A BENEFIT ASSESSMENT of PEGCETACOPLAN DOSE INCREASE in the PHASE 3 PEGASUS TRIAL of PNH PATIENTS with DIFFICULT-TO-CONTROL DISEASE.

Abstract

Background Paroxysmal nocturnal haemoglobinuria (PNH) is caused by complement-mediated haemolysis, resulting in increased thrombosis risk and a substantial symptom burden. Complement 5 inhibitors (C5i) reduce intravascular haemolysis (IVH); however, residual IVH and emerging extravascular haemolysis (EVH) can lead to persistent anaemia and possible transfusions in C5i-treated patients (pts). Pegcetacoplan is a complement C3/C3b inhibitor providing broad control over IVH and EVH. In the Phase 3 PEGASUS trial of pts with persistent anaemia despite C5i treatment, pegcetacoplan demonstrated significant and sustained improvements in haematologic and clinical parameters versus C5i eculizumab. Pegcetacoplan is approved by FDA for adult PNH pts and by EMA for adult PNH pts with haemolytic anaemia. A serum concentration threshold of 442 mug/mL is required for pegcetacoplan to produce 90% of the proportional maximal change from baseline (EC90) in lactate dehydrogenase (LDH) improvement for C5i-treated pts (data on file). According to the EMA label, pegcetacoplan dose can be increased from 1080 mg twice weekly (BIW) to 1080 mg every three days (Q3D) when a patient experiences an LDH increase of >2x upper limit of normal (ULN), potentially indicating an acute haemolysis event that is pharmacokinetic or pharmacodynamic in nature.AimsPost-hoc analysis to assess the benefits of pegcetacoplan dose frequency increase in PEGASUS.MethodsPts from PEGASUS who had a dose up-titration from BIW to Q3D were included. Length of Q3D dosing (>=30 days), serum pegcetacoplan concentration, LDH decrease, resolution of haemolysis and/or occurrence of further haemolysis, study completion status, and adverse events during Q3D dosing were evaluated.Results15 pts had dose up-titration to Q3D (13 pts due to acute haemolysis, 10 of whom had a potential complement-amplifying condition before haemolysis, 1 pt due to haemolytic anaemia, and 1 pt due to fatigue). 12/15 pts received Q3D dosing for >=30 days and were further evaluated (Table). 8/12 pts benefited from dose increase and experienced an LDH decrease, of whom 7/8 had increased haemoglobin (Hb). 7/8 pts completed PEGASUS, entered the open-label 307 extension study (NCT03531255), and continued Q3D dosing. In 6/8 pts who benefited from Q3D dosing, serum pegcetacoplan concentration was <450 mug/mL during or before haemolysis and increased to >500 mug/mL after dose up-titration. Therefore, increased serum pegcetacoplan concentration with Q3D dosing may have contributed to improvements in LDH and Hb, and resolution of haemolysis. No significant benefit was shown with Q3D dosing in 4/12 pts, in whom serum pegcetacoplan concentration reached >EC90 for LDH in 3 pts, indicating other factors may have influenced response in these pts. During or after dose up-titration, 13/15 pts (87%) experienced >=1 treatment-emergent adverse event (TEAE). TEAEs were consistent with those observed in the BIW group and the known pegcetacoplan safety profile.Summary/ConclusionThe majority of evaluable PEGASUS pts (8/12) who received pegcetacoplan Q3D upon LDH >2x ULN benefited from dose up-titration. These 8 pts experienced LDH decrease with no new safety signals. As per pegcetacoplan's label, dose increase from 1080 mg BIW to Q3D should be considered if a patient experiences an LDH increase of >2x ULN.