Simufilam for Liver Failure

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Cassava Sciences, Inc.

Must not be taking: CYP2C19 inhibitors, CYP2C19 inducers

Disqualifiers: Hepatitis B, HIV, Alcohol abuse, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

27 Participants Needed

Trial Summary

What is the purpose of this trial?

Evaluate simufilam levels in the blood of hepatically impaired individuals compared to Healthy individuals of similar demographics

Do I need to stop my current medications to join the trial?

The trial protocol does not specify that you must stop all current medications. If you have normal liver function, you should not use prescription or OTC medications within 7 days before the Check-In visit, except for certain exceptions like hormonal contraceptives and multivitamins. If you have liver impairment, you can continue medications for managing your liver condition or stable chronic conditions, but they must be on a stable dose and approved by the Medical Monitor.

What data supports the idea that Simufilam for Liver Failure is an effective treatment?

The available research does not provide any data supporting the effectiveness of Simufilam for treating liver failure. The studies mentioned focus on other drugs and treatments for liver injury, but Simufilam is not included in the analysis. Therefore, there is no evidence from the provided information to suggest that Simufilam is effective for liver failure. ^{1 2 3 4 5}

What safety data exists for Simufilam in treating liver failure?

The provided research does not contain specific safety data for Simufilam (also known as PTI-125 or sumifilam) in the context of liver failure or drug-induced liver injury. The studies focus on other drugs and approaches related to liver injury, but Simufilam is not mentioned among the investigated agents. ^{1 6 7 8 9}

Is the drug Simufilam a promising treatment for liver failure?

Based on the provided research articles, there is no information about Simufilam being used or tested for liver failure. The articles focus on other drugs like simeprevir and sofosbuvir for hepatitis C and liver-related issues, but not Simufilam. Therefore, we cannot say if Simufilam is a promising treatment for liver failure. ^{10 11 12 13 14}

Eligibility Criteria

This trial is for adults aged 18-75 with a BMI of 18-40 kg/m2 who can follow the study's procedures. They must understand English, consent to participate, use birth control if applicable, and stay at the study site. Participants need normal or mildly impaired kidney function and be COVID-negative.

Inclusion Criteria

My BMI is between 18 and 40.

I agree to follow the birth control requirements relevant to me.

I have tested negative for COVID-19 at both the screening and check-in visits.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of simufilam 100 mg

1 day

Follow-up

Participants are monitored for pharmacokinetic parameters such as Area Under the Curve, Time max, Elimination rate constant, Half-life, and Concentration max

5 days

Treatment Details

Interventions

• Simufilam

Trial Overview The trial is testing how simufilam behaves in the bloodstreams of people with liver problems compared to healthy individuals. It aims to understand differences in drug levels due to hepatic impairment.

Participant Groups

Group I: Moderate Hepatic Impairment Experimental Treatment 1 Intervention

Group II: Mild Hepatic Impairment Experimental Treatment 1 Intervention

Group III: Healthy Volunteer Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Cassava Sciences, Inc.

Lead Sponsor

Trials

9

Recruited

3,400+

Findings from Research

Among the novel therapies for drug-induced liver injury (DILI), magnesium isoglycyrrhizinate (MgIG) showed moderate-certainty evidence of effectively normalizing alanine aminotransferase (ALT) levels compared to placebo in treated patients.

Bicyclol also demonstrated a potential benefit in reducing ALT levels compared to phosphatidylcholine, but the evidence for this was of low certainty, highlighting the need for more robust clinical trials to confirm the efficacy of various treatments for DILI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review. Benić, MS., Nežić, L., Vujić-Aleksić, V., et al.[2023]

The study developed a computer-assisted tool called DILI-CAT to assess drug-specific liver injury phenotypes, using data from published case series for four drugs, including amoxicillin-clavulanate and cyproterone.

Significant differences in liver injury characteristics were found among the drugs, with cyproterone showing a much longer latency period and higher R-value compared to amoxicillin-clavulanate and cefazolin, indicating that DILI-CAT can effectively differentiate between drugs based on their liver injury profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT). Tillmann, HL., Suzuki, A., Merz, M., et al.[2022]

A case of drug-induced liver injury (DILI) was identified in a renal transplant patient due to the antibiotic Trimethoprim-sulfamethoxazole (TMP-SMX), highlighting the potential for hepatic toxicity associated with this medication.

The diagnosis was confirmed through thorough history taking and the reversal of liver damage after stopping TMP-SMX, indicating that while liver toxicity from this drug is known, it is unpredictable and not frequently reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trimethoprim-Sulfamethoxazole-induced Hepatotoxicity in a Renal Transplant Patient. Slim, R., Asmar, N., Yaghi, C., et al.[2020]

The FDA initiated annual conferences starting in 1999 to address drug-induced liver injury (DILI) following serious cases of liver toxicity from drugs like troglitazone and bromfenac, leading to increased awareness and improved monitoring practices.

The development of the eDISH program in 2004 allowed for better assessment of DILI in clinical trials by plotting liver test results, contributing to the FDA's success in not having to withdraw any drugs for post-marketing hepatotoxicity since 1997.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Senior, JR.[2021]

In a study testing the hepatotoxicity of various antimycotics on liver cells, azoles like fluconazole and voriconazole showed higher levels of liver cell damage across all tested concentrations, indicating a significant risk for liver injury.

Anidulafungin, while showing mild hepatotoxicity at standard doses, caused severe liver cell impairment at higher concentrations, suggesting that careful monitoring is essential when using these drugs, especially in patients with existing liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results. Doß, S., Potschka, H., Doß, F., et al.[2018]

In a large clinical trial program involving approximately 11,000 patients with type 2 diabetes, fasiglifam was associated with significant liver toxicity, as indicated by a higher frequency of liver enzyme elevations compared to placebo and active controls.

Despite no alarming trends reported by local investigators, systematic central monitoring revealed a 3- to 7-fold increased risk of liver enzyme elevation in fasiglifam recipients, leading to the program's termination due to safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program. Shavadia, JS., Sharma, A., Gu, X., et al.[2020]

A novel approach combining pharmacoepidemiology and in silico modeling identified 18 drugs linked to immune-mediated drug-induced liver injury (IMDILI), with a high statistical significance (P < 0.00015).

The study developed a pharmacophore model with 75% sensitivity and 85% specificity to predict IMDILI, suggesting that interactions with the major histocompatibility complex and Toll-like receptors, particularly TLR-7, may play critical roles in the immune response leading to liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury. Ho, SS., McLachlan, AJ., Chen, TF., et al.[2018]

A new predictive model using support vector machine (SVM) techniques has been developed to assess the risk of drug-induced liver injury (DILI) based on the physicochemical and structural properties of drug candidates, achieving an average sensitivity and specificity of 70%.

This in silico approach shows promise for early identification of safety alerts in drug development, potentially allowing for better screening of compounds alongside traditional in vitro safety tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A compound attributes-based predictive model for drug induced liver injury in humans. Liu, Y., Gao, H., He, YD.[2020]

In a study of 38 elderly patients with drug-induced liver injury (DILI), approximately 32.3% of DILI-drug pairs were deemed 'avoidable' using the Liverpool adverse drug reactions avoidability tool (LAAT), indicating potential for prevention strategies.

The findings suggest that a significant portion of DILI cases in this population could be prevented, highlighting the importance of using tools like LAAT for improving patient safety and reducing healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score. Danjuma, MI., Almasri, H., Alshokri, S., et al.[2020]

In a study of 1114 patients undergoing hepatectomy for hepatocellular carcinoma, the use of nafamostat mesilate (NM) significantly reduced the incidence of posthepatectomy liver failure (PHLF) compared to a control group, with a notable decrease in complications.

Patients receiving NM also showed lower levels of liver enzymes and bilirubin post-surgery, along with shorter hospital stays and fewer major complications, indicating its potential efficacy in improving postoperative outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of postoperative administration of nafamostat mesilate on posthepatectomy liver failure. Lee, B., Cho, JY., Han, HS., et al.[2022]

A 51-year-old female patient with compensated cirrhosis and HbS beta 0-thalassemia experienced benign hyperbilirubinemia while being treated with simeprevir and sofosbuvir for chronic hepatitis C, but did not show signs of liver decompensation.

Despite the elevated bilirubin levels peaking in the third month of treatment, the hyperbilirubinemia was fully reversible, and the patient achieved a sustained virological response 24 weeks after completing the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simeprevir and Sofosbuvir Combination Treatment in a Patient with HCV Cirrhosis and HbS Beta 0-Thalassemia: Efficacy and Safety despite Baseline Hyperbilirubinemia. Papadopoulos, N., Deutsch, M., Georgalas, A., et al.[2020]

The combination of simeprevir (SMV) and sofosbuvir (SOF) achieved a sustained virologic response (SVR) of 81% in patients with cirrhosis and contraindications to peginterferon/ribavirin, indicating it is an effective treatment option for this challenging population.

Patients with more advanced liver disease (Child class B and C) had lower SVR rates (77% and 67%, respectively), highlighting the importance of liver function in treatment outcomes, while 11% experienced severe adverse events, underscoring the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of chronic HCV with sofosbuvir and simeprevir in patients with cirrhosis and contraindications to interferon and/or ribavirin. Shiffman, ML., James, AM., Long, AG., et al.[2022]

In a study of 192 chronic hepatitis C patients treated with simeprevir, pegylated interferon, and ribavirin, hyperbilirubinemia was observed, peaking at 2 weeks after treatment initiation, with 18% of patients experiencing levels over 2 mg/dl.

The increase in bilirubin levels was significantly associated with the ITPA genotype, indicating that patients with the non-CC genotype may require closer monitoring to avoid misdiagnosis of liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin. Tahata, Y., Hiramatsu, N., Oze, T., et al.[2022]

A new spectrofluorimetric method was developed to accurately and simultaneously measure the levels of Simeprevir (SMV) and Ledipasvir (LDS) in various samples, including human plasma, demonstrating high sensitivity and specificity.

The method showed excellent accuracy and precision, with detection limits as low as 6.0 ng/mL for LDS and 9.0 ng/mL for SMV, making it a reliable tool for monitoring these drugs in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micelle sensitized synchronous spectrofluorimetric approaches for the simultaneous determination of simeprevir and ledipasvir: Application to pharmaceutical formulations and human plasma. Hamad, AE., Mohammed, BS., Derayea, SM., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review. [2023]

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

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT). [2022]

3. India pubmed.ncbi.nlm.nih.gov

Trimethoprim-Sulfamethoxazole-induced Hepatotoxicity in a Renal Transplant Patient. [2020]

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

Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. [2021]

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

Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program. [2020]

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

Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury. [2018]

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

A compound attributes-based predictive model for drug induced liver injury in humans. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Effect of postoperative administration of nafamostat mesilate on posthepatectomy liver failure. [2022]

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

Simeprevir and Sofosbuvir Combination Treatment in a Patient with HCV Cirrhosis and HbS Beta 0-Thalassemia: Efficacy and Safety despite Baseline Hyperbilirubinemia. [2020]

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

Treatment of chronic HCV with sofosbuvir and simeprevir in patients with cirrhosis and contraindications to interferon and/or ribavirin. [2022]

13. Japan pubmed.ncbi.nlm.nih.gov

The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Micelle sensitized synchronous spectrofluorimetric approaches for the simultaneous determination of simeprevir and ledipasvir: Application to pharmaceutical formulations and human plasma. [2021]