POS-337 CANADIAN REAL-WORLD ASSESMENT OF TOLVAPTAN IN ADPKD: C-MAJOR STUDY AND SAFETY MONITORING AND DISTRIBUTION PROGRAM

Abstract

Tolvaptan is the only approved treatment in Canada for slowing renal function decline and kidney enlargement in ADPKD patients. As per Health Canada requirements, a patient registry evaluating long-term clinical outcomes (the C-MAJOR study) and a hepatic safety monitoring and distribution program (the HSMDP) to mitigate the risk of liver injury were implemented and have been ongoing nationally for 5 years. The aim of this interim analysis is to describe baseline characteristics of patients at initiation of tolvaptan through the C-MAJOR study and to report on rates of treatment persistence and liver test abnormalities through the HSMDP. C-MAJOR is a non-interventional, multi-centre study of Canadian ADPKD patients treated with tolvaptan. The HSMDP ensures tolvaptan is dispensed under controlled liver enzyme and function monitoring. As of April 2020, 398 patients, 51% female, were enrolled in C-MAJOR. At baseline, mean (SD) age was 45.1 (11.5) years, BP was 129.4 (13.4)/83.1 (10.0) mmHg and eGFR was 63.6 (27.8) mL/min/1.73 m2. Total kidney volume was 1949 (1562) mL, 80.7% of patients had family history of ADPKD and 39.4% had family history of early end-stage renal disease. As per Mayo classification, 90.2% were at high risk of disease progression (1C-D-E). Most common ADPKD clinical manifestations were hypertension (83.2%), hepatic cysts (69.6%) and kidney pain (24.1%). Over a mean (SD) follow-up of 2.0 (1.0) years, adverse events were reported in 82.7% of patients, most common being polyuria (19.6%), fatigue (18.6%), and nocturia (15.1%). Over a mean follow-up of 23.0 (SD = 17.6) months in the HSMDP, 2.4% (n=39) of the 1,600 patients who received at least one shipment of tolvaptan reported an elevation of transaminases >3x ULN. There were 0.3% (n=5) of patients meeting the guidelines for permanent discontinuation. No cases of drug-induced liver injury were reported. Treatment discontinuation rates at 12, 24 and 36 months were 14%, 21% and 26%, respectively. This analysis provides Canadian real-world evidence of high-risk for disease progression at tolvaptan initiation, 3-y persistence data similar to phase III studies and HSMDP data showing that tolvaptan was permanently discontinued in 0.3% of patients because of hepatic effects. This abstract was also submitted for the ASN 2020 congress.