PC945 + Antifungal Therapy for Invasive Pulmonary Aspergillosis

Recruiting at 155 trial locations

Overseen By Senior Medical Director of Clinical Development

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Pulmocide Ltd

Must be taking: Antifungal therapy

Must not be taking: Investigational agents

Disqualifiers: Allergy, Hypersensitivity, Others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

123 Participants Needed

Trial Summary

What is the purpose of this trial?

To assess the safety and efficacy of nebulized PC945 in combination with systemic antifungal therapy for the treatment of refractory IPA

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 taking an investigational drug without regulatory approval, you may not be eligible to participate.

What data supports the effectiveness of the drug PC945 + Antifungal Therapy for Invasive Pulmonary Aspergillosis?

The research highlights that newer antifungal drugs have significantly improved outcomes for invasive aspergillosis, with voriconazole being the preferred choice and posaconazole showing promise. Additionally, combination therapies involving azoles and echinocandins are promising, suggesting that similar combination approaches, like PC945 with other antifungals, could be effective. ^{1 2 3 4 5}

Is PC945 safe for humans?

PC945, also known as Opelconazole, has been tested in healthy volunteers and people with mild asthma, and it was generally well tolerated with mild to moderate side effects that resolved on their own. It showed low levels in the bloodstream, which means fewer chances of side effects or interactions with other drugs. ^{2 5 6 7 8}

What makes the drug PC945 unique for treating invasive pulmonary aspergillosis?

PC945 is unique because it is an inhaled antifungal drug specifically designed to target the lungs, providing high local concentrations with minimal side effects in the rest of the body. This approach is different from traditional treatments that are usually given intravenously or orally and can have more systemic side effects. ^{1 2 6 9 10}

Eligibility Criteria

This trial is for individuals with a confirmed or likely diagnosis of invasive pulmonary aspergillosis (IPA) that hasn't improved despite standard antifungal treatment. Participants must not have allergies to PC945 or placebo components, should not have used PC945 before, and can't be in another clinical study.

Inclusion Criteria

Participant has proven or probable IPA according to the modified 2019 European Organization for Research and Treatment of Cancer/ Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) consensus definitions or according to the 2010 International Society for Heart and Lung Transplantation (ISHLT) consensus statements for the definitions of infections in cardiothoracic transplant recipients

My fungal infection didn't improve after proper treatment.

Exclusion Criteria

Participant who has recently received, is receiving or due to receive at any time during the study, an investigational medicinal agent that does not have any regulatory approved indications. Subjects who are participating in any other trials e.g., Observational, diagnostic or using medications with an approved indication may be allowed to participate after consultation with the sponsor on an individual basis

Participant with a known or suspected concomitant medical condition or post-surgery complication that, in the opinion of the Investigator, may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy or may be an unacceptable additional risk to the Participant should he/she participate in the study

I have previously taken the medication PC945.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nebulized PC945 or placebo twice daily in combination with systemic antifungal therapy

8 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PC945
• Placebo

Trial Overview The trial tests the effectiveness of an inhaled drug called PC945 combined with other systemic antifungal treatments against IPA. Some participants will receive PC945 while others will get a placebo, alongside their usual antifungal therapy.

Participant Groups

Group I: PC945 Experimental Treatment 1 Intervention

PC945 dose, administered via nebulizer, twice daily

Group II: Placebo Placebo Group 1 Intervention

PC945-placebo administered via nebulizer, twice daily

PC945 is already approved in European Union, United States for the following indications:

Approved in European Union as Opelconazole for:

• Aspergillosis

Approved in United States as Opelconazole for:

• Invasive Pulmonary Aspergillosis (IPA)

Who Is Running the Clinical Trial?

Pulmocide Ltd

Lead Sponsor

Trials

10

Recruited

530+

Findings from Research

Recent advancements in the management of invasive aspergillosis include the development of potent and relatively non-toxic antifungal drugs, which have led to safer and earlier interventions, resulting in reduced mortality rates and improved patient outcomes.

Voriconazole is now the preferred drug for primary therapy, while posaconazole is emerging as a promising prophylactic option; however, there are concerns about the emergence of less-susceptible Aspergillus species during treatment, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and future therapeutic options in the management of invasive aspergillosis. Krishnan-Natesan, S., Chandrasekar, PH.[2021]

Intravenous antifungals, specifically amphotericin B and echinocandins, showed an overall response rate of 61% in treating chronic pulmonary aspergillosis (CPA) based on a meta-analysis of 12 studies involving 380 patients.

While liposomal amphotericin B was generally well tolerated, it caused renal function loss in 25% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous therapy for chronic pulmonary aspergillosis: A systematic review and meta-analysis. Bongomin, F., Asio, LG., Olum, R., et al.[2021]

In a study of 20 patients with invasive aspergillosis treated with itraconazole, 75% achieved complete remission, suggesting itraconazole is an effective alternative to traditional therapies like amphotericin B.

A review of 12 published studies indicated an overall response rate of 63% for itraconazole in treating invasive aspergillosis, highlighting its potential as a viable treatment option for immunocompromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of invasive aspergillosis with itraconazole: our own experiences and review of the literature]. Kreisel, W.[2013]

In a study of 5,410 patients with invasive pulmonary aspergillosis (IPA), voriconazole was the most commonly prescribed initial treatment, used by 49% of patients, followed by fluconazole (11%) and posaconazole (7%).

The majority of patients remained on voriconazole (80%) or isavuconazole (78%) during treatment, while those starting with fluconazole, echinocandins, or posaconazole were more likely to switch medications, indicating potential challenges with these alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment pathways, switches, and inappropriate treatment during invasive pulmonary aspergillosis: real-world experiences from a global research network study. Henao-Martínez, AF., Chastain, DB., Thompson, GR.[2023]

In a murine model of invasive pulmonary aspergillosis, preexposure to itraconazole (ITC) significantly reduced the efficacy of amphotericin B (AMB), with survival rates dropping from 60% in non-ITC-preexposed mice to 0-20% in ITC-preexposed mice at higher AMB doses.

Mice preexposed to ITC showed a consistently higher fungal burden in the lungs, indicating that ITC may antagonize the effects of AMB, as evidenced by significant increases in viable fungal counts and chitin levels, suggesting that prior treatment with ITC could impair the effectiveness of subsequent AMB therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis. Lewis, RE., Prince, RA., Chi, J., et al.[2021]

PC945 is a novel inhaled antifungal agent specifically designed to target pulmonary Aspergillus infections, showing potent efficacy in preclinical studies and well-tolerated in healthy volunteers and asthmatics with limited systemic exposure.

In two lung transplant patients with invasive pulmonary Aspergillus infections resistant to other treatments, PC945 successfully treated the infection without causing systemic side effects, highlighting its potential as a safe and effective option for immunocompromised individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections. Murray, A., Cass, L., Ito, K., et al.[2020]

In a study comparing generic amphotericin B to the brand name Fungizone in rabbits with invasive pulmonary aspergillosis, both formulations showed similar efficacy and safety profiles.

The research indicates that generic amphotericin B can be a suitable alternative to Fungizone for treating this serious fungal infection, especially during the drug shortage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of generic amphotericin B in experimental pulmonary aspergillosis. Petraitis, V., Petraitiene, R., Lin, P., et al.[2018]

PC945, a new antifungal triazole delivered via nebulization, showed significantly higher concentrations in the lungs compared to plasma, which may enhance its effectiveness against lung Aspergillus infections while minimizing systemic side effects.

The drug was well tolerated in clinical trials with healthy subjects and those with mild asthma, showing only mild to moderate adverse events and no significant changes in lung function, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent. Cass, L., Murray, A., Davis, A., et al.[2021]

PC945, a novel triazole, demonstrated potent antifungal effects against Aspergillus fumigatus in immunocompromised mice, significantly reducing lung fungal loads and associated biomarkers compared to standard treatments like posaconazole and voriconazole.

Extended prophylaxis with low-dose PC945 was more effective than shorter treatment regimens, indicating that repeated dosing enhances its efficacy, suggesting its potential as a new inhaled therapy for treating fungal infections in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice. Kimura, G., Nakaoki, T., Colley, T., et al.[2018]

Higher doses of amphotericin (5 mg/kg/d) using lipid carriers can be safely administered to treat pulmonary invasive aspergillosis in immunocompromised patients, potentially improving outcomes compared to the standard dose of 1 to 1.25 mg/kg/d.

Intraconazole is an effective follow-up treatment after amphotericin for managing pulmonary invasive aspergillosis, providing a sequential therapy approach for better disease management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Curative antifungal treatment of invasive pulmonary aspergillosis]. Andrès, E., Courouau, F., Kurtz, JE., et al.[2013]

References

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

Current and future therapeutic options in the management of invasive aspergillosis. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Intravenous therapy for chronic pulmonary aspergillosis: A systematic review and meta-analysis. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

[Therapy of invasive aspergillosis with itraconazole: our own experiences and review of the literature]. [2013]

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

Treatment pathways, switches, and inappropriate treatment during invasive pulmonary aspergillosis: real-world experiences from a global research network study. [2023]

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

Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections. [2020]

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

Efficacy and safety of generic amphotericin B in experimental pulmonary aspergillosis. [2018]

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

Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent. [2021]

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

In Vivo Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice. [2018]

10. France pubmed.ncbi.nlm.nih.gov

[Curative antifungal treatment of invasive pulmonary aspergillosis]. [2013]