SYNOPSIS Name of Sponsor/Company: Fujisawa GmbH Name of ...€¦ · Criteria for Evaluation:All patients who received at least 1 dose of FK463 (full analysis set) were included in

FK463Protocol No. 98-0-046/FG463-21-01Report FG02-463-01, August 2, 2002

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SYNOPSIS

Name of Sponsor/Company:Fujisawa GmbHName of Finished Product:Norcandin®Name of Active Ingredient:Micafungin, JPN (FK463)Title of Study: An Open-Label, Non-Comparative Study Of FK463 For The Treatment Of Invasive Aspergillosis (98-0-046/FG463-21-01)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., Ph.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., Ph.D.; D.O.; , M.D. (who

replaced , M.D.); M.D.; , M.D.; , D.O., PharmD. (who replaced , M.D., who replaced , M.D.);

, M.D.; M.D. (who replaced , 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. (who replaced M.D.); , M.D.; , M.D.; , M.D.; M.D.; , M.D., Ph.D.; , M.D.; , M.D.; , M.D.; , M.D.; , M.D. Study Centers: Data from 58 sites worldwide are included in this interim report: 33 sites in the United States of America, 5 sites in Brazil, 4 sites in Canada, 4 sites in Germany, 3 sites in Peru, 2 sites in South Africa, 2 sites in the United Kingdom, 2 sites in France, 1 site in Italy, 1 site in Spain and 1 site in Sweden.


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Publication (reference): noneStudy Period: (Date of first enrollment): January 29, 1999(Date of last evaluation): Ongoing; January 31, 2002 cut-

off date for last CRF collected for this interim report

Phase of Development:Phase II

Objectives: To evaluate the safety and efficacy of FK463 in patients with proven or probable invasive infections due to Aspergillus species.Methodology: Open-label, non-comparative, multinational study in adult and pediatric patients. Patients underwent physical examination and evaluation of vital signs (baseline only); and blood collection for determination of clinical laboratory profile, and assessment of fungal cultures at baseline, at scheduled times during therapy; and at week 6 post-treatment. Adverse events with onset during therapy through 72 hours post-treatment were recorded.

This study was conducted under 2 protocols: Protocol 98-0-046 (in non-European countries) and Protocol FG463-21-01 (in European countries).Number of Patients (planned and analyzed): At least 100 efficacy evaluable patients planned. Data from 288 patients whose case report forms (CRFs) were collected by Fujisawa Healthcare, Inc. and Fujisawa GmbH by January 31, 2002 are included in this interim report. The full analysis set included 283 patients (23 in the de novo group, 225 in the efficacy failure FK463 and other therapy group, 19 in the efficacy failure FK463 alone group, and 16 in the toxicity failure group). The per protocol set included 228 patients (17 in the de novo group, 182 in the efficacy failure FK463 and other therapy group, 15 in the efficacy failure FK463 alone group, and 14 in the toxicity failure group). The full analysis and per protocol sets included interim data for 1 patient (Patient Number ) who continued to receive study drug at the time of the data cut-off.


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Diagnosis and Main Criteria for Inclusion: Adult and pediatric patients with a proven or probable (pulmonary only) invasive disseminated infection due to Aspergillus species. Patients may have been de novo patients (newly diagnosed with aspergillosis who received no more than 48 hours of systemic antifungal therapy) or efficacy failure patients (inadequate response to ≥72 hours of systemic antifungal therapy), or toxicity failure patients (failed systemic antifungal therapy due to toxicity). Efficacy failure patients were further categorized into 2 groups: patients who received FK463 in addition to their current antifungal therapy (FK463 and other therapy) and patients who received only FK463 (FK463 alone). Only patients ≥18 years of age were enrolled at the European sites. No de novo patients were enrolled at the European sites.

Patients were excluded from the study if they were pregnant or nursing; had markedly abnormal liver test parameters; had no evidence of invasive aspergillosis; had a life expectancy judged to be less than 5 days; had been previously enrolled in this study; had a history of allergy, hypersensitivity, or any serious reaction to the echinocandin class of antifungals; had allergic bronchopulmonary aspergillosis or external otitis; or had a concomitant medical condition that the investigator considered would have created an unacceptable risk. Test Product, Dose and Mode of Administration: Treatment could be administered in an inpatient or outpatient setting. Patients with proven or probable invasive Aspergillus infection were to receive FK463 once daily as a 1-hour infusion at an initial dose of 75 mg per day (1.5 mg/kg per day for patients weighing ≤40 kg). If FK463 was well tolerated, the dose of FK463 could be increased in 75 mg increments (1.5 mg/kg per day increments for patients weighing ≤40 kg) after at least 7 days of therapy on the current dose of FK463, at the investigator’s discretion. For patients enrolled in the non-European protocol, dose increases above 225 mg (4.5 mg/kg per day for patients weighing ≤40 kg) required the approval of the Fujisawa Healthcare, Inc. (FHI) medical monitor. Dose escalation was not allowed above 200 mg per day for patients enrolled in the European protocol. De novo and toxicity failure patients received FK463 alone. Efficacy failure patients received FK463 alone or in addition to their current systemic antifungal therapy.

Protocol Amendment Number 3, dated April 5, 1999, altered the initial dose from 50 mg per day (1.0 mg/kg per day for patients weighing ≤40 kg) to 75 mg (1.5 mg/kg per day for patients weighing ≤40 kg).


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Lot Numbers: FK463:25 mg vials:

50 mg vials:

Duration of Study and Treatment: FK463 was administered intravenously as a 1-hour infusion daily for at least 7 days and up to a maximum of 90 days. 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. The duration of therapy could be extended beyond 90 days with the approval of the medical monitor. The duration of follow-up post-treatment was 6 weeks.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 7 doses of study drug and had a proven or probable (pulmonary only) invasive aspergillosis at baseline.

Refractory patients were defined as those patients who were efficacy failure (FK463 and other or FK463 alone) and toxicity failure patients.

The primary efficacy endpoint was the investigator’s global assessment of treatment success, which was defined as complete response, partial response, or stabilization of disease, based on mycological and clinical evidence of infection. Secondary endpoints were clinical response (complete response, partial response, stabilization, or progression) and mycological response (eradication, presumed eradication, or persistence) at the end of therapy. The re-emergence of Aspergillusinfection or a new fungal infection and the use of additional antifungal therapy during the 6-week post-treatment period were also assessed.

All efficacy analyses were performed on both the

per protocol set and the full analysis set. Results from the per protocol set analysis are considered primary.


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Criteria for Evaluation: continuedSafety assessment was based on 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.Statistical Methods: Demographic variables, e.g., gender and baseline characteristics, and underlying disease, were tabulated for all patients and by patient group.

Treatment success rate was based on the investigator’s global assessment of efficacy at the end of therapy, and a 2-sided 95% confidence interval (CI) was constructed based on the large sample normal approximation of the binomial distribution. The primary endpoint was analyzed by key demographic variables and fungal infection risk factors.

Selected laboratory data, including hematology and serum chemistry data, were tabulated by patient group (de novo, efficacy failure FK463 and other, efficacy failure FK463 alone, and toxicity failure). 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, relationship to study drug, intensity, and for those patients who discontinued study drug.RESULTS:Demographics and Baseline Conditions: In the full analysis set, a total of 225/283 (79.5%) patients received FK463 in combination with another systemic antifungal agent. Patients who received FK463 monotherapy comprised 23/283 (8.1%) patients in the de novo group, 19/283 (6.7%) in the efficacy failure FK463 alone group and 16/283 (5.7%) toxicity failure patients.

In the full analysis set, the mean ± standard deviation (SD) age was 37.0 ± 20.46 years (range 0.2 to 84.0 years); the youngest treated patient was 9 weeks old. A total of 63/283 (22.3%) patients were <16 years of age and the majority of patients (247/283, 87.3%) were Caucasian; 181/283 (64.0%) were male.


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RESULTS: continuedDemographics and Baseline Conditions: continuedFor the per protocol set, the mean age ± SD for patients was 36.9 ± 20.40 years (range 0.2 to 82.0 years), which included 51/228 (22.4%) patients <16 years of age (5 patients 1 month to 1 year, 28 patients 2 to 11 years, and 18 patients 12 to 15 years). The youngest patient treated was 9 weeks old. Caucasian patients comprised 85.5% (195/228) of the patients, and 62.7% (143/228) were male.

A total of 225/283 (79.5%) patients in the full analysis set and 178/228 (78.1%) patients in the per protocol set received a bone marrow transplant or intensive antineoplastic chemotherapy.

A total of 166/283 (58.7%) patients in the full analysis set received systemic immunosuppressive and/or corticosteroid therapy during treatment and 138/283 (48.8%) patients received therapy prior to study drug administration. A total of 81/283 (28.6%) full analysis set patients were neutropenic at baseline.

Baseline Aspergillus InfectionIn the per protocol set, 122/228 patients (53.5%) patients had proven invasive aspergillosis documented by histology and/or culture results, and 106/228 patients (46.5%) patients had probable pulmonary aspergillosis at baseline. A total of 75.0% (171/228) of these patients were enrolled with pulmonary aspergillosis, 10.1% (23/228) were enrolled with disseminated aspergillosis, and 6.6% (15/228) were enrolled with Aspergillus sinusitis. Pulmonary aspergillosis was the most common infection for all patient groups.

In the per protocol set, 39.5% (90/228) of patients had an infection due to A. fumigatus, 10.5% (24/228) had an infection due to A. flavus, and 47.8% (109/228) had nonspeciated Aspergillus infections.

Among the 211 efficacy failure and toxicity failure patients in the per protocol set, 168/211 (79.6%) patients were described as having disease progression and 43/211 (20.4%) patients as having stable disease at baseline.


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RESULTS: continuedDrug Administration:In the full analysis set (n=283), 18 patients received an initial dose of 50 mg (1 mg/kg), 248 patients an initial dose of 75 mg (1.5 mg/kg), 4 patients received an initial dose of 100 mg (2 mg/kg), 5 patients received an initial dose of 150 mg, and 3 patients received an initial dose of 225 mg. In addition, 1 patient received an initial dose of 1.29 mg/kg, 1.31 mg/kg, 1.64 mg/kg or 1.67 mg/kg.

For adult patients in the per protocol set, the mean ± SD daily dose of FK463 was 107.9 ± 51.24 mg per day (1.6 ± 0.82 mg/kg per day) with a median of 80.6 mg per day (1.4 mg/kg per day). The mean ± SD maximum daily dose of FK463 was 138.8 ± 73.43 mg (2.1 ± 1.14 mg/kg) with a median of 100.0 mg (1.7 mg/kg). The median duration of study drug exposure was 34 days; 28 patients received FK463 for longer than 90 days. The maximum dose received was 375.0 mg per day for 6 days. A total of 45/177 (25.4%) patients received a dose of 200 mg per day or higher. A total of 59.9% (106/177) of adult patients had their FK463 dose increased to improve therapeutic effect.

For pediatric patients (<16 years old) in the per protocol set, the median average dose was 1.6 mg/kg and the median maximal dose was 2.0 mg/kg. Therapy was received for a median of 37 days; 16 pediatric patients received FK463 longer than 90 days. Ten pediatric patients (19.6%) received a dose of 4.0 mg/kg per day or higher, and 5 patients received a dose of 200 mg per day or higher. The highest dose administered in a pediatric patient (Patient Number ) was 325.0 mg per day for 1 day (6.8 mg/kg per day). This patient received intermittent doses of between 70 and 325 mg for 681 days.


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RESULTS: continuedEfficacy Results:Primary Endpoint: In the per protocol set, 62.7% (143/228) of patients were considered a treatment success (95% CI: 56.4%, 69.0%). Complete response (CR) occurred in 25.0%, partial response (PR) in 24.1%, and stabilization (S) in 13.6% of patients. Treatment success rates (CR+PR+S) were 82.4% in the de novo group, 59.9% in the efficacy failure FK463 and other therapy group, 53.3% in the efficacy failure FK463 alone group, and 85.7% in the toxicity failure group. Comparable results were seen in male versus female and adult versus pediatric patients. The success rate for patients with baseline absolute neutrophil count (ANC) <500cells/mm3 was 58.5% compared with 64.2% for patients with ANC ≥500cells/mm3.

In the FK463 monotherapy groups, the CR+PR rate was 12/17 (70.6%) for de novo patients, 7/15 (46.7%) for efficacy failure patients receiving FK463 alone and 10/12 (83.3%) for toxicity failure patients. For efficacy failure patients receiving FK463 with another systemic antifungal drug, 83/182 (45.6%) of patients experienced a complete or partial response. Given that investigators were unwilling to stop present therapy at the time of enrollment, efficacy failure patients who had FK463 added to their current antifungal drug regimen can be considered the most difficult to treat.

Among efficacy failure and toxicity failure patients, 168/211 had disease progression at baseline and 43/211 had stable disease at baseline. Patients enrolled with progressive disease had the following outcomes: CR, 22.0%; PR, 21.4%; S, 13.1%. Patients enrolled with stable disease had: CR, 23.7%; PR 23.7%; S, 13.7%.

Success was documented across a variety of Aspergillus species, including A. niger(87.5%, 7/8), A. flavus (75.0%, 18/24), A. fumigatus (56.7%, 51/90), A. nidulans(50.0%, 2/4), A. terreus (14.3%, 1/7) and A. versicolor (100.0%, 1/1).


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RESULTS: continuedEfficacy Results: continuedPrimary Endpoints: continuedIn the per protocol set, 64.3% (110/171) of patients with pulmonary aspergillosis experienced treatment success at the end of therapy; 40 (23.4%) experienced a complete response. The success rate was highest for the toxicity failure patients (91.7%) and lowest in the efficacy failure FK463 alone group (54.5%). Treatment success was documented across most Aspergillus species including A. fumigatus(58.1%, 43/74), A. flavus (77.8%, 7/9), A. niger (66.7%, 2/3), A. nidulans (50.0%, 1/2), and A. terreus (16.7%, 1/6). Aspergillus species were not specified for 80 patients with pulmonary aspergillosis; 72.5% (58/80) of these patients had treatment success.

The treatment success rate was 9/15 (60.0%) for patients with sinus aspergillosis and 2/3 (66.7%) for patients with pulmonary and sinus aspergillosis. Of the patients with disseminated aspergillosis, 43.5% (10/23) experienced treatment success at the end of therapy, and 21.7% (5/23) experienced a complete response.

Of the 143 patients who experienced treatment success, 96 had an average daily dose of <100 mg per day. The success rate for the 122 patients who received 50 to <100 mg per day was 64.5% (78/121). Higher doses of ≥100 mg per day led to treatment success in 58.6% (47/80) of patients.

Secondary Endpoints: In the per protocol set, 25.4% (58/228) of patients experienced a complete clinical response at the end of therapy. The highest rate of complete clinical response was 41.2% (7/17) in the de novo group and the lowest rate was 21.4% (3/14) in the toxicity failure group. The results of the analyses for the full analysis set were similar.


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RESULTS: continuedEfficacy Results: continuedSecondary Endpoints: continuedThe majority of patients, 78.5% (179/228), did not have a mycological assessment performed at the end of therapy. Overall, 8.8% (20/228) of per protocol set patients had documented eradication and 7.9% (18/228) experienced presumed eradication at the end of therapy. A total of 4.8% (11/228) had documented persistence of the Aspergillus infection at the end of therapy. Of the 49 patients with an end of therapy mycological assessment, 40.8% experienced eradication, 36.7% experienced presumed eradication, and 22.4% had documented persistence of the Aspergillus infection.

A total of 45/143 (31.5%) patients who had treatment success at the end of therapy received additional systemic antifungal therapy during the post-treatment period for treatment or empirical therapy.

Safety Results:Overall, the most common adverse events included vomiting (33.2%), abdominal pain (32.9%), nausea (31.8%), and diarrhea (30.7%). In general, a smaller proportion of adult patients, compared with pediatric patients, reported adverse events in each body system with the exception of the nervous system. There were no clinically apparent differences in the adverse events reported in adult versus pediatric patients. Underscoring the severity of the patient’s disease, 38.9% (110/283) of all patients experienced at least 1 adverse event that was categorized as life-threatening.

Adverse events that were considered by the investigator to be related to study drug were reported for 93 patients (32.9%). Overall, the most common study drug related adverse events were bilirubinemia (4.6%) and nausea (4.2%).

A total of 194/283 patients (68.6%) experienced 1 or more serious treatment emergent adverse events. Overall, the most common serious adverse events were respiratory failure (12.4%), dyspnea (9.2%), sepsis (8.5%), fever (6.0%), and shock (6.0%). In adult patients, the most common serious adverse events were respiratory failure (30/220, 13.6%) shock (16/220, 7.3%) and sepsis (14/220, 6.4%). In children, the most common serious adverse events were sepsis (10/63, 15.9%), dyspnea (9/63, 14.3%), fever (6/63, 9.5%), infection (5/63, 7.9%), hypotension (5/63, 7.9%), convulsion (5/63, 7.9%), respiratory failure (5/63, 7.9%), procedural complication (4/63, 6.3%) and respiratory distress syndrome (4/63, 6.3%).


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RESULTS: continuedSafety Results: continuedOverall (n=283), the most common serious adverse events considered related to study drug were dyspnea (1.4%), hypertension (0.7%), leukopenia (0.7%), increased creatinine (0.7%), and pulmonary embolus (0.7%). In adults (n=220), the most common serious adverse events (≥2 patients, 0.9%) considered related to study drug were leukopenia (0.9%), creatinine increased (0.9%), dyspnea (0.9%) and pulmonary embolus (0.9%). In children (n=63), the most common serious adverse events (≥2 patients, 3.2%) were hypertension (3.2%), and dyspnea (3.2%).

A total of 165 patients (58.3%) died during the study; 1 of these deaths (pancytopenia resulting in pulmonary bleeding) was considered by the investigator to be related to study drug. A total of 99 patients (35.0%) patients died due to a fungal infection or a fungal infection was listed as a contributory cause. The remaining patients died of progression of disease or complications related to their underlying disease. Thirty patients died (10.6%) during the first week of the study, which reflects the serious condition of the patients enrolled in this study.

In this study population, liver-related adverse events were relatively common with 84/283 (29.7%) patients experiencing an hepatic adverse event; 26/283 (9.2%) patients had events that were considered by the investigator to be related to study drug. The majority of hepatic events considered related to study drug were mild or moderate in intensity.

There was little evidence of nephrotoxicity, injection-site reactions, or infusion-related reactions related to study drug in this study. A total of 13/283 (4.6%) patients had a potential allergic-type or histamine-like reactions considered by the investigator to be related to study drug during the study. The most common of these events was vasodilatation in 6 patients and rash in 3 patients.SUMMARY / CONCLUSIONS:Because of its documented efficacy, safety, dosing flexibility, and ability to be used in combination therapy, FK463 represents an important new agent for the treatment of invasive aspergillosis.

Date of Report: August 2, 2002

Key Tables


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Synopsis Table 1: Study Population

Efficacy Failure

De NovoFK463 &

OtherFK463 Alone

Toxicity Failure Total

All Enrolled Patients† 23 230 19 16 288Full Analysis Set 23 (100.0%) 225 (97.8%) 19 (100.0%) 16 (100.0%) 283 (98.3%)Per Protocol Set 17 (73.9%) 182 (79.1%) 15 (78.9%) 14 (87.5%) 228 (79.2%)

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); patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.† This interim report includes data from 288 patients whose case report forms were collected by January 31, 2002 including interim data for 1 patient (Patient Number ).Source: Table 13.1.1


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Synopsis Table 2: Patient Status at End of Study

Efficacy Failure

De Novo(n=23)

FK463 & Other

(n=230)FK463 Alone

(n=19)

Toxicity Failure(n=16)

Total(n=288)

All enrolled patients n=23 n=230 n=19 n=16 n=288Completed Study 10 (43.5%) 77 (33.5%) 6 (31.6%) 11 (68.8%) 104 (36.1%)Death 9 (39.1%) 138 (60.0%) 13 (68.4%) 5 (31.3%) 165 (57.3%)Lost to Follow-up 3 (13.0%) 5 (2.2%) 0 0 8 (2.8%)Other† 1 (4.3%) 9 (3.9%) 0 0 10 (3.5%)Interim‡ 0 1 (0.4%) 0 0 1 (0.3%)

Full analysis set n=23 n=225 n=19 n=16 n=283Completed Study 10 (43.5%) 77 (33.5%) 6 (31.6%) 11 (68.8%) 104 (36.1%)Death 9 (39.1%) 138 (60.0%) 13 (68.4%) 5 (31.3%) 165 (57.3%)Lost to Follow-up 3 (13.0%) 5 (2.2%) 0 0 8 (2.8%)Other 1 (4.3%) 4 (1.7%) 0 0 5 (1.7%)Interim‡ 0 1 (0.4%) 0 0 1 (0.3%)

Per protocol set n=17 n=182 n=15 n=14 n=228Completed Study 10 (43.5%) 70 (30.4%) 6 (31.6%) 9 (56.3%) 95 (33.0%)Death 5 (21.7%) 105 (45.7%) 9 (47.4%) 5 (31.3%) 124 (43.1%)Lost to Follow-up 2 (8.7%) 4 (1.7%) 0 0 6 (2.1%)Other 0 2 (0.9%) 0 0 2 (0.7%)Interim‡ 0 1 (0.4%) 0 0 1 (0.3%)

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); patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.†Other (full analysis set): de novo: diagnosed with mucor (Patient Number ); FK463 & other: patient refusal (Patient Number ), did not receive study drug (Patient Numbers , , and ), disease progression (Patient Numbers and ), no Aspergillus infection (Patient Number

), withdrawn as a result of an adverse event (Patient Number ) and patient withdrew consent (Patient Number ).‡Patient Number . Source: Table 13.1.1


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Synopsis Table 3: Reasons for Treatment Discontinuation

Efficacy Failure

De NovoFK463 &

Other FK463 AloneToxicity Failure Total

Full analysis set n=23 n=225 n=19 n=16 n=283Completed Therapy 10 (43.5%) 73 (32.4%) 6 (31.6%) 7 (43.8%) 96 (33.9%)Discontinued Therapy 13 (56.5%) 151 (67.1%) 13 (68.4%) 9 (56.3%) 186 (65.7%)Adverse Event 7 (30.4%) 61 (27.1%) 6 (31.6%) 5 (31.3%) 79 (27.9%)Lack of Efficacy 1 (4.3%) 61 (27.1%) 5 (26.3%) 1 (6.3%) 68 (24.0%)Administrative 5 (21.7%) 29 (12.9%) 2 (10.5%) 3 (18.8%) 39 (13.8%)

Interim† 0 1 (0.4%) 0 0 1 (0.3%)Per protocol set n=17 n=182 n=15 n=14 n=228Completed Therapy 10 (58.8%) 68 (37.4%) 6 (40.0%) 5 (35.7%) 89 (39.0%)Discontinued Therapy 7 (41.2%) 113 (62.1%) 9 (60.0%) 9 (64.3%) 138 (60.5%)Adverse Event 4 (23.5%) 43 (23.6%) 3 (20.0%) 3 (21.4%) 55 (24.1%)Lack of Efficacy 1 (5.9%) 49 (26.9%) 4 (26.7%) 1 (7.1%) 55 (24.1%)Administrative 1 (11.8%) 21 (11.5%) 2 (13.3%) 3 (21.4%) 28 (12.3%)

Interim† 0 1 (0.4%) 0 0 1 (0.3%)Patient base: all patients who received at least 1 dose of FK463 (full analysis set); patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.† Patient Number . Source: Tables 13.1.2.1 and 13.1.2.2


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Synopsis Table 4: Demographics and Baseline Characteristics, Full Analysis Set

Efficacy Failure

De Novo(n=23)

FK463 & Other

(n=225)FK463 Alone

(n=19)


Total(n=283)

SexMale 20 (87.0%) 136 (60.4%) 14 (73.7%) 11 (68.8%) 181 (64.0%)Female 3 (13.0%) 89 (39.6%) 5 (26.3%) 5 (31.3%) 102 (36.0%)

RaceCaucasian 17 (73.9%) 202 (89.8%) 13 (68.4%) 15 (93.8%) 247 (87.3%)Black 1 (4.3%) 15 (6.7%) 1 (5.3%) 0 17 (6.0%)Mestizo 4 (17.4%) 2 (0.9%) 4 (21.1%) 1 (6.3%) 11 (3.9%)Oriental 1 (4.3%) 2 (0.9%) 0 0 3 (1.1%)Other† 0 4 (1.8%) 1 (5.3%) 0 5 (1.8%)

Age (years)Mean ± SD 42.8 ± 24.99 35.1 ± 20.28 40.2 ± 15.15 51.3 ± 14.13 37.0 ± 20.46Range 2.0 - 79.0 0.2 - 84.0 14.0 - 58.0 19.0 - 68.0 0.2 - 84.0

Weight (kg)Mean ± SD 61.6 ± 21.64 60.0 ± 23.03‡ 67.4 ± 14.42¶ 71.9 ± 10.51 61.3 ± 22.08§Range 9.0 - 89.2 4.7 - 137.4‡ 42.0 - 93.2¶ 52.1 - 85.6 4.7 - 137.4§

Neutropenic Status (ANC)≥500 cells/ mm3 19 (82.6%) 151 (67.1%) 16 (84.2%) 12 (75.0%) 198 (70.0%)<500 cells/ mm3 2 (8.7%) 73 (32.4%) 2 (10.5%) 4 (25.0%) 81 (28.6%)

Patient base: all patients who received at least 1 dose of FK463 (full analysis set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.† Other: Asian Indian, Eastern Indian, Southeast Asian, Colored, Asian. ‡ n=222; ¶ n=18; § n=279.ANC: absolute neutrophil count.Source: Table 13.2.1.1 and Appendix 14.4.4


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Synopsis Table 5: Demographics and Baseline Characteristics, Per Protocol Set

Efficacy Failure

De Novo(n=17)

FK463 & Other

(n=182)FK463 Alone

(n=15)


Total(n=228)

SexMale 16 (94.1%) 108 (59.3%) 10 (66.7%) 9 (64.3%) 143 (62.7%)Female 1 (5.9%) 74 (40.7%) 5 (33.3%) 5 (35.7%) 85 (37.3%)

RaceCaucasian 12 (70.6%) 160 (87.9%) 10 (66.7%) 13 (92.9%) 195 (85.5%)Black 1 (5.9%) 14 (7.7%) 1 (6.7%) 0 16 (7.0%)Mestizo 4 (23.5%) 2 (1.1%) 4 (26.7%) 1 (7.1%) 11 (4.8%)Oriental 0 2 (1.1%) 0 0 2 (0.9%)Other† 0 4 (2.2%) 0 0 4 (1.8%)

Age (years)Mean ± SD 37.9 ± 25.80 35.5 ± 20.16 38.8 ± 16.34 52.2 ± 14.76 36.9 ± 20.40Range 2.0 - 78.0 0.2 - 82.0 14.0 - 58.0 19.0 - 68.0 0.2 - 82.0

Weight (kg)Mean ± SD 59.2 ± 24.12 60.3 ± 23.12‡ 65.5 ± 14.72¶ 71.4 ± 10.49 61.2 ± 22.27§Range 9.0 - 89.2 4.7 - 137.4‡ 42.0 - 89.5¶ 52.1 - 83.5 4.7 - 137.4§

Neutropenic Status (ANC)≥500 cells/ mm3 13 (76.5%) 124 (68.1%) 12 (80.0%) 10 (71.4%) 159 (69.7%)<500 cells/ mm3 2 (11.8%) 57 (31.3%) 2 (13.3%) 4 (28.6%) 65 (28.5%)

Patient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.ANC: absolute neutrophil count.† Other: Asian Indian, Eastern Indian, Colored, Asian‡ n=180; ¶ n=14; § n=225.Source: Table 13.2.1.2


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Synopsis Table 6: Summary of FK463 Administration, Adult Patients, Per Protocol Set

Efficacy Failure

De Novo(n=13)

FK463 & Other

(n=137)FK463 Alone

(n=13)


Total(n=177)

Days on Therapy nMean ± SDMedian(Range)

1338.3 ± 20.89

36.0(7 to 90)

13753.8 ± 50.99

35.0(7 to 284)

1341.2 ± 30.29

28.0(7 to 90)

1442.1 ± 39.41

21.0(7 to 126)

17750.8 ± 47.41

34.0(7 to 284)

Average Daily Dose (mg)nMean ± SDMedian(Range)

13141.8 ± 72.87

140.9(56.9 to 251.2)

137108.8 ± 48.94

91.7(33.3 to 291.7)

1393.6 ± 51.29

75.0(32.9 to 229.2)

1481.5 ± 32.37

75.0(53.6 to 183.6)

177107.9 ± 51.24

80.6(32.9 to 291.7)

Average Daily Dose (mg/kg)nMean ± SDMedian(Range)

132.0 ± 1.05

2.0(0.7 to 3.9)

1351.7 ± 0.79

1.5(0.5 to 4.4)

121.5 ± 0.99

1.1(0.4 to 3.5)

141.1 ± 0.40

1.0(0.7 to 2.4)

1741.6 ± 0.82

1.4(0.4 to 4.4)

Maximum Dose Received (mg)nMean ± SDMedian(Range)

13192.3 ± 101.23

225.0(75.0 to 350.0)

137139.3 ± 70.91

150.0(50.0 to 375.0)

13119.2 ± 70.82

75.0(75.0 to 300.0)

14101.8 ± 39.79

75.0(75.0 to 200.0)

177138.8 ± 73.43

100.0(50.0 to 375.0)

Maximum Dose Received (mg/kg)nMean ± SDMedian(Range)

132.8 ± 1.51

3.0(0.9 to 5.7)

1352.1 ± 1.09

1.9(0.5 to 5.1)

121.9 ± 1.41

1.3(0.8 to 5.0)

141.4 ± 0.56

1.4(0.9 to 2.6)

1742.1 ± 1.14

1.7(0.5 to 5.7)

Table continued on next pagePatient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set). Adult: ≥16 years of age.De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone. Source: Table 13.3.4.2


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Synopsis Table 6: Continued

Efficacy Failure

De Novo(n=13)

FK463 & Other

(n=137)FK463 Alone

(n=13)


Total(n=177)

Cumulative Dose (mg)nMean± SDMedian(Range)

135886.5 ± 4486.025775.0

(525.0 to 15075.0)

1376337.0 ± 7271.443675.0

(525.0 to 36600.0)

133771.9 ± 3597.672925.0

(600.0 to 13150.0)

143742.9 ± 4589.641462.5

(525.0 to 16525.0)

1775910.9 ± 6746.953300.0

(525.0 to 36600.0)

Cumulative Dose (mg/kg)nMean ± SDMedian(Range)

1387.6 ± 72.16

81.8(6.6 to 243.1)

13593.9 ± 106.67

55.3(5.6 to 577.8)

1262.1 ± 60.58

37.4(8.6 to 215.6)

1452.7 ± 60.95

21.8(6.4 to 212.7)

17487.9 ± 99.30

51.8(5.6 to 577.8)

Patient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set). Adult: ≥16 years of age.De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen. Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone. Source: Table 13.3.4.2


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Synopsis Table 7: Summary of FK463 Administration, Pediatric Patients, Per Protocol Set

Efficacy failureDe Novo

(n=4)FK463 & Other

(n=45)FK463 Alone

(n=2)Total

(n=51)Days on Therapy nMean ± SDMedian(Range)

423.5 ± 11.21

27.5(7 to 32)

4575.0 ± 98.76

47.0(7 to 638)

211.5 ± 0.71

11.5(11 to 12)

5168.5 ± 94.46

37.0(7 to 638)

Average Daily Dose (mg/kg)nMean ± SDMedian(Range)

41.6 ± 0.13

1.6(1.5 to 1.8)

452.0 ± 1.19

1.5(0.5 to 7.2)

21.9 ± 0.13

1.9(1.8 to 2.0)

512.0 ± 1.13

1.6(0.5 to 7.2)

Maximum Dose Received (mg/kg)nMean ± SDMedian(Range)

41.6 ± 0.13

1.6(1.5 to 1.8)

452.6 ± 1.64

2.0(0.7 to 8.6)

22.0 ± 0.36

2.0(1.8 to 2.3)

512.5 ± 1.57

2.0(0.7 to 8.6)

Cumulative Dose (mg/kg)nMean ± SDMedian(Range)

438.2 ± 18.55

46.6(10.5 to 49.1)

45182.1 ± 325.73

75.0(11.3 to 1960.5)

221.6 ± 2.77

21.6(19.6 to 23.6)

51164.6 ± 309.45

63.4(10.5 to 1960.5)

Patient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set). Pediatric patients: <16 years of age.De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.Source: Table 13.3.3.2


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Synopsis Table 8: Investigator Global Assessment at End of Therapy

Efficacy Failure

De Novo(n=17)

FK463 & Other

(n=182)FK463 Alone

(n=15)

Toxicity Failure (n=14)

Total[95% CI]†

(n=228)Success 14 (82.4%) 109 (59.9%) 8 (53.3%) 12 (85.7%) 143 (62.7%)

[56.4%, 69.0%]Complete Response

7 (41.2%) 44 (24.2%) 3 (20.0%) 3 (21.4%) 57 (25.0%)

Partial Response

5 (29.4%) 39 (21.4%) 4 (26.7%) 7 (50.0%) 55 (24.1%)

Stabilization 2 (11.8%) 26 (14.3%) 1 (6.7%) 2 (14.3%) 31 (13.6%)Failure (Progression)

3 (17.6%) 67 (36.8%) 6 (40.0%) 1 (7.1%) 77 (33.8%)

Not Evaluable 0 6 (3.3%) 1 (6.7%) 1 (7.1%) 8 (3.5%)Complete or partial response

12 (70.6%) 83 (45.6%) 7 (46.7%) 10 (71.4%) 112 (49.1%)

Patient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with nonspeciated Aspergillus and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.† Confidence interval is provided only for treatment success.Treatment success: complete response, partial response, or stabilization.CI: confidence interval; constructed using the large sample normal approximation of the binomial distribution.Investigator global assessment: based on mycologic, histologic, radiologic, and clinical evidence of infection. Source: Table 13.4.1.2


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Synopsis Table 9: Treatment Success by Baseline Aspergillus Species

Efficacy Failure

De Novo(n=17)

FK463 & Other

(n=182)FK463 Alone

(n=15)


Total(n=228)

Aspergillus speciesA. niger 0/0 5/6 (83.3%) 1/1 (100.0%) 1/1 (100.0%) 7/8 (87.5%)A. flavus 1/1 (100.0%) 15/21 (71.4%) 1/1 (100.0%) 1/1 (100.0%) 18/24 (75.0%)A. fumigatus 4/5 (80.0%) 40/75 (53.3%) 1/4 (25.0%) 6/6 (100.0%) 51/90 (56.7%)A. nidulans 0/0 2/4 (50.0%) 0/0 0/0 2/4 (50.0%)A. terreus 0/0 1/6 (16.7%) 0/1 0/0 1/7 (14.3%)A. flavipes 0/0 0/1 0/0 0/0 0/1A. versicolor 0/0 1/1 (100.0%) 0/0 0/0 1/1 (100.0%)

AspergillusNOS† 9/11 (81.8%) 52/83 (62.7%) 5/8 (62.5%) 5/7 (71.4%) 71/109 (65.1%)

Patient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.Treatment Success: Complete response, partial response, or stabilization.The denominator represents the number of patients in each category of Aspergillus species at baseline. Patients may have had >1 Aspergillus species infection reported at baseline. † NOS: not speciated.Source: Table 13.4.2.3.2


- XXII -

Synopsis Table 10: Treatment Success by Primary Site of Infection

Efficacy Failure

De Novo(n=17)

FK463 & Other

(n=182)FK463 Alone

(n=15)


Total(n=228)

Primary Site of InfectionLungs 9/11

(81.8%)84/137 (61.3%)

6/11(54.5%)

11/12(91.7%)

110/171(64.3%)

Disseminated 0/1 10/22 (45.5%) 0/0 0/0 10/23 (43.5%)Sinus 1/1 (100.0%) 8/12 (66.7%) 0/1 0/1 9/15 (60.0%)Blood 2/2 (100.0%) 1/1 (100.0%) 1/1 (100.0%) 0/0 4/4 (100.0%)Skin 1/1 (100.0%) 1/3 (33.3%) 0/0 0/0 2/4 (50.0%)Lungs + Sinus 0/0 2/3 (66.7%) 0/0 0/0 2/3 (66.7%)Liver 0/0 1/1 (100.0%) 0/0 0/0 1/1 (100.0%)CNS/Brain 0/0 0/0 0/1 0/0 0/1Other 1/1 (100.0%) 2/3 (66.7%) 1/1 (100.0%) 1/1 (100.0%) 5/6 (83.3%)

Patient base: patients who received at least 7 doses of study drug and have a proven or probable (lungs only) invasive aspergillosis at baseline (per protocol set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.Treatment Success: complete response, partial response, or stabilization.Other: otitis internal, eye, oropharyngeal/endocardium, sternum, toe, and face.Source: Table 13.4.2.2


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Synopsis Table 11: Incidence of Common Treatment Emergent Adverse Events Including Non-Fungal Infections

Efficacy Failure

Body SystemCOSTART Term

De Novo(n=23)

FK463 & Other

(n=225)

FK463Alone(n=19)


Total(n=283)

Any adverse event 23 (100.0%) 225 (100.0%) 19 (100.0%) 16 (100.0%) 283 (100.0%)Body as a Whole

Abdominal Pain 7 (30.4%) 80 (35.6%) 3 (15.8%) 3 (18.8%) 93 (32.9%)Procedural Complication‡

7 (30.4%) 64 (28.4%) 2 (10.5%) 3 (18.8%) 76 (26.9%)

Sepsis 3 (13.0%) 69 (30.7%) 2 (10.5%) 2 (12.5%) 76 (26.9%)Fever 9 (39.1%) 55 (24.4%) 2 (10.5%) 3 (18.8%) 69 (24.4%)Nonfungal Infection

4 (17.4%) 54 (24.0%) 4 (12.1%) 5 (31.3%) 67 (23.7%)

Asthenia 0 50 (22.2%) 3 (15.8%) 1 (6.3%) 54 (19.1%)Cardiovascular System

Hypotension 5 (21.7%) 55 (24.4%) 4 (21.1%) 3 (18.8%) 67 (23.7%)Digestive System

Vomiting 5 (21.7%) 81 (36.0%) 4 (21.1%) 4 (25.0%) 94 (33.2%)Nausea 6 (26.1%) 75 (33.3%) 5 (26.3%) 4 (25.0%) 90 (31.8%)Diarrhea 4 (17.4%) 79 (35.1%) 2 (10.5%) 2 (12.5%) 87 (30.7%)Constipation 4 (17.4%) 52 (23.1%) 1 (5.3%) 2 (12.5%) 59 (20.8%)Anorexia 3 (13.0%) 36 (16.0%) 3 (15.8%) 4 (25.0%) 46 (16.3%)

Hemic & Lymphatic SystemLeukopenia 6 (26.1%) 30 (13.3%) 2 (10.5%) 5 (31.3%) 43 (15.2%)

Continued on next pagePatient base: all randomized patients who received at least 1 dose of FK463 (full analysis set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.Common: experienced by at least 20% of patients in any patient group. Within a body system, patients may have experienced more than 1 event.‡ Procedural Complication: Events related to post-surgical complications (pain or swelling) or catheters/lines (leaking, pain, clotting, or bleeding), and complications from chemotherapy.Source: Table 13.5.1.1


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Synopsis Table 11: ContinuedEfficacy Failure


De Novo(n=23)

FK463 & Other

(n=225)

FK463Alone(n=19)


Total(n=283)

Metabolic and Nutritional DisordersHypokalemia 6 (26.1%) 63 (28.0%) 3 (15.8%) 1 (6.3%) 73 (25.8%)Hypomagnesemia 4 (17.4%) 39 (17.3%) 5 (26.3%) 2 (12.5%) 50 (17.7%)Hyperkalemia 2 (8.7%) 32 (14.2%) 4 (21.1%) 1 (6.3%) 39 (13.8%)Hypercalcemia 5 (21.7%) 25 (11.1%) 2 (10.5%) 0 32 (11.3%)SGOT increased 5 (21.7%) 14 (6.2%) 2 (10.5%) 2 (12.5%) 23 (8.1%)

Nervous SystemHeadache 5 (21.7%) 59 (26.2%) 4 (21.1%) 5 (31.3%) 73 (25.8%)Insomnia 5 (21.7%) 22 (9.8%) 2 (10.5%) 3 (18.8%) 32 (11.3%)Dizziness 5 (21.7%) 17 (7.6%) 1 (5.3%) 0 23 (8.1%)

Respiratory SystemDyspnea 6 (26.1%) 61 (27.1%) 7 (36.8%) 3 (18.8%) 77 (27.2%)Lung disorder 0 35 (15.6%) 4 (21.1%) 0 39 (13.8%)Respiratory Failure

1 (4.3%) 34 (15.1%) 4 (21.1%) 0 39 (13.8%)

Skin and AppendagesRash 2 (8.7%) 47 (20.9%) 2 (10.5%) 0 51 (18.0%)

Patient base: all randomized patients who received at least 1 dose of FK463 (full analysis set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.Common: experienced by at least 20% of patients in any patient group. Within a body system, patients may have experienced more than 1 event.‡ Procedural Complication: Events related to post-surgical complications (pain or swelling) or catheters/lines (leaking, pain, clotting, or bleeding), and complications from chemotherapy.Source: Table 13.5.1.1


- XXV -

Synopsis Table 12: Summary of Common Adverse Events Considered to be Related to Study Drug

Efficacy Failure


De Novo(n=23)

FK463 & Other

(n=225)

FK463Alone(n=19)


Total(n=283)

Any AE 9 (39.1%) 68 (30.2%) 8 (42.1%) 8 (50.0%) 93 (32.9%)Cardiovascular System

Hypertension 0 7 (3.1%) 0 0 7 (2.5%)Vasodilatation 1 (4.3%) 5 (2.2%) 0 0 6 (2.1%)

Digestive SystemNausea 0 10 (4.4%) 0 2 (12.5%) 12 (4.2%)Diarrhea 0 7 (3.1%) 0 0 7 (2.5%)Vomiting 0 6 (2.7%) 0 1 (6.3%) 7 (2.5%)

Metabolic and Nutritional DisordersBilirubinemia 1 (4.3%) 12 (5.3%) 0 0 13 (4.6%)Alk Phos Increased 0 6 (2.7%) 2 (10.5%) 0 8 (2.8%)SGPT increased 0 6 (2.7%) 1 (5.3%) 0 7 (2.5%)

Respiratory SystemDyspnea 0 5 (2.2%) 1 (5.3%) 0 6 (2.1%)

Patient base: all randomized patients who received at least 1 dose of FK463 (full analysis set).De novo: patients must have had proven or probable invasive infection with Aspergillus species and have received no more than 48 hours of standard systemic antifungal therapy prior to study entry.Efficacy failure: patients with inadequate response or failure after ≥72 hours of standard antifungal therapy for proven or probable invasive aspergillosis prior to study entry; these patients received either a regimen of FK463 alone or FK463 was added to their prior systemic antifungal regimen.Toxicity failure: patients who failed systemic antifungal therapy due to toxicity; they received FK463 alone.Within a body system, patients may have experienced more than 1 event.Common: experienced by at least 2% of the patients overall. Related: possible or probable or highly probable, as determined by the investigator. AE: adverse event; Alk phos: alkaline phosphatase; SGPT: serum glutamic pyruvic transaminase. Source: Table 13.5.3.1

SYNOPSIS Name of Sponsor/Company: Fujisawa GmbH Name of ...€¦ · Criteria for Evaluation:All patients who received at least 1 dose of FK463 (full analysis set) were included in

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