EFFICACY and SAFETY of INTENSIVE PEGCETACOPLAN DOSING for the TREATMENT of ACUTE HEMOLYSIS in PATIENTS with PAROXYSMAL NOCTURNAL HEMOGLOBINURIA.

Griffin, M.; Patriquin, C.J.; Usuki, K.; Surova, E.; Zhang, D.; Szamozi, J.; Uchendu, U.; Szer, J.

EFFICACY and SAFETY of INTENSIVE PEGCETACOPLAN DOSING for the TREATMENT of ACUTE HEMOLYSIS in PATIENTS with PAROXYSMAL NOCTURNAL HEMOGLOBINURIA.

All Authors

Griffin, M.

Patriquin, C.J.

Usuki, K.

Surova, E.

Zhang, D.

Szamozi, J.

Uchendu, U.

Szer, J.

LTHT Author

Griffin, Morag

LTHT Department

Oncology
Haematology

Publication Date

2024

Item Type

Conference Abstract

Subject

ADOLESCENT , ADULT , CONTROLLED CLINICAL TRIALS AS TOPIC , DRUG THERAPY , FATIGUE , WOMEN , OUTCOME ASSESSMENT , HAEMOGLOBINURIA , DRUG DOSAGE CALCULATIONS , MEN , HAEMOGLOBINS

Abstract

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated hemolysis and increased thrombosis risk. Pegcetacoplan (PEG) is the first complement C3 inhibitor approved by the EMA/FDA for treatment of adults with PNH, and targets both intravascular and extravascular hemolysis. The ongoing open-label extension (OLE) APL2-307 study (NCT03531255) evaluates the long-term safety and efficacy of PEG in patients with PNH who had completed previous Phase 1-3 PEG trials. All patients with PNH on complement inhibitors are at risk of acute hemolysis (AH) events. As expected, some PEG-treated patients in the OLE study experienced AH events. We hypothesized that higher PEG dosing may help manage AH by achieving an immediate increase in PEG concentration. Aim(s): Examine efficacy and safety of intensive subcutaneous (SC) or intravenous (IV) PEG dosing to manage AH in a subset of patients from the OLE study. Method(s): Patients enrolled in the OLE study who experienced AH events warranting immediate intervention were offered intensive PEG at the discretion of the investigator and medical monitor. Eligibility criteria for intensive dosing included lactate dehydrogenase (LDH) >2x the upper limit of normal (ULN) and 1 new or worsening sign/symptom of hemolysis (e.g. decreased hemoglobin [Hb], hemoglobinuria, thrombosis, or fatigue). Patients with AH on a steady-state PEG dose of 1080 mg SC twice weekly received a single dose of 1080 mg IV, or 1080 mg SC on 3 consecutive days (intensive PEG treatment), followed by an increased maintenance regimen of 1080 mg SC every 3 days. For those receiving 1080 mg SC every 3 days or 3 times weekly when experiencing an event, intensive PEG treatment was followed by maintenance doses of 1080 mg SC 3 times weekly. A patient may receive repeated rounds of intensive dosing with a minimum gap of 14 days between rounds. Changes in Hb, LDH, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score were described. Adverse events were recorded and evaluated. Result(s): As of data cutoff (31/1/2023), 22 of 137 patients who entered the OLE study received intensive PEG to manage an AH event. Among them, mean (standard deviation [SD]) age was 45.7 (17.2) years, and 45.5% were female at OLE study entry. Baseline characteristics were representative of the overall OLE study population. Patients (N=22) had a median (interquartile range) LDH of 1566.7 (976.0, 2615.0) U/L (ULN: 226 U/L) prior to intensive dosing. Mean (SD) Hb level and FACIT-Fatigue score were 9.0 (1.9) g/dL and 31.4 (15.9), respectively. Dosing prior to intensive PEG was twice weekly (n=11), every 3 days (n=6), and 3 times weekly (n=5). Overall, 22 AH events (9 severe; 10 moderate; 3 mild) led to initiation of Round 1 of intensive dosing (SC n=15, IV n=7), after which the AH event resolved in 77% of patients (17/22). After 2 rounds of intensive dosing, AH events resolved in 4 patients and did not resolve in 1 patient. Median time to AH resolution was 14.5 days, as reported by investigators. Within 1 week of intensive dosing, there was a rapid decrease in median LDH level and concomitant improvements in Hb and FACITFatigue score (Figure). Throughout the study, most treatment-emergent adverse events (TEAEs) were mild/moderate, no cases of meningitis, thrombosis, or death occurred; in Round 1 (Day 1-21) of intensive dosing, there were no TEAEs leading to PEG discontinuation (Table). There were no new safety signals. Conclusion(s): Preliminary data suggest that intensive SC or IV PEG dosing was effective, safe, and well-tolerated in managing AH events in patients receiving PEG. (Table present).