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

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.
• Baseline eGFR > 20 ml/min/1.73 m2.
• Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) at the time of Screening.

• Documented history of:

  • At least 2 elevated alanine aminotransferase (ALT) levels, 1 ALT level >2 times (x) the upper limit of normal (ULN) and 1 ALT level >3 x ULN while the subject 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
  • At least 2 elevated ALT levels, 1 ALT level >2 x the subject's stable baseline level and 1 ALT level >3 x the subject's stable baseline level while the subject 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 tolvaptan 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 subject) without the use of a diuretic in concert with Kidney Disease: Improving Global Outcomes (KDIGO) "Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease".

Exclusion Criteria:

• Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds.
• Hypovolemia or inability to perceive thirst
• 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.
• Prior use of tolvaptan within the past 3 months or until a previously elevated ALT level has returned to ≤1 x ULN.
• Prior 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 past 3 months
• Requirement for chronic diuretic use
• 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 past 6 months (including cyst drainage or fenestration) or acute kidney injury within past 6 months
• 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 subject.
• Clinically significant liver disease or impairment or active chronic hepatitis at Screening.
• Elevated baseline levels of serum ALT or total bilirubin.
• History of drug or alcohol abuse in the past 2 years.