FK463 Protocol No /FG Report FG , July 29, I -

Transcription

1 - I - SYNOPSIS Name of Sponsor/Company: Fujisawa GmbH Name of Finished Product: Not Yet Named Name of Active Ingredient: Micafungin, JPN (FK463) Title of Study: An Open-Label, Non-Comparative Study Of FK463 In The Treatment Of Candidemia Or Invasive Candidiasis ( /FG ) Study Chair or Responsible Medical Officer:, M.D., Fujisawa Healthcare, Inc. Investigator(s): M.D.; M.D.; M.D.;, M.D.;, M.D., Ph.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.; M.D.;, M.D.; M.D.;, M.D.;, M.D.;, M.D.; M.D.;, M.D.; M.D.; M.D.; M.D., Ph.D.;, M.D., Sc.D.; M.D.;, M.D.;, M.D.;, M.D.;, M.D. (replaced, M.D.);, D.O., Pharm.D (replaced, M.D., replaced, M.D.);, M.D.;, M.D.; M.D.;, M.D.;, M.D.; M.D.; M.D.;, M.D.;, M.D.;, M.D.; M.D.; M.D.;, M.D.;, M.D.;, M.D.; M.D.;, M.D.;, M.D., Ph.D.; M.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.;, M.D.; M.D.; M.D. Study Center(s): Data from 59 sites worldwide are included in this report: 30 sites in the United States; 6 sites in Canada; 5 sites in South Africa; 6 sites in Brazil; 3 sites in Peru; 1 site in Chile; 1 site in Guatemala; 2 sites in France; 2 sites in Italy, and 1 site in Sweden, 1 site in Germany, 1 site in the United Kingdom. Publication (reference): None. Study Period: (Date of first enrollment): February 27, 1999 (Date of last evaluation): Ongoing; January 27, 2002 was the cut-off date for CRF collection for this interim report Phase of Development: Phase II

2 - II - Objectives: To evaluate the safety and efficacy of FK463 in the treatment of patients with confirmed candidemia or invasive candidiasis caused by both Candida albicans and non-c. albicans organisms. Methodology: Open-label, noncomparative, multinational study in adult and pediatric patients. Patients underwent physical examination and evaluation of vital signs (baseline only); blood collection for determination of clinical laboratory profile, and assessment of fungal infection at baseline, at scheduled times during treatment, and at week 6 post-treatment. Adverse events with onset during the study through 72 hours post-treatment were recorded. This study was conducted under 2 protocols: Protocol (in non-european countries) and Protocol FG (in European countries). Number of Patients (planned and analyzed): At least 100 evaluable patients planned. Data from 336 case report forms (CRFs) collected at Fujisawa Healthcare, Inc. (FHI) by January 27, 2002 are included in this interim report. The full analysis set included 336 patients (215 in the de novo group, 70 in the efficacy failure FK463 and other therapy group, and 51 in the efficacy failure FK463 alone group). The per protocol set included 272 patients (183 in the de novo group, 49 in the efficacy failure FK463 and other therapy group, and 40 in the efficacy failure FK463 alone group). Diagnosis and Main Criteria for Inclusion: Adult and pediatric patients with a confirmed diagnosis of candidemia or invasive candidiasis were enrolled. Patients could be de novo patients (newly diagnosed with candidiasis who received less than 48 hours of prior systemic antifungal therapy) or efficacy failure patients (patients with confirmed candidiasis who received 5 or more days of prior systemic antifungal therapy). Efficacy failure patients were further broken down into 2 groups: those patients who received FK463 in addition to their current antifungal therapy (FK463 and other therapy) and those patients who received only FK463 (FK463 alone). Only patients ³18 years of age were enrolled at the European sites.

3 - III - Diagnosis and Main Criteria for Inclusion (continued): The following patients were not eligible for the study: patients who were pregnant or nursing; had abnormal liver test parameters; had a life expectancy judged to be less than 5 days; had a history of allergy, hypersensitivity, or any serious reaction to the echinocandin class of antifungals; had prior antifungal medication administration which was in violation of the entry criteria; required treatment with systemic antifungal agents for conditions other than candidemia or invasive candidiasis; had been previously enrolled into this study; or had a concomitant medical condition that may have created unacceptable additional risk for the patient. No de novo patients were enrolled at the European sites. Test Product, Dose and Mode Of Administration: Treatment was administered in an inpatient or outpatient setting. FK463 was administered once daily as a 1-hour infusion. The protocol stated an initial dose of 25 mg per day, but only 2 patients received this dose before the protocol was amended for an initial dose of 50 mg per day. After this amendment, all patients received FK463 at an initial dose of 50 mg per day (1 mg/kg per day for patients weighing 40 kg) until Amendment Number 4, when the initial dose was increased to 100 mg per day (2 mg/kg per day, patients weighing 40 kg) for patients with non-c. albicans (germ tube negative) organism infections. If there were continued positive culture findings, or if the patient experienced stable or progressive disease based on clinical signs and symptoms (after at least 5 days of therapy on the current dose), and if FK463 was well tolerated, then the investigator (at his or her discretion) could increase the dose of FK463 in 50 mg increments (1 mg/kg increments for patients weighing 40 kg) up to a maximum of 200 mg per day (4 mg/kg per day for patients weighing 40 kg). The approval of the medical monitor was required for higher dose increases. Prior to Amendment Number 4, dosing increments were 25 mg (0.5 mg/kg for patients weighing 40 kg) up to a maximum of 150 mg per day. FK463 could have been administered intermittently, a minimum of 3 days a week, if daily therapy was no longer feasible and the patient responded to FK463.

4 - IV - Lot Numbers: FK463: 25mg: 50 mg: Reference Product: none Duration of Study and Treatment: FK463 was administered intravenously as a daily 1-hour infusion for at least 5 days and up to a maximum of 6 weeks. FK463 could have been administered intermittently (a minimum of 3 days a week) if daily therapy was no longer feasible, and the patient had responded to FK463. Criteria for Evaluation: All patients who received at least 1 dose of FK463 (full analysis set) were included in the safety analysis. The per protocol set was defined as those patients who received at least 5 days of FK463 therapy and had a confirmed diagnosis of candidemia or invasive candidiasis at baseline. The per protocol set was the primary efficacy data set. The primary efficacy endpoint was the investigator s global assessment of treatment success, which was defined as complete or partial response. Secondary endpoints were clinical response at the end of therapy (complete response, partial response, stabilization, or progression) and mycological response at the end of therapy (eradication, presumed eradication, or persistence). The incidence of relapse and the use of additional systemic antifungal medications during the 6-week post-treatment period were also assessed. Safety assessment was based upon adverse events and laboratory profiles. All adverse events through 72 hours after the last administration of study drug, whether ascertained through patient interview, physical examination, laboratory findings, or other means, were recorded. Ongoing adverse events were followed for as long as necessary to adequately evaluate the patient s safety or until the event stabilized.

5 - V - Statistical Methods: Demographic variables, e.g. gender and baseline characteristics, and underlying disease, were tabulated for all patients and by patient group using descriptive statistics. Treatment success rate was estimated based on the investigator s global assessment of efficacy at the end of therapy, and a 2-sided 95% confidence interval (CI) was constructed. This endpoint was summarized by demographic variables, and baseline characteristics. Laboratory data, including hematology and serum chemistry data, were tabulated by age group and patient group (de novo, efficacy failure FK463 and other therapy, efficacy failure FK463 alone). Summary statistics for each assessment time and changes from baseline were generated. Adverse events, coded using a modified Coding System for Thesaurus of Adverse Reactions Terms (COSTART) dictionary, were tabulated by patient group, age group, severity, and relationship to study drug. RESULTS: Demographics and Baseline Characteristics: Of the 336 patients enrolled, 151 were from the United States, 66 from Brazil, 40 from Peru, 29 from South Africa, 28 from Canada, 7 from Guatemala, 5 from Chile, 1 from Germany, 2 from France, 2 from United Kingdom, 3 from Italy, 2 from Sweden. The mean age ± standard deviation (SD) for patients in the per protocol set was 40.3 ± years (range 2 weeks to 92.0 years), which included 31 patients <16 years of age (3 patients <1 month, 10 patients 1 month to 1 year, 14 patients 2 to 11 years, and 4 patients 12 to 15 years). Caucasian patients comprised 171/272 (62.9%) of the patients, and 158/272 (58.1%) were male. The overall mean APACHE II score at baseline was 12.3 ± 5.68 in the full analysis set and 11.6 ± 5.08 in the per protocol set. APACHE II scores were higher in the efficacy failure groups than in the de novo group. A total of 30/269 (11.2%) per protocol set patient were neutropenic at baseline; 22 of these patients were in the efficacy failure groups.

6 - VI - RESULTS (continued): Demographics and Baseline Characteristics (continued): The most common underlying disease for all patients in the per protocol set was human immunodeficiency virus (HIV) (95/272, 34.9%). The most common underlying disease in the de novo group was HIV (83/183, 45.4%) compared with antineoplastic chemotherapy in the efficacy failure groups (FK463 alone 11/40, 27.5% and FK463 and other therapy 19/49, 38.8%). A total of 49/272 per protocol set patients were enrolled in the efficacy failure FK463 and other group and 40/272 in the efficacy failure FK463 alone group. Among these 89 patients, 51 (57.3%) had candidemia, 11 (12.4%) had esophageal candidiasis, and 18 (20.2%) had disseminated candidiasis. Baseline Candida Infection In the per protocol set, 167/272 (61.4%) patients had an infection due to C. albicans, 111/272 (40.8%) had an infection due to non-c. albicans organisms, and 13/272 (4.8%) had non-speciated Candida infections. The more common non- C. albicans species were C. glabrata 51/272 (18.8%), C. parapsilosis 24/272 (8.8%), C. krusei 19/272 (7.0%), and C. tropicalis 15/272 (5.5%). In the per protocol set, 267/272 (98.2%) patients had proven invasive candidiasis or candidemia documented by histology and/or culture and 6/272 (2.2%) patients had probable disseminated or hepatosplenic candidiasis (1 patient in the efficacy failure plus other therapy group had both a proven and probable Candida infection at a disseminated site). A total of 119/272 (43.8%) had candidemia and 99/272 (36.4%) patients had esophageal candidiasis. A total of 89/272 (32.7%) per protocol set patients were enrolled as efficacy failure patients. Of the efficacy failure patients, 48/89 (53.9%) patients had experienced no improvement in their infection at the time FK463 was initiated and 41/89 (46.1%) patients experienced progression of the infection.

7 - VII - RESULTS (continued): Study Drug Administration: In the full analysis set (N=332), an initial dose of 20.0 mg was received by 1 patient; 25.0 mg by 1 patient; 50 mg/day (approximately 1.0 to 1.26 mg/kg) by 270 patients and by one additional patient (1.68 mg/kg); 59.4 mg (1.68 mg/kg) for one patient; 75 mg (approximately 1.5 mg/kg) by 7 patients, and 100 mg (approximately 2 mg/kg) by 51 patients. In the per protocol set, the mean ± SD duration of dosing for adults was 19.7 ± days in the de novo group, 29.9 ± in the efficacy failure FK463 and other therapy group, and 21.2 ± in the efficacy failure FK463 alone group. Among adult patients, the mean ± SD daily dose of FK463 for de novo patients was 64.5 ± mg (1.1 ± 0.39 mg/kg) compared with 89.0 ± mg (1.3 ± 0.56 mg/kg) for efficacy failure FK463 and other therapy patients, and 80.8 ± mg (1.2 ± 0.48 mg/kg) for efficacy failure FK463 alone patients. The highest dose administered was 400 mg (1 patient) and the longest duration of dosing was 102 days. Overall, 133/272 (48.9%) per protocol patients had their FK463 dose increased for therapeutic effect; 81/183 (44.3%) of de novo patients and 52/89 (58.4%) of the efficacy failure patients (both groups combined) had a dose increase. In the per protocol set, adult patients with C. albicans infections received the lowest average dose of FK643 (61 mg, n=170). The highest average daily dose was received by patients treated for C. krusei infections (85 mg, n=23). Infections with other types of non-candida species were treated at average doses of between 80 mg and 84 mg. The results for the full analysis set were similar to those in the per protocol set.

8 - VIII - RESULTS (continued): Efficacy Results: Primary Endpoint: The overall treatment success rate for the investigator global assessment at the end of therapy in the per protocol set was 82.4% (224/272) (95% CI: 77.8%, 86.9%) with complete response achieved in 176/272 (64.7%) patients. The success rates for each patient group were: 86.9% (159/183) in the de novo group, 65.3% (32/49) in the efficacy failure FK463 and other therapy group, and 82.5% (33/40) in the efficacy failure FK463 alone group. The full analysis set results were comparable. Success was documented in the per protocol set across most Candida species, including C. albicans (142/167, 85.0%), C. glabrata (43/51, 84.3%), C. parapsilosis (20/24, 83.3%), C. tropicalis (12/15, 80.0%) and C. krusei (14/19, 73.7%). Other treatment successes included infections with C. lusitaniae, C. pelliculosa, and C. inconspicua (1 or 2 patients each). A total of 83.2% (99/119) of per protocol set candidemia patients were considered a treatment success at the end of therapy; success was documented across the following Candida species: C. albicans (39/46, 84.8%), C. glabrata (23/30, 93.3%), C. parapsilosis (18/21, 85.7%), C. tropicalis (9/11, 81.8%) and C. krusei (6/9, 66.7%). Other successes were seen with C. pelliculosa, C. inconspicua, and C. lusitaniae (1 or 2 patients each). A total of 91.9% (91/99) of patients with esophageal candidiasis experienced treatment success at the end of therapy. Of the patients enrolled with disseminated disease, 65.2% (15/23) were a treatment success at the end of therapy. There was a small difference in the overall success rates between male and female patients (134/158, 84.8% versus 90/114, 78.9%, respectively) and a larger difference between adult and pediatric patients (203/241, 84.2% and 21/31, 67.7%, respectively) in the per protocol set. Patients with a higher APACHE II score tended to have less treatment success than those with lower scores. The success rate for patients with a baseline ANC <500 cells/µl was 20/30 (66.7%) compared with 201/239 (84.1%) for patients with baseline ANC ³500 cells/µl. For the 14 patients who were persistently neutropenic (ANC <500 cells/µl), the success rate was 10/14 (71.4%).

9 - IX - RESULTS (continued): Efficacy Results (continued): Secondary Endpoints: In the per protocol set, 185/272 (68.0%) patients experienced a complete clinical response at the end of therapy. The rate of complete clinical response was 129/183 (70.5%) in the de novo group, 27/49 (55.1%) in the efficacy failure FK463 and other therapy group, and 29/40 (72.5%) in the efficacy failure FK463 alone group. Complete clinical response was highest in candidemia (94/119, 79.0%) and esophageal candidiasis (67/99, 67.7%) patients, and lowest in patients with disseminated disease (10/23, 43.5%) and peritoneal infection (2/7, 28.6%). The results of the analyses for the full analysis set were similar to the per protocol set. Overall, 68.8% (187/272) of per protocol set patients experienced eradication or presumed eradication of their Candida infection at the end of therapy; 15.1% (41/272) had persistence. Additionally, 16.2% (44/272) of patients did not have a mycological assessment performed. A total of 68.9% (68/99) of esophageal candidiasis patients experienced eradication or presumed eradication of disease; 19.2% (19/99) experienced persistence. Candidemia patients experienced a eradication/presumed eradication rate of 79.0% (94/119) and a persistence rate of 10.9% (13/119). A total of 28/224 (12.5%) patients experienced a relapse of their baseline infection (same site, same organism) during the 6-week post-treatment period. The majority of these patients were infected with C. albicans. Additional systemic antifungal agents were administered for treatment or empirical reasons during the posttreatment period in 28.6% (64/224) of the patients.

10 - X - RESULTS (continued): Safety Results: All enrolled patients who received at least 1 dose of study drug were included in the safety analysis (n=332). Overall, 322/332 patients (97.0%) experienced 1 or more adverse events during the study (204/211, 96.7%, in the de novo group; 68/70, 97.1% in the efficacy failure FK463 and other therapy group; and 50/51, 98.0%, in the efficacy failure FK463 alone group). The more common adverse events across all patient groups were fever (84/332, 25.3%), vomiting (81/332, 24.4%), hypomagnesemia (70/332, 21.1%), hypokalemia (64/332, 19.3%), non-fungal infection (62/332, 18.7%), and nausea (61/332, 18.4%). Adverse events considered to be related to study drug were reported for 144/332 patients (43.4%); the more common events related to study drug were SGOT increase (28/332, 8.4%), hypomagnesemia (24/332, 7.2%), and SGPT increase (23/332, 6.9%). Most of these events were mild to moderate in intensity. One hundred and thirty-one patients experienced 1 or more serious adverse events. The more common events were sepsis (23/332, 6.9%), shock (23/332, 6.9%), respiratory failure (18/332, 5.4%), and pneumonia (11/332, 3.3%). Twenty patients (6.0%) experienced serious adverse events that were considered by the investigator to be related to study drug; events reported in more than 1 patient were hypokalemia (4/332, 1.2%), thrombocytopenia (3/332, 0.9%), and alkaline phosphatase increased (2/332, 0.6%). A total of 99/332 (29.8%) patients died during the study, 54/211 (25.6%) in the de novo group, 28/70 (40.0%) in the efficacy failure FK463 and other therapy group, and 17/51 (33.3%) in the efficacy failure FK463 alone group. Twelve patients died during study drug treatment and 87 patients died during the post-treatment period. Additionally, 1 patient died prior to receiving the first dose of study drug. None of the deaths were assessed by the investigator as causally related to the study drug. A total of 22/332 patients (6.6%) experienced adverse events leading to discontinuation of study drug, 14/211 (6.6%) in the de novo group, 6/70 (8.6%) in the efficacy failure FK463 and other therapy group, and 2/51 (3.9%) in the efficacy failure FK463 alone group. The most common adverse event leading to discontinuation was alkaline phosphatase increase which was experienced by 4 patients.

11 - XI - RESULTS (continued): Safety Results (continued): A total of 21/332 (6.3%) patients developed phlebitis (14 patients) or thrombophlebitis (7 patients). Seven of these events were considered related to study drug; 5 were mild and 2 were moderate in intensity. Additionally 7 patients experienced injection-site pain. Treatment was not interrupted or discontinued for any of these patients. A total of 90/332, (27.1%) patients experienced hepatic adverse event(s); 54/332 (16.3%) patients had 1 or more events considered to be related to study drug. The more common hepatic-related events were SGOT increased (11.7%), alkaline phosphatase increased (11.4%), and SGPT increased (9.6%). Mean levels of alkaline phosphatase, SGOT, SGPT and total bilirubin increased from baseline to end of therapy. Mean values at baseline and end of therapy were U/L and U/L for alkaline phosphatase, 45.8 U/L and U/L for SGOT, 40.3 U/L and 58.8 U/L for SGPT, 27.6 µmol/l and 37.2 µmol/l for total bilirubin.. However, for SGOT, SGPT and total bilirubin the median values were essentially unchanged. Median levels of alkaline phosphatase increased from baseline (164.0 U/L) to the end of therapy (182.0 U/L). Twelve patients (12/332, 3.6%) discontinued study drug therapy due to hepatic-related events. There was minimal evidence of nephrotoxicity due to study drug; 5 (5/332, 1.5%) patients experienced increased serum creatinine and 3 (3/332, 0.9%) patients experienced increased BUN which were considered by the investigator to be related to study drug. One patient discontinued study drug due to acute renal failure and increased creatinine that was considered by the investigator to be related to study drug. A total of 85/332 (25.6%) patients had potential allergic-type or histamine-like reactions during the study; 25/332 (7.5%) patients had events that the investigator considered to be related to study drug. A total of 15/332 (4.5%) patients had a rash or maculopapular rash considered by the investigator to be related to study drug; 8 were mild in intensity, 3 were moderate, and 4 were severe. In addition, two events coded as allergic reaction were described by the investigator as mild maculopapular rash allergic reaction and moderate allergic rash, respectively..

12 - XII - SUMMARY / CONCLUSIONS: FK463 is effective and safe in treating C. albicans infections and non-c. albicans infections, including patients with candidemia, disseminated disease or esophageal candidiasis; patients who are newly diagnosed (de novo); and patients who had not adequately responded to standard systemic antifungal therapy, even though these patients had prognostic factors that predicted a poorer outcome (higher rate of neutropenia and higher APACHE II scores). FK463 showed high success rates when administered as a monotherapy and when added to the patient s current antifungal regimen for particularly difficult to treat cases. Doses can be safely increased in this patient population. The treatment success rate was high for patients who had their dose increased to gain added therapeutic benefit. Date of Report: July 29, 2002

13 - XIII - Key Tables: Synopsis Table 1: Study Population FK463 & De Novo Other FK463 Alone Total All Enrolled Patients Full Analysis Set 211 (98.1%) 70 (100.0%) 51 (100.0%) 332 (98.8%) Per Protocol Set 183 (85.1%) 49 (70.0%) 40 (78.4%) 272 (81.0%) Patient base: all enrolled patients, irrespective of whether FK463 was administered (all enrolled patients); all patients who received at least 1 dose of FK463 (full analysis set); all patients who received at least 5 doses of FK463 and had proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. This interim report includes data from 336 patients whose CRFs were collected by January 27, 2002 Source: Table

14 - XIV - Synopsis Table 2: Patient Status at End of Study De Novo FK463 & Other FK463 Alone Total All Enrolled n=215 n=70 n=51 n=336 Completed Study 137 (63.7%) 42 (60.0%) 28 (54.9%) 207 (61.6%) Death 55 (25.6%) 27 (38.6%) 17 (33.3%) 99 (29.5%) Lost to Follow-up 13 (6.0%) 0 (0.0%) 3 (5.9%) 16 (4.8%) Other 10 (4.7%) 1 (1.4%) 3 (5.9%) 14 (4.2%) Full Analysis Set n=211 n=70 n=51 n=332 Completed Study 137 (63.7%) 42 (60.0%) 28 (54.9%) 207 (61.6%) Death 54 (25.1%) 27 (38.6%) 17 (33.3%) 98 (29.2%) Lost to Follow-up 13 (6.0%) 0 (0.0%) 3 (5.9%) 16 (4.8%) Other 7 (3.3%) 1 (1.4%) 3 (5.9%) 11 (3.3%) Per Protocol Set n=183 n=49 n=40 n=272 Completed Study 124 (57.7%) 30 (42.9%) 25 (49.0%) 179 (53.3%) Death 43 (20.0%) 18 (25.7%) 11 (21.6%) 72 (21.4%) Lost to Follow-up 12 (5.6%) 0 (0.0%) 3 (5.9%) 15 (4.5%) Other 4 (1.9%) 1 (1.4%) 1 (2.0%) 6 (1.8%) All enrolled patients: All patients in study for whom CRFs were collected by January 27, 2002 Full analysis set: all patients who received at least 1 dose of FK463 Per protocol set: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline One de novo patient (Patient Number ) died without ever having received study drug. Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Other: 4 patients did not meet enrollment criteria (Patient Numbers,,, ), 4 patients withdrew consent (Patient Numbers,,, ), 3 patients did not receive study medication (Patient Numbers ), 1 patient was noncompliant with follow-up (Patient Number ), 1 patient did not return for follow-up visit (Patient Number ), and 1 patient was considered not evaluable (Patient Number ) Source: Table and Appendix

15 - XV - Synopsis Table 3: Reason for Treatment Discontinuation FK463 & De Novo Other FK463 Alone Total Full Analysis Set n=211 n=70 n=51 n=332 Completed Therapy 139 (65.9%) 35 (50.0%) 33 (64.7%) 207 (62.3%) Discontinued Therapy Adverse Event 37 (17.5%) 18 (25.7%) 11 (21.6%) 66 (19.9%) Lack of Efficacy 19 (9.0%) 11 (15.7%) 4 (7.8%) 34 (10.2%) Administrative 16 (7.6%) 6 (8.6%) 3 (5.9%) 25 (7.5%) Per Protocol Set n=183 n=49 n=40 n=272 Completed Therapy 129 (70.5%) 27 (55.1%) 30 (75.0%) 186 (68.4%) Discontinued Therapy Adverse Event 27 (14.8%) 11 (22.4%) 5 (12.5%) 43 (15.8%) Lack of Efficacy 17 (9.3%) 8 (16.3%) 3 (7.5%) 28 (10.3%) Administrative 10 (5.5%) 3 (6.1%) 2 (5.0%) 15 (5.5%) Full analysis set: all patients who received at least 1 dose of FK463 Per protocol set: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Administrative (full analysis set): De novo, 6 patients withdrew consent, 6 patients did not meet the inclusion/exclusion criteria, 1 patient was noncompliant, 1 patient was withdrawn in error, 1 patient was withdrawn based on a positive blood culture, and 1 patient was withdrawn from the study by the investigator; FK463 and other, 3 patients withdrew consent 1 patient had supportive care withdrawn, 1 patient did not meet enrollment criteria, and 1 patient had a protocol deviation; FK463 alone, 2 patients withdrew consent, and 1 patient did not meet the inclusion criteria. Source: Table and and Appendix

16 - XVI - Synopsis Table 4: Demographics and Baseline Characteristics De Novo (n=211) FK463 & Other (n=70) FK463 Alone (n=51) Total (n=332) Sex Male 123 (58.3%) 36 (51.4%) 32 (62.7%) 191 (57.5%) Female 88 (41.7%) 34 (48.6%) 19 (37.3%) 141 (42.5%) Race Caucasian 131 (62.1%) 48 (68.6%) 33 (64.7%) 212 (63.9%) Mestizo 46 (21.8%) 1 (1.4%) 5 (9.8%) 52 (15.7%) Black 26 (12.3%) 15 (21.4%) 8 (15.7%) 49 (14.8%) Oriental 2 (0.9%) 3 (4.3%) 3 (5.9%) 8 (2.4%) American Indian 1 (0.5%) 0 (0.0%) 0 (0.0%) 1 (0.3%) Other 5 (2.4%) 3 (4.3%) 2 (3.9%) 10 (3.0%) Neutropenic status ANC<500/µl 11/210 (5.2%) 15/69 (21.7%) 12/50 (24.0%) 38/329 (11.6%) Age (years) Mean ± SD 43.2 ± ± ± ± Range 0.0 to to to to 92.0 Weight (kg) n Mean ± SD 61.9 ± ± ± ± APACHE II Scores n Mean ± SD 11.7 ± ± ± ± 5.68 Patient base: all enrolled patients who received at least 1 dose of FK463 (full analysis set). Efficacy failure: patients must have had documented clinical and mycological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Mestizo: a person of mixed ancestry. One Mestizo patient is listed in the appendix table as race=other and is included as a Mestizo for this table. Other: Colored, Cape Colored, Hindu, Aboriginal, Polynesian. APACHE II Scores were collected only for patients ³18 years of age Source: Tables and and Appendix

17 - XVII - Synopsis Table 5: Underlying Disease or Condition De Novo (n=183) FK463 & Other (n=49) FK463 Alone (n=40) Total (n=272) Bone Marrow (or Other Progenitor Cell) Transplant Allogeneic 3 (1.6%) 9 (18.4%) 5 (12.5%) 17 (6.3%) Autologous 2 (1.1%) 1 (2.0%) 2 (5.0%) 5 (1.8%) HIV 83 (45.4%) 4 (8.2%) 8 (20.0%) 95 (34.9%) Antineoplastic Chemotherapy 20 (10.9%) 19 (38.8%) 11 (27.5%) 50 (18.4%) Bacterial Infection/ Antibiotic Use 15 (8.2%) 0 (0.0%) 0 (0.0%) 15 (5.5%) Solid Organ Transplant 6 (3.3%) 2 (4.1%) 5 (12.5%) 13 (4.8%) Post-Surgical Fungal Infection 10 (5.5%) 1 (2.0%) 0 (0.0%) 11 (4.0%) Neoplasm 8 (4.4%) 1 (2.0%) 1 (2.5%) 10 (3.7%) Liver Disease 2 (1.1%) 2 (4.1%) 1 (2.5%) 5 (1.8%) Kidney Disorder 4 (2.2%) 0 (0.0%) 0 (0.0%) 4 (1.5%) Heart Disorder 3 (1.6%) 0 (0.0%) 0 (0.0%) 3 (1.1%) Corticosteroid Therapy 3 (1.6%) 0 (0.0%) 0 (0.0%) 3 (1.1%) Aplastic Anemia 1 (0.5%) 1 (2.0%) 0 (0.0%) 2 (0.7%) Immune Disorder 1 (0.5%) 0 (0.0%) 0 (0.0%) 1 (0.4%) Other 22 (12.0%) 9 (18.4%) 7 (17.5%) 38 (14.0%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. HIV: Human immunodeficiency virus Other: prematurity (4 patients), trauma or multiple trauma (3 patients), diabetes mellitus (2 patients), bowel obstruction (2 patients), burn (2 patients), pancreatitis (4 patients), and 1 patient each with enterocutaneous fistulas, VP shunt, intravenous drug abuse, malnutrition, idiophathic immunosuppression, cerebral vascular accident, gangrene, respiratory distress, ileal perforasion, prematurity and gastroschisis, disseminated strongyloidosis, achalasia, tracheal esophageal fistula, myelofibrosis, sacral chordoma, non-ruptured cerebral aneurysm, respiratory syncytial virus, ischemic bowel, chronic obstructive pulmonary disease, neonatal hypoxia, yatal hernia causing esophageal and gastric perforation Source: Table and Appendix

18 - XVIII - Synopsis Table 6: Systemic Candida Infections at Baseline at Primary Site of Infection by Organism FK463 & De Novo Other FK463 Alone Total (n=183) (n=49) (n=40) (n=272) C. albicans 137 (74.9%) 15 (30.6%) 15 (37.5%) 167 (61.4%) Non-C. albicans 54 (29.5%) 32 (63.3) 25 (62.5%) 111 (40.8%) C. glabrata 25 (13.7%) 16 (32.7%) 10 (25.0%) 51 (18.8%) C. parapsilosis 8 (4.4%) 8 (16.3%) 8 (20.0%) 24 (8.8%) C. krusei 8 (4.4%) 5 (10.2%) 6 (15.0%) 19 (7.0%) C. tropicalis 10 (5.5%) 4 (8.2%) 1 (2.5%) 15 (5.5%) C. lusitaniae 1 (0.5%) 1 (2.0%) 0 (0.0%) 2 (0.7%) C. pelliculosa 2 (1.1%) 0 (0.0%) 0 (0.0%) 2 (0.7%) C. famata 1 (0.5%) 0 (0.0%) 0 (0.0%) 1 (0.4%) C. inconspicua 0 (0.0%) 1 (2.0%) 0 (0.0%) 1 (0.4%) C. kefyr 0 (0.0%) 0 (0.0%) 1 (2.5%) 1 (0.4%) C. pseudotropicalis 0 (0.0%) 1 (2.0%) 0 (0.0%) 1 (0.4%) C. rugosa 1 (0.5%) 0 (0.0%) 0 (0.0%) 1 (0.4%) Candida sp. NOS 3 (1.6%) 8 (16.3%) 2 (5.0%) 13 (4.8%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. NOS: not speciated A patient may have had more than 1 organism at baseline. Source: Table

19 - XIX - Synopsis Table 7: Primary Sites of Systemic Candida Infections at Baseline De Novo (n=183) FK463 & Other (n=49) FK463 Alone (n=40) Total (n=272) Primary Site of Candida Infection Blood 68 (37.2%) 27 (55.1%) 24 (60.0%) 119 (43.8%) Esophageal 88 (48.1%) 2 (4.1%) 9 (22.5%) 99 (36.4%) Disseminated proven 5 (2.7%) 11 (22.4%) 3 (7.5%) 19 (7.0%) probable 0 (0.0%) 5 (10.2%) 0 (0.0%) 5 (1.8%) Abscess 6 (3.3%) 1 (2.0%) 1 (2.5%) 8 (2.9%) Peritoneal 5 (2.7%) 1 (2.0%) 1 (2.5%) 7 (2.6%) Lungs 3 (1.6%) 0 (0.0%) 0 (0.0%) 3 (1.1%) Liver (probable) 0 (0.0%) 0 (0.0%) 1 (2.5%) 1 (0.4%) Oropharyngeal 1 (0.5%) 0 (0.0%) 0 (0.0%) 1 (0.4%) Other 7 (3.8%) 3 (6.1%) 1 (2.5%) 11 (4.0%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Type of infection is proven unless otherwise noted. One patient in the efficacy failure plus other therapy group had both a proven and probable Candida infection at a disseminated site, hence the sum of the individual sites is 273. Other: bile duct, knee infection, biliary tree, mediastineal wound, abdominal wound, urinary tract, meninges, bone, perinephretic, colon, bile. Source: Tables and , and Appendix

20 - XX - Synopsis Table 8: Duration and Last Dose of Systemic Antifungal Therapy Prior to First Dose of Study Drug for Patients Azoles n Mean ± SD Median; (Range) Amphotericin B Deoxycholate n Mean ± SD Median; (Range) Amphotericin B Lipid Agents n Mean ± SD Median; (Range) FK463 & Other FK463 Alone (n=49) (n=40) Duration (days) ± ; (3.0 to 408.0) ± ; (1.00 to 47.00) ± ; (2.00 to ) Last Dose (mg/kg) Azoles n 32 Mean ± SD 6.01 ± 3.05 Median; (Range) 5.60; (1.75 to 13.00) Amphotericin B Deoxycholate n Mean ± SD Median; (Range) Amphotericin B Lipid Agents n Mean ± SD Median; (Range) ± ; (0.13 to 1.20) ± ; (0.42 to 11.80) ± ; (2.0 to 895.0) ± ; (1.00 to 28.00) ± ; (2.00 to 13.00) ± ; (1.25 to 14.50) ± ; (0.36 to 1.10) ± ; (2.88 to 6.90) Table continued on next page Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Patients could receive more than one type of amphotericin B agent. Source: Table

21 - XXI - Synopsis Table 8: continued Azoles n Mean ± SD Median; (Range) Amphotericin B Deoxycholate n Mean ± SD Median; (Range) Amphotericin B Lipid Agents n Mean ± SD FK463 & Other FK463 Alone (n=49) (n=40) Last Dose (mg) ± ; (5.0 to 800.0) ± ; (10.0 to 75.0) ± ; (7.5 to ) ± ; (17.0 to 800.0) ± ; (8.0 to 75.0) ± ; (6.55 to 490.0) Median; (Range) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Patients could receive more than one type of amphotericin B agent. Source: Table

22 - XXII - Synopsis Table 9: Investigator Global Assessment at End of Therapy Total De Novo FK463 & Other FK463 Alone [95% CI] (n=183) (n=49) (n=40) (n=272) Success 159 (86.9%) 32 (65.3%) 33 (82.5%) 224 (82.4%) [77.8%, 86.9%] Complete response 124 (67.8%) 26 (53.1%) 26 (65.0%) 176 (64.7%) Partial response 35 (19.1%) 6 (12.2%) 7 (17.5%) 48 (17.6%) Failure 22 (12.0%) 16 (32.7%) 5 (12.5%) 43 (15.8%) Stabilization 10 (5.5%) 8 (16.3%) 3 (7.5%) 21 (7.7%) Progression 12 (6.6%) 8 (16.3%) 2 (5.0%) 22 (8.1%) Not Evaluable 2 (1.1%) 1 (2.0%) 2 (5.0%) 5 (1.8%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Investigator global assessment: based on mycologic, histologic, radiologic, and clinical evidence of the infection. CI: confidence interval; constructed using the large sample normal approximation of the binomial distribution. Source: Table

23 - XXIII - Synopsis Table 10: Treatment Success by Candida Species Candida Species De Novo FK463 & Other FK463 Alone Total (n=183) (n=49) (n=40) (n=272) C. albicans 119/137 (86.9%) 10/15 (66.7%) 13/15 (86.7%) 142/167 (85.0%) Non-C. albicans 47/54 (87.0%) 20/32 (62.5%) 21/25 (84.0%) 88/111 (79.3%) C. glabrata 22/25 (88.0%) 11/16 (68.8%) 10/10 (100.0%) 43/51 (84.3%) C. parapsilosis 8/8 (100.0%) 6/8 (75.0%) 6/8 (75.0%) 20/24 (83.3%) C. tropicalis 9/10 (90.0%) 2/4 (50.0%) 1/1 (100.0%) 12/15 (80.0%) C. krusei 7/8 (87.5%) 2/5 (40.0%) 5/6 (83.3%) 14/19 (73.7%) C. lusitaniae 1/1 (100.0%) 1/1 (100.0%) - 2/2 (100.0%) C. pelliculosa 2/2 (100.0%) - - 2/2 (100.0%) C. inconspicua - 1/1 (100.0%) - 1/1 (100.0%) C. rugosa 0/1 (0.0%) - - 0/1 (0.0%) C. kefyr - - 0/1 (0.0%) 0/1 (0.0%) C. pseudotropicalis - 0/1 (0.0%) - 0/1 (0.0%) C. famata 0/1 (0.0%) - - 0/1 (0.0%) Candida sp NOS 3/3 (100.0%) 5/8 (62.5%) 1/2 (50.0%) 9/13 (69.2%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Treatment success: complete or partial response. NOS: non-speciated Source: Table

24 - XXIV - Synopsis Table 11: Treatment Success by Primary Site of Infection De Novo (n=183) FK463 & Other (n=49) FK463 Alone (n=40) Total (n=272) Site of Candida Species Infection Esophageal 82/88 (93.2%) 1/2 (50.0%) 8/9 (88.9%) 91/99 (91.9%) Blood 60/68 (88.2%) 20/27 (74.1%) 19/24 (79.2%) 99/119 (83.2%) Abscess 5/6 (83.3%) 0/1 (0.0%) 1/1 (100.0%) 6/8 (75.0%) Disseminated 3/5 (60.0%) 9/15 (60.0%) 3/3 (100.0%) 15/23 (65.2%) Peritoneal 2/5 (40.0%) 0/1 (0.0%) 1/1 (100.0%) 3/7 (42.9%) Lungs 2/3 (66.7%) - - 2/3 (66.7%) Oropharyngeal 1/1 (100.0%) - - 1/1 (100.0%) Liver - - 0/1 (0.0%) 0/1 (0.0%) Other 4/7 (57.1%) 2/3 (66.7%) 1/1 (100.0%) 7/11 (63.6%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Investigator global assessment: based on mycologic, histologic, radiologic, and clinical evidence of the infection. Treatment success: complete or partial response. Other: bile duct, knee infection, biliary tree, mediastineal wound, abdominal wound, urinary tract, meninges, bone, perinephretic, colon, bile. Source: Table

25 - XXV - Synopsis Table 12: Treatment Success and Average Daily Dose Treatment Outcome De Novo FK463 & Other FK463 Alone Total Adult Patients Success Average Daily Dose ± SD (mg) C. albicans (n=128) 59.4 ± ± ± ±18.72 Non-C. albicans (n=83) 76.3 ± ± ± ± Candida sp. NOS (n=9) 72.9 ± ± ± Not Success Average Daily Dose ± SD (mg) C. albicans (n=17) 57.8 ± ± ± Non-C. albicans (n=21) 88.4 ± ± ± ± Candida sp. NOS (n=4) ± ± Success Average Daily Dose ± SD (mg/kg) C. albicans (n=128) 1.1 ± ± ± ± 0.36 Non-C. albicans (n=83) 1.1 ± ± ± ± 0.49 Candida sp. NOS (n=9) 1.3 ± ± ± 0.50 Not Success Average Daily Dose ± SD (mg/kg) C. albicans (n=17) 1.0 ± ± ± 0.40 Non-C. albicans (n=21) 1.3 ± ± ± ± 0.59 Candida sp. NOS (n=4) ± ± 0.42 Pediatric Patients Success Average Daily Dose ± SD (mg/kg) C. albicans (n=14) 1.2 ± ± ± ± 0.30 Non-C. albicans (n=7) 1.4 ± ± ± ± 0.98 Candida sp. NOS (n=2) ± ± 1.05 Not Success Average Daily Dose ± SD (mg/kg) C. albicans (n=8) 1.1 ± ± ± 0.44 Non-C. albicans (n=3) ± ± 0.61 Candida sp. NOS (n=1) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set). Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Success: complete or partial response. n: total number of patients. NOS: not speciated Source: Tables , , and

26 - XXVI - Synopsis Table 13: Candidemia, Treatment Success by Species Candida Species De Novo FK463 & Other FK463 Alone Total (n=68) (n=27) (n=24) (n=119) Any Candida sp. 60/68 (88.2%) 20/27 (74.1%) 19/24 (79.2%) 99/119 (83.2%) C. albicans 29/34 (85.3%) 5/6 (83.3%) 5/6 (83.3%) 39/46 (84.8%) Non-C. albicans 33/36 (91.7%) 15/21 (71.4%) 14/18 (77.8%) 62/75 (82.7%) C. glabrata 14/15 (93.3%) 8/9 (88.9%) 6/6 (100.0%) 28/30 (93.3%) C. parapsilosis 7/7 (100.0%) 5/6 (83.3%) 6/8 (75.0%) 18/21 (85.7%) C. tropicalis 7/7 (100.0%) 1/3 (33.3%) 1/1 (100.0%) 9/11 (81.8%) C. krusei 2/2 (100.0%) 2/4 (50.0%) 2/3 (66.7%) 6/9 (66.7%) C. pelliculosa 2/2 (100.0%) - - 2/2 (100.0%) C. inconspicua - 1/1 (100.0%) - 1/1 (100.0%) C. lusitaniae 1/1 (100.0%) - - 1/1 (100.0%) C. famata 0/1 (0.0%) - - 0/1 (0.0%) C. kefyr - - 0/1 (0.0%) 0/1 (0.0%) C. rugosa 0/1 (0.0%) - - 0/1 (0.0%) Candida sp. NOS - 0/1 (0.0%) - 0/1 (0.0%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set); primary site = proven blood. Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease within 48 hours prior to initiating FK463, despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Success: complete or partial response per Investigator global assessment: based on mycologic, histologic, radiologic, and clinical evidence of the infection. NOS: not speciated A patient could have been diagnosed with more than 1 species. Source: Table

27 - XXVII - Synopsis Table 14: Esophageal Candidiasis, Treatment Success by Candida Species Candida Species De Novo FK463 & Other FK463 Total (n=88) (n=2) Alone(n=9) (n=99) Any Candida sp. 82/88 (93.2%) 1/2 (50.0%) 8/9 (88.9%) 91/99 (91.9%) C. albicans 78/84 (92.9%) 0/1 (0.0%) 5/6 (83.3%) 83/91 (91.2%) Non-C. albicans 7/8 (87.5%) - 4/4 (100.0%) 11/12 (91.7%) C. glabrata 4/5 (80.0%) - 2/2 (100.0%) 6/7 (85.7%) C. krusei 3/3 (100.0%) - 2/2 (100.0%) 5/5 (100.0%) Candida sp. NOS 3/3 (100.0%) 1/1 (100.0%) - 4/4 (100.0%) Patient base: all patients who received at least 5 doses of FK463 and have proven or probable (liver, spleen, or disseminated only) invasive candidiasis at baseline (per protocol set); primary site = esophageal. Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Investigator global assessment: based on mycologic, histologic, radiologic, and clinical evidence of the infection. NOS: not speciated A patient could have been diagnosed with more than 1 species. Source: Table

28 - XXVIII - Synopsis Table 15: Incidence of Common Treatment Emergent Adverse Events, Including Non-fungal Infections Body System De Novo FK463 & Other FK463 Alone Total COSTART Term (n=211) (n=70) (n=51) (n=332) n (%) Any Adverse Event 204 (96.7%) 68 (97.1%) 50 (98.0%) 322 (97.0%) Body as a Whole Fever 56 (26.5%) 14 (20.0%) 14 (27.5%) 84 (25.3%) Non-fungal Infection 40 (19.0%) 15 (21.4%) 7 (13.7%) 62 (18.7%) Abdominal Pain 41 (19.4%) 15 (21.4%) 3 (5.9%) 59 (17.8%) Sepsis 33 (15.6%) 15 (21.4%) 11 (21.6%) 59 (17.8%) Procedural 20 (9.5%) 15 (21.4%) 11 (21.6%) 46 (13.9%) Complication Digestive System Vomiting 52 (24.6%) 20 (28.6%) 9 (17.6%) 81 (24.4%) Nausea 33 (15.6%) 18 (25.7%) 10 (19.6%) 61 (18.4%) Diarrhea 22 (10.4%) 17 (24.3%) 9 (17.6%) 48 (14.5%) Constipation 18 (8.5%) 16 (22.9%) 3 (5.9%) 37 (11.1%) Metabolic and Nutritional Disorders Hypomagnesemia 44 (20.9%) 17 (24.3%) 9 (17.6%) 70 (21.1%) Hypokalemia 35 (16.6%) 18 (25.7%) 11 (21.6%) 64 (19.3%) Respiratory System Cough Increased 22 (10.4%) 14 (20.0%) 5 (9.8%) 41 (12.3%) Patient base: all randomized patients who received at least 1 dose of FK463. Common: experienced by at least 20% of the patients in any of the patient groups Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Procedural complications: includes complications associated with central venous catheter and intravenous line, bleeding from tracheostomy, incision pain, cystoscopy, and bruising from phlebotomy. Within a body system, patients may have reported more than 1 event. Source: Table

29 - XXIX - Synopsis Table 16: Summary of Common Adverse Events Considered to be Related to Study Drug: Excluding Non-fungal Infections Body System De Novo FK463 & Other FK463 Alone Total COSTART Term (n=211) (n=70) (n=51) (n=332) n (%) Any Adverse Event 109 (51.7%) 19 (27.1%) 16 (31.4%) 144 (43.4%) Digestive System Vomiting 11 (5.2%) 2 (2.9%) 1 (2.0%) 14 (4.2%) Nausea 4 (1.9%) 1 (1.4%) 4 (7.8%) 9 (2.7%) Hemic & Lymphatic System Leukopenia 21 (10.0%) 1 (1.4%) 0 (0.0%) 22 (6.6%) Metabolic and Nutritional Disorders SGOT Increased 26 (12.3%) 1 (1.4%) 1 (2.0%) 28 (8.4%) Hypomagnesemia 22 (10.4%) 0 (0.0%) 2 (3.9%) 24 (7.2%) SGPT Increased 22 (10.4%) 1 (1.4%) 0 (0.0%) 23 (6.9%) Alk Phos Increased 20 (9.5%) 1 (1.4%) 0 (0.0%) 21 (6.3%) Hypocalcemia 19 (9.0%) 0 (0.0%) 1 (2.0%) 20 (6.0%) Patient base: all randomized patients who received at least 1 dose of FK463. Common: experienced by at least 5% of the patients in any of the patient groups. Efficacy failure: patients must have had documented clinical and microbiological evidence of continuing disease despite ³5 days of therapy with systemic antifungal agents prior to study entry; patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Related: possible, probable, or highly probable Within a body system, patients may have reported more than 1 event. Alk Phos: alkaline phosphatase; SGOT: serum glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase. Source: Table