Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease (ALERT)

Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease

An Open-Label Study of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease Who Previously Experienced Abnormal Liver Chemistry Test Results While Receiving Tolvaptan: The ALERT Study

The decision is based on a thorough reassessment of the commercial potential of lixivaptan as a potential best-in-class therapy for patients with ADPKD

This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver safety, and efficacy of lixivaptan in participants who previously experienced liver chemistry test abnormalities while treated with tolvaptan and were permanently discontinued from the drug for that reason. Up to 50 eligible participants will be enrolled and treated with lixivaptan for 52 weeks following titration to an optimal dose.

This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver safety, and efficacy of lixivaptan in participants who previously experienced liver chemistry test abnormalities while treated with tolvaptan and were permanently discontinued from the drug for that reason. Up to 50 participants will be enrolled and treated. Evaluations will include frequent testing of liver chemistry (every week during the Baseline and Titration Periods and every 4 weeks during the Maintenance Period), physical examinations, vital signs, safety labs (serum chemistry, hematology, urinalysis), estimated glomerular filtration rate (eGFR), urine specific gravity and osmolality determinations and trough serum concentration of lixivaptan. After meeting entry criteria during a 1- to 3-week Screening Period that can extend up to 8 weeks for medication adjustment, participants will enter a 3-week no study treatment Baseline Period to obtain baseline measurements followed by a 3- to 6-week Titration Period during which lixivaptan administered twice daily (BID) will be titrated to a dose that is tolerated and results in a reduced trough urine specific gravity, or to the maximum dose level. The minimum dose to enter the Maintenance Period is 100 mg BID. Treatment will continue for up to 52 weeks (12 months) after which study drug will be held, and final assessments obtained during the Follow-up Period of 4 weeks. The total study duration will be up to approximately 73 weeks (16.8 months).

Number of Participants Who Develop Serum Alanine Aminotransferase (ALT) Levels >3 × ULN During the Titration or Maintenance Periods Assessed to be Related to Lixivaptan and Result in Discontinuation of Lixivaptan Treatment

Number of participants who develop serum ALT levels >3 x ULN which are assessed by the independent Hepatic Events Review Committee (HERC) to be at least probably related to lixivaptan and result in the discontinuation of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.

Number of Participants Who Develop Serum ALT Levels >5 × ULN During the Titration or Maintenance Periods Assessed to be Related to Lixivaptan and Result in Discontinuation of Lixivaptan Treatment

Number of participants who develop serum ALT levels >5 x ULN which are assessed by the independent HERC to be at least probably related to lixivaptan and result in the discontinuation of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.

Number of Participants Who Develop Serum ALT Levels >3 × ULN During the Titration or Maintenance Periods Assessed to be Related to Lixivaptan and Result in Dose Reduction of Lixivaptan Treatment

Number of participants who develop serum ALT levels >3 x ULN which are assessed by the independent HERC to be at least probably related to lixivaptan and result in the dose reduction of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.

Number of participants with TEAEs during the Titration Period, the Maintenance Period, or the Follow-up Period.

Number of participants with clinical laboratory findings (non-hepatic clinical chemistry, hematology, and urinalysis) recorded during the Titration Period, the Maintenance Period, or the Follow-up Period, and considered to be potentially clinically important.

Number of participants with vital signs findings (heart rate, diastolic and systolic blood pressure, weight) recorded during the Titration Period, the Maintenance Period, or the Follow-up Period, and considered to be potentially clinically important.

Number of Participants With Potentially Clinically Important 12-lead Electrocardiogram (ECG) Findings

Number of participants with ECG findings recorded during the Titration Period, the Maintenance Period, or the Follow-up Period, and considered to be potentially clinically important (defined as a QT interval corrected for heart rate according to Fridericia's formula [QTcF] ≥ 450 msec).

Baseline eGFR is defined as the mean of the 3 eGFR assessments obtained during the Baseline Period (if any values are missing, the remaining values will be used to determine the baseline eGFR). The endpoint eGFR is defined as the mean of 3 eGFR assessments obtained during the Follow-up Period (if any values are missing, the remaining values will be used to determine the endpoint eGFR). The change in eGFR from Baseline to Final Assessment will be provided.

Inclusion Criteria: Male or female, between 18 and 65 years of age (inclusive) at the time of Screening. Documented diagnosis of ADPKD by imaging or genetic analysis previously treated with tolvaptan for that indication. Screening eGFR ≥ 20 mL/min/1.73 m^2. Body mass index (BMI) between 18 and 35 kg/m^2 (inclusive) at the time of Screening. Documented history of: Based on upper limit of normal (ULN): At least 2 elevated alanine aminotransferase (ALT) levels; 1 ALT level >2 x ULN and 1 ALT level >3 x ULN while the participant was receiving tolvaptan, or within 4 weeks after tolvaptan discontinuation, with no other explanation for the ALT elevations. The 2 elevated ALT measurements could be recorded during the same instance of liver injury or during distinct instances; OR Based on the participant's stable baseline as determined by the Investigator: At least 2 elevated ALT levels; 1 ALT level >2 x the participant's stable baseline level and 1 ALT level >3 x the participant's stable baseline level while the participant was receiving tolvaptan, or within 4 weeks after tolvaptan discontinuation, with no other explanation for the ALT elevations; provided that at least one ALT elevation was >2 x ULN. The 2 elevated ALT measurements could be recorded during the same instance of liver injury or during distinct instances; OR A pattern of ALT elevations deemed by the Investigator to be consistent with tolvaptan liver injury with no other explanation for the ALT elevations and agreement of the medical monitor and sponsor. Permanent discontinuation of prior tolvaptan treatment because of the ALT abnormality. If re-challenge with tolvaptan was performed, the ALT level must have increased to >2 x ULN upon rechallenge or the ALT level was increasing but tolvaptan was stopped for patient safety reasons before it reached > 2 x ULN after having previously normalized. Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the participant) without the use of a diuretic in concert with Kidney Disease: Improving Global Outcomes "Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease". Willing to practice acceptable methods of birth control (both males who have partners of child-bearing potential and females of childbearing potential). Able to provide informed consent. Exclusion Criteria: Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds. Hypovolemia at Screening. Abnormal serum sodium concentration at Screening. Subjects who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to Screening. Subjects who are taking, have taken within the past 2 weeks, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John's wort. Simvastatin at total daily doses >10 mg or amlodipine at total daily doses >5 mg. Use of tolvaptan within the 3 months prior to Screening or until a previously elevated ALT level has returned to ≤1 x ULN for at least 3 months. Use of lixivaptan or participation in a clinical study with lixivaptan within the 3 months prior to Screening. Use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, venglustat, demeclocycline, or mammalian Target of Rapamycin (mTOR) kinase inhibitors (e.g., everolimus, sirolimus, etc.) to treat ADPKD within the 3 months prior to Screening. Requirement for chronic diuretic use. History of advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant renal disease, transplanted kidney, recent kidney surgery within the 6 months prior to Screening (including cyst drainage or fenestration) or acute kidney injury within the 6 months prior to Screening. Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia). New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the participant. Clinically significant liver disease or impairment or active chronic hepatitis at Screening. Positive test results for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) antibody. History of infection with human immunodeficiency virus (HIV) unless the participant is stable and doing well on a non-CYP interacting anti-retroviral therapy (ART) regimen and who has not required more than 2 changes in their ART regimen. ALT or aspartate aminotransferase (AST) values >1.5 x ULN during Screening/Baseline. Total bilirubin values >1.0 x ULN during Screening/Baseline. History of drug or alcohol abuse in the 2 years prior to Screening. Any malignancy within the 5 years prior to Screening except for basal cell carcinoma successfully treated with local therapy. Medical history or findings that preclude safe participation in the study or who are likely to be non-compliant with study procedures in the opinion of the Investigator or medical monitor.

Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009;32(1):55-68. doi: 10.2165/00002018-200932010-00005.