AUTHORS
Johan A. Maertens, MD, Drew Winston, MD2, Shariq Haider, MD3, Javier López Jimenez, MD, PhD4, Matthias Breugelmans, Pharm D, PhD5, Hosnieh Fathi, MD, FFPM6, Yuri Martina, MD, PhD7, Federica SORA, MD, PhD, MBBS8
AFFILIATIONS
1 University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium
2 UCLA Medical Center, University of California, Los Angeles, United States
3 Juravinski Hospital and Cancer Center, McMaster University, Hamilton, Ontario, Canada
4 Hospital Universitario Ramon y Cajal, IRYCIS, University of Alcalá Henares, Madrid, Spain
5 Mundipharma Research Ltd, Cambridge, United Kingdom
6 Mundipharma Research Ltd, Cambridge, United Kingdom
7 Mundipharma Research Ltd, Cambridge, United Kingdom
8 University Cattolica del Sacro Cuore and Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
ABSTRACT
Background
Antifungal prophylaxis is standard of care for allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients. Current regimens are limited by drug toxicities, drug–drug interactions (DDIs), antifungal resistance, and challenges of daily (QD) administration. Rezafungin, a next-generation echinocandin with a low propensity for DDIs and broad antifungal activity (including Candida spp., Aspergillus spp., some fungi with reduced susceptibility/resistance to standard antifungals, and Pneumocystis jirovecii [PJ]), is indicated to treat invasive candidiasis. The differentiated pharmacokinetic/pharmacodynamic profile of rezafungin enables high front-loaded dosing and once-weekly (QW) IV administration.
Aims
We describe key outcomes from ReSPECT, a Phase 3 study assessing single-agent rezafungin QW vs QD standard antimicrobial regimen (SAR) for preventing invasive fungal disease (IFD) after allo-HSCT (to Week 13).
Methods
This multicentre, randomized, double-blind, double-dummy study enrolled adults receiving allo-HSCT. Participants were randomized 2:1 to rezafungin or SAR, stratified by underlying disease, donor source, and initial SAR. Participants received rezafungin IV infusion QW (400 mg loading dose on Day 1, 200 mg on subsequent weeks) or SAR (oral fluconazole [FLZ] 400 mg QD or posaconazole [PCZ; Day 1 300 mg BID, then 300 mg QD] capsules plus trimethoprim/sulfamethoxazole [TMP/SMX] 80 mg/400 mg QD post engraftment). Rezafungin or azole was initiated after cell infusion for 13 weeks.
The primary objective was to demonstrate the non-inferiority of rezafungin vs SAR for fungal-free survival (FFS: survival with no proven or probable IFD [per modified 2020 EORTC-MSGERC criteria] and no non-study systemic antifungal therapy for >10 days [cumulative]) on Day 90 (±7 days) post HSCT. Non-inferiority was achieved with the 95% CI lower limit for the treatment difference (rezafungin minus SAR) > -12.5%. Secondary endpoints included treatment discontinuation due to toxicity/intolerance, cumulative incidence of IFD, time to IFD or death, all-cause mortality, and safety.
Results
Overall, 402 patients were randomized to rezafungin and 200 patients to SAR (FLZ n=172, PCZ n=25 [n=3 did not receive SAR]). A permanent switch from FLZ to PCZ was permitted for clinically significant acute graft vs host disease (GvHD, n=20).
Demographic, underlying disease, and allo-HSCT characteristics were balanced for the rezafungin vs SAR cohorts: mean age 55.0 vs 54.4 years, male 64.4% vs 58.5%, Sorror Score ≥3 31.3% vs 28.5%, acute myeloid leukemia 40.3% vs 40.0%, myelodysplastic syndrome 21.6% vs 19.0%, received peripheral blood stem cells 95.5% vs 94.5%, HLA mismatched (related or unrelated) or haploidentical donor 41.8% vs 33.5%; myeloablative conditioning regimen 47.8% vs 45.5%. Incidence of on-study Grade ≥2 GvHD was 22.1% and 27.0% for rezafungin and SAR.
Rezafungin was non-inferior to SAR for the primary endpoint of Day 90 FFS: 60.7% vs 59.0%, respectively (treatment difference 1.6% adjusted for randomization stratification factors [95% CI -6.2, 9.3], P=0.0002). Most Day 90 FFS failures were due to use of non-study systemic antifungal drugs for >10 days (rezafungin vs SAR: 27.4% vs 32.5%). Proportions of Day 90 FFS failures due to death (4.5% vs 5.5%) and IFD (3.5% vs 4.5%) were similar in the rezafungin vs SAR groups. Incidences of IFDs due to Candida spp. (1.2% vs 1.0%), Aspergillus spp. (2.0% vs 3.0%), and PJ (0.2% vs 0%) were also similar with rezafungin vs SAR. Time to IFD or death (Day 120) favoured rezafungin (adjusted HR 0.729 [95% CI 0.412, 1.291]).
Treatment-emergent adverse event (TEAE) incidence was similar across the cohorts (99.7% vs 100%). Rezafungin was associated with a lower incidence of acute kidney injury vs SAR (17.1% vs 25.9%) and no apparent hepatic toxicity. The rezafungin vs SAR cohort experienced fewer TEAEs leading to dose reduction, interruption, or withdrawal of study drug (31.0% vs 47.7%).
Conclusion
The ReSPECT study met its primary endpoint: rezafungin (IV, QW) was non-inferior to SAR (azole plus TMP/SMX, oral, QD) for IFD prophylaxis (per Day 90 FFS) in adults undergoing allo-HSCT. Additionally, rezafungin had a favourable safety profile consistent with its licensed indication for invasive candidiasis with no new safety signals identified in allo-HSCT recipients. These results support rezafungin as a simplified dosing regimen (IV, QW) for antifungal prophylaxis in adult allo-HSCT recipients.
DISCLOSURES
Shariq Haider, MD: AVIR Pharmaceuticals - Honoraria; Cidara Pharmaceuticals - Research Funding; AVIR Pharmaceuticals - Research Funding; Merck - Consultancy (Includes expert testimony)