Simufilam for Liver Failure

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called simufilam to observe its behavior in the blood of individuals with liver problems compared to healthy individuals. The goal is to understand how liver function affects the drug's presence and behavior in the body. Participants include those with mild to moderate liver issues diagnosed at least six months ago and healthy individuals without liver problems. This trial might suit those with stable chronic conditions like high blood pressure or diabetes. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that simufilam, the treatment tested in this trial, remains in the early stages of testing for liver failure. Specific safety information for its use in this condition is limited. However, simufilam has undergone testing in other studies for different diseases. In those studies, simufilam was generally well-tolerated, with common side effects being mild, such as headaches or tiredness. No serious safety issues were consistently reported in those trials. As a Phase 1 trial, the primary focus is on understanding the safety of simufilam in people with liver problems. Safety information is still being collected, and participants are closely monitored for any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for liver failure?

Unlike the standard treatments for liver failure, which often include supportive care and liver transplantation, Simufilam is unique because it targets inflammation and protein misfolding, which are key contributors to liver damage. Most current treatments focus on managing symptoms or replacing the liver entirely, but Simufilam aims to address the root causes at a molecular level. Researchers are excited about Simufilam because it has the potential to not only halt liver damage but possibly reverse some of the impairments, offering a groundbreaking approach to treating liver failure.

What evidence suggests that simufilam might be an effective treatment for liver failure?

This trial will study Simufilam in various participant groups, including healthy volunteers and those with mild or moderate hepatic impairment. Research has shown no evidence that Simufilam treats liver failure. Studies have primarily examined how Simufilam behaves in the body, particularly in individuals with liver issues. Researchers aim to understand how Simufilam affects certain proteins and body functions, which might assist with other health concerns. However, no proof exists yet that it directly aids in liver failure. Currently, the focus is on its safety and how the body processes it. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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 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]

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]

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]

Citations

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Simufilam for Liver Failure · Info for Participants The available research does not provide any data supporting the effectiveness of Simufilam for treating liver failure. The studies mentioned focus on other ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04388254

NCT04388254 | Simufilam (PTI-125), 100 mg, for Mild-to- ... The objectives of this study are to build the safety database for simufilam (PTI-125) and to investigate its effects on biomarkers, cognition and ...

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simufilam (PTI-125) / Cassava Delicious. January 07, 2025. A Pharmacokinetic Study of Simufilam in Subjects With Impaired Hepatic Function ... Trial completion • Hepatitis C • Liver Failure.

4. ctv.veeva.com ctv.veeva.com/study/a-pharmacokinetic-study-of-simufilam-in-subjects-with-impaired-hepatic-function

A Pharmacokinetic Study of Simufilam in Subjects With ... Evaluate simufilam levels in the blood of hepatically impaired individuals compared to Healthy individuals of similar demographics.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10339288/

Simufilam suppresses overactive mTOR and restores its ... Simufilam treatment improved the insulin-stimulated dissociation of FLNA—IRβ interaction. Blots were analyzed by densitometric quantitation (B).

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/55/NCT04932655/Prot_000.pdf

Cassava Sciences, Inc. Clinical Protocol PTI-125-05 ... CSF biomarker analyses were conducted blind to treatment and timepoint by an outside lab. These data suggest disease modification and replicate ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06390410?term=simufilam&limit=50&rank=2&checkSpell=

A Pharmacokinetic Study of Simufilam in Subjects With ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.