NEWS
Pegcetacoplan Improves Hematologic Response in PNH Treated With Eculizumab
For patients with paroxysmal nocturnal hemoglobinuria ( PNH ) who are receiving eculizumab yet have residual anemia , treatment with pegcetacoplan led to broad hemolysis control and improved hematologic response , according to results from a phase Ib study published in the American Journal of Hematology .
PNH is characterized by complementmediated hemolysis , explained the authors , led by Carlos de Castro , MD , from Duke University School of Medicine in Durham , North Carolina . While the FDA-approved C5 inhibitor eculizumab reduces intravascular hemolysis , it does not target C3-mediated extravascular hemolysis . Pegcetacoplan binds specifically to C3 and C3b , meaning it has the potential to block both intravascular and extravascular hemolysis .
With this phase Ib trial , Dr . de Castro and researchers hypothesized that , in individuals with PNH who remained anemic during treatment with eculizumab , complement blockade with pegcetacoplan would improve hemoglobin ( Hb ) levels and provide more complete hemolysis control .
The trial consisted of four cohorts ; the present report covers results from cohort 4 , in which patients with PNH who were taking eculizumab received pegcetacoplan 270 mg / day , in multiple doses , for 28 days . Patients experiencing a clinical benefit from treatment continued receiving daily doses of pegcetacoplan for up to two years , after which they could either enter an eight-week follow-up period or enroll in an extension study evaluating the long-term safety and efficacy of pegcetacoplan . Any patient who discontinued eculizumab therapy continued to receive pegcetacoplan monotherapy .
Primary endpoints included the number and severity of treatment-emergent adverse events ( AEs ) and pegcetacoplan pharmacokinetic parameters . The investigators also analyzed pharmacodynamic endpoints such as Hb , lactate dehydrogenase ( LDH ), total bilirubin , and serum C3 levels . The number of packed red blood cell ( RBC ) transfusions administered during the study also was recorded .
At the time of this report , six patients had received treatment for up to two years , including four who were enrolled in the extension phase and had discontinued eculizumab . A total of 427 treatment-emergent AEs were reported , of which 68 were considered possibly related to the study drug . Of these , 48 were related to the injection site .
Two patients experienced a total of 12 serious AEs , of which eight were considered treatment emergent . These included :
• pyrexia
• anemia
• lower gastrointestinal hemorrhage
• pancreatitis
• portal vein thrombosis
• sepsis
• urinary tract infection
• alanine aminotransferase / aspartate aminotransferase elevation
Pharmacokinetic analyses revealed a doseresponse relationship , the researchers reported , with higher pegcetacoplan serum concentration with increasing dose . Peak serum concentration was generally observed a week after dosing , reflecting a slow absorption phase by subcutaneous administration . An increase in serum C3 levels was observed in all participants , rising to 270 % of baseline values by two years of treatment .
The investigators also observed improvements in hematologic response from baseline , including increased in Hb levels by day 29 of pegcetacoplan treatment and reductions in the need for RBC transfusions .
“ The changes observed in biochemical markers over the course of this study support the broad control of hemolysis by pegcetacoplan , which allowed for a dose reduction in eculizumab therapy and , ultimately , a switch to pegcetacoplan monotherapy in all four subjects who completed the study ,” the researchers wrote . These four patients also achieved transfusion avoidance .
The findings of this early-phase study are limited by its open-label design and small number of patients . The authors noted that pegcetacoplan is being evaluated patients with treatment-naïve PNH and other studies are evaluating the optimal dosing regimen .
Study authors report relationships with Apellis Pharmaceuticals , the manufacturer of pegcetacoplan .
Reference de Castro C , Grossi F , Weitz IC , et al . C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab . Am J Hematol . 2020 ; 95:1334-1343 .
DDAVP Prevents Post-Intervention Bleeding Complications in Patients With Low von Willebrand Factor Levels
A recent study suggests 1-desamino-8-D-arginine vasopressin ( DDAVP ) prevents bleeding in patients with low von Willebrand factor ( VWF ) levels undergoing major and minor elective procedures . The researchers , led by Dearbhla Doherty , MD , of the St . James ’ s Hospital in Dublin , Ireland , added that while DDAVP is effective for certain subgroups of patients with low VWF levels , a personalized approach to management may also be important for the prevention of bleeding complications .
“[ Recent studies ] have demonstrated that a significant number of patients with plasma VWF : Ag in the 30-50 IU / dL range have a bleeding phenotype [ but the ] reason why some of these patients with mild to moderate reductions in plasma VWF display a significant bleeding phenotype remains unclear ,” Dr . Doherty and coauthors wrote . “ Given all these unanswered questions , the management of patients with low VWF , particularly at times of hemostatic challenge , continues to pose significant challenges for physicians .”
The retrospective study evaluated the efficacy and safety of various peri-procedure management options among 60 patients with well characterized low VWF . Patients included in the retrospective cohort were enrolled in the Low Von Willebrand in Ireland Cohort ( LoVIC ) study . Overall , patients underwent a total of 160 invasive procedures , at a median of two procedures per patient . Procedures were classified as either minor ( 68.1 %), major ( 6.9 %), or dental ( 25 %).
Approximately 87 % of patients in LoVIC study who underwent a procedure were female , and 90 % of patients were blood group O . The median age of the patients with low VWF who had undergone a procedure was significantly higher compared with the overall LoVIC cohort ( 45 vs . 41 years ; p < 0.01 ).
Dental procedures were mostly tooth extractions , while minor procedures largely included endoscopies as well as arthroscopies , joint injections , and skin lesion excision . Most of the major procedures included orthopedic , tonsillectomy , and abdominal surgery .
Bleeding complications were rare , occurring in only 3.8 % of the reviewed procedures . The mean age of patients who developed bleeding complications was 53.8 years .
Clinicians developed periprocedural management plans for patients based on personal bleeding histories , DDAVP trial responses , basal VWF levels , and the nature of the procedure . Treatment options were :
ASHClinicalNews . org ASH Clinical News
33