|OC123

  15. Systemic absorption and pharmacokinetic profile of fidaxomicin and its metabolite (OP-1118) Negligible systemic absorption1,2 Plasma levels often below quantifiable limits Plasma concentrations observed within 15 minutes post-dose and detectable for up to 24 hours post-dose1 Even at the highest doses, no evidence of drug accumulation after multiple dosing for 10 consecutive days1,2 Maximum plasma concentrations reduced in the fed vs fasted state3 Not considered significant because systemic exposure is not relevant to the efficacy of fidaxomicin in CDI FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699); European Public Assessment Report, 22 September 2011 (EMA/857570/2011); AstellasPharma Europe Ltd. DIFICLIR (fidaxomicin). Summary of Product Characteristics, 19 December 2011. FDX/12/0076/EUj| OC110

  16. Systemic absorption of fidaxomicin and OP-1118 Plasma levels of OP-1118 are ~2-fold higher than parent drug, but still close to quantifiable limits of 5 ng/mL1 Plasma levels of fidaxomicin and OP-1118 slightly elevated in patients ≥65 years,1 but still in the low nanogram range and not considered clinically meaningful2 Peak plasma concentrations 2–6-fold higher in patients withCDI administered fidaxomicin (200 mg bid) for 10 days vs healthy subjects2 Varied considerably (several 100-fold) from patient to patient1 Mean plasma concentrations still in the nanogram range1 No evidence of drug accumulation1 FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699); AstellasPharma Europe Ltd. DIFICLIR (fidaxomicin). Summary of Product Characteristics, 19 December 2011. bid, twice daily FDX/12/0087/EUu|slide 070

  17. Systemic absorption of fidaxomicin and OP-1118 after multiple dosing in CDI patients Mean peak plasma concentrations of fidaxomicin and OP-1118 following oral administration of 200 mg bid to CDI patients for up to 10 consecutive days bid, twice daily FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699). FDX/12/0087/EUu| slide 072

  18. Faecal concentrations of fidaxomicin and OP-1118 Near-complete faecal recovery of parent drug and its metabolite1 Faecal concentrations of parent drug and metabolite appear to be dose related1 Faecal concentrations of fidaxomicin are in the microgram to milligram range1 In patients with CDI, mean faecal concentrations far exceed MIC90for C. difficile2 No association between faecal concentration and outcome observed Comparison of faecal concentrations of fidaxomicin and OP-1118 in CDI patients in the phase 3 trials showed similar findings to those seen in healthy volunteers2 This suggests the gastrointestinal route of elimination is not influenced by the CDI disease process Shue YK, et al. Antimicrob Agents Chemother 2008;52:1391–5; FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699). FDX/12/0076/EUj| OC111

  19. Faecal concentrations of fidaxomicin and OP-1118 in healthy subjects Faecal concentrations of fidaxomicin and OP-1118 following daily oral administration of fidaxomicin 150 mg, 300 mg or 450 mg to healthy volunteers for 10 consecutive days Shue YK, et al. Antimicrob Agents Chemother 2008;52:1391–5. Near-complete faecal recovery of parent drug and its metabolite Most drug remains in the gastrointestinal tract, the prime site of drug exposure FDX/12/0087/EUu| slide 074

  20. Faecal concentrations of fidaxomicin and OP-1118 in patients with CDI Faecal concentrations of fidaxomicin and OP-1118 following oral administration of 200 mg bid to CDI patients FDA Meeting Briefing Document for Anti-Infective Drugs Advisory Committee, 5 April 2011 (NDA 201699). Mean faecal concentrations exceed the MIC90 for C. difficile FDX/12/0087/EUu| slide 075

  21. Overview of fidaxomicin drug interactions: cytochrome P450 (CYP) system • No dose adjustment is necessary when fidaxomicin is co-administered with drugs that are CYP substrates European Public Assessment Report, 22 September 2011 (EMA/857570/2011). FDX/12/0076/EUj| OC112

  22. Overview of fidaxomicin drug interactions: P-glycoprotein (P-gp) system Fidaxomicin and OP-1118 are substrates of P-gp and may be mild-to-moderate inhibitors of intestinal P-gp Fidaxomicin should not be co-administered with drugs that are potent P-gpinhibitors AstellasPharma Europe Ltd. DIFICLIR (fidaxomicin). Summary of Product Characteristics, 19 December 2011. FDX/12/0076/EUj| OC113

  23. Use of fidaxomicin in specific patient populations AstellasPharma Europe Ltd. DIFICLIR (fidaxomicin). Summary of Product Characteristics, 19 December 2011. FDX/12/0087/EUu| slide 078

  24. Fidaxomicin (DIFICLIR™) clinical development programme Louie TJ, et al. Antimicrob Agents Chemother 2009;53:223–8; Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. bid, twice daily; qid, four-times daily FDX/12/0076/EUj|OC124

  25. Phase 3 registration trials:study design Fidaxomicin 200 mg bid Baseline assessment Assessment at end of treatment Assessment at end of study 28-day follow-up 10 days of treatment Vancomycin 125 mg qid Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. bid, twice daily; qid, four-times daily FDX/12/0076/EUj| OC125

  26. Phase 3 registration trials:inclusion/exclusion criteria *≤4 doses and ≤24 hours of pre-treatment allowed Louie TJ, et al. N Engl J Med 2011;364:422–31; Suppl to: Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9; Suppl to: Cornely OA, et al. Lancet Infect Dis 2012;12:281–9; European Public Assessment Report, 22 September 2011 (EMA/857570/2011). UBM, unformed bowel movement FDX/12/0076/EUj| OC128

  27. Phase 3 registration trials:analysis populations Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. FDX/12/0076/EUj| OC126

  28. Phase 3 registration trials: endpoints UBM, unformed bowel movement;EOT, end of treatment Louie TJ, et al. N Engl J Med 2011;364:422–31; CornelyOA, et al. Lancet Infect Dis 2012;12:281–9. FDX/12/0076/EUj| OC127

  29. Demographic and baseline clinical characteristics *Percentages based on patients with typed isolates only (Study 003, n=415; Study 004, n=377); Data from mITT population; SD, standard deviation; UBM, unformed bowel movement; mITT, modified intent to treat Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. FDX/12/0076/EUj| OC129

  30. Disease severity at baseline Baseline disease severity categories defined as: Mild, 4–5 UBM/day or WBC ≤12,000/mm3; Moderate, 6–9 UBM/day or WBC 12,001–15,000 mm3; Severe, ≥10 UBM/day or WBC ≥15,001/mm3 Data from mITT population; mITT, modified intent to treat; UBM, unformed bowel movement;WBC, white blood cell European Public Assessment Report, 22 September 2011 (EMA/857570/2011). FDX/12/0076/EUj| OC130

  31. Fidaxomicin pivotal trial results Difference(confidence interval) [p value] 2.4 (–3.1, 7.8) [p=NS] –9.9 (–16.6, –2.9) [p=0.005] 10.5 (3.1, 17.7) [p=0.0006] 0.9 (–4.9, 6.7) [p=NS] –14.2 (–21.4, –6.8) [p=0.0002] 13.2 (5.2, 20.9) [p=0.001] 88.2 87.7 86.8 85.8 76.6 74.6 64.1 63.4 Subjects achieving endpoint (%) 26.9 25.3 15.4 12.7 253/ 287 265/ 309 39/ 253 67/ 265 214/287 198/ 309 221/ 252 223/ 257 28/ 221 60/ 223 193/ 252 163/ 257 Study 0031,2 Study 0043 NS, not significant European Public Assessment Report, 22 September 2011 (EMA/857570/2011); Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. FDX/12/0076/EUf| EK217

  32. Time to resolution of diarrhoea • No statistically significant differences between treatments with respect to time to resolution of diarrhoea1,2 Louie TJ, et al. N Engl J Med 2011;364:422–31; Cornely OA, et al. Lancet Infect Dis 2012;12:281–9. Data from mITT population FDX/12/0076/EUj| OC134

  33. Fidaxomicin Vancomycin Fidaxomicin pivotal phase 3 trials: time to recurrence Early recurrence (relapse): Fidaxomicin: 7.4% Vancomycin: 19.3% Late recurrence (relapse/reinfection): Fidaxomicin: 7.3% Vancomycin: 8.4% p<0.001 p=0.560 14 12 10 Number of patients withrecurrence of CDI 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Day of follow-up after completion of therapy for CDI European Public Assessment Report, 22 September 2011 (EMA/857570/2011). FDX/12/0076/EUr| SJ203

  34. Fidaxomicin Vancomycin Clinical cure and sustained clinical cure in patients aged ≥65 years p=NS 224/264 239/283 188/264 169/283 AstellasPharma Europe Ltd. Data on file, FDX/13/0001/EU. NS, not significant FDX/13/0034/EU | ACE10

  35. Fidaxomicin Vancomycin Fidaxomicin – rates of sustained clinical cure in cases of severe CDI 95% CI*: 5.2, 17.1 95% CI*: 1.6, 24.2 Note: CDI severity was determined using European Society of Clinical Microbiology and Infectious Diseases (ESCMID) criteria – i.e. fever (core body temperature >38.5°C); marked leucocytosis(leucocyte count >15 × 109/L) and rise in serum creatinine (≥1.5 mg/dL); *2-sided 95% CI around the difference (fidaxomicin minus vancomycin) in response rates; CI, confidence interval European Public Assessment Report, 22 September 2011 (EMA/857570/2011). FDX/13/0017/EUb| VZ117

  36. Effect of concomitant antibiotics on CDI recurrence p=NS p<0.001 p=0.048 p=NS p<0.001 p<0.001 Data from pooled analysis; –CA, without concomitant antibiotics;+CA , with concomitant antibiotics;NS, not significant Mullane KM, et al. Clin Infect Dis 2011;53:440–7. FDX/12/0076/EUr| SJ233

  37. Fidaxomicin Vancomycin Recurrence in patients with renal impairment at baseline –10.2% (–17.2, 3.1) –10.0% (–19.4, –0.6) –11.6% (–24.5, 1.3) –16.9% (–35.9, 2.1) Difference(95% confidence interval) [p value] 22/207 41/197 18/126 34/140 19/89 30/91 5/34 12/38 CI, confidence interval; CrCl, creatinine clearance; NS, not significant; post hoc analysis; Data from pooled analysis Mullane KM, et al. Am J Nephrol 2013;38:1–11. EPG01

  38. Rates of CDI recurrence in patients with a prior episode p=0.045 A priori analysis Data from pooled analysis and collected from 128 patients who had recurrent CDI CornelyOA, et al. Clin Infect Dis 2012;55(Suppl 2):S154–61. EPG05

  39. Fidaxomicin Vancomycin Response to treatment of CDI in patients with and without cancer p=NS p=NS p<0.001 p=0.021 p=0.001 p=0.003 Data from pooled analysis;NS, not significant; post hoc analysis Cornely OA, et al. J Clin Oncol 2013;31:2493–9. EPG04

  40. Time to resolution of diarrhoea in patients with cancer 1.0 Log rank p-value = 0.045 0.8 0.6 Fidaxomicin (n=87) Vancomycin (n=96) Proportion of subjects with ≤3 UBM/day 0.4 0.2 0.0 0 24 48 72 96 120 144 168 192 216 240 Time to resolution of diarrhoea (hours) UBM, unformed bowel movement; Data from pooled analysis Cornely OA, et al. J Clin Oncol 2013;31:2493–9. EPG02

  41. Time to resolution of diarrhoea in patients with cancer (n=183) p=0.045 Post hoc analysis; Data from pooled analysis Cornely OA, et al. J Clin Oncol 2013;31:2493–9. EPG03

  42. Overview of AEs in phase 3 trials Pooled data from phase 3 trials; AE, adverse event European Public Assessment Report, 22 September 2011 (EMA/857570/2011). FDX/12/0076/EUj| OC135

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