Drug Trials Snapshots: REZZAYO
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug and whether there were differences among sex race age and ethnic groups. The “MORE INFO” bar shows more detailed technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the REZZAYO Prescribing Information for all the approved conditions of use of this drug (e.g. indication(s) population(s) dosing regimen(s) safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
REZZAYO (rezafungin)
rez aye’ oh
Cidara Therapeutics Inc.
Original Approval date: March 22 2023
DRUG TRIALS SNAPSHOT SUMMARY
What is the drug for?
REZZAYO is an echinocandin antifungal that is indicated in patients 18 years of age or older who have limited or no alternative options for the treatment of candidemia and invasive candidiasis (IC).
How is this drug used?
REZZAYO is administered once weekly by intravenous (IV) infusion.
Who participated in the clinical trials?
The FDA approved REZZAYO based on evidence from a phase 3 clinical trial of 199 patients with candidemia and/or invasive candidiasis. The trial was conducted at 66 sites in 15 countries including Australia, Belgium, Bulgaria, China, Colombia, Spain, France, Greece, Israel, Italy, South Korea, Singapore, Thailand, Taiwan, and the United States.
Trial 1 was used to assess efficacy and safety. Trial 2 was an exploratory phase 2 trial that was used mainly for safety and the combined results from Trial 1 and Trial 2 were used to evaluate the side effects of REZZAYO.
How were the trials designed?
REZZAYO was evaluated for efficacy in one clinical trial of 199 patients with candidemia and/or IC (Trial 1). The trial was a multicenter randomized double-blind active-controlled noninferiority trial. The primary efficacy endpoint was Day 30 all-cause mortality. Patients were randomized in a 1:1 ratio to receive REZZAYO or caspofungin. Randomization was stratified based on diagnosis (candidemia only or IC) and by Acute Physiology and Chronic Health Evaluation II score (APACHE II) or absolute neutrophil count (ANC) at screening.
How were the trials designed?
Patients with candidemia and/or IC were enrolled. 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 at least three 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.
The primary efficacy endpoint was Day 30 all-cause mortality.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many males and females were enrolled in the clinical trial used to evaluate the efficacy of REZZAYO.
Figure 1. Baseline Demographics by Sex Intent-to-Treat Population Trial 1
Source: Adapted from FDA Review
Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial used to evaluate the efficacy of REZZAYO.
Figure 2. Baseline Demographics by Race Intent-to-Treat Population Trial 1
Source: Adapted from FDA Review
Figure 3 summarizes the percentage of patients by age enrolled in the clinical trial used to evaluate the efficacy of REZZAYO.
Figure 3. Baseline Demographics by Age Intent-to-Treat Population Trial 1
Source: Adapted from FDA Review
Figure 4 summarizes the percentage of patients by ethnicity enrolled in the clinical trial used to evaluate the efficacy of REZZAYO.
Figure 4. Baseline Demographics by Ethnicity Intent-to-Treat Population Trial 1
Source: Adapted from FDA Review
Figure 5 summarizes how many patients by sex were in the combined trials (Trials 1 and 2) used to evaluate the side effects of REZZAYO.
Figure 5. Baseline Demographics by Sex Safety Population Trials 1 and 2
Source: Adapted from FDA Review
Figure 6 summarizes how many patients by race were in the combined trials used to evaluate the side effects of REZZAYO.
Figure 6. Baseline Demographics by Race Safety Population Trials 1 and 2
Source: Adapted from FDA Review
Figure 7 summarizes how many patients by age were in the combined trials used to evaluate the side effects of REZZAYO.
Figure 7. Baseline Demographics by Age Safety Population Trials 1 and 2
Source: Adapted from FDA Review
Figure 8 summarizes how many patients by ethnicity were in the combined trials used to evaluate the side effects of REZZAYO.
Figure 8. Baseline Demographics by Ethnicity Safety Population Trials 1 and 2
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Demographics of Efficacy Trial Intent-to-Treat Population Trial 1
| Parameter | REZZAYO N=100 |
Caspofungin N=99 |
| Sex n (%) | ||
| Female | 33 (33.0) | 43 (43.4) |
| Male | 67 (67.0) | 56 (56.6) |
| Age years | ||
| Median | 59.0 | 62.0 |
| Min max | 19.0, 89.0 | 20.0, 91.0 |
| Age group years n (%) | ||
| <65 | 60 (60.0) | 58 (58.6) |
| ≥65 | 40 (40.0) | 41 (41.4) |
| Race n (%) | ||
| American Indian or Alaska Native | 1 (1.0) | 1 (1.0) |
| Asian | 27 (27.0) | 31 (31.3) |
| Black or African American | 5 (5.0) | 4 (4.0) |
| Other | 1 (1.0) | 2 (2.0) |
| White | 61 (61.0) | 60 (60.6) |
| Not reported | 5 (5.0) | 1 (1.0) |
| Ethnicity n (%) | ||
| Hispanic or Latino | 7 (7.0) | 4 (4.0) |
| Not Hispanic or Latino | 89 (89.0) | 94 (94.9) |
| Not reported | 4 (4.0) | 1 (1.0) |
Source: Adapted from FDA Review
Table 2. Demographics of Safety Population Trials 1 and 2
| Characteristic | REZZAYO 400/200 mg N=151 |
Caspofungin N=166 |
| Sex n (%) | ||
| Female | 53 (35.1) | 73 (44.0) |
| Male | 98 (64.9) | 93 (56.0) |
| Age years | ||
| Median (min max) | 60 (19, 91) | 62 (20, 93) |
| Age group years n (%) | ||
| 18 to <65 | 87 (57.6) | 98 (59.0) |
| ≥65 | 64 (42.4) | 68 (41.0) |
| Age group ≥75 years n (%) | 26 (17.2) | 33 (19.9) |
| Race n (%) | ||
| American Indian or Alaska Native | 1 (0.7) | 1 (0.6) |
| Asian | 27 (17.9) | 34 (20.5) |
| Black or African American | 12 (7.9) | 8 (4.8) |
| Not reported | 5 (3.3) | 1 (0.6) |
| Other | 3 (2.0) | 2 (1.2) |
| White | 100 (66.2) | 117 (70.5) |
| Missing | 3 (2.0) | 3 (1.8) |
| Ethnicity n (%) | ||
| Hispanic or Latino | 15 (9.9) | 12 (7.2) |
| Not Hispanic or Latino | 131 (86.8) | 150 (90.4) |
| Not reported | 5 (3.3) | 4 (2.4) |
Source: Adapted from FDA Review
What are the benefits of this drug?
A single clinical trial was used to evaluate the efficacy of REZZAYO compared to another antifungal drug regimen for the treatment of adults with candidemia or IC, which are life-threatening infections caused by yeast. The trial showed the number of patients who died during the first 30 days of the study was similar for both treatments.
What are the benefits of this drug (results of trials used to assess efficacy)?
The safety and efficacy of REZZAYO in the treatment of patients with candidemia and/or 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. After at least three 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.
The intent-to-treat (ITT) population included 199 patients that were randomized. The age range was 19 to 91 years; the gender distribution was 62% male and 38% female; and the race distribution was 61% White, 5% Black or African American, 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 four 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%). Twenty-four percent were mechanically ventilated (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 or unknown survival status at Day 30 was determined in the mITT population. Additional efficacy outcomes were global cure (mycological eradication or presumed eradication, clinical cure, or radiological cure for patients with documented IC by radiologic or other imaging findings at baseline), mycological eradication or presumed eradication, and investigator’s assessment of clinical cure. Results of the efficacy endpoints are shown in Table 3.
Table 3. Summary of Efficacy Results From Phase 3 Trial mITT Population
| Parameter | REZZAYO N=93 n (%) |
Caspofungin N=94 n (%) |
Difference % (95% CI)a |
| All-cause mortality (Day 30)b | 22 (23.7) | 20 (21.3) | 2.4 (-9.7, 14.4) |
| Global curec | |||
| Day 5 | 52 (55.9) | 49 (52.1) | 3.8 (-10.5, 17.9) |
| Day 14 | 55 (59.1) | 57 (60.6) | -1.5 (-15.4, 12.5) |
| Clinical cured | |||
| Day 5 | 59 (63.4) | 70 (74.5) | -11.0 (-24.0, 2.3) |
| Day 14 | 62 (66.7) | 63 (67.0) | -0.4 (-13.8, 13.1) |
| Day 30 | 51 (54.8) | 52 (55.3) | -0.5 (-14.6, 13.7) |
| Mycological eradication or presumed eradicatione | |||
| Day 5 | 64 (68.8) | 58 (61.7) | 7.1 (-6.6, 20.6) |
| Day 14 | 63 (67.7) | 62 (66.0) | 1.8 (-11.7, 15.2) |
Source: REZZAYO Prescribing Information
aTwo-sided 95% CIs for the observed differences in cure rates (REZZAYO minus caspofungin) is calculated using the unadjusted methodology of Miettinen and Nurminen.
bPatients who died on or before Day 30 or with unknown survival status.
cPatients with a mycological eradication or 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.
dInvestigator’s assessment of clinical response based on resolution of attributable systemic signs and symptoms of candidemia or IC, no new systemic signs or symptoms attributable to candidemia or IC, no new systemic antifungal therapy to treat candidemia or IC, and the subject is alive.
eNegative 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.
Abbreviations: CI confidence interval; IC invasive candidiasis; mITT modified intent-to-treat
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: The observed effect of REZZAYO was better for females than males. Because of limited data, this difference may be due to chance.
- Race: The number of patients of races other than White was small; therefore, differences in how well REZZAYO worked among races could not be determined.
- Age: The observed effect of REZZAYO was better for patients aged 65 or older than those aged less than 65. Because of limited data, this difference may be due to chance.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Subgroup analyses were conducted to assess the potential for differences in the treatment effect for various demographic groups (Table 4). For each age group, there was no statistically significant treatment effect between the two treatment arms. However, there were potentially different treatment effects of REZZAYO compared to caspofungin in the two age groups. For sex and race, no statistically significant treatment effects were noted between groups of each variable. Of note, the sample sizes for these subgroups were small, which limits the ability to identify trends with certainty.
Table 4. Subgroup Analyses of All-Cause Mortality at Day 30 Phase 3 Study mITT Population
| Subgroup | REZZAYO N=93 n/Ns (%) |
Caspofungin N=94 n/Ns (%) |
Difference % (95% CI) |
| Age years | |||
| <65 | 15/55 (27.3) | 8/56 (14.3) | 13 (-2.2, 28.1) |
| ≥65 | 7/38 (18.4) | 12/38 (31.6) | -13.2 (-32.3, 6.6) |
| Sex | |||
| Male | 18/62 (29.0) | 11/56 (19.6) | 9.4 (-6.4, 24.6) |
| Female | 4/31 (12.9) | 9/38 (23.7) | -10.8 (-28.9, 8.6) |
| Race | |||
| American Indian or Alaska Native | 0/1 (0) | 0/1 (0) | NA |
| Asian | 8/23 (34.8) | 10/31 (32.3) | 2.5 (-22.2, 28.0) |
| Black or African American | 1/5 (20.0) | 0/4 (0) | NA |
| Not reported | 1/4 (25.0) | 0/1 (0) | NA |
| Other | 0/1 (0) | 0/2 (0) | NA |
| White | 12/59 (20.3) | 10/55 (18.2) | 2.2 (-12.8, 16.8) |
Source: Adapted from FDA Review
Abbreviations: CI confidence interval; mITT modified intent-to-treat; N number of patients in treatment arm; n number of patients with adverse event; NA not applicable; Ns total number of patients for each specific subgroup and were assigned to that specific arm
What are the possible side effects?
The most common side effects noted with REZZAYO treatment were diarrhea, vomiting, nausea, abdominal pain, constipation, low blood potassium, low blood magnesium, low blood phosphate, fever, and anemia.
Reactions such as feelings of warmth or nausea may occur during infusion of the medication. Damage to the skin may occur with sun exposure while taking this medication. Abnormalities in laboratory tests of liver function may occur while taking this medication and require close monitoring if treatment with REZZAYO is continued.
What are the possible side effects (results of trials used to assess safety)?
The safety of REZZAYO was assessed in 76 subjects in phase 1 studies and 232 patients with candidemia and IC in the previously described efficacy trial (Trial 1) and a multicenter randomized dose-finding exploratory double-blind study that evaluated safety and tolerability (Trial 2) who received a 400 mg loading dose of REZZAYO followed by a 200 mg dose once weekly or higher (please note that after the loading dose of 400 mg, weekly doses higher than 200 mg are not approved). A total of 151 patients received an initial 400 mg loading dose followed by a 200 mg dose once weekly thereafter (400 mg/200 mg dose); the maximum duration of dosing was four weekly doses (including the loading dose).
In the pooled Trial 1 and 2 safety population of REZZAYO patients treated with the 400 mg/200 mg dose, the age range was 19 to 91 years; the gender distribution was 64.9% male and 35.1% female; and the race distribution was 66.2% White, 7.9% Black or African American, 17.9% Asian, 2.7% other, and 5.3% not reported.
The number of patients with an adverse reaction leading to discontinuation of study medication was 9.3% in the REZZAYO arm and 9.0% in the caspofungin arm. In Trial 1, patients with a history (or presenting with significant symptoms) of severe ataxia, tremor, or neuropathy, or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson’s disease or Huntington’s disease), or currently taking a known neurotoxic medication were excluded from the trial.
Selected adverse reactions occurring in 5% or more of the patients who received a 400 mg loading dose followed by a 200 mg dose of REZZAYO once weekly are shown in Table 5.
Table 5. Adverse Reactions Reported in ≥5% of Adult Patients Receiving REZZAYO Therapy for Candidemia or Invasive Candidiasis
| Adverse Reaction | REZZAYO N=151 n (%) |
Caspofungin N=166 n (%) |
| Gastrointestinal disorders | ||
| Diarrhea | 17 (11) | 17 (10) |
| Vomiting | 14 (9) | 7 (4) |
| Nausea | 13 (9) | 8 (5) |
| Abdominal pain | 11 (7) | 9 (5) |
| Constipation | 8 (5) | 8 (5) |
| Metabolism and nutrition disorders | ||
| Hypokalemia | 22 (15) | 17 (10) |
| Hypomagnesemia | 12 (8) | 5 (3) |
| Hypophosphatemia | 8 (5) | 5 (3) |
| General disorders | ||
| Pyrexia | 18 (12) | 11 (7) |
| Blood and lymphatic system disorders | ||
| Anemia | 15 (10) | 13 (8) |
Source: REZZAYO Prescribing Information
The following selected adverse reactions occurred in <5% of patients receiving REZZAYO: infusion-related reactions, tremor, disseminated intravascular coagulation, dysphagia, gastrointestinal hemorrhage, fluid overload, insomnia, erythema, headache, dizziness, acute kidney injury, abnormal liver tests (including hypertransaminasemia and increased gamma-glutamyltransferase), and peripheral neuropathy (includes neuropathy peripheral, polyneuropathy, and peroneal nerve palsy).
Tremors were reported in 4/151 (2.6%) of REZZAYO-treated patients and none of the caspofungin-treated patients in Trials 1 and 2. All tremors developed in the second or third week after initiation of REZZAYO treatment and resolved within a month of onset.
Were there any differences in side effects among sex, race, and age?
- Sex: The safety database is small and does not provide meaningful data on whether different kinds of adverse events differed in various subgroups.
- Race: The safety database is small and does not provide meaningful data on whether different kinds of adverse events differed in various subgroups.
- Age: The safety database is small and does not provide meaningful data on whether different kinds of adverse events differed in various subgroups.
Clinical studies of REZZAYO did not include sufficient numbers of individuals to analyze and interpret differences in side effects among sex, race, and age.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 6. Overview of Adverse Events by Demographic Subgroup Safety Population Trial ISS
| Characteristic | Pooled REZZAYO (400/200 mg) N=151 n/Ns (%) |
Pooled Caspofungin N=166 n/Ns (%) |
Risk Difference % (95% CI) |
| Sex | |||
| Female | 50/53 (94.3) | 66/73 (90.4) | 3.9 (-5.3, 13.1) |
| Male | 88/98 (89.8) | 72/93 (77.4) | 12.4 (2.0, 22.8) |
| Age group years | |||
| 18 to <65 | 79/87 (90.8) | 76/98 (77.6) | 13.3 (3.0, 23.5) |
| ≥65 | 59/64 (92.2) | 62/68 (91.2) | 1.0 (-8.4, 10.4) |
| Age group ≥75 years | |||
| ≥75 | 24/26 (92.3) | 27/33 (81.8) | 10.5 (-6.2, 27.2) |
| Race | |||
| American Indian or Alaska Native | 1/1 (100) | 1/1 (100) | 0 (0, 0) |
| Asian | 26/27 (96.3) | 32/34 (94.1) | 2.2 (-8.5, 12.8) |
| Black or African American | 11/12 (91.7) | 8/8 (100) | -8.3 (-24.0, 7.3) |
| Not reported | 4/5 (80.0) | 1/1 (100) | -20.0 (-55.1, 15.1) |
| Other | 3/3 (100) | 2/2 (100) | 0 (0, 0) |
| White | 90/100 (90.0) | 91/117 (77.8) | 12.2 (2.7, 21.8) |
| Missing | 3/3 (100) | 3/3 (100) | 0 (0, 0) |
| Ethnicity | |||
| Hispanic or Latino | 14/15 (93.3) | 11/12 (91.7) | 1.7 (-18.4, 21.8) |
| Not Hispanic or Latino | 121/131 (92.4) | 125/150 (83.3) | 9.0 (1.5, 16.5) |
| Not reported | 3/5 (60.0) | 2/4 (50.0) | 10.0 (-55.2, 75.2) |
Source: Adapted from FDA Review
Abbreviations: CI confidence interval; N number of patients in treatment arm; n number of patients meeting criteria; Ns total number of patients for each specific subgroup and were assigned to that specific arm
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as and is given the same way as an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.