What is the clinical data for rezafungin? How does rezafungin compare to other antifungals?

Comment by InpharmD Researcher

Rezafungin is a recent FDA-approved (March 2023) antifungal agent characterized by a longer half-life and greater stability compared to first-generation echinocandins, making it suitable for weekly intravenous injections. The current available clinical trials suggest a similar efficacy and safety profile to caspofungin for the treatment of candidemia and invasive candidiasis, but patients with more complex infections were excluded in the landmark study (ReSTORE).

Background

A 2020 single-author review of rezafungin, which was not yet FDA-approved at the time of the study’s publication, summarizes the properties and potential uses of the novel antifungal agent. First-generation antifungal agents commonly used in current clinical practice (anidulafungin, caspofungin, and micafungin) are characterized by poor oral absorption and a half-life of 14 hours in mouse models, requiring daily intravenous administration. The drugs are also prone to thermal and hydrolytic degradation which micafungin also degrades in light. Rezafungin attempts to improve upon stability and solubility with studies suggesting retained activity when stored at high temperature (37-40°C), in saline and dextrose 5% solution, and exposed to light and acidic conditions. Rezafungin also exhibits a half-life of > 130 hours and is currently marketed as a once-weekly intravenous injection. New formulations such as topical and subcutaneous may also be considered. In vitro activity for growth inhibition is similar to older echinocandins based on the Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC50) and half enzyme maximal inhibitory concentration of 50% (IC50). Rezafungin shares a similar spectrum of activity while clinical trials suggest a similar efficacy and safety profile to caspofungin (see Tables 1-3). Like the other echinocandins, rezafungin remains ineffective against Fusarium spp., Scedosporium spp., Lomentospora prolificans, Mucorales, Histoplasma capsulatum, and Basydiomycetes and resistance will remain a concern. Therefore, the spectrum for use is narrow but effective against Aspergillus spp. [1, 2]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Please summarize literature and guidelines surrounding rezafungin. Please compare to comparable products/antifungals.

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-3 for your response.

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial
Design	Multicenter, double-blind, double-dummy, randomized phase 3 trial N= 199
Objective	To compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis
Study Groups	Rezafungin (n= 100) Caspofungin (n= 99)
Inclusion Criteria	Age 18 years or older, systemic signs of infection attributable to candidemia or invasive candidiasis, mycological evidence of candidemia or invasive candidiasis from blood or normally sterile site 96 hours before randomization, had blood cultures drawn 12 hours before randomization
Exclusion Criteria	Septic arthritis in a prosthetic joint, osteomyelitis, endocarditis, or myocarditis, meningitis, chorioretinitis, any CNS infection, chronic disseminated candidiasis, or urinary tract candidiasis; > 48 hours of previous antifungal therapy; alanine aminotransferase or aspartate aminotransferase concentrations more than ten times the upper limit of normal, or severe hepatic impairment with a history of chronic cirrhosis (Child-Pugh score >9); indwelling catheter or device that could not be removed
Methods	Patients were randomized (1:1) to receive intravenous (IV) rezafungin once weekly (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or IV caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary analysis consisted of the modified intention-to-treat (mITT) of patients that excluded patients with no documentation of Candida infection.
Duration	4 weeks of treatment
Outcome Measures	Primary: global cure (clinical cure, radiological cure, and mycological eradication) at day 14, 30-day all-cause mortality
Baseline Characteristics		Rezafungin (n= 100)	Caspofungin (n= 99)
	Age, years	59.5	62.0
	Female	33	43
	Race Asian Black or African American White Other or not reported	27 5 61 7	31 4 60 4
	Diagnosis Candidemia only Invasive candidiasis	70 30	68 31
	Mean modified APACHE II score ≥ 20 < 20	15 84	18 81
	Absolute neutrophil count < 500 cells per μL	9	6
Results	Endpoint	Rezafungin (n= 93)	Caspofungin (n= 94)	Treatment difference (95% confidence interval [CI])
	Global cure at day 14 Cure Failure Indeterminate	55 (59%) 28 (30%) 10 (11%)	57 (61%) 29 (31%) 8 (9%)	-1.1 (-14.9 to 12.7) -- --
	All-cause mortality Died Death in candidemia patients only Death due to invasive candidiasis	22 (24%) 18/64 (28%) 4/29 (14%)	20 (21%) 17/67 (25%) 3/27 (11%)	2.4 (-9.7 to 14.4) 2.8 (-12.5 to 18.0) 2.7 (-16.7 to 21.7)
Adverse Events	89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events.
Study Author Conclusions	Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development.
InpharmD Researcher Critique	The study excluded pediatric patients and those with certain forms of candidiasis that require long courses of antifungal treatment or occur at sites where echinocandin penetration is poor, which limits the generalizability of the results.

References:

Thompson GR 3rd, Soriano A, Cornely OA, et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet. 2023;401(10370):49-59. doi:10.1016/S0140-6736(22)02324-8

Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial
Design	phase 2, randomized, double-blind, double-dummy, multicenter trial N= 183
Objective	To compare the safety and efficacy of rezafungin once weekly to caspofungin once daily for treatment of candidemia and/or invasive candidiasis (IC)
Study Groups	Rezafungin 400 mg (n= 81) Rezafungin 400/200 mg (n= 57) Caspofungin 70/50 mg (n= 69)
Inclusion Criteria	Age 18 years or older, systemic signs of infection, and mycological evidence of candidemia and/or IC from a sample within 96 hours of randomization
Exclusion Criteria	Certain IC (septic arthritis in a prosthetic joint, osteomyelitis, endocarditis, or myocarditis), Candida eye infection or central nervous system infection, neutropenia, alanine aminotransferase or aspartate aminotransferase levels > 10x upper limit of normal, severe hepatic impairment with history of chronic cirrhosis, > 48 hours of prior systemic antifungal therapy
Methods	Patients were randomized (1:1:1) to receive rezafungin 400 mg once weekly (400 mg), rezafungin 400 mg on week 1 then 200 mg once weekly (400/200 mg), or caspofungin 70 mg as a loading dose followed by 50 mg daily for ≤ 4 weeks
Duration	30-day follow-up
Outcome Measures	Primary: overall cure at day 14 Secondary: investigator-assessed clinical response at day 14, 30-day all-cause mortality
Baseline Characteristics		Rezafungin 400 mg (n= 81)	Rezafungin 400/200 mg (n= 57)	Caspofungin 70/50 mg (n= 69)
	Age, years	59	60	59
	Male	54.3%	63.2%	55.1%
	White	85.2%	77.2%	85.5%
	Candidemia Invasive candidiasis	76.5% 23.5%	80.7% 19.3%	81.2% 18.8%
	APACHE II score	13.4	14.1	14.0
Results	Endpoint	Rezafungin 400 mg (n= 81)	Rezafungin 400/200 mg (n= 57)	Caspofungin 70/50 mg (n= 69)
	Overall cure	46/76 (60.5%)	35/46 (76.1%)	41/61 (67.2%)
	Investigator-assessed clinical cure rate	53/76 (69.7%)	37/46 (80.4%)	43/61 (70.5%)
	30-day all-cause mortality	15.8%	4.4%	13.1%
Adverse Events	Treatment-emergent adverse events (TEAEs) occured in 87.7% in the rezafungin 400 mg group, 92.5% in the rezafungin 400/200 mg group, and 80.9% in the caspofungin group. Severe TEAEs were reported in 35.8%, 32.1%, and 38.2% of patients in each group, respectively. Serious TEAEs (SAEs) were reported in 43.2%, 52.8%, and 42.6% in each group, respectively. Study drug-related TEAEs were reported in 8.6% of patients in the rezafungin 400 mg group, 11.3% of patients in the rezafungin 400/200 mg group, and 13.2% of patients in the caspofungin group. The most common events were hypokalemia, diarrhea, and vomiting.
Study Author Conclusions	Rezafungin was safe and efficacious in the treatment of candidemia and/or IC.
InpharmD Researcher Critique	The study was not powered to draw conclusions about statistical significance which limits the findings to descriptive or exploratory information. Rezafungin appears to be as safe and effective, but cannot be concluded with this study alone.

References:

Thompson GR, Soriano A, Skoutelis A, et al. Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial [published correction appears in Clin Infect Dis. 2021 Aug 2;73(3):561-562]. Clin Infect Dis. 2021;73(11):e3647-e3655. doi:10.1093/cid/ciaa1380

CD101 Topical Compared With Oral Fluconazole for Acute Vulvovaginal Candidiasis: A Randomized Controlled Trial
Design	Phase 2, randomized, multicenter, open-label, sponsor-blinded, controlled trial N= 99
Objective	To study an ointment and a gel formulation of CD101 (rezafungin) in the treatment of moderate-to-severe vulvovaginal candidiasis (VVC), with the goal of assessing both efficacy and safety
Study Groups	Rezafungin 3% gel (n= 40) Rezafungin 6% ointment (n= 40) Oral fluconazole 150 mg (n= 19)
Inclusion Criteria	Women 18 years or older, moderate-to-severe acute VVC with a severity score of more than 7 and positive microscopy for fungal elements
Exclusion Criteria	Received intravaginal or systemic antifungal therapy within 7 days of randomization, known or suspected infectious causes of vulvovaginitis other than candidiasis, history of genital herpes, a vaginal pH of greater than 4.5, in treatment or surgery during the study period for cervical intraepithelial neoplasia or cervical carcinoma, need for non-protocol systemic or vaginal antifungal therapy, a history of any hypersensitivity or allergic reaction to echinocandins, azoles, or their excipients, pregnant, breastfeeding, or intending to become pregnant during the study period
Methods	Participants were randomly assigned to one of three treatment groups. In the first group (cohort 1), participants applied a 4g dose of rezafungin vaginal gel with a concentration of 3% on both day 1 and day 2. In the second group (cohort 2), participants applied a 4g dose of rezafungin vaginal ointment with a concentration of 6% on day 1. The participants in the third group (cohort 3) received a single dose of oral fluconazole, specifically 150 mg, at the clinic on day 1. Participants in cohorts 1 and 2 were allowed to use rezafungin external gel with a concentration of 1% or rezafungin external ointment with a concentration of 1%, respectively, for relief of symptoms, as needed, for up to 72 hours. After randomization, subjects were seen on Day 7 (+/-2 days), Day 14 (+/- 2 days), & Day 28 (+/-7 days) to assess therapeutic cure and safety. Clinical cure was determined by the complete absence of all signs and symptoms, indicated by a score of 0. On the other hand, clinical failure was defined as the presence of any of the six signs and symptoms of VVC, with a score greater than 1. Mycological eradication was confirmed by a negative vaginal culture for Candida species at the specified assessment time point. The efficacy analyses were performed on the modified intent-to-treat population. Safety was assessed in all patients who received at least 1 dose of the study drug. Subjects were excluded from the modified intent-to-treat population analysis population when they did not receive the study drug, did not have a positive yeast culture, or had a vaginal or cervical co-infection.
Duration	Enrolment: June 2016 to November 2016 Follow-up assessments: 28 days
Outcome Measures	Clinical, mycological, and therapeutic cure by treatment day
Baseline Characteristics		Rezafungin 3% vaginal gel (n= 40)	Rezafungin 6% vaginal ointment (n= 40)	Oral fluconazole 150 mg (n= 19)
	Age, years	36 ± 11.4	33 ± 9.5	31 ± 8.9
	Premenopausal	72.5%	82.5%	78.9%
	Postmenopausal	12.5%	2.5%	0
	Race Black or African American White Other	37.5% 55.0% 7.5%	30.0% 67.5% 2.5%	26.3% 73.7% 0
	Recurrent candidiasis Yes (≥3 episodes) No (<3 episodes)	30.0% 70.0%	42.5% 57.5%	36.8% 63.2%
	Infection severity Moderate (score 7–12) Severe (score ≥ 13)	82.5% 17.5%	82.5% 17.5%	94.7% 5.3%
	Fungal pathogens Candida albicans Non-albicans Candida	90% 10.0%	90% 10%	89.5% 10.5%
Results	Endpoint	Rezafungin 3% vaginal gel (n= 40)	Rezafungin 6% vaginal ointment (n= 40)	Oral fluconazole 150 mg (n= 19)
	Day 7 (±2 d) Clinical Mycological Therapeutic	15 (37.5%) 22 (55.0%) 8 (20.0%)	16 (40.0%) 16 (40.0%) 8 (20.0%)	9 (47.4%) 13 (68.4%) 6 (31.6%)
	Day 14 (±2 d) Clinical Mycological Therapeutic	16 (40.0%) 15 (37.5%) 8 (20.0%)	16 (40.0%) 16 (40.0%) 8 (20.0%)	11 (57.9%) 9 (47.4%) 5 (26.3%)
	Day 28 (±7 d) Clinical Mycological Therapeutic	14 (35.0%) 18 (45.0%) 9 (22.5%)	12 (30.0%) 16 (40.0%) 6 (15.0%)	10 (52.6%) 11 (57.9%) 6 (31.6%)
Adverse Events	Common Adverse Events (n= 122): infections in all treatment groups, including bacterial vaginosis, nasopharyngitis, trichomoniasis, upper respiratory infection, and gastroenteritis. Nausea was also seen across all treatment groups with 2 (4.1%) of 49, 1 (2.1%) of 48, and 1 (4%) of 25 subjects experiencing this in the rezafungin 3%, rezafungin 6%, and fluconazole arms, respectively. Vaginal symptoms such as pain, dyspareunia, edema, or a burning sensation were most commonly seen in the rezafungin 6% ointment group.
Study Author Conclusions	CD101 3% gel and CD101 6% ointment were well tolerated and produced similar rates of clinical and mycological cure in patients with an acute,moderate-to-severe episode of VVC. However, cure rates for these 2 formulations and regimens of CD101 were lower than those in patients treated with fluconazole.
InpharmD Researcher Critique	One notable limitation of the current study was the small sample size, which hampers the ability to draw definitive conclusions regarding the effectiveness of rezafungin in treating the specified indication. In order to gain a clearer understanding of the potential benefits of topical rezafungin, future studies should consider exploring alternative formulations. This could involve investigating different vehicles that may enhance or extend vaginal exposure to the active medication. Additionally, longer treatment durations or even higher concentrations of rezafungin may be worth evaluating.

References:

Nyirjesy P, Alessio C, Jandourek A, Lee JD, Sandison T, Sobel JD. CD101 Topical Compared With Oral Fluconazole for Acute Vulvovaginal Candidiasis: A Randomized Controlled Trial. J Low Genit Tract Dis. 2019;23(3):226-229. doi:10.1097/LGT.0000000000000473