Fosmanogepix for Liver Disease

No longer recruiting at 2 trial locations

Overseen By Thomas Kaindl, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Basilea Pharmaceutica

Disqualifiers: Neurological disorders, Hepatic carcinoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how the drug fosmanogepix works in people with varying liver function levels. Researchers aim to understand how the body processes this drug to determine its safety. Participants will receive a single oral dose, and blood samples will track its effects. The trial seeks individuals with stable liver conditions or normal liver function who haven't experienced significant recent changes in their condition. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new drug.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should have stable concomitant medications for managing their medical history, suggesting you may continue your current meds if they are stable.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that fosmanogepix is safe in various studies. It has been tested on healthy individuals and patients with conditions like leukemia, and these studies found that participants generally tolerated the treatment well. Some side effects occurred, but they were usually mild and manageable.

Another study on fosmanogepix for different conditions also suggested it might be safe and effective. Participants in those studies did not report major safety concerns. The current trial is in its early phase, focusing primarily on checking safety and understanding how the drug works in the body.

Overall, fosmanogepix has been used safely in different situations, but researchers continue to collect data to confirm these findings for people with liver issues. Participants in this trial will be closely monitored to ensure their safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Fosmanogepix is unique because it targets liver disease through a novel mechanism, acting on the fungal enzyme Gwt1. This is different from standard treatments like antifungals and antivirals, which often target the pathogen's cell membrane or replication process. Researchers are excited about fosmanogepix because it offers a new way to tackle liver disease, especially in patients with varying degrees of liver function, from normal to severely impaired. By potentially providing a more effective and targeted approach, fosmanogepix could change how we manage liver conditions and improve patient outcomes.

What evidence suggests that fosmanogepix might be an effective treatment for liver disease?

Research has shown that fosmanogepix yields promising results in treating fungal infections, particularly Candida auris, by significantly reducing the fungus in the brain. Previous studies found that fosmanogepix is safe and well-tolerated, with no signs of liver or kidney damage. This trial will evaluate fosmanogepix in participants with varying degrees of hepatic function, including mild, moderate, and severe hepatic impairment, as well as normal hepatic function. The treatment disrupts crucial fungal functions, contributing to its effectiveness. These early findings suggest that fosmanogepix could be a promising option for managing infections, even in patients with liver disease. ^{1 2 4 6 7}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

This trial is for people with stable liver dysfunction of mild to severe levels who have a BMI between 17.5 and 40 kg/m2, weigh over 50 kg, and are on steady medications for their condition. It's not open to those with conditions affecting drug absorption, neurological disorders (except stable peripheral neuropathy), hepatic carcinoma, hepatorenal syndrome or acute ongoing liver issues.

Inclusion Criteria

Body mass index (BMI) of 17.5 to 40.0 kg/m2, inclusive; and a total body weight greater than 50 kg (greater than 110 lb)

Stable hepatic impairment that meets the criteria for Class A, B, or C of the Child Pugh classification with no clinically significant change in disease status within the 28 days prior to the screening visit

Stable concomitant medications for the management of individual participants' medical history

Exclusion Criteria

You have had certain surgeries that may affect how the drug is absorbed in your body.

You have a history of ongoing neurological disorders like abnormal movements or seizures, unless you have a stable history of peripheral neuropathy.

You have liver cancer or a condition called hepatorenal syndrome, or your doctor doesn't expect you to live much longer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single oral dose of fosmanogepix, with serial blood samples collected to assess pharmacokinetics and safety

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-8 weeks

1-3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Fosmanogepix

Trial Overview The study tests how the body processes fosmanogepix in patients with different stages of liver disease. Participants will take one dose orally and undergo blood sampling to see how the drug is metabolized and cleared from the body over a period of up to 9 weeks.

How Is the Trial Designed?

Group I: Cohort 5: Fosmanogepix Participants with severe hepatic impairment (new dose level) Experimental Treatment 1 Intervention

Participants with severe hepatic impairment will receive a single dose of fosmanogepix, administered orally as 2 fosmanogepix tablets under fasted conditions.

Group II: Cohort 4: Fosmanogepix Participants with normal hepatic function (control group) Experimental Treatment 1 Intervention

Participants with normal hepatic function will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.

Group III: Cohort 3: Fosmanogepix Participants with severe hepatic impairment Experimental Treatment 1 Intervention

Participants with severe hepatic impairment will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.

Group IV: Cohort 2: Fosmanogepix Participants with moderate hepatic impairment Experimental Treatment 1 Intervention

Participants with moderate hepatic impairment will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.

Group V: Cohort 1: Fosmanogepix participants with mild hepatic impairment Experimental Treatment 1 Intervention

Participants with mild hepatic impairment will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.

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

Approved in European Union as Fosmanogepix for:

• Orphan designation for various fungal infections

Approved in United States as Fosmanogepix for:

• Fast Track and Orphan Drug designations for seven separate indications including candidemia, invasive mold infections, and others

Who Is Running the Clinical Trial?

Basilea Pharmaceutica

Lead Sponsor

Trials

53

Recruited

9,900+

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Biomedical Advanced Research and Development Authority

Collaborator

Trials

108

Recruited

574,000+

Published Research Related to This Trial

In a 12-week phase II study involving 52 patients with primary sclerosing cholangitis (PSC), cilofexor demonstrated significant improvements in liver biochemistry, particularly with a 21% reduction in serum alkaline phosphatase (ALP) at the 100 mg dose compared to placebo.

Cilofexor was well tolerated, with adverse events similar to those in the placebo group, indicating its potential as a safe treatment option for PSC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Trauner, M., Gulamhusein, A., Hameed, B., et al.[2021]

New contrast agents for liver MRI, including hepatobiliary agents and nanoparticulate agents, significantly enhance the visibility of liver lesions, improving diagnostic accuracy.

Hepatobiliary agents brighten liver images while particulate agents darken them, both leading to better detection and characterization of focal liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast agents in magnetic resonance imaging of the liver: present and future. Clément, O., Siauve, N., Lewin, M., et al.[2005]

Tropifexor, a non-bile acid FXR agonist, showed comparable pharmacokinetics in participants with hepatic impairment (HI) and those with normal liver function, indicating its potential safety for use in patients with liver disease.

The study found that tropifexor was well tolerated and demonstrated a relative insensitivity to HI, suggesting that it may not require dose adjustments for patients with severe liver impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment. Chen, J., Gu, J., Shah, B., et al.[2022]

In patients with cirrhosis, the uptake of 68Ga-FAPI in the liver was significantly higher compared to those without cirrhosis, but this did not affect the sensitivity for detecting intrahepatic tumors, which remained high at 98%.

68Ga-FAPI PET/CT demonstrated superior sensitivity and maximum standardized uptake values for detecting intrahepatic tumors compared to 18F-FDG PET/CT in cirrhotic patients, indicating it may be a more effective diagnostic tool in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Cirrhosis on 68Ga-FAPI PET/CT in Intrahepatic Tumors. Peng, D., Cao, J., Guo, C., et al.[2023]

In a study involving 18 patients with lipodystrophies, cholic acid (CA) therapy did not significantly reduce hepatic triglyceride (TG) content compared to placebo, indicating it may not be effective for this condition.

While CA was well tolerated, with only mild gastrointestinal side effects in some patients, it did not lead to improvements in liver enzyme levels or serum TG, suggesting limited therapeutic benefit for hepatic steatosis in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholic acid for hepatic steatosis in patients with lipodystrophy: a randomized, controlled trial. Ahmad, Z., Subramanyam, L., Szczepaniak, L., et al.[2021]

Gd-EOB-DTPA-enhanced MRI effectively assesses liver function in patients with primary biliary cholangitis (PBC), showing significant differences in liver signal enhancement across different Child-Pugh classes among 45 PBC patients.

While the MRI can evaluate liver function, it does not differentiate between PBC and posthepatitic cirrhosis patients within the same Child-Pugh class, indicating a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver assessment using Gd-EOB-DTPA-enhanced magnetic resonance imaging in primary biliary cholangitis patients. Han, D., Liu, J., Jin, E., et al.[2020]

In a study of 38 patients with hepatocellular carcinoma (HCC) who underwent liver transplantation, 13 showed positive PET scans, indicating a significant association between higher preoperative alpha-fetoprotein (AFP) levels and vascular invasion with increased PET uptake.

Patients with negative PET scans had a much higher 2-year recurrence-free survival rate (85.1%) compared to those with positive scans (46.1%), suggesting that PET imaging can effectively predict the risk of tumor recurrence post-transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of (18)F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Yang, SH., Suh, KS., Lee, HW., et al.[2022]

In a trial involving 36 patients with non-alcoholic fatty liver disease (NAFLD), the pan-phosphodiesterase inhibitor ZSP1601 was found to be well-tolerated, with 75% of participants experiencing mild to moderate treatment-emergent adverse events, but no serious adverse events reported.

ZSP1601 demonstrated effective improvements in liver chemistries, liver fat content, and fibrosis, suggesting it could be a promising treatment option for NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial. Hu, Y., Li, H., Zhang, H., et al.[2023]

Long-term topical administration of griseofulvin (GRIS) led to significant liver damage indicators, including a three-fold increase in direct bilirubin levels after just 7 days of treatment.

The study confirmed hepatopathy through a six-fold increase in free bilirubin and elevated levels of alkaline phosphatase and GOT, indicating cholestasis, although some liver damage may also be due to reactions to other substances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Griseofulvin-induced hepatopathy due to abnormalities in heme pathway. Polo, CF., Buzaleh, AM., Vazquez, ES., et al.[2019]

In a study involving 145 patients, Mn-DPDP-enhanced magnetic resonance imaging (MRI) correctly classified focal liver lesions in 74% of cases, significantly outperforming dual-phase spiral computed tomography (CT), which only achieved 57% accuracy (P = 0.001).

Enhanced MRI also excelled in distinguishing between malignant and benign lesions (85% accuracy) and identifying hepatocellular versus nonhepatocellular lesions (90% accuracy), compared to 68% and 64% for dual-phase CT, respectively, indicating its superior diagnostic capability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of liver lesions with mangafodipir trisodium-enhanced MR imaging: multicenter study comparing MR and dual-phase spiral CT. Oudkerk, M., Torres, CG., Song, B., et al.[2015]

In a study involving 592 patients across 17 European centers, the use of the contrast agent mangafodipir trisodium (MnDPDP) significantly improved the detection of liver lesions in MR imaging, with a notable increase in detected lesions compared to unenhanced images (p = 0.0014).

The study found that T1-weighted gradient-echo sequences provided superior imaging quality and confidence in diagnosing lesions after MnDPDP administration, with statistically significant improvements in lesion delineation and conspicuity (p < 0.0001).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MnDPDP for MR imaging of the liver. Results of an independent image evaluation of the European phase III studies. Rummeny, EJ., Torres, CG., Kurdziel, JC., et al.[2022]

A study involving 37 adult subjects, including those with mild and moderate hepatic impairment, found that a single dose of liposomal mifamurtide did not significantly alter its pharmacokinetics compared to healthy individuals, indicating that no dose modifications are necessary for these patients.

Pharmacodynamic effects, such as changes in inflammatory markers, were generally similar across all groups, with no serious adverse events reported, suggesting that mifamurtide is safe for use in patients with mild to moderate liver impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment. Venkatakrishnan, K., Liu, Y., Noe, D., et al.[2021]

Cilofexor, a drug being developed for nonalcoholic steatohepatitis, showed significantly increased plasma levels in participants with hepatic impairment, with concentrations being 2.5 to 6.3 times higher in those with moderate to severe impairment compared to healthy controls.

The drug was generally well tolerated, with all related adverse events being mild, indicating it can be safely administered to patients with mild hepatic impairment without dose adjustment, but caution is needed for those with moderate or severe impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist. Younis, IR., Hsueh, CH., Nelson, C., et al.[2023]

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Hepatic Impairment (HI) (DBCOND0166870) Associated Data ; NCT04469920. Hepatic Impairment, Cholestatic Liver Disease, & NASH with Advanced Fibrosis & Normal Hepatic Function. Saroglitazar ; NCT04573582.