REZZAYO Powder for solution for injection Ref.[107368] Active ingredients: Rezafungin

Rezafungin exposures achieved with the recommended dosage regimen appear to be on the plateau of the observed flat exposure-efficacy response curve in clinical studies.

Cardiac Electrophysiology

Rezafungin does not prolong the QTc interval to any clinically relevant extent at a dose 3.5 times the maximum approved recommended loading dose.

Following single and multiple dosing, the C_max and AUC of rezafungin increase in a dose-proportional manner over a dose range of 50 mg (0.125 times the approved maximum recommended loading dose) to 400 mg.

Rezafungin population PK model derived pharmacokinetics (in patients with candidemia and invasive candidiasis (IC)) following administration of REZZAYO are provided in Table 3 and presented as mean ± standard deviation (SD). The mean rezafungin AUC_0-168h decreased approximately 30% and C_max decreased approximately 19% in patients with candidemia and IC compared to healthy participants.

Table 3. Population Pharmacokinetic (PK) Parameters of Rezafungin in Patients with Candidemia or IC Following REZZAYO (initial 400 mg loading dose, followed by a 200 mg dose once weekly):

C_max= maximum plasma concentration; C_min= trough plasma concentration; AUC_0–168h= area under the plasma concentration-time curve from time zero to 168 hours post dose
^* Mean ± SD
^† Time to C_max is 1hr post-start of infusion (i.e., end of infusion)
^‡ Excretion studied in healthy subjects

Specific Populations

No clinically relevant effects on the pharmacokinetics of rezafungin were observed based on age (range: 20 to 89 years), sex (60.6% male), race (~10% Asian, 10% Black, 77% White), weight (range: 34 to 154.5 kg), or hepatic impairment (Child Pugh Class B or C). No clinically relevant effect on the pharmacokinetics of rezafungin were observed based on renal impairment (creatinine clearance: 9.3 mL/min to above 120 mL/min) and no effect is expected in patients undergoing hemodialysis.

Drug Interaction Studies

Clinical Studies

Drug-drug interaction studies' findings in healthy subjects show that at the recommended rezafungin dosing regimen, no clinically significant effect is expected of rezafungin treatment on the pharmacokinetics of substrates of cytochrome P450 (CYP) enzymes and/or drug transporters (repaglinide [CYP2C8], cyclosporine [CYP3A and P-gp], tacrolimus [CYP3A and P-gp], caffeine [CYP1A2], midazolam [CYP3A]), metformin [OCT-1 and OCT-2 and MATE-1 and MATE-2], pitavastatin [OATP], rosuvastatin [BCRP and OATP], digoxin [P-gp]). These studies also show no clinically significant effect expected of rezafungin treatment on the pharmacokinetics of other drugs likely to be co-administered (ibrutinib, venetoclax, efavirenz, or mycophenolate mofetil).

In vitro Studies

Rezafungin is not a substrate of CYP enzymes or drug transporter systems. Rezafungin is not an inhibitor or inducer of common drug metabolizing CYP enzymes or transporter systems.

Mechanism of Action

Rezafungin is a semi-synthetic echinocandin. Rezafungin inhibits the 1,3-β-D-glucan synthase enzyme complex, which is present in fungal cell walls but not in mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall of many fungi, including Candida species (spp.). Inhibition of 1,3-β-D-glucan synthesis results in concentration-dependent in vitro fungicidal activity against Candida spp., however, the clinical significance of this activity is unknown.

Resistance

Reduced susceptibility to echinocandins predominantly arises from mutations in glucan synthase catalytic subunit-encoding FKS genes (FKS1 and/or FKS2) that impact residues comprising “hot spot” (HS) regions of the Fks protein. Rezafungin exhibits some degree of cross-resistance to all fks mutations that confer reduced susceptibility to echinocandins. The relevance of fks-based reduced susceptibility to clinical outcome has not been fully characterized for rezafungin.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between rezafungin and azoles, amphotericin B, or flucytosine. In vitro studies have not demonstrated antagonism for rezafungin versus bacteria in combination with the following antibacterial drug classes: aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, glycopeptides, macrolides, monobactams, oxazolidinones, polypeptides, rifamycins, sulfonamides, and tetracyclines, as well as daptomycin.

Antifungal Activity

Rezafungin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections.

Candida albicans
Candida glabrata
Candida parapsilosis
Candida tropicalis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for rezafungin against isolates of a similar genus or organism group. However, the efficacy of rezafungin in treating clinical infections caused by these fungi has not been established in adequate and well-controlled clinical trials.

Candida krusei
Candida auris
Candida dubliniensis
Candida fabianii
Candida guilliermondii
Candida inconspicua
Candida kefyr
Candida lusitaniae
Candida metapsilosis
Candida orthopsilosis
Candida pulcherrima
Candida rugosa
Candida sojae

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis

Carcinogenicity studies with rezafungin have not been conducted.

Mutagenesis

Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

Rezafungin did not affect mating or fertility in male and female rats following IV administration once every 3 days at doses up to 45 mg/kg (6 times the clinical exposure, based on AUC determined in a separate rat study). Decreased sperm motility was noted at ≥30 mg/kg and most males at 45 mg/kg showed mild/moderate hypospermia and had no detectable motile sperm. At rezafungin doses ≥30 mg/kg there was an increased incidence of sperm with abnormal morphology as well as mild to moderate degeneration of the seminiferous tubules. In a 3-month study of every 3 day IV rezafungin in rats, males dosed at 45 mg/kg showed minimal tubular degeneration/atrophy in the testes and cellular debris in the epididymides at the end of 3 months. The incidence of this finding reduced by the end of a 4-week reversibility period. In contrast, sperm concentration, production rate, morphology and motility were unaffected in adult monkeys dosed weekly with rezafungin, up to 30 mg/kg (about 6 times the clinical dose based on AUC comparisons) for 11 or 22 weeks or after a 52-week recovery period.

In one 3-month study in monkeys using every-3-day dosing, tremors were observed, beginning 35 to 43 days after the beginning of dosing at and above 30 mg/kg (9 times the clinical exposure based on AUC comparison). Increased cellularity/hyperplasia of Schwann cells and nerve fiber degeneration (affecting axons and/or myelin) were observed at 30 mg/kg (9 times the clinical exposure based on AUC comparison) and above. Tremors and demyelination persisted in the fourth week of a 4-week reversibility period. A subsequent 26-week monkey study using weekly rezafungin dosing up to 30 mg/kg (6 times the clinical exposure based on AUC comparison) showed a non-dose dependent increase in tremors, axonal degeneration, or demyelination compared to controls beginning at doses similar to human exposures (5 mg/kg). In one animal in the 15 mg/kg cohort (3 times the clinical exposure based on AUC comparison), tremors persisted to the end of the 52-week reversibility period. In rats dosed weekly for 26 weeks, intravenous rezafungin was associated with an increased incidence of axonal/nerve fiber degeneration at 25 and 45 mg/kg (2- and 4-times the clinical dose based on AUC comparison) at the end of the 26-week reversibility period.

Rezafungin induced an acute transient histamine-release response in rats. In monkeys, both the vehicle and rezafungin induced a mild transient histamine-like response in some studies.

The safety and efficacy of REZZAYO in the treatment of patients with candidemia and/or invasive candidiasis (IC) were evaluated in a multicenter, randomized, double-blind study (Trial 1; NCT03667690). Patients were randomized in a 1:1 ratio to receive REZZAYO or caspofungin. Randomization was stratified based on diagnosis (candidemia only; IC) and by Acute Physiology and Chronic Health Evaluation II score (APACHE II)/absolute neutrophil count (ANC) at screening. Patients with septic arthritis in a prosthetic joint, osteomyelitis, endocarditis or myocarditis, meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection, chronic disseminated candidiasis, or urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract were excluded.

Patients in the REZZAYO arm were to receive a single 400 mg loading dose on Day 1 of Week 1, followed by 200 mg once weekly, for a total of two to four doses. Patients in the caspofungin arm were to receive a single 70 mg IV loading dose, followed by caspofungin 50 mg IV once daily treatment for a total of 2 to 4 weeks. After ≥3 days of IV therapy, patients in the caspofungin group could be switched to oral step-down therapy (fluconazole), if the patient met the criteria for cure and was preparing to be discharged.

One hundred and ninety-nine patients in the intent-to-treat (ITT) population were randomized. The age range was 19-91 years, the gender distribution was 62% male and 38% female, and the race distribution was 61% White, 5% Black, 29% Asian, and 5% other races or not reported. The median duration of therapy was 14 days in the two treatment arms.

The modified ITT (mITT) population included 187 patients with a culture positive for Candida species within 4 days before randomization and who received at least one dose of study drug. The most frequent species isolated at baseline was C. albicans (42%), followed by C. glabrata (26%), C. tropicalis (20%), and C. parapsilosis (13%). The majority (70%) of patients had a diagnosis of candidemia only. The majority (93%) of patients were not neutropenic (ANC ≥500) and 84% had APACHE II scores less than 20. Risk factors for candidemia were: receipt of broad-spectrum antibacterial drugs (71%), presence of a central venous catheter (60%), major surgery (35%), diabetes mellitus (29%), active malignancy (25%), and total parenteral nutrition (20%). Mechanically ventilated patients were 24% (17% and 30% in the REZZAYO and caspofungin group, respectively).

Efficacy was assessed by all-cause mortality at Day 30. The number and percentage of patients in each treatment group who were alive and deceased/unknown survival status at Day 30 was determined in the mITT population. Additional efficacy outcomes were global cure (mycological eradication/presumed eradication, clinical cure, and radiological cure [for patients with documented IC by radiologic or other imaging findings at baseline]), mycological eradication/presumed eradication, and investigator’s assessment of clinical cure. Results of the efficacy endpoints are shown in Table 4.

Table 4. Summary of Efficacy Results from Trial 1 (mITT Population):

^* Two-sided 95% confidence intervals (CIs) for the observed differences in cure rates (REZZAYO minus caspofungin) is calculated using the unadjusted methodology of Miettinen and Nurminen.
^† Patients who died on or before Day 30, or with unknown survival status.
^‡ Patients with a mycological eradication/presumed eradication, clinical cure and radiologic cure (for patients with IC documented by radiologic or other imaging findings at baseline), as adjudicated by the Data Review Committee.
^§ Investigator’s assessment of clinical response based on resolution of attributable systemic signs and symptoms of candidemia/IC, no new systemic signs or symptoms attributable to candidemia/IC, no new systemic antifungal therapy to treat candidemia/IC, and the subject is alive.
^¶ Negative blood culture or culture from a normally sterile site and no change in antifungal therapy for the treatment of candidemia and/or IC. For IC patients, if the normally sterile baseline site of Candida infection was not accessible, the patient was presumed to have an eradication if the clinical outcome and radiologic outcome (if assessed) was a cure.

A multicenter, randomized, dose-finding, exploratory, double-blind study was conducted in subjects with candidemia and/or invasive candidiasis (Trial 2: NCT02734862). The primary objectives of this study were to evaluate safety and tolerability of rezafungin and overall success (mycological eradication and resolution of systemic signs attributable to candidemia and/IC) at Day 14. The study provides safety and supportive efficacy data.