PF348 LONG TERM FOLLOW‐UP OF PNH PATIENTS TREATED WITH THE SMART ANTI‐HC5 ANTIBODY (SKY59/RO7112689) IN THE OPEN LABEL EXTENSION (OLE) OF THE COMPOSER TRIAL

Background: SKY59 is an anti‐C5 antibody applying SMART ∗ [Fukuzawa et al., SciRep 2017] to allow for infrequent, low volume SC dosing. Clinical results of healthy volunteers (Röth et al., Blood 2017 130:4750), PNH patients without prior anti C5 treatment (COMPOSER Part 2 (P2)) and PNH patients who were switched from eculizumab to SKY59 treatment (COMPOSER Part 3 (P3)) have been reported previously (Röth et al., Blood 2018 132:535). All patients included in P2 and P3 of COMPOSER had the possibility to roll over after 20 weeks into an OLE for continued treatment. Long term follow‐up data including the OLE are reported here. Aims: To study the long term safety and efficacy of SKY59. Methods: In the OLE patients stayed on the same treatment schedule they were using in the treatment phase. The study was approved by Ethics Committees and Health Authorities and conducted according to the principles of the declaration of Helsinki. Data of patients who were at least 20 weeks in the OLE are reported here. Results: 25 of 26 patients who participated in COMPOSER P2 and P3 chose to roll over to the OLE. At the time of submitting this abstract data of 15 patients (8 from part 2 and 7 from part 3) >20 weeks in the OLE were available (Table 1). The median total duration on treatment with SKY59 including the OLE was 68 weeks; 77 weeks for patients from P2 and 57 weeks for patients from P3. All 8 patients from P2 were on 170 mg QW s.c.. For patients originally enrolled in P3, 2 were on 170 mg QW, 3 were on 340 mg Q2W and 2 were on 680 mg Q4W, all s.c.. Patient baseline characteristics at the start of OLE are shown in table 1. Exposure/plasma levels of SKY59 in patients across the different dosing schedules support SC dosing. All patients maintained a minimal plasma level of 150 μg/ml of SKY59 at all times. Markers of terminal complement activation and intravascular hemolysis (CH50, LDH) remained at stable low values with no signs of loss of response throughout the observation period. No BTH events were reported in the OLES. No additional doses or dose intensification of SKY59 were observed. Hemoglobin levels remained stable with extended treatment duration. Transfusion requirements are shown in Table 1. Mean BL total C5 (TC5) concentration (n = 15, week 16: 195.5 μg/mL) (range: 106 ‐ 293 μg/mL) stabilized during long term follow‐up (week 36; n = 15) at 224.5 μg/mL (range: 144 – 355 μg/mL) Table 2. Although patients previously treated with eculizumab (P3) had started on a significantly higher TC5 level of 295 μg/mL (205 – 354 μg/mL) than eculizumab naïve patients (P2) with 140 μg/mL (73.6 – 184 μg/mL; p  < 0.001)), the mean TC5 concentration at week 36 was 225 μg/mL across all patients manifesting effective antigen disposing activity of SKY59. Safety: OLE treatment with SKY59 was well tolerated, particularly, no injection site AEs and a low incidence of headache was observed. There were 4 SAEs in 3 patients and all were not related to study drug (coronary stenosis, atrial fibrillation, abdominal pain and choledocholithiasis). No AEs resulted in withdrawal from the study or death. No clinically significant drug‐related trends were observed for laboratory parameters, vital signs or ECGs. Summary/Conclusion: SKY59 administered SC in a low volume is very well tolerated, has a good benefit/risk ratio and is efficacious in long term treatment of naive and eculizumab‐treated patients with PNH in all dosing regimens tested.Updated data will be presented at the meeting.