Rezafungin (CD101 IV) Overview
Rezafungin is a novel molecule in the echinocandin class of antifungals, considered to be the safest class of antifungals. It is a broad spectrum, long-lasting echinocandin with demonstrated potent in vivo activity against representative strains of:
- Candida spp.
- Aspergillus spp.
- Pneumocystis spp.
- Trichophyton mentagrophytes
- Trichophyton rubrum
- Microsporum gypseum
Rezafungin is being studied to address unmet needs in:
Current treatment alternatives for systemic fungal infections, including polyenes, azoles, and currently-approved echinocandins, have significant limitations. Toxicities, drug-drug interactions, low or variable exposure, daily intravenous administration and increasing resistance, are all issues which complicate therapy today in patients who are already inherently complex and very ill. Rezafungin offers a potential new solution for patients and clinicians to solve for these significant limitations.
Rezafungin has a prolonged half-life and front-loaded plasma exposure which, in contrast to all other echinocandins, allows for once-weekly IV therapy. This pharmacokinetic profile may overcome limitations of the current standard of care. Rezafungin has potential to:
Rezafungin: First Echinocandin with Significant Potential to Penetrate Azole and Bactrim Markets
- be the only single-agent prophylaxis across several fungal pathogens – Candida, Aspergillus and Pneumocystis, displacing azoles and Bactrim
- be the only echinocandin to facilitate shorter and less costly hospital stays
- be the only echinocandin to provide more cost effective and compliant outpatient echinocandin treatment and prophylaxis
- treat less susceptible pathogens by achieving high human exposures
The U.S. Food and Drug Administration (FDA) has designated rezafungin as a Qualified Infectious Disease Product (QIDP) with Fast Track status and orphan drug designation. The designations are for the use of rezafungin in the treatment of candidemia and invasive candidiasis. The seven-year period of marketing exclusivity provided through orphan designation combined with an additional five years of marketing exclusivity provided by the QIDP designation positions rezafungin for a total of 12 years of potential marketing exclusivity to be granted at the time of FDA approval. We intend to seek QIDP, fast track and orphan drug designations for rezafungin for prophylaxis.
Candidemia and Invasive Candidiasis
Phase 3 Initiated
Candida, PCP and Aspergillus in alloBMT
Phase 3 Planned Start 1H 2019
Phase 1 Planned Start 1H 2019
Plans and timelines for clinical studies are subject to successful outcome of ongoing discussions with regulatory authorities.
Opportunity: Invasive Fungal Infections
Invasive fungal infections (IFIs) are a serious threat to millions of patients around the globe, resulting in more than 1.5 million deaths annually. These infections continue to be a global health issue, especially for critically ill patients in hospitals and patients with compromised immune systems.
Of the most significant IFIs, approximately 90% of related deaths are caused by 4 types of fungi: Candida, Aspergillus, Cryptococcus, and Pneumocystis. Candida species are most common in hospital-acquired infections, while Aspergillus species are predominant in immunocompromised patients. Cryptococcus and Pneumocystis contribute to the significant morbidity and mortality associated with IFI. While the incidence of life threatening Mucormycosis is low, the mortality rates associated with this disease ranges from 30-90%.
We estimate that the annual worldwide sales of prescription systemic antifungals are approximately $4.2 billion. This includes therapies used as prophylaxis (preventive) in the inpatient and outpatient setting, and therapies used for the treatment of suspected or documented infections in hospitalized patients and patients who have been discharged from the hospital and need continued outpatient antifungal treatment.
Incidence & Mortality
Disease (most common species)
Estimated life-threatening infections/year at that location*
Mortality rates (% in infected populations)*
|Opportunistic invasive mycoses|
|Aspergillosis (Aspergillus fumigatus)||Worldwide||>200,000||30–95|
|Candidiasis (Candida albicans)||Worldwide||>400,000||46–75|
|Cryptococcosis (Cryptococcus neoformans)||Worldwide||>1,000,000||20–70|
|Mucormycosis (Rhizopus oryzae)||Worldwide||>10,000||30–90|
|Pneumocystis (Pneumocystis jirovecii)||Worldwide||>400,000||20–80|
|Endemic dimorphic mycoses*†|
|Blastomycosis (Blastomyces dermatitidis)||Midwestern and Atlantic United States||~3,000||<2–68|
|Coccidioidomycosis (Coccidioides immitis)||Southwestern United States||~25,000||<1–70|
|Histoplasmosis (Histoplasma capsulatum)||Midwestern United States||~25,000||28–50|
|Paracoccidioidomycosis (Paracoccidioides brasiliensis)||Brazil||~4,000||5–27|
|Penicilliosis (Penicillium marneffei)||Southeast Asia||>8,000||2–75|
*Estimates based on available data.
†Endemic dimorphic mycoses can occur at many locations throughout the world. However, data for most of those locations are severely limited. These are estimates of infections per year and mortality at a specific location, where the most data are available.
From Brown et al. Sci Transl Med.2012;4:165:165v13. Reprinted with permission from AAAS.
Clinical Program for Rezafungin
The Phase 3 program will allow Cidara to study rezafungin broadly across distinct and large patient populations where there is an urgent need for innovation.
The prophylaxis trial has the potential to shift the fungal prevention paradigm in vulnerable transplant and cancer patients from more toxic and complicated regimens to a simple one-drug regimen with a potentially superior safety profile. The treatment trial is designed to evaluate rezafungin for tough-to-treat invasive Candida infections and enable hospital discharge on an echinocandin with once-weekly dosing.
- Phase 3 ReSTORE (Treatment) Trial: A single, global, randomized, double-blind, controlled Phase 3 pivotal clinical trial in patients with candidemia and/or invasive candidiasis. The design is similar to the STRIVE trial, except that the only rezafungin dosing regimen that will be studied is 400 mg for the first week followed by 200 mg once weekly for up to four weeks in total, in comparison to caspofungin in a 1:1 randomization regime. The primary efficacy outcome for the FDA is all-cause mortality at day 30, and the primary efficacy outcome for the EMA is global response (clinical, radiological, and mycological response) at day 14. We expect this trial to enroll approximately 184 mITT patients. This trial began in the third quarter of 2018.
- Phase 3 ReSPECT Prophylaxis (Prevention) Trial: A single, global, randomized, double-blind, controlled Phase 3 pivotal clinical trial in patients undergoing allogeneic blood and marrow transplant to assess rezafungin in a 90-day prophylaxis regimen to prevent infections due to Candida, Aspergillus and Pneumocystis. Rezafungin will be dosed once weekly and compared to a regimen containing two drugs (an azole and Bactrim) dosed once daily for 90 days. The primary efficacy outcome for the FDA is expected to be fungal-free survival at day 90. The primary efficacy outcome for the EMA is expected to be prophylaxis success at day 90. We expect this trial to enroll approximately 462 patients. Assuming the successful outcome of ongoing discussions with regulatory authorities, we anticipate commencing the trial with the above design in the first half of 2019.
Phase 2: STRIVE
We have completed STRIVE, our Phase 2 global trial of rezafungin in the treatment of candidemia and invasive candidiasis. STRIVE met all of its primary objectives, as once-weekly intravenous dosing of rezafungin was observed to be generally well tolerated and safe in patients with candidemia and/or invasive candidiasis. The data also showed evidence of the efficacy of rezafungin, which was defined in the trial by clearance of Candida from the blood or other normally sterile sites, resolution of signs related to the infection, investigator assessment of clinical response and overall survival.
STRIVE was an international, multicenter, double-blind trial evaluating the safety, tolerability and efficacy of once-weekly dosing of rezafungin acetate compared to once-daily dosing of caspofungin in patients with candidemia and/or invasive candidiasis. The trial enrolled 92 patients in the microbiological intent-to-treat, or mITT, population, and these patients were randomized to one of two rezafungin arms or the comparator arm, in which patients received caspofungin. In the two rezafungin arms of the trial, patients received either 400 mg of rezafungin administered intravenously once weekly for two to four weeks (Group 1), or 400 mg for the first week followed by 200 mg once weekly for up to four weeks in total (Group 2). In the comparator arm (Group 3), patients received daily caspofungin administered intravenously according to the approved prescribing information, with an optional step down to oral fluconazole.
STRIVE Part B: With the expected size of the ReSTORE Phase 3 trial, we estimate that the total number of patients exposed to our selected dose and duration of rezafungin treatment will be less than the target safety database of 300 patients. For this reason, as well as to maintain enrollment momentum at each site prior to switching to participation in the Phase 3 trial, we are continuing enrollment at several STRIVE Phase 2 trial sites. Topline data from this continued enrollment of the STRIVE trial, which we call STRIVE Part B, is expected in mid-2019.
We have completed two Phase 1 clinical trials for rezafungin: a single ascending dose trial (SAD) and a multiple ascending dose (MAD) trial. These studies established the safety and PK profile of rezafungin in healthy subjects, demonstrating that up to 400 mg once weekly for 3 consecutive weeks was safe and well tolerated.
Key results of rezafungin multiple ascending dose trial include:
- Safely achieved very high front-loaded plasma exposures potentially improving treatment outcomes
- Long half-life enables weekly dosing
- Well tolerated across entire dose range
- No serious or severe adverse events
- No clinical chemistry, hematology or ECG safety concerns
These data supported the continued development of rezafungin. Additional Phase 1 trials are planned or underway.
We also plan to conduct a trial with the NIH to evaluate safety, tolerability, and pharmacokinetics for a subcutaneous formulation of rezafungin. We expect to commence this trial in the first half of 2019.