Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy

Abstract

Purpose: Hematopoietic stem-cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA.

Methods: In this single-arm open-label pivotal trial (NCT02222545), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed.

Results: The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern.

Conclusion: In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

FIG 1.

Definition of primary efficacy end point. Freedom from transfusion represented an absence of any combination of RBC transfusions and/or platelet transfusions for at least 4 weeks. Transfusion of any type was not an inclusion criterion; however, freedom from transfusion was included in the end point because it is a clinical benefit. GVHD, graft versus host disease; LDH, lactate dehydrogenase; MAGIC, Mount Sinai Acute GVHD International Consortium; TMA, thrombotic microangiopathy.

FIG 2.

Flow diagram. Patient disposition during the core study period. Completion of study drug administration was defined by the assigned treatment (ie, eight once-weekly doses in stage III). aHUS, atypical hemolytic uremic syndrome; HSCT-TMA, hematopoietic stem-cell transplantation–associated thrombotic microangiopathy; QTc, corrected QT interval; TTP, thrombotic thrombocytopenic purpura.

FIG 3.

Survival with narsoplimab treatment. (A) 100-day survival after HSCT-TMA diagnosis. (B) Kaplan-Meier plot of overall survival after HSCT-TMA diagnosis. HSCT-TMA, hematopoietic stem-cell transplantation–associated thrombotic microangiopathy; NE, not estimable.

FIG 4.

Change in laboratory markers. LS mean change from baseline over time for FAS: (A) platelet count (10⁹ per L), (B) LDH (U/L), (C) hemoglobin (g/dL), (D) haptoglobin (mg/dL), and (E) creatinine (mg/dL). No data were imputed; all available data were included. P-values from time-weighted average change from baseline using one-sample t-test. FAS, full analysis set; LDH, lactate dehydrogenase; LS, least squares.