Rezafungin (CD101) Prophylaxis

Prevention of Invasive Fungal Infections (IFI)

Challenges in timely identification and diagnosis of IFI pose a great barrier to successful outcomes. In one of the largest reports of autopsy data from more than 1,000 patients with hematological malignancies treated at MD Anderson Cancer Center, 31% of patients had invasive fungal disease at autopsy and the majority (75%) of these infections were undiagnosed prior to death.

Some important life-threatening consequences contributing to the morbidity and mortality caused by IFI are delay or interruption of treatment(s) for an underlying disease and prolonged hospitalization, increasing the risk of hospital-acquired infection and increased healthcare utilization. Patients who develop an IFI may also require additional interventions to address side effects of antifungal treatment and drug-drug interactions.

Evidence-based prevention strategies can provide an approach to minimizing or avoiding all of these complications. Key to determining the right antifungal strategy is understanding the various approaches within the treatment continuum. Reducing rates of IFI and improving morbidity and mortality may require a combination of prevention and treatment strategies with the current antifungal armamentarium.

Risk Factors for Invasive Fungal Infections

Invasive Candidiasis (IC) Invasive Aspergillosis (IA) Pneumocystis Carinii Pneumonia
Malignancy (hematologic or solid)
Neutropenia
Renal failure
Severe acute pancreatitis
Need for organ transplantation
Surgical procedures
Acute Myeloid Leukemia (AML)
neutropenia
lymphocytopenia
Needing a HSCT or solid organ transplantation
Allogeneic HSCT recipients
Autologous HSCT recipients
Non HSCT recipients
Acute Lymphoblastic leukemia
Chronic Lymphocytic Leukemia
Non Hodgkins Lymphoma
Multiple Myeloma
Pre-existing lung disease
COPD
Asthma
Invasive Candidiasis (IC) Invasive Aspergillosis (IA) Pneumocystis Carinii Pneumonia
Long hospitalization in the ICU
Hemodialysis
Mechanical ventilation
Central venous catheter
Total parenteral nutrition
GVHD
Mucositis
Respiratory viral infections
Mechanical ventilation
Bacterial infections
Diabetes
Renal impairment
Hepatic impairment
GVHD
Invasive Candidiasis (IC) Invasive Aspergillosis (IA) Pneumocystis Carinii Pneumonia
Prior use of broad spectrum antibiotics
Immunosuppressive therapies
Conditioning regimens
Corticosteroids
Chemotherapy agents
Corticosteroids
Monoclonal antibodies
Invasive Candidiasis (IC) Invasive Aspergillosis (IA) Pneumocystis Carinii Pneumonia
Construction work
Colonization/pre-exposure
Potted plants/gardens

Strategies for Prevention and Management of IFI

There is no “one size fits all” strategy to antifungal therapy or prophylaxis. Clinical decisions must consider patient-specific factors that may increase susceptibility to fungal infection (risk stratification) and effects of treatment(s) for the underlying disease. In patients with hematologic malignancies undergoing chemotherapy, this can be a particularly complex issue. Other important considerations are the local epidemiology of fungal infections in the country, region, and institution, and the efficacy and tolerability profiles of available antifungal agents.

Invasive aspergillosis and invasive candidiasis are predominant causes of morbidity and mortality in immunocompromised patients, including patients with hematological malignancies, solid tumors, as well as patients who have received a hematopoeitic stem cell transplant (HSCT) or solid organ transplant. Patients may receive prophylaxis for Candida and Aspergillus for several weeks to over a year depending on the period of immunosuppression.

Pneumonia caused by Pneumocystis jirovecii, also known as PCP (Pneumocystis carinii pneumonia, based on the pathogen’s previous name), is a growing concern in a broader population of people with compromised immune systems. This includes patients receiving immunosuppressive treatment, such as HSCT and solid organ transplantation, and/or therapies that suppress cellular immunity. Given the risk of PCP in these populations, anti-PCP prophylaxis is recommended for allogeneic HSCT recipients for up to 1 year after transplant, and some risk factors may warrant longer periods of prophylaxis. Additionally, the risk for PCP increases with commonly seen complications, such as severe graft-versus-host disease (GVHD).

On the continuum of antifungal strategies, prophylaxis is an early defense to minimize or altogether avoid the need for treatment and the related complications of IFIs.

International guidelines across hematology, infectious disease and solid organ transplant recommend antifungal prophylaxis for patients at high risk for IFI, as attributable mortality is high with established infection.

Current Antifungal Prophylaxis Options and Limitations

Antifungal prophylaxis has been shown to be efficacious as well as cost-effective in many situations. However, despite advances in identifying the right strategy and the availability of antifungal agents, there is a significant unmet need in prevention of IFIs.

Azoles have been the most widely used antifungal class for primary antifungal prophylaxis against Candida and Aspergillus based on high-quality evidence from randomized clinical trials, as well as published real-world evidence. Although they are the current standard of care for prophylaxis against these infections, they are associated with serious limitations, such as hepatotoxicity, gastrointestinal intolerance, drug-drug interactions, varying drug levels that might require therapeutic drug monitoring, and development of resistance.

For prevention of PCP, trimethoprim/sulfamethoxazole (TMP/SMX) is the agent of choice for first-line prophylaxis. Challenges with TMP/SMX include bone marrow suppression, allergies, and nephrotoxicity.

Current prophylaxis requires multiple drugs for coverage of common pathogens. The complex nature of the immunocompromised patient and the complexity of the current antifungal drugs used today for prophylaxis (azoles and TMP/SMX), create significant opportunity for improvement.

Current Prophylaxis in Patients Undergoing Bone Marrow Transplantation Requires Multiple Drugs for Coverage

The Echinocandin Class of Antifungals

Echinocandins were initially discovered as agents to treat PCP in HIV-positive patients, but with the relative successes of HAART and TMP/SMX, echinocandins became more widely used in the prevention and treatment of infections caused by Candida and Aspergillus.

Many patients requiring antifungal prophylaxis receive therapy on both an inpatient and outpatient basis. Currently available echinocandins (anidulafungin, caspofungin and micafungin) are administered intravenously, once-daily. Daily IV administration is impractical on an outpatient basis, limiting the current agents. Only one echinocandin is indicated for prophylaxis (micafungin), however it is limited to short term prophylaxis for Candida only.

Despite these limitations however, the spectrum and safety profile of the echinocandin class makes them attractive agents in highly vulnerable patients. Echinocandins may also play a larger role in PCP prevention given other challenges with TMP/SMX.

Rezafungin: a Novel Echinocandin for the Prevention of IFI

Rezafungin is a novel, broad-spectrum, once-weekly echinocandin with excellent activity against both wild-type and azole- and echinocandin-resistant strains of Candida, as well as Aspergillus and Pneumocystis, and is currently in mid-late stage clinical trials.

No one agent is approved today to prevent Candida, Aspergillus and PCP. The unique spectrum of rezafungin, along with a long half-life, favorable drug-drug interaction and tolerability profiles, with no signals of myelosuppression or hepatotoxicity, make rezafungin an attractive candidate to potentially address the significant unmet needs in prevention of IFI in immunocompromised patients, particularly those with hematologic malignancies and/or those undergoing a bone marrow or solid organ transplant.

We intend to start an international Phase 3 registration trial for rezafungin for the prophylaxis of Candida, Aspergillus and Pneumocyctis in patients undergoing allogeneic BMT in early 2019.

Key Attributes and Data

Structural modification yields improved chemical and biological properties

Rezafungin has demonstrated potent in vivo activity against representative strains of important fungi, including Candida spp., Aspergillus spp., Pneumocystis spp., Trichophyton mentagrophytes, Trichophyton rubrum, and Microsporum gypseum.

  • Prolongs PK: once weekly dosing in clinical studies
  • Allows high exposures: improved efficacy
  • Eliminates toxic degradation products: improved safety
  • Enables multiple formulations: intravenous and subcutaneous

Comparative potency in vitro, against representative strains of Candida spp., Aspergillus spp.

The efficacy of rezafungin for prophylaxis has been established compared with standards of care in animal models.

* CLSI methodology was employed for MIC/MEC determination, MECs vs Aspergillus were determined for CD101, anidulafungin and caspofungin. Combined JMI and Micromyx US and international surveillance studies, ICAAC 2014 & 2015

Excellent efficacy compared with standards of care in animal models

Aspergillus prophylaxis with rezafungin was 100% successful at humanized doses.

A. fumigatus Prophylaxis in Immunocompromised Mice
Study Design
  • 6 mice per arm
  • Controls: Amphotericin B  control 3 mg/kg; CD101 at 3 mg/kg; one hour after infection
  • 9 CD101 groups at 5, 10 and 20 mg/kg as prophylaxis was once at Day -5, -3 or -1 before infection
  • All animals immunosuppressed
  • Day 0, infected with A. fumigatus

Rezafungin shows equivalent efficacy to TMP/SMX in PCP prophylaxis mouse model.

CD101 Nuclei Counts

Republished with permission of ASH from Efficacy of CD101, a Novel Echinocandin, in Prevention of Pneumocystis Pneumonia (PCP): Thwarting the Biphasic Life Cycle of Pneumocystis, M. Cushion et al, 2016;128:3396; permission conveyed through Copyright Clearance Center, Inc.

Study Design
  • 10 mice per arm
  • Infected with P. murina by intranasal inoculation
  • Immunosuppression with dexamethasone throughout study
  • CD101 was administered at the same time the mice were infected
  • Quantification of PCP from lung

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