Pharmacokinetics, Safety and Tolerability of ITF2357 in Participants With Chronic Hepatic Impairment and With Normal Hepatic Function

Inclusion Criteria

• •1. Male or female participants, between 18 and 75 years of age, inclusive.
• •2. Body weight between 60.0 and 110.0 kg, inclusive if male, and between 50.0 and 100.0 kg, inclusive if female, body mass index (BMI) between 18.00 and 34.99 kg/m2, inclusive.
• •3. Stable chronic liver disease assessed by medical history, physical examination, laboratory values.
• •4. Vital signs after 10 minutes resting in supine position within the following range \[or if out of range, considered not clinically significant (NCS) by the Investigator\]: 95 mmHg \< systolic blood pressure (SBP) \< 180 mmHg; 45 mmHg \< diastolic blood pressure (DBP) \< 100 mmHg; 40 bpm \< heart rate (HR) \< 100 bpm.
• •5. 12-lead ECG without clinically significant abnormality, in the judgment of the Investigator; in no circumstances were participants enrolled with corrected QT according to Fridericia (QTcF) \> 450 ms.
• •6. Any confirmed clinically relevant abnormal laboratory test that, on Investigator's judgment, was inconsistent with the subject's status as a patient with hepatic impairment. However, renal function assessed using the estimated glomerular filtration rate (eGFR) calculated by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula had to be strictly above 60 mL/min/1.73m².
• •7. Female participants who were not pregnant or nursing at screening and D-1, or who were not planning to become pregnant during study period and until 90 days after the IMP administration.
• •8. Female participants of non-childbearing potential, defined as one of the following:
• •1. At least 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. appropriate age) and follicle-stimulating hormone (FSH) in the range for menopausal female confirmed by blood test according to current local standards at screening;
• •2. Those with history of hysterectomy or surgical removal of both ovaries or bilateral tubal ligation performed at least 90 days prior to screening.
• •9. Female participant of childbearing potential and male participant (if sexually active with a woman of childbearing potential and not sterile) and his partner had to agree to use an adequate and highly effective method of contraception (according to Clinical Trials Coordination Group \[CTCG\] recommendations) during the study and for at least 90 days after the study drug administration for women and for men. Such methods include:
• •1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation oral, intravaginal or transdermal;
• •2. progestogen-only hormonal contraception associated with inhibition of ovulation oral, injectable or implantable;
• •3. intrauterine device (IUD);
• •4. intrauterine hormone-releasing system (IUS);
• •5. bilateral tubal occlusion;
• •6. vasectomized partner;
• •7. sexual abstinence (when in line with the preferred and usual subject's lifestyle).
• •Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception.
• •10. Had given written informed consent prior to any procedure related to the study.
• •11. Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research.
• •12. Not under any administrative or legal supervision.
• •13. For moderate HI cohort: Child-Pugh total score ranging from 7 to 9, inclusive.
• •14. For mild HI cohort: Child-Pugh total score ranging from 5 to 6, inclusive.
• •15. Male participants had to agree not to donate sperm from inclusion up to 3 months after ITF2357 dosing.
• •1. Male or female participants, between 18 and 75 years of age, inclusive.
• •2. Body weight within 10% of the mean body weight of the participants with moderate HI, and BMI between 18.00 and 34.99 kg/m2, inclusive.
• •3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
• •4. Vital signs after 10 minutes resting in the supine position within the following range (or if out of range, considered NCS by the Investigator): 95 mmHg \< SBP \< 140 mmHg; 45 mmHg \< DBP \< 90 mmHg; 40 bpm \< HR \< 100 bpm.
• •5. 12-lead ECG without clinically significant abnormality, in the judgment of the Investigator; in no circumstances participants could have been enrolled with QTcF \> 450 ms.
• •6. Laboratory parameters within the normal range, unless the Investigator considered an abnormality to be clinically irrelevant for healthy participants, except in the case of platelets, white blood cells and hemoglobin below lower limit of normal (LLN). However serum creatinine, alkaline phosphatase, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase), total bilirubin (unless the participant has documented Gilbert's syndrome, with a maximum bilirubin level lower than 3 x upper limit of normal (ULN), and any parameter for which there was an explicit stopping rule could not exceed the upper laboratory range; renal function assessed using the eGFR calculated by the 2021 CKD-EPI formula had to be strictly above 60 mL/min/1.73m².
• •7. Female participants who were not pregnant or nursing at screening and D-1, or who were not planning to become pregnant during study period and until 90 days after the IMP administration.
• •8. Female participants of non-childbearing potential, defined as one of the following:
• •1. At least 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. appropriate age) and FSH in the range for menopausal female confirmed by blood test according to current local standards at screening.
• •2. Those with history of hysterectomy or surgical removal of both ovaries or bilateral tubal ligation performed at least 90 days prior to screening.
• •9. Female participant of childbearing potential and male participant (if sexually active with a woman of childbearing potential and not sterile) and his partner had to agree to use an adequate and highly effective method of contraception (according to CTCG recommendations) during the study and for at least 90 days after the study drug administration for women and for men. Such methods include:
• •1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation oral, intravaginal or transdermal;
• •2. progestogen-only hormonal contraception associated with inhibition of ovulation oral, injectable or implantable;
• •3. intrauterine device (IUD);
• •4. intrauterine hormone-releasing system (IUS);
• •5. bilateral tubal occlusion;
• •6. vasectomized partner;
• •7. sexual abstinence (when in line with the preferred and usual subject's lifestyle).
• •Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM were not acceptable methods of contraception.
• •10. Had given written informed consent prior to any procedure related to the study.
• •11. Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research.
• •12. Not under any administrative or legal supervision.
• •13. Male participants had to agree not to donate sperm from inclusion up to 3 months after ITF2357 dosing.