What is the trial and post-marketing data on hepatic cases of fezolinetant?

Of the patients meeting criteria of drug-related hepatic disorders, 528 were from post-marketing sources and 36 from trials after the SKYLIGHT program.

• More than 270,000 patients have been treated with fezolinetant worldwide since it was available in May 2023.¹ 
• Limitations of assessing post-marketing data include missing information (e.g. laboratory values, medical history), lack of follow-up, potential contributing factors not reported (e.g. comorbidities, concomitant medication), continually changing data and potential underreporting.¹ 
• As of November 2025, a total of 564 cases meeting the search criteria of drug-related hepatic disorders were retrieved cumulatively from the Astellas Global Safety Database; 528 cases were reported from post-marketing sources and 36 cases occurred in clinical trials after the SKYLIGHT program.¹ 
• Of the reported cases, 84% (475/564) were non-serious, with reported events being non-serious or ALT/AST (alanine aminotransferase/aspartate aminotransferase) elevations < 3 x ULN (upper limits of normal) or included qualitative statements about liver enzyme elevations without reporting laboratory values, and 16% (89/564) were serious based on events of interest.¹ 
• In 6% (24/391) of cases additional signs or symptoms of hepatotoxicity were reported, although the timing relative to liver test abnormalities was unclear due to limited information.¹
• In 4% (7/173) of reported cases, patients had concurrent increases in transaminases (> 3 x ULN) and bilirubin (> 2 x ULN).¹ 
• Drug-induced liver injury (DILI): there is no universal definition of DILI. The International DILI Expert Working Group definition² has been used for measuring DILI in the pharmacovigilance setting. Once other causes of liver injury have been excluded, DILI is defined as any of the following:
  • ALT ≥ 5 × ULN OR
  • ALT ≥ 3 × ULN, and total bilirubin > 2 × ULN, and no / minimal elevations in ALP OR (alkaline phosphatase)
  • ALP ≥ 2 × ULN when the source of increased ALP levels is the liver.
• The severity of DILI is further defined according to the presence or absence of clinical signs and symptoms.
• Overall, when laboratory details were reported, analysis revealed that 32 out of the 89 serious cases met the definition of DILI.¹ 
  • A committee of hepatology experts theorize that DILI of fezolinetant may be an idiosyncratic type which is a rare, unpredictable liver reaction that occurs in a small number of people, independent of dose.¹ It is often delayed in onset and driven by individual factors such as genetics, adaptive immune response with or without other factors such as mitochondrial stress. Diagnosis is by exclusion, and treatment involves stopping the drug and monitoring liver function.