Micafungin, a new Echinocandin: Pediatric Development Andreas H. Groll, M.D. Infectious Disease Research Program Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology University Children s Hospital Muenster
Micafungin: Pediatric Indications and Dosages Indication Body weight > 4 kg Dose Body weight 4 kg Treatment of invasive candidiasis Prophylaxis of Candida infection 1 mg/day* 2 mg/kg/day* 5 mg/day 1 mg/kg/day * If the patient s response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, the dose may be increased to 2 mg/day in patients weighing > 4 kg or 4 mg/kg/day in patients weighing 4 kg MYCAMINE (micafungin sodium) for injection SmPC. Astellas Pharma Europe Ltd., September 28
Micafungin Pediatric Program Pediatric PK Study in Adolescents or Older Children 2-17 Years Old (n = 77) Dose selection P III Candida (n = 52) P III Prophylaxis (n = 39) P II Candida (n = 53) P II Aspergillus (n = 7) Pediatric PK Studies in Premature Neonates ( 4 weeks, 5g) (n = 23)
Clinical Efficacy
Pediatric Phase III Substudy: MICA vs. L-AMB for Invasive Candidiasis Double-blind, multicenter comparative study evaluating micafungin vs. AMBISOME in pts with inv. candidiasis subpopulation of pediatric patients <15 years Candidemia or invasive candidiasis primary endpoint: Clinical + mycological response @ EOT 1:1 stratified randomization MICA 2mg/kg/d vs. LAMB (3 mg/kg/d) for minimum of 14 days Full analysis set (all randomized patients) Per protocol set ( 5 doses of study drug) Queiroz-Telles et al. PIDJ 8
Pediatric Substudy MICA vs. L-AMB: Baseline Characteristics Parameter FAS, n (%) PPS, n (%) MICA (n = 52) L-AmB (n = 54) MICA (n = 41) L-AmB (n = 42) Age in years, mean (range) 4. (<1 15) 2.2 (<1 15) 3.1 (<1 14) 2. (<1 15) Neutropenic 7 (13.5) 13 (24.1) 5 (12.2) 1 (23.8) Hospitalized in ICU 3 (57.7) 22 (4.7) 24 (58.5) 16 (38.1) Underlying disorder* # Haematological malignancy Prematurity at birth Gastrointestinal disorder Risk category* Intravenous line/device Antibiotic use Corticosteroid therapy Other immunosuppressive Total parenteral nutrition Other 15 (28.8) 1 (19.2) 1 (19.2) 19 (36.5) 14 (26.9) 13 (25.) 11 (21.2) 7 (13.5) 12 (23.1) 12 (22.2) 11 (2.4) 8 (14.8) 13 (24.1) 12 (22.2) 7 (13.) 12 (22.2) 4 (7.4) 8 (14.8) 8 (19.5) 9 (22.) 9 (22.) 17 (41.5) 13 (31.7) 11 (26.8) 7 (17.1) 7 (17.1) 11 (26.8) 1 (23.8) 7 (16.7) 7 (17.7) 11 (26.2) 1 (23.8) 6 (14.3) 9 (21.4) 4 (9.5) 6 (14.3) *Patients could be included in more than one category # Only top 3 underlying disorders are shown Queiroz-Telles et al. PIDJ 8
Pediatric Substudy MICA vs. L-AMB: Site and Species MICA (n = 52) FAS, n (%) PPS, n (%) L-AmB (n = 54) MICA (n = 41) L-AmB (n = 42) Candidemia 47 (9.4) 51 (94.4) 38 (92.7) 4 (95.2) Invasive candidiasis 5 (9.6) 3 (5.6) 3 (7.3) 2 (4.8) Infecting species* Candida albicans Non-albicans Candida C. parapsilosis C. tropicalis C. krusei C. guilliermondii C. lipolytica Other non-albicans Candida 19 (36.5) 31 (59.6) 12 (23.1) 1 (19.2) 4 (7.7) 3 (5.8) 2 (3.8) 3 (5.8) 15 (27.8) 38 (7.4) 17 (31.5) 13 (24.1) 1 (1.9) 2 (3.7) 5 (9.3) 16 (39.) 25 (61.) 11 (26.8) 7 (17.1) 3 (7.3) 2 (4.9) 1 (2.4) 2 (4.9) 14 (33.3) 8 (19.) 14 (33.3) 8 (19.) 1 (2.4) 2 (4.8) 3 (7.1) *Patients could have an infection caused by more than one Candida species Including C. pelliculosa, C. utilis, C. rugosa, C. keyfr and C. glabrata Queiroz-Telles et al. PIDJ 8
Pediatric Substudy MICA vs. L-AMB: Treatment Success Treatment success rate 1 8 6 4 2 52 54 MICA 7 13 L-AmB 41 42 5 1 Overall Neutropenic Overall Neutropenic patients patients Full analysis set Per-protocol set Queiroz-Telles et al. PIDJ 8
Pediatric Substudy MICA vs. L-AMB: Success by Species 1 15 MICA L-AmB 3 1 9 8 5 53 19 31 38 4 12 17 1 13 6 4 5 2 Any Candida spp. C. albicans Non-albicans Candida C. parapsilosis C. tropicalis C. krusei C. guilliermondii Other Queiroz-Telles et al. PIDJ 8 Treatment success rate (%)
Pediatric Substudy MICA vs. L-AMB: Success by Infection Site Treatment success rate (%) 1 8 6 4 2 47 5 51 3 38 3 4 2 MICA L-AmB MICA L-AmB FAS PPS Queiroz-Telles et al. PIDJ 8
Pediatric Subset, Phase III trial Micafungin vs. Fluconazole Randomisation (1:1) Micafungin 5 mg/day (1 mg/kg/day for patients weighing < 5 kg) Fluconazole 4 mg/day (8 mg/kg/day for patients weighing < 5 kg) Treatment continued until one of the following, whichever occurred first: 5 days after engraftment (defined as an absolute neutrophil count of 5 cells/μl after the nadir absolute count) treatment day 42 after HSCT development of proven, probable or suspected invasive fungal infection development of unacceptable drug toxicity death withdrawal from study participation (patient s decision) discontinuation of study treatment (investigator s decision) van Burik JA et al. CID 24; 39:147 16
Pediatric subset, MICA vs. FLU: Treatment success 8 Treatment success rate (%) 7 6 5 4 3 2 1 69.2 53.3 n = 39 45 Micafungin Fluconazole Modified intent-to-treat (mitt) population van Burik JA et al. CID 24; 39:147 16
Micafungin: Phase II, Systemic Candidiasis Pediatric patients ( 15 years) with confirmed SCI de novo: newly diagnosed, with 48 hours prior systemic antifungal therapy Efficacy failure: >5 days prior systemic antifungal therapy with no response MICA alone (n=16) MICA alone (n=8) MICA in combination with existing antifungal therapy at study entry (n=31) MICA dose was 5 mg/day (1 mg/kg/day if weight 4 kg) or 1 mg/day (2 mg/kg/day) in pts with germ-tube negative infection / non-albicans Candida Option to dose-escalate in 1 mg/kg increments Arrieta, ECCMID 7
Micafungin: Phase II, Systemic Candidiasis 9 9 5 Treatment success (%) 8 7 6 5 4 3 2 1 28 11 53 2 3 7 8 12 13 15 All Age group (years) Arrieta, ECCMID 7
Micafungin: Phase II, Invasive Aspergillosis Multinational, non-comparative study of MICA alone or in combination in pediatric pts. with proven/probable IA EORTC/MSG criteria; independent DRC Initial dose: 1.5mg/kg; dose escalation permitted 58 patients; 9 ±4.3 years (3mo-16y) 54 refractory, 4 newly diagnosed 56 pts. combination therapy, 2 MICA alone Mean of 2.±1.2 mg/kg/d for median of 67±85 days Flynn, ICAAC 6
Micafungin: Phase II, Invasive Aspergillosis Overall response rate: 26/58 (45%) Complete response, 9 (16%) Partial response, 17 (29%) Stable disease, 6 (1%) Pulmonary IA, 2/49 (41%), dissem. IA 4/6 (67%) 13/58 (22%) discontinued prematurely, mostly due progression of underlying disease or IA Flynn ICAAC 6
Micafungin in Pediatric Patients: Efficacy in Clinical Trials Therapeutic Category Phase III Invasive candidiasis or candidemia Prophylaxis of fungal infections Phase II Invasive aspergillosis Invasive candidiasis or candidemia Phase I PK, safety, and tolerability *Either alone or in combination. Treatment Micafungin 52 24/3 (8.) Liposomal Amphotericin B N 54 31/4 (77.5) Micafungin 39 6/7 (85.7) Treatment Response, n/n (%) by Age Group (years) to 2 3 to 7 8 to 12 13 to <16 Overall 5/7 (71.4) 6/9 (66.7) Fluconazole 45 6/13 (46.2) 4/7 (57.1) Micafungin* 58 2/5 (4.) Micafungin 53 19/28 (67.9) 7/11 (63.6) Micafungin 69 4/5 (8.) 3/8 (37.5) 1/3 (33.3) 4/7 (57.1) 2/2 (1) 1/14 (71.4) 7/12 (58.3) 4/6 (66.7) 1/19 (52.6) 4/6 (66.7) 36/52 (69.2) 4/54 (74.1) 27/39 (69.2) 24/45 (53.3) 7/16 (43.8) 5/18 (27.8) 12/19 (63.2) 26/58 (44.8) 8/9 (88.9) 4/5 (8.) 38/53 (71.7) 23/3 (76.7) 13/22 (59.1) 9/12 (75.) 49/69 (71.) Arrieta et al. 29
Clinical Safety
Pediatric Substudy MICA vs. L-AMB: Treatment related AEs 45 4 35 36.5 (n = 19) 42.6 (n = 23) MICA (n = 52) L-AmB (n = 54) Patients, % 3 25 2 15 1 5 3.8 (n = 2) 9.3 (n = 5) Overall AEs Serious AEs Queiroz-Telles et al. PIDJ 8
Pediatric Substudy MICA vs. L-AMB: Treatment-related AEs MICA (n = 52) L-AmB (n = 54) Overall 19 (36.5%) 23 (42.6%) Serious 2 (3.8%) 5 (9.3%) Common AEs (>5% in either group) Fever Vomiting LFT abnormal Thrombocythemia Hypokalemia AEs leading to treatment discontinuation 2 (3.8%) 1 (1.9%) 1 (1.9%) 3 (5.8%) 6 (11.1%) 4 (7.4%) 3 (5.6%) 3 (5.6%) 6 (11.1%) Any Kidney failure Bilirubinemia Liver damage Sepsis 1 (1.9%) 1 (1.9%) 3 (5.6%) 1 (1.9%) 1 (1.9%) 1 (1.9%) Queiroz-Telles et al. PIDJ 8
Overall Safety in Clinical Trials (n=296) Incidence of AEs All causality (>2%) At least possibly related* to micafungin (>2%) At least possibly related* to micafungin and leading to treatment discontinuation (7 patients - < 2.5%) vomiting (31.8%), pyrexia (22.3%), diarrhea (21.6%), nausea (21.3%), hypokalemia (2.9%) hypokalemia (3.%), ALT increased (3.%), hyperbilirubinemia (2.%), AST increased (2.%), LFT abnormal (2.%), AP increased (2.%), hypertension (2.%) neutropenia, AST/ALT increased, rash, (3 patients with underlying leukemia); jaw and joint pain, hyperbilirubinemia, creatinine increased (3 patients with underlying HSCT); creatinine increased (1 patient with premature birth). *Investigator-assessed causal relationship Arrieta et al. 29
Hepatic tolerability in clincal trials (n=296) Normal at baseline to > ULN at EOT Normal at baseline to 2.5 x ULN at EOT High at baseline to normal at EOT 5 Patients (%) 4 3 2 1 n = 168 168 81 162 162 89 AST ALT ALT: alanine aminotransferase; AST: aspartate aminotransferase; EOT: end of treatment ULN: upper limit of normal; normal: ULN; high > ULN Increase is measured as ULN at EOT Arrieta A et al. 47th ICAAC (27)
Conclusions
Conclusions Micafungin has demonstrated efficacy in pediatric patients with SCIs Micafungin as effective as L-AmB in both neutropenic and non-neutropenic patients Micafungin effective against both C. albicans and non-albicans Candida species Micafungin effective as prophylaxis against IFIs in children undergoing HSCT Well tolerated in clinical trials across all age groups with low (<2.5%) AE-related discontinuation rates