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637. Outcomes by Body Mass Index (BMI) in the STRIVE Phase 2 Trial of Once-Weekly Rezafungin for Treatment of Candidemia and Invasive Candidiasis Compared with Caspofungin

ABSTRACT: Abstract

Background

There is increasing evidence of antifungal underdosing in the treatment of invasive disease, particularly in special populations such as the obese. Body size is often an important variable affecting drug exposure, and pharmacokinetic (PK) models of antifungal dosing have suggested size-based dose adjustments to achieve target drug exposure. Rezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. Distinctive PK properties of RZF (e.g., long half-life, extensive tissue distribution, and front-loaded drug exposure) lend themselves to RZF once-weekly (QWk) dosing and antifungal efficacy. In this sub-analysis of the Phase 2 STRIVE trial of RZF in the treatment of candidemia and/or IC, outcomes based on patient BMI were evaluated.

Methods

The STRIVE trial (NCT02734862) compared the safety and efficacy of RZF QWk compared with once-daily caspofungin (Fig. 1). For this subanalysis, data were stratified by BMI categories of < 30 kg/m2 and ? 30 kg/m2. Efficacy (overall response [resolution of clinical signs of infection + mycological eradication], mycological response, and investigator assessment of clinical response) and safety (treatment-emergent adverse events [TEAEs]) endpoints by treatment group were evaluated, as well as PK data (area under the curve [AUC]) from RZF-treated patients. Figure 1.

Results

Mean BMI values were similar across treatment arms (26.9 kg/m2 in RZF Group 1 and 26.8 kg/m2 in RZF Group 2 and CAS arms). Efficacy outcomes at Day 14 were similar between BMI categories (Table 1). Rates of TEAEs were generally similar between BMI categories as well (Table 2), with no concerning safety trends. Following one dose of RZF 400 mg (Week 1), the ranges of AUCs by BMI category overlapped and there was a minor mean difference of ~20% (lower for those with BMI ? 30 kg/m2) (Fig. 2). Table 1 Table 2 Figure 2.

Conclusion

The safety, efficacy, and PK of RZF in the Phase 2 STRIVE trial was consistent across BMI categories. These results suggest that dose adjustments in obese patients are not necessary. These findings contribute to the evaluation of RZF in a range of patient populations and its ongoing development.

Disclosures

Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder) Patrick M. Honore, MD, PhD, FCCM, Cidara Therapeutics, Inc. (Scientific Research Study Investigator)

SUBMITTER: Vazquez J

PROVIDER: S-EPMC7777904 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Rezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. This analysis of the completed Phase 2 STRIVE trial (NCT02734862) of RZF treatment was conducted to evaluate outcomes based on baseline pathogen and susceptibility. Methods In STRIVE, adults (≥ 18 y) with systemic signs and mycological evidence of candidemia and/or IC were randomized to either RZF once weekly or caspofungin (CAS) once daily for ≥ 14 days (Fig. 1). The primary efficacy endpoint was Overall Response (resolution of clinical signs of infection + mycological eradication) at Day 14. For this analysis, outcomes by treatment group were stratified by Candida species and by its in vitro susceptibility (CLSI broth microdilution MIC values; M27-Ed4). Figure 1. Treatment Groups of the Phase 2 STRIVE Trial Results A total of 196 Candida isolates were recovered from 183 patients across all treatment groups (Fig. 2). C. albicans was the most common species, followed by C. glabrata, C. parapsilosis, and C. tropicalis; non-albicans Candida comprised 54% of all baseline isolates (Fig. 2). Among all clinical isolates, MIC distributions and ranges for RZF were generally lower than or comparable to those for CAS (Table 1). The rate of Overall Response (as defined above) against C. parapsilosis was lower for CAS than for RZF (Table 2). Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either RZF or CAS (Table 1). Figure 2. Candida Species Distribution and MIC ranges in the Phase 2 STRIVE Trial (mITT) Table 1. Overall Response Rates (%) for Most Frequently Isolated Candida Species at Baseline by Treatment Group and MIC Values (mITT) Table 2. Overall Response Rates (%) for Most Frequently Isolated Candida Species at Baseline by Treatment Group (mITT) Conclusion This analysis demonstrated RZF efficacy across multiple Candida species. RZF outcomes were similar to or better than those for CAS regardless of species identified. There was no clear correlation between increased MICs and clinical outcomes although, based on MICs, all isolates exhibited a wild-type in vitro susceptibility profile. These findings from STRIVE, together with future analyses from the ongoing Phase 3 trial of RZF treatment of candidemia and IC (ReSTORE; NCT03667690), will further our understanding of the relationships between MIC values and clinical outcomes in patients with candidemia or IC. Disclosures Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Rolando Viani, MD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Mahmoud Ghannoum, PhD, Amplyx (Grant/Research Support)Cidara (Grant/Research Support)Scynexis (Consultant, Grant/Research Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

Project description:During the past decade, the incidence of Candida infections in hospitalized patients has increased, with fluconazole being the most commonly prescribed systemic antifungal agent for these infections. However, the 2009 Infectious Diseases Society of America (IDSA) candidiasis guidelines recommend an echinocandin for the treatment of candidemia/invasive candidiasis in patients who are considered to be "moderately severe or severely" ill. To validate these guidelines, clinical trial data were reviewed.A secondary analysis of data from a previously published prospective, randomized, double-blind clinical trial was performed; it compared anidulafungin with fluconazole for the treatment of invasive candidiasis and candidemia. Patients with critical illness were identified at study entry by using the following criteria: Acute Physiology and Chronic Health Evaluation (APACHE) II score of ? 15, evidence of severe sepsis (sepsis and one or more end-organ dysfunctions) present, and/or patient was in intensive care. Global response rates were compared at the end of intravenous study treatment (the primary end point of the original study) and all-cause mortality at 14 and 28 days from study entry in this group.The patients (163 (66.5%) of 245) fulfilled at least one criterion for critical illness (anidulafungin, n = 89; fluconazole, n = 74). No significant differences were found in baseline characteristics between the two treatment groups. The global response rate was 70.8% for anidulafungin and 54.1% for fluconazole (P = 0.03; 95% confidence interval (CI): 2.0 to 31.5); all-cause mortality was 10.1% versus 20.3% at 14 days (P = 0.08; 95% CI, -0.9 to 21.3) and was 20.2% versus 24.3% at 28 days (P = 0.57; 95% CI, -8.8 to 17.0) for anidulafungin and fluconazole, respectively.In this post hoc analysis, anidulafungin was more effective than fluconazole for treatment of severely ill patients with candidemia, thus supporting the 2009 IDSA guidelines.Clinicaltrials.gov NCT00058682.

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