Rezafungin

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.
  • dermatophytes

Rezafungin is being studied to address unmet needs in:

Current treatment alternatives for systemic fungal disease, 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 a single-agent for prophylaxis of several fungal pathogens – Candida, Aspergillus and Pneumocystis, displacing azoles and trimethoprim/sulfamethoxazole (TMP/SMX)
  • 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) Fast Track Product and orphan drug for 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.

Pipeline

  IND-Enabling
Phase 1
Phase 2
Phase 3

Candidemia and Invasive Candidiasis

Phase 3 Initiated

82%

Candida, PCP and Aspergillus in alloBMT

78%

Opportunity: Invasive Fungal Disease

Invasive fungal disease (IFD) is a serious threat to millions of patients around the globe, resulting in more than 1.5 million deaths annually. IFD continues to be a global health issue, especially for critically ill patients in hospitals and patients with compromised immune systems.

Approximately 90% of IFD-related deaths are caused by 4 genera of fungi: CandidaAspergillusCryptococcus, and PneumocystisCandida 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 IFD. 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 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.

Estimated U.S. Deaths in Patients with Hospital Treated Fungal Infections

Incidence & Mortality

Disease (most common species)
Location
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
PCP (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

Phase 3 Planned

The clinical development program for rezafungin includes two phase 3 trials: one ongoing trial for treatment and a second planned trial for prophylaxis of invasive fungal disease. The development program includes the study of rezafungin broadly across distinct and large patient populations where there is an urgent need for innovation.

The treatment trial is designed to evaluate rezafungin for difficult-to-treat invasive Candida infections. 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 improved safety profile.

  • Phase 3 ReSTORE (Treatment) Trial: An ongoing single global, randomized, double-blind, controlled Phase 3 pivotal clinical trial to evaluate the safety, efficacy and tolerability of rezafungin compared to caspofungin for the treatment of candidemia/invasive candidiasis in approximately 184 mITT patients. The trial design is similar to the Phase 2 STRIVE trial below. The primary efficacy outcome measure for the FDA is All-Cause Mortality at Day 30, while Global Cure at Day 14 is the primary efficacy outcome measure for the EMA.
  • Phase 3 ReSPECT Prophylaxis (Prevention) Trial: A planned single, global, randomized, double-blind, controlled Phase 3 pivotal clinical trial of rezafungin compared to standard antimicrobial regimen (SAR) in patients undergoing blood or marrow transplant (BMT) to prevent infections due to CandidaAspergillus and Pneumocystis. Rezafungin will be dosed once weekly and compared to a regimen containing two drugs (an azole + TMP/SMX ) dosed once daily, for 90 days, at which time fungal-free survival (FFS) will be measured (the primary efficacy outcome measure). The primary efficacy outcome is the same for both the FDA and the EMA. The trial will include adults with underlying conditions such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome(s), lymphoma and aplastic anemia.

Phase 2

STRIVE is 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.

Efficacy measures in the trial included clearance of Candida from the blood or other normally sterile sites, resolution of systemic signs attributed to the Candida infection, investigator assessment of clinical response and overall survival.

STRIVE was comprised of two parts, Part A and Part B.

STRIVE Part A, enrolled 92 patients in the microbiological intent-to-treat, or mITT, population, and these patients were randomized in a 1:1:1 fashion into one of two rezafungin arms or the comparator arm, in which patients received caspofungin with an optional step down to oral fluconazole. 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.

The study met all of its primary objectives, as once-weekly intravenous dosing of rezafungin appeared to be generally safe and well tolerated in patients with candidemia and/or invasive candidiasis. The data also showed evidence of the efficacy of rezafungin, as defined in the trial.

STRIVE Part B, enrolled an additional 91 patients in the microbiological intent-to-treat, or mITT, population. Patients were randomized to receive either 400 mg of rezafungin administered intravenously once weekly or daily caspofungin administered intravenously according to the approved prescribing information, with an optional step down to oral fluconazole. To align with the chosen dosing regimen in the Phase 3 program, STRIVE B was amended midway to use rezafungin 400 mg for the first week followed by 200 mg once weekly for up to four weeks in total.

The topline results from STRIVE Part B show that patients treated with rezafungin had numerically improved outcomes compared to caspofungin across all efficacy measures at the 400 mg/200 mg dosing regimen, which is the dosing regimen chosen for the ongoing Phase 3 ReSTORE trial. An analysis combining data across STRIVE Parts A and B also demonstrates that rezafungin achieves meaningful improvement in outcomes compared to caspofungin across all efficacy endpoints at the same 400 mg/200 mg dose. The STRIVE trial was not powered to show statistically significant differences or non-inferiority between treatment arms.

The topline results indicate that rezafungin was generally safe and well-tolerated at both dosing regimens. There were no unexpected or concerning adverse event trends among STRIVE B trial participants.

Phase 1

A single ascending dose trial (SAD) and a multiple ascending dose (MAD) trial were completed. 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 studies recently completed include:

  • QT Study: A Phase 1, single-center, randomized, double-blind, comparative study evaluated the effects of rezafungin on the QTcF (corrected using Fridericia’s formula) interval, heart rate, and other cardiac parameters. The study included three dose groups, IV rezafungin (600 mg or 1400 mg), IV placebo, and oral moxifloxacin (positive control). Results of this study demonstrate that rezafungin, in single IV doses up to 1400 mg, does not prolong the QT interval. There was no effect of either rezafungin dose on repolarization or QRS duration (Flanagan S et al, Poster presentation, ID WEEK 2018).
  • Drug-Drug Interaction Study: Clinical in vivo evaluations of rezafungin drug interaction potential were performed proactively. Results indicate that clinically significant drug interactions with rezafungin are not expected (Flanagan S et al, Poster presentation, EBMT 2018).

Continued evaluation of the safety of rezafungin is ongoing.

Expanded Access Policy

Cidara is a clinical-stage biotechnology company focused on the discovery, development and commercialization of novel anti-infectives for the treatment or prevention of diseases that are inadequately addressed by current standard of care therapies. We conduct clinical trials to assess the safety and efficacy of our investigational new drugs. The establishment of the safety and efficacy of our investigational new drugs helps us obtain approvals from regulatory agencies such as the FDA. Regulatory approvals are required before these investigational new drugs can be made generally available to patients. We encourage awareness of our clinical trials and believe that participating in clinical trials is an appropriate way for patients to access investigational new drugs prior to regulatory approval.

At this time, we do not have an expanded access program that allows patients to have access to our investigational new drugs prior to FDA approval. Individuals interested in clinical trials sponsored by Cidara may visit www.clinicaltrials.gov for information on our ongoing clinical trials.

Cidara may revise this expanded access policy at any time. Additionally, the posting of this policy by Cidara shall not serve as a guarantee of access to any specific investigational new drug by any individual patient.

We will update this page as we grow and reassess our approach to expanded access programs. If you have any questions, please contact clinicaltrialinfo@cidara.com.

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