CONSISTENT AND SUSTAINED EFFICACY AND SAFETY OF IPTACOPAN IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA REGARDLESS OF PRIOR HISTORY OF MAJOR ADVERSE VASCULAR EVENTS IN APPLY, APPOINT AND EXTENSION PROGRAM
Bing Han et al
Peking Union Medical College Hospital, Beijing, China
Background
- In the phase 3 APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) studies and the roll-over extension program (PNH-REP; NCT04747613) iptacopan showed sustained hematologic control and a favorable safety profile in patients with paroxysmal nocturnal hemoglobinuria (PNH). Patients with a prior history of major adverse vascular events (MAVEs) are a clinically important high-risk subgroup.
- The aim of the study is to report the safety and efficacy of iptacopan in patients from APPLY-PNH, APPOINT-PNH and the PNH-REP, according to prior history of MAVEs.
Methods
- All patients received iptacopan monotherapy 200 mg twice daily during the parent studies and the PNH-REP. The first dose was considered baseline. Efficacy assessments included levels of hemoglobin and lactate dehydrogenase (LDH), absolute reticulocyte count, transfusion avoidance, FACIT-fatigue score, breakthrough hemolysis (BTH) rates and prevention of MAVEs.
- Safety assessments included incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
Results
- The analysis population comprised 136 patients; 27 (19.9%) had a history of MAVE (HoM) and 109 (80.1%) had no history of MAVE (NHoM). Baseline demographics and clinical characteristics were similar between the subgroups. At data cut-off, study participation was completed or ongoing in 23/27 (85.1%) of HoM patients and 99/109 (90.8%) of NHoM patients.
- Hemolytic control was consistently sustained with up to 4 years’ follow up, regardless of whether patients had a prior history of MAVE (Figure). BTH occurred in 2/27 HoM patients (2.3 events/100 patient-years [py]) and 21/109 NHoM patients (9.7 events/100 py). A total of 6 MAVEs occurred in 5 patients, originating from the APPLY-PNH study (1.3 events/100 py). MAVEs occurred in 2/27 (7.4%) HoM patients.
- Of these, 1 patient with a history of portal thrombosis had another portal thrombosis (this patient had chosen to discontinue anticoagulation 2 weeks prior to the event) and an intestinal infarction (resulted in death); the other, with history of thrombophlebitis/deep vein thrombosis, had another event of thrombophlebitis/deep vein thrombosis, while not receiving anticoagulation. MAVEs occurred in 3/109 (2.8%) NHoM patients; all had ≥1 cardiovascular or cardiometabolic risk factor. Each had an event of transient ischemic attack.
- No patient in whom MAVEs occurred had BTH at any time. Overall, the most frequent TEAEs were COVID-19, nasopharyngitis and headache, which occurred in 44.4% and 50.5%, 18.5% and 26.6%, and 3.7% and 28.4% of patients with and without HoM, respectively. One patient in each subgroup had adverse events leading to treatment discontinuation. SAEs occurred in a higher proportion of HoM patients (14 [51.9%]; 33.8 events/100 py) than NHoM patients (36 [33.0%]; 20.3 events/100 py). SAEs related to infections occurred in 6 (22.2%; 13.5 events/100 py) and 18 (16.5%; 7.5 events/100 py) of HoM and NHoM patients, respectively.
Conclusion
- Hematologic control was consistent and sustained with iptacopan treatment in patients with PNH with or without prior history of MAVE. On-study MAVEs were rare and occurred in patients with pre-study MAVE history or cardiovascular or cardiometabolic risk factors. Iptacopan was well tolerated in both subgroups.
- These findings suggest durable hematologic control with iptacopan in patients with PNH, accompanied by low incidence of MAVEs, including in patients with prior events.
