Decisions regarding caplacizumab and eculizumab are complex, and include considerations over costs, side effects, and efficacy

Decisions regarding caplacizumab and eculizumab are complex, and include considerations over costs, side effects, and efficacy. ADAMTS13 (congenital TTP or Upshaw-Schulman Syndrome), compliment mediated TMA (atypical hemolytic uremic syndrome, aHUS), bacterial endotoxin mediated TMA K-7174 2HCl (classic hemolytic uremic syndrome, HUS) or TMA secondary to medication use, organ transplantation, cobalamin deficiency, HIV, lupus, and pregnancy [1]. Prior to the FDA approval of eculizumab for aHUS in 2011, no targeted therapies were available for the acute management of TMA aside from plasma exchange and immunosuppression if immune-mediated TTP was suspected. Recently however the von Willebrand K-7174 2HCl factor targeted nano-body caplacizumab was approved for immune-mediated TTP, bringing with it a novel mechanism in the acute management of TMA. While caplacizumab improved certain clinical endpoints as outlined below, it increases bleeding risks and adds substantial costs to the treatment of TTP [2]. Furthermore, it may take several days to arrive at an accurate diagnosis of immune-mediated TTP. The sine qua non of immune-mediated TTP is the detection of deficient ADAMTS13 activity (generally 10%) in the presence of an auto-antibody [1]. ADAMTS13 activity and antibody testing is performed at only a few commercial laboratories in the United States. Turnaround times vary between 1 and 3 days before results return, with some labs omitting weekend testing. Lack of immediate TTP diagnostics has mandated the use of empiric treatments for TMA until an accurate diagnosis can be made. The aforementioned factors (unclear clinical benefit, bleeding risks, costs, and potentially several days of diagnostic ambiguity) have led to equipoise at our center and likely others over the appropriate algorithm for the management of patients with acute idiopathic TMA. In the following manuscript we outline our discussions on potential approaches to acute TMA in the post caplacizumab era, highlighting the potential positives and negatives of each. Clinical data on the use of caplacizumab In February of 2019, the FDA approved caplacizumab for adult patients with immune-mediated TTP in combination with plasma exchange and immunosuppressive therapy based on the results of the Hercules trial [2]. In this randomized, placebo controlled trial caplacizumab use resulted in quicker normalization of platelet counts, (2.69 days vs. 2.88 days P = 0.01) and a decrease in the composite outcome of TTP-related death, recurrence of TTP, or of major thromboembolic events (12% vs. 49% P 0.001). However, benefits came with costs, as caplacizumab had increased rates of bleeding related adverse events (65% vs. LASS2 antibody 48%) and bleeding events defined as serious by the trial (11% vs. 1%). Patients may have only received 1 day of plasma exchange prior to enrollment and while a definitive diagnosis of immune-mediated TTP was not required for enrollment, ADAMTS13 activity at enrollment was ultimately below 10% in 85% of included patients [2]. The HERCULES trial also evaluated health care resource utilization noting that caplacizumab use led to fewer days of plasma exchange, lower volumes of plasma infusion, K-7174 2HCl and on average 65% shorter ICU stays, and 31% shorter duration of hospitalization [2]. The U.S. list price, or wholesale acquisition cost, for treating a typical case of immune-mediated TTP with Caplacizumab is estimated to be approximately $270,000 for a full treatment course [3]. The heterogeneity of TMA and predictors of immune-mediated TTP The incidence of true ADAMTS13 deficiency ( 10%) in patients with TMA is not well described. In two large cohorts of US TMA patients the incidence of severe ADAMTS13 deficiency was 62/214 (29%) and 71/152 (47%) with detectable inhibiting ADAMTS13 antibodies in 52/214 (24%) and 64/152 (42%) respectively [4]. The same cohorts were utilized for the.