K-877-ER + CSG452 for NASH

Recruiting at 151 trial locations

Overseen By Director, Clinical Operations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Kowa Research Institute, Inc.

Disqualifiers: Other liver diseases, Alcohol use, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

200 Participants Needed

Trial Summary

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the study team for guidance.

What data supports the effectiveness of the drug CSG452 (Tofogliflozin) for treating NASH?

Research shows that drugs similar to CSG452, known as SGLT2 inhibitors, have been effective in reducing liver fat and improving liver function in conditions like nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). For example, studies on other SGLT2 inhibitors like luseogliflozin and ipragliflozin have shown improvements in liver enzyme levels and liver fat content, suggesting potential benefits for NASH treatment. ^{1 2 3 4 5}

Is the combination of K-877-ER and CSG452 safe for humans?

Tofogliflozin, a component of the treatment, has been studied in mice and shown to reduce liver inflammation and fat accumulation without major safety concerns. In a human study with a similar drug, licogliflozin, diarrhea was common but mild, and no other major safety issues were found. ^{1 6 7 8 9}

How does the drug K-877-ER + CSG452 for NASH differ from other treatments?

The drug K-877-ER + CSG452 for NASH is unique because it includes tofogliflozin, a selective SGLT2 inhibitor, which works by promoting glucose excretion in urine, a mechanism primarily used for treating type 2 diabetes. This approach is novel for NASH, as there are no standard treatments for this condition. ^{10 11 12 13 14}

What is the purpose of this trial?

This trial is testing two new experimental drugs used together to treat adults with a serious liver disease. The combination is expected to be more effective than using each drug alone.

Research Team

Shona Pendse, MD, MMSc

Principal Investigator

Kowa Research Institute, Inc.

Eligibility Criteria

Adults with Nonalcoholic Steatohepatitis (NASH) and liver fibrosis can join this trial. They must have a minimum score on a liver health test, not be in another study recently, and not drink significant alcohol. Other chronic liver diseases or conditions outlined in the protocol also disqualify them.

Inclusion Criteria

My liver biopsy shows a NAS of 4 or more with some steatosis, inflammation, and ballooning.

My liver fibrosis stage is between 1 and below 4.

Meet all inclusion criteria outlined in clinical study protocol

Exclusion Criteria

I have a long-term liver condition.

Does not meet any other exclusion criteria outlined in clinical study protocol

Participation in another clinical trial involving an investigational agent within 30 days prior to signing the Informed Consent Form (ICF) for this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination therapy with K-877-ER and CSG452 for the treatment of NASH

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CSG452
• K-877-ER
• Placebo

Trial Overview The trial is testing two experimental drugs, K-877-ER and CSG452, against a placebo to see if they're effective for treating NASH with liver fibrosis. Participants will randomly receive either the drugs or placebo.

Participant Groups

Group I: K-877-ER Experimental Treatment 2 Interventions

K-877-ER and CSG452 Placebo QD

Group II: K-001 Experimental Treatment 2 Interventions

K-877-ER and CSG452 Once daily (QD)

Group III: CSG452 Experimental Treatment 2 Interventions

CSG452 and K-877-ER Placebo QD

Group IV: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Kowa Research Institute, Inc.

Lead Sponsor

Trials

46

Recruited

16,400+

Findings from Research

In a study of 107 patients with nonalcoholic steatohepatitis (NASH), the 150 mg dose of licogliflozin resulted in a significant 32% reduction in serum alanine aminotransferase levels after 12 weeks, indicating its potential efficacy in treating NASH.

While licogliflozin was generally well-tolerated, diarrhea was reported in a majority of patients, particularly at the higher dose, suggesting that while the drug shows promise, its side effects need to be monitored in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. Harrison, SA., Manghi, FP., Smith, WB., et al.[2023]

SGLT-2 inhibitors, tested in 12 randomized controlled trials involving 850 overweight or obese individuals with NAFLD, significantly reduced liver enzyme levels and liver fat content over a median treatment period of 24 weeks.

Specifically, treatment with SGLT-2 inhibitors led to a decrease in serum alanine aminotransferase by 10.0 IU/L and gamma-glutamyltransferase by 14.49 IU/L, indicating their potential efficacy in managing nonalcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Mantovani, A., Petracca, G., Csermely, A., et al.[2021]

In a case study of a 67-year-old woman with type 2 diabetes and NASH, the SGLT2 inhibitor ipragliflozin led to significant clinical and histological improvements in liver function after four months of treatment.

Key markers of liver health, including serum ALT and fibrotic markers, returned to normal levels, and imaging studies showed a reduction in liver fat deposits, suggesting ipragliflozin could be a promising treatment for NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Improvement of the Hepatic Histological Findings in a Patient with Non-alcoholic Steatohepatitis with Type 2 Diabetes after the Administration of the Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin. Takeda, A., Irahara, A., Nakano, A., et al.[2022]

In a rodent model of non-alcoholic steatohepatitis (NASH), the SGLT2 inhibitor luseogliflozin significantly improved glucose levels and reduced liver damage caused by a high-fat diet, indicating its potential efficacy in treating NASH.

Luseogliflozin not only decreased liver weight gain and lipid accumulation but also normalized fibrotic changes and inflammatory responses in the liver, suggesting it could be a promising treatment for NASH associated with diabetes in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Qiang, S., Nakatsu, Y., Seno, Y., et al.[2022]

In the EFFECT-II study involving 84 participants with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), the combination of dapagliflozin and omega-3 carboxylic acids significantly reduced liver fat content by 21% compared to placebo, indicating a strong therapeutic effect.

Dapagliflozin alone also demonstrated a disease-modifying effect by reducing biomarkers of hepatocyte injury, suggesting it may help improve liver health in patients with NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Eriksson, JW., Lundkvist, P., Jansson, PA., et al.[2021]

A 60-year-old woman with type 2 diabetes and diagnosed non-alcoholic steatohepatitis (NASH) showed significant improvement in liver function and glycemic control after 15 months of treatment with luseogliflozin, an SGLT2 inhibitor.

The treatment led to better liver enzyme levels and histological improvements in liver biopsies, suggesting that luseogliflozin could be a promising long-term therapy for patients with diabetes-related liver diseases like NAFLD/NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term luseogliflozin therapy improves histological activity of non-alcoholic steatohepatitis accompanied by type 2 diabetes mellitus. Fujimori, N., Tanaka, N., Kimura, T., et al.[2022]

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, significantly improved nonalcoholic steatohepatitis (NASH) in db/db mice over a 12-week treatment period, as indicated by decreased liver enzymes and NAFLD activity scores.

The drug works by reducing lipid accumulation, inflammation, and fibrosis in the liver, suggesting it could be a potential treatment option for NASH in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin protects against nonalcoholic steatohepatitis in db/db mice. Qiao, P., Jia, Y., Ma, A., et al.[2022]

In a study involving obese and diabetic mice, the sodium glucose cotransporter 2 inhibitor tofogliflozin significantly reduced the development of liver tumors and improved liver health by decreasing hepatic steatosis and inflammation.

Tofogliflozin showed potential as a chemopreventive agent against obesity-related liver cancer by lowering pro-inflammatory markers and serum glucose levels, although it did not inhibit the growth of liver cancer cells directly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Obara, K., Shirakami, Y., Maruta, A., et al.[2018]

Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have shown efficacy in improving liver conditions like non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in patients with type 2 diabetes mellitus (T2DM), based on a systematic review of 21 randomized controlled trials.

These medications, including dapagliflozin, empagliflozin, and canagliflozin, work by enhancing insulin sensitivity, promoting weight loss, and reducing glucotoxicity and lipotoxicity, leading to significant improvements in liver health markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. Bica, IC., Stoica, RA., Salmen, T., et al.[2023]

In a 24-month study involving 6,897 patients with type 2 diabetes, tofogliflozin was found to be safe and well-tolerated, with low incidence rates of adverse drug reactions (11.25%) and serious adverse reactions (1.21%).

Tofogliflozin significantly reduced glycated hemoglobin A1c by -0.70% and body weight by -2.95 kg, indicating its effectiveness in managing diabetes and promoting weight loss over the observation period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus: Results of 24-month interim analysis of a long-term post-marketing study (J-STEP/LT). Utsunomiya, K., Kakiuchi, S., Senda, M., et al.[2022]

Tofogliflozin, an oral medication for type 2 diabetes, works by promoting glucose excretion in urine without being affected by other common anti-diabetes drugs, indicating its unique mechanism of action.

In a study involving 108 healthy male volunteers, tofogliflozin did not alter the effectiveness or safety of other diabetes medications, suggesting it can be safely combined with them without adverse interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pharmacokinetic/Pharmacodynamic Drug-Drug Interaction Study of Tofogliflozin (a New SGLT2 Inhibitor) and Selected Anti-Type 2 Diabetes Mellitus Drugs. Kasahara, N., Fukase, H., Ohba, Y., et al.[2018]

Canagliflozin is effective in improving glycemic control in adults with type 2 diabetes, specifically by inhibiting SGLT2 to increase urinary glucose excretion, with a focus on patients having a baseline eGFR of 45 mL/min/1.73 m² or higher.

The safety analyses conducted during the clinical development of canagliflozin provided a comprehensive understanding of its impact on renal function, allowing for informed dosing recommendations in patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. Khurana, M., Vaidyanathan, J., Marathe, A., et al.[2022]

Tofogliflozin, a medication for type 2 diabetes, showed no clinically significant changes in its pharmacokinetics across patients with normal to severe renal impairment, suggesting it is safe for use in these populations.

While renal impairment did lead to decreased urinary glucose excretion, which may affect glycemic control, the overall safety profile remained positive, indicating no need for dose adjustments in patients with renal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus. Ikeda, S., Takano, Y., Schwab, D., et al.[2019]

Tofogliflozin, an oral medication for type 2 diabetes, was found to be rapidly absorbed and eliminated, with a dose-proportional increase in exposure up to 320 mg, indicating its effective pharmacokinetics in both Japanese and Caucasian subjects.

The drug was generally well tolerated with no serious adverse events or hypoglycemia reported, and it effectively increased urinary glucose excretion in a dose-dependent manner, suggesting its efficacy in managing blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects. Kasahara-Ito, N., Fukase, H., Ogama, Y., et al.[2022]

References

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

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. [2021]

3. Japan pubmed.ncbi.nlm.nih.gov

The Improvement of the Hepatic Histological Findings in a Patient with Non-alcoholic Steatohepatitis with Type 2 Diabetes after the Administration of the Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. [2021]

6. Japan pubmed.ncbi.nlm.nih.gov

Long-term luseogliflozin therapy improves histological activity of non-alcoholic steatohepatitis accompanied by type 2 diabetes mellitus. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Dapagliflozin protects against nonalcoholic steatohepatitis in db/db mice. [2022]

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

Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. [2023]

10. Japan pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus: Results of 24-month interim analysis of a long-term post-marketing study (J-STEP/LT). [2022]

11. Germany pubmed.ncbi.nlm.nih.gov

A Pharmacokinetic/Pharmacodynamic Drug-Drug Interaction Study of Tofogliflozin (a New SGLT2 Inhibitor) and Selected Anti-Type 2 Diabetes Mellitus Drugs. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. [2022]

13. Germany pubmed.ncbi.nlm.nih.gov

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus. [2019]

14. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects. [2022]