Olorofim vs AmBisome® for Aspergillosis

(OASIS Trial)

Recruiting at141 trial locations

Overseen by Johan MAERTENS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: F2G Biotech GmbH

Must be taking: Antifungals

Must not be taking: Echinocandins

Disqualifiers: Pregnancy, HIV without ART, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing a new antifungal drug called olorofim against an existing treatment, AmBisome®, in patients with tough fungal infections. These patients have limited options because their infections resist current treatments or they can't tolerate them. Olorofim works differently from other drugs, can be taken orally, and has fewer interactions with other medications. AmBisome is a liposomal formulation of amphotericin B, known for its broad-spectrum antifungal activity and reduced toxicity compared to conventional amphotericin B.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on a mould-active azole, you may need to switch to a different antifungal agent.

What data supports the effectiveness of the drug AmBisome for treating aspergillosis?

Research shows that AmBisome, a liposomal form of amphotericin B, is effective in increasing survival and reducing the spread of aspergillosis in animal models. It was found to be more effective than Fungizone in preventing the spread of infection in the lungs and other organs. ^{1 2 3 4 5}

Is AmBisome safe for human use?

AmBisome, a liposomal formulation of amphotericin B, is generally considered safe for human use, with a much improved safety profile compared to conventional amphotericin B. The main side effects are elevations in serum potassium and creatinine, but these rarely lead to treatment withdrawal. ^{1 2 4 6 7}

How does the drug Olorofim differ from AmBisome for treating aspergillosis?

AmBisome is a liposomal formulation of amphotericin B, which is known for its broad-spectrum antifungal activity and reduced toxicity compared to traditional formulations. It is particularly effective in reducing the spread of infection in aspergillosis. Olorofim, on the other hand, is a novel antifungal agent with a different mechanism of action, targeting a specific enzyme in the fungal cell, which may offer an alternative for patients who do not respond to or cannot tolerate existing treatments like AmBisome. ^{1 2 4 5 8}

Research Team

Johan MAERTENS

Principal Investigator

UZ Leuven

Eligibility Criteria

Adults over 18 years old, weighing more than 40 kg with proven or probable invasive aspergillosis (IA) who need non-azole antifungal therapy due to azole resistance, infection despite azole use, or potential drug interactions. Not for pregnant/breastfeeding women, those with chronic aspergillosis forms, other active fungal infections except certain candidiasis cases, hepatic dysfunction, known allergies to study drugs, suspected mucormycosis, echinocandin-treated Candida prophylaxis patients or untreated HIV.

Inclusion Criteria

I have been diagnosed with invasive aspergillosis.

I am over 18 years old and weigh more than 40 kg.

I need a different antifungal treatment because the usual one doesn't work for me.

Exclusion Criteria

You have had a serious allergic reaction or bad side effects from any part of the study drug.

My heart's electrical cycle is longer than normal or I'm at high risk for it.

I am HIV positive but not on antiretroviral therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either olorofim or AmBisome followed by standard of care for up to 84 days

12 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Follow-up visit at 4 weeks post-treatment

Treatment Details

Interventions

• AmBisome® (Liposomal Amphotericin B)
• Olorofim (Azole Antifungal)

Trial Overview The trial is testing the effectiveness of a new antifungal treatment called Olorofim compared to AmBisome® followed by standard care in patients with invasive Aspergillus infections. It aims to see if Olorofim can be a better option for those who cannot take mould-active azoles.

Participant Groups

Group I: Olorofim Active Control 1 Intervention

Olorofim versus AmBisome followed by Standard of Care (SOC)

Group II: AmBisome Active Control 1 Intervention

Olorofim versus AmBisome followed by Standard of Care (SOC)

AmBisome® is already approved in Canada, Japan for the following indications:

Approved in Canada as AmBisome for:

• Systemic or disseminated infections due to Candida, Aspergillus, or Cryptococcus in patients who are refractory to or intolerant of conventional amphotericin B therapy, or have renal impairment

Approved in Japan as AmBisome for:

• Systemic mycosis, respiratory mycosis, fungal meningitis, and disseminated visceral mycosis caused by Aspergillus species, Candida species or Cryptococcus species
• Visceral leishmaniasis

Who Is Running the Clinical Trial?

F2G Biotech GmbH

Lead Sponsor

Trials

21

Recruited

1,800+

Shionogi

Industry Sponsor

Trials

122

Recruited

42,100+

Dr. Isao Teshirogi

Shionogi

Chief Executive Officer since 2008

PhD in Pharmaceutical Sciences from the University of Tokyo

Dr. Takuko Sawada

Shionogi

Chief Medical Officer since 2022

MD from a recognized institution (specific details not found)

Iqvia Pty Ltd

Industry Sponsor

Trials

120

Recruited

177,000+

Ari Bousbib

Iqvia Pty Ltd

Chief Executive Officer since 2016

MBA from Columbia University, Master of Science in Mathematics and Mechanical Engineering from Ecole Superieure des Travaux Publics, Paris

Jeffrey Spaeder

Iqvia Pty Ltd

Chief Medical Officer

MD

Findings from Research

All formulations of amphotericin B tested, including Fungizone, AmBisome, Amphocil, and Abelcet, were effective in prolonging survival in mice with systemic aspergillosis, with AmBisome showing results nearly equivalent to Fungizone.

No lipid-based formulation consistently outperformed Fungizone, and while all treatments showed efficacy, none resulted in complete cures in both kidneys and brain, indicating a need for further research on optimal treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacies of four amphotericin B formulations--Fungizone, amphotec (Amphocil), AmBisome, and Abelcet--against systemic murine aspergillosis. Clemons, KV., Stevens, DA.[2021]

In a rat model of pulmonary aspergillosis, AmBisome (10 mg/kg) was more effective than Fungizone (1 mg/kg) in reducing fungal growth and improving survival rates after infection with Aspergillus fumigatus.

AmBisome not only reduced the spread of infection from the left lung to the right lung but also completely prevented liver and spleen complications at the higher dosage, suggesting its potential for use in prophylactic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal amphotericin B (AmBisome) reduces dissemination of infection as compared with amphotericin B deoxycholate (Fungizone) in a rate model of pulmonary aspergillosis. Leenders, AC., de Marie, S., ten Kate, MT., et al.[2019]

In a study using immunocompromised mice, aerosolized AmBisome (liposomal amphotericin B) demonstrated superior prophylactic efficacy against pulmonary aspergillosis compared to Fungizone (non-liposomal amphotericin B), particularly at medium levels of Aspergillus fumigatus exposure.

AmBisome not only cleared 80% of the fungal load in the lungs at a medium challenge level but also showed significantly higher lung drug retention, while both formulations were safe with no elevated kidney function markers in treated animals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic efficacy of aerosolized liposomal (AmBisome) and non-liposomal (Fungizone) amphotericin B in murine pulmonary aspergillosis. Allen, SD., Sorensen, KN., Nejdl, MJ., et al.[2022]

AmBisome, a liposomal formulation of amphotericin B, demonstrated high prophylactic efficacy against fungal infections in both immunocompetent and immunosuppressed mice, with all treated mice surviving after exposure to Histoplasma capsulatum and significant reductions in fungal burden.

In comparison to the conventional amphotericin B (Fungizone), AmBisome showed lower kidney fungal burdens and improved survival rates, indicating its potential as a safer and more effective antifungal treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose AmBisome (Liposomal amphotericin B) as prophylaxis for murine systemic candidiasis and histoplasmosis. Garcia, A., Adler-Moore, JP., Proffitt, RT.[2021]

AmBisome, a liposomal formulation of amphotericin B, is effective for treating severe fungal infections in febrile neutropenic patients and those resistant to standard amphotericin B, demonstrating a unique pharmacokinetic profile with increased plasma concentration and lower clearance.

The mechanism of action involves AmBisome accumulating at fungal infection sites, where it disrupts its liposomal structure upon binding to the fungal cell wall, allowing amphotericin B to bind to ergosterol in the fungal membrane, leading to cell lysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AmBisome (liposomal amphotericin B): a comparative review. Boswell, GW., Buell, D., Bekersky, I.[2019]

Inadvertent administration of amphotericin B instead of liposomal amphotericin has led to patient harm, highlighting the critical need for healthcare practitioners to be aware of the differences between these two formulations.

The similarity in packaging and dosing recommendations between AmBisome and Fungizone increases the risk of medication errors, suggesting that both organizational strategies and product design improvements are necessary to enhance patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Problem with Amphotericin. Cavell, G.[2020]

AmBisome, a formulation of amphotericin B, has been shown to be safe and effective in both therapeutic and prophylactic settings for adult and pediatric patients undergoing transplantation, significantly reducing fungal colonization and invasive Candida infections compared to placebo.

In a study involving 14 children undergoing bone marrow transplantation, AmBisome eradicated invasive fungal infections in 86% of cases, with minimal treatment withdrawals due to side effects, despite its higher cost compared to conventional amphotericin B.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years' experience with liposomal amphotericin B in transplant recipients at Huddinge University Hospital. Ringdén, O.[2019]

In a study involving mice with pulmonary aspergillosis, AmBisome significantly improved survival rates and reduced fungal burden compared to Fungizone, especially at higher doses (10 mg/kg).

AmBisome was found to localize effectively at the infection site in the lungs, which likely contributes to its superior efficacy in treating this type of fungal infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study on the efficacy of AmBisome and Fungizone in a mouse model of pulmonary aspergillosis. Takemoto, K., Yamamoto, Y., Ueda, Y., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Comparative efficacies of four amphotericin B formulations--Fungizone, amphotec (Amphocil), AmBisome, and Abelcet--against systemic murine aspergillosis. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Liposomal amphotericin B (AmBisome) reduces dissemination of infection as compared with amphotericin B deoxycholate (Fungizone) in a rate model of pulmonary aspergillosis. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Prophylactic efficacy of aerosolized liposomal (AmBisome) and non-liposomal (Fungizone) amphotericin B in murine pulmonary aspergillosis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Single-dose AmBisome (Liposomal amphotericin B) as prophylaxis for murine systemic candidiasis and histoplasmosis. [2021]

5. England pubmed.ncbi.nlm.nih.gov

AmBisome (liposomal amphotericin B): a comparative review. [2019]

6. New Zealand pubmed.ncbi.nlm.nih.gov

The Problem with Amphotericin. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Ten years' experience with liposomal amphotericin B in transplant recipients at Huddinge University Hospital. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Comparative study on the efficacy of AmBisome and Fungizone in a mouse model of pulmonary aspergillosis. [2013]