Sustained Improvements in Transfusion Requirements, Fatigue and Thrombosis with Eculizumab Treatment in Paroxysmal Nocturnal Hemoglobinuria.
Authors: Socié Gerard , Hillmen Peter , Muus Petra , Schubert Jörg , Dührsen Ulrich , Risitano Antonio M. , Rother Russell P. , Brodsky Robert A. , Szer Jeffrey 
Published: April 2020

Abstract
The long-term safety and efficacy of eculizumab (Soliris™) were examined in 187 patients with PNH initially enrolled in one of 3 parent trials (N=195) who continued to receive eculizumab in an extension trial for a median of 22 mos. All but 2 patients (99%) who enrolled in the extension trial (Phase 2 Pilot, Phase 3 TRIUMPH and SHEPHERD studies; N=187) were fully blocked at the prescribed dose (900 mg every 14±2 days); adjustment to 1200 mg every 14 days maintained complete complement blockade in the other 2 patients. Clinical benefits of eculizumab were sustained throughout the treatment period. Hemolysis (assessed by LDH) was reduced from a median of 2165 U/L at baseline to 274 U/L at 18 mos (p&lt;0.001, n=171), and 277 U/L at 54 mos (p=0.002, n=10). Transfusion requirements decreased from a median of 8 units (mean 8.7) during the 6 mos pre-treatment period to 0 units (mean 3.3) during the first and 0 (mean, 2.8) during the most recent 6 mos of eculizumab (p&lt;0.001 for each). FACIT-Fatigue instrument showed a median increase from baseline of 4.7 points in the first 6 mos (n=174) and a further improvement to 7.1 points in the most recent 6 mos (n=166) of treatment (p&lt;0.001 for each); an increase of 3 or more points is considered clinically meaningful. Multivariate analysis indicated that reduction in hemolysis was predictive of improvement in fatigue, independent of improvement in anemia (p=0.028). Improvements in global health, patient functioning, pain and dyspnea continued (p≤0.011; EORTC QLQ-C30). Reduction of thromboembolism (TE) with eculizumab was maintained. In matched time periods pre and post treatment, the TE event rate was reduced 90% from 12.53 (45 events/359 patient yrs) to 1.31 events/100 patient yrs (5 events/382 patient yrs, p&lt;0.001). The TE event rate was also reduced 91% (10.61 to 0.93 events/100 patient yrs) for patients receiving concomitant antithrombotics (p&lt;0.001, n=103). Eculizumab was well tolerated. Patients who discontinue eculizumab therapy should be monitored for risk of serious hemolysis; 16 patients discontinued treatment and none experienced serious hemolysis (LDH above pretreatment levels with adverse sequelae). Rates of infection-related AEs and serious AEs were similar for the first 6 mos (75.4%, 3.7%, respectively) and most recent 6 mos (64.2%, 5.9%) of treatment and were similar to 6 mos of placebo treatment in the TRIUMPH study (77.3%, 11.4%). Rates of sepsis-related AEs were similar for the first and most recent 6 mos (1.1% for each). All patients were vaccinated against Neisseria meningitidis; during 382 patient yrs of treatment, there were 2 cases of meningococcal septicemia (0.52 per 100 patient yrs) which were promptly treated and recovered without sequelae. The most common AEs were headache (55%), nasopharyngitis (46%), and upper respiratory tract infection (40%). SAEs were reported by 33% of patients; rates were similar during the first and most recent 6 mos of treatment (11% and 12%, respectively) and were less than that during 6 mos of placebo treatment (20%). These findings demonstrate that long-term eculizumab therapy provides sustained clinical benefit to and is well tolerated by patients with PNH.