Fosmanogepix for Liver Disease
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Basilea Pharmaceutica
Disqualifiers: Neurological disorders, Hepatic carcinoma, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?The primary purpose of this open-label study is to characterize the plasma pharmacokinetics (PK) of manogepix (active moiety of fosmanogepix) in participants with varying degrees of hepatic function following administration of a single oral dose of fosmanogepix.
All participants will receive 1 dose of fosmanogepix by mouth before breakfast on the first day at the study clinic. Serial blood samples will be collected to understand how fosmanogepix is changed and eliminated from the body. Participants will also receive physical examination and other tests. This will help to understand if fosmanogepix is safe.
Participants will be involved in this study for 4 to 9 weeks (maximum). There will be 2 to 4 study visits at the study clinic.
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.
What data supports the idea that Fosmanogepix for Liver Disease is an effective drug?
The available research does not provide any data supporting the effectiveness of Fosmanogepix for Liver Disease. Instead, the studies focus on imaging techniques and other treatments for liver conditions. For example, one study evaluates the effectiveness of cilofexor, a different drug, in improving liver health markers in patients with a specific liver disease. However, there is no mention of Fosmanogepix being tested or compared in these studies.
12345What safety data is available for Fosmanogepix in liver disease treatment?
The provided research does not contain any safety data for Fosmanogepix (also known as APX001, E1211, PF-07842805) in the treatment of liver disease. The studies mentioned focus on other drugs such as ZSP1601, Tropifexor, Griseofulvin, Cilofexor, and liposomal mifamurtide, none of which are related to Fosmanogepix.
36789Is the drug Fosmanogepix a promising treatment for liver disease?
The provided research articles do not mention Fosmanogepix or its potential as a treatment for liver disease. Therefore, based on the available information, we cannot determine if Fosmanogepix is a promising treatment for liver disease.
310111213Eligibility Criteria
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.
+2 more
Trial Timeline
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)
Participant Groups
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.
4Treatment groups
Experimental Treatment
Group I: Cohort 4: Fosmanogepix Participants with normal hepatic function (control group)Experimental Treatment1 Intervention
Participants with normal hepatic function will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.
Group II: Cohort 3: Fosmanogepix Participants with severe hepatic impairmentExperimental Treatment1 Intervention
Participants with severe hepatic impairment will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.
Group III: Cohort 2: Fosmanogepix Participants with moderate hepatic impairmentExperimental Treatment1 Intervention
Participants with moderate hepatic impairment will receive a single dose of fosmanogepix, administered orally as 1 fosmanogepix tablet under fasted conditions.
Group IV: Cohort 1: Fosmanogepix participants with mild hepatic impairmentExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Genesis Clinical ResearchTampa, FL
Inland Empire Liver FoundationRialto, CA
Genesis Clinical Research, LLCTampa, FL
Loading ...
Who Is Running the Clinical Trial?
Basilea PharmaceuticaLead Sponsor
PfizerLead Sponsor
Biomedical Advanced Research and Development AuthorityCollaborator
References
Characterization of liver lesions with mangafodipir trisodium-enhanced MR imaging: multicenter study comparing MR and dual-phase spiral CT. [2015]To evaluate whether mangafodipir trisodium (Mn-DPDP)-enhanced magnetic resonance (MR) imaging surpasses dual-phase spiral computed tomography (CT) in differentiating focal liver lesions.
MnDPDP for MR imaging of the liver. Results of an independent image evaluation of the European phase III studies. [2022]To evaluate the diagnostic efficacy of mangafodipir trisodium (MnDPDP, Teslascan) as a new contrast agent for MR imaging of the liver based on an independent evaluation of the MR images from the European phase III studies.
The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. [2021]Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double-blind, placebo-controlled study, we tested the safety and efficacy of cilofexor (formerly GS-9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large-duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α-hydroxy-4-cholesten-3-one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288-439) and 0.7 mg/dL (0.5-1.0), respectively. Dose-dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction -21%; P = 0.029 versus placebo), gamma-glutamyl transferase (-30%; P
Liver assessment using Gd-EOB-DTPA-enhanced magnetic resonance imaging in primary biliary cholangitis patients. [2020]To evaluate the feasibility of utilizing gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for the assessment of Child-Pugh class and for differentiating between patients with primary biliary cholangitis (PBC) and posthepatitic cirrhosis.
Contrast agents in magnetic resonance imaging of the liver: present and future. [2005]New contrast agents are being developed by drug companies to better image the liver magnetic resonance imaging (MRI). They can be divided into hepatobiliary agents (Gd-EOB-DTPA, Gd-BOPTA, Mangafodipir) and nanoparticulate agents directed to the reticulo-endothelial system (ferumoxides, SHU 555A). After intravenous injection, all these agents concentrate in the liver and induce profound signal changes. Particulate agents induce predominantly a darkening of the liver parenchyma, while hepatobiliary agents induce a brightening. In both cases, liver-lesion conspicuity is enhanced, leading to a better visualization of the lesion. After a description of the principal pharmacokinetic characteristics of the compounds, this review paper summarizes the utility of the agents in the detection and characterization of focal liver diseases.
ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial. [2023]Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.
Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment. [2022]Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-μg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf,u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf,u , 1.64 [90%CI, 1.25-2.16]; Cmax,u , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf,u (1.61 [90%CI, 1.04-2.49]) and comparable Cmax,u (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.
Griseofulvin-induced hepatopathy due to abnormalities in heme pathway. [2019]1. The effect of long-term griseofulvin (GRIS) topical administration on some indicators of liver damage was examined. 2. Liver porphyrin accumulation was significant; however, no porhyrin crystals were observed under light microscopy. 3. An earlier onset of hepatopathy was established (3-fold) increase of direct bilirubin values after 7 days of treatment; hepatic injury was confirmed by measuring a 6-fold increase of free bilirubin. 4. Enhanced values of alkaline phosphatase and glutamic oxalacetic transaminase (GOT) confirmed the onset of cholestasis. 5. Topical application of GRIS induced measurable hepatopathy. Nevertheless, we cannot discard the possibility that this hepatopathy could also be attributed in part to a direct reaction to xenobiotics.
Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment. [2021]To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function.
The role of (18)F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. [2022]Positron emission tomography (PET) using F-18 fluoro-2-deoxy-d-glucose ((18)F-FDG) is now well established as a noninvasive diagnostic tool for the detection of a variety of malignant tumors. However, in the case of hepatocellular carcinoma (HCC), several investigators have reported controversial conclusions and an inadequate sensitivity for PET (50-55%). Nevertheless, a high positive rate of (18)F-FDG accumulation has been reported in patients with high-grade HCC and in those with markedly elevated alpha-fetoprotein (AFP) levels. Here, we retrospectively reviewed 38 HCC cases that received liver transplantation (LT) at our center between November 2000 and July 2004 and underwent whole-body PET imaging. (18)F-FDG uptake was assessed in the liver, and its prognostic significance was investigated. Of 38 patients enrolled, 13 patients had positive PET scans for a liver tumor. When we analyzed the association between tumor factors and PET+ (greater PET lesion uptake) in the liver, preoperative AFP level and vascular invasion were found to be significantly associated with PET+ (P = 0.003 and P
Influence of Cirrhosis on 68Ga-FAPI PET/CT in Intrahepatic Tumors. [2023]Background Gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) is of great diagnostic value for intrahepatic tumors. However, cirrhosis may lead to increased 68Ga-FAPI uptake in background liver, affecting the diagnostic ability of 68Ga-FAPI. Purpose To assess the effect of cirrhosis on liver parenchyma and intrahepatic tumor uptake of 68Ga-FAPI and to compare the ability of 68Ga-FAPI and fluorine 18 (18F)-labeled fluorodeoxyglucose (FDG) PET/CT to depict intrahepatic tumors in patients with cirrhosis. Materials and Methods In this secondary analysis of a prospective trial, patients who underwent both 68Ga-FAPI and 18F-FDG PET/CT and those who underwent only 68Ga-FAPI PET/CT between August 2020 and May 2022 were considered for inclusion in the cirrhotic or noncirrhotic group, respectively. Patients with cirrhosis were chosen via a comprehensive assessment of imaging and clinical data, and patients without cirrhosis were randomly selected. 68Ga-FAPI and 18F-FDG PET/CT data were measured by two radiologists. Between-groups and within-group data were tested with the Mann-Whitney U test and the Wilcoxon signed-rank test, respectively. Results A total of 39 patients with cirrhosis (median age, 58 years [IQR, 50-68]; 29 male; 24 intrahepatic tumors) and 48 patients without cirrhosis (median age, 59 years [IQR, 51-67]; 30 male; 23 intrahepatic tumors) were evaluated. In patients without intrahepatic tumors, the liver 68Ga-FAPI average standardized uptake value (SUVavg) was higher in the cirrhotic group than in the noncirrhotic group (median SUVavg, 1.42 [IQR, 0.55-2.85] vs 0.45 [IQR, 0.41-0.72]; P = .002). However, no difference was observed in the diagnosis of intrahepatic tumor sensitivity (98% vs 93%, respectively). When compared with 18F-FDG, the sensitivity of 68Ga-FAPI PET/CT in the detection of intrahepatic tumors in patients with cirrhosis (41% vs 98%, respectively) and maximum standardized uptake value of tumors (median SUVmax, 2.60 [IQR, 2.14-4.49] vs 6.68 [IQR, 4.65-10.08]; P < .001) were higher. Conclusion The sensitivity of 68Ga-FAPI in the diagnosis of intrahepatic tumors was not affected by cirrhosis, and diagnostic accuracy of 68Ga-FAPI was higher than that of 18F-FDG in patients with cirrhosis. © RSNA, 2023 Supplemental material is available for this article.
Cholic acid for hepatic steatosis in patients with lipodystrophy: a randomized, controlled trial. [2021]Hepatic steatosis is a common complication in patients with lipodystrophies and can lead to cirrhosis. There is no proven effective therapy for hepatic steatosis, but cholic acid (CA), a farnesoid X receptor agonist, has previously been shown to reduce hepatic triglyceride (TG) content in mice and serum TG in humans. Our objective was to assess clinical efficacy and tolerability of CA therapy in patients with lipodystrophy and hepatic steatosis.
Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist. [2023]Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.