Narsoplimab Shows Impressive Responses, Survival Benefit in High-Risk HSCT-TMA


February 8, 2021 — Narsoplimab demonstrated clinical activity and a favorable survival benefit in patients with high-risk hematopoietic stem cell transplant-associated thrombotic microangiopathy, according to updated results of a pivotal phase 2 trial.

Samer K. Khaled, MD, of City of Hope

Samer K. Khaled, MD

Narsoplimab (OMS721) demonstrated clinical activity and a favorable survival benefit in patients with high-risk hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), according to updated results of a pivotal phase 2 trial (NCT02222545) that were virtually presented at the 2021 Transplantation & Cellular Therapy Meetings.

Findings showed that narsoplimab elicited a 61% objective response rate (ORR; 95% CI, 40.6%-78.5%; P <.0001) in the full analysis set of patients (n = 28) and a 74% ORR (95% CI, 51.6%-89.8%; P <.0001) in the per-protocol group (n = 23).

The post HSCT-TMA 100-day survival rates were 68% and 83%, respectively; in those who had complete responses (CRs), the 100-day survival rate was 94%. The median overall survival (OS) in the full analysis, per-protocol, and CR populations were 274 days, 361 days, and not estimable, respectively.

Additionally, 74% and 77% of patients, in the full-analysis and PP sets, respectively, experienced substantial improvements in organ function.

“There was a substantial survival benefit across all groups, especially among responders,” lead study author Samer K. Khaled, MD, medical director of Hematology/HCT Clinical Operations, director of the Hematology/HCT BMT Fellowship, and associate clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, said in a presentation during the meeting. “Narsoplimab was well tolerated in this high-risk population and there were no safety concerns that were observed in narsoplimab-treated patients.”

Endothelial injury mediated by conditioning regimens, immunosuppressants, infection, and graft-versus-host disease (GVHD) appear to be a common pathway for several early transplant complications, Khaled explained. Moreover, it is linked with significant morbidity and mortality. Currently, there are no approved therapies for this condition, which reportedly occurs in 12% to 39% of patients undergoing allogeneic transplant.

Narsoplimab is an investigational, fully human IgG4 monoclonal antibody that inhibits mannan-binding lectin-associated serine protease-2 (MASP-2). MASP-2 is the effector enzyme of the lectin pathway of complement, and narsoplimab is designed to leave the classical pathway function fully intact.

In January 2021, the FDA granted a priority review designation to a biologics license application for narsoplimab for the treatment of HSCT-TMA, according to an announcement from Omeros Corporation, the manufacturer of the agent. The regulatory agency is expected to make a decision on the application by July 17, 2021.

In earlier results of the phase 2 trial, narsoplimab was found to also induce CRs, show improved laboratory markers, and demonstrate promising 100-day survival rates in patient with HSCT-TMA.

In the single-arm, open-label, phase 2 trial, investigators enrolled 28 patients to receive narsoplimab intravenously once weekly for 4 or 8 weeks, along with a 6-week follow-up period. Patients came from 10 study centers across 8 countries that had enrolled at least 1 patient between 2014 and 2019. Following the FDA breakthrough therapy designation of narsoplimab, this trial was converted to a pivotal study.

Patients were at least 18 years old at screening and had persistent HSCT-TMA, which must have fit the following criteria at least 2 weeks following medication or discontinuation of calcineurin inhibitors: platelet count <150,000 uL, evidence of microangiopathic hemolysis, and renal dysfunction. Those who received prior eculizumab (Soliris) within 3 months prior to screening, had a positive direct Coombs test, and had serious uncontrolled infections at entry. However, those with controlled serious infections receiving anti-infective treatment at study entry were permitted.

Khaled also noted that patients who had coexisting conditions that generally increase the risk of poor outcomes were not excluded from study enrollment. These included patients with GVHD, recent controlled infection, refractory underlying disease or relapse, and multiple organ dysfunction.

The coprimary end points were safety and tolerability, as well as efficacy, which was measured in 2 areas: improvement in laboratory TMA markers, through platelet count and lactate dehydrogenase (LDH) levels, and improvement in clinical status. Secondary end points included 100-day survival rate and change from baseline in laboratory markers.

The FDA-agreed efficacy threshold for the response rate end point was 15%.

The data presented at the 2021 Transplantation & Cellular Therapy Meetings comprised the full analysis set of patients receiving at least 1 dose of narsoplimab (n = 28), and those in the per-protocol (PP) population, whom received the protocol-specified narsoplimab treatment for at least 4 weeks (n = 23).

In the full analysis set, the median age was 48 years (range, 22-68), and 71.4% of patients were male. Most (61%) were White or Asian (25%), and 96.4% of patients had a hematologic cancer. The median baseline platelet count was 26 x 109/L, the median baseline LDH was 558.5 IU/L, and the median baseline creatinine was 1.65 mg/dL. Moreover, the median baseline hemoglobin and haptoglobin was 8.9 g/dL and 2.9 mg/dL.

Most patients had multiple comorbidities, putting them at high risk, including renal dysfunction (75%), pulmonary dysfunction (17.9%), neurological dysfunction (57.1%), GVHD (67.9%), and significant infection (85.7%). Most patients (89%) had transfusions within 2 weeks prior to or on the first dose of narsoplimab, and half of patients had multiple organ TMA involvement.

The median time from transplant to HSCT-TMA diagnosis was 73.5 days and the median time from current HSCT-TMA diagnosis to first dose of narsoplimab was 13.5 days. The median time from transplant to first narsoplimab treatment was 119 days.

“It is important to note that 93% of the patients had multiple risk factors for poor outcomes,” said Khaled.

Additional data showed that similar responses were observed across all prespecified patient subgroups. Moreover, narsoplimab led to improvements in platelet count (P <.001) and LDH (P = .007) from baseline, as well as hemoglobin (P = .164) and haptoglobin (P <.001), in the full analysis set.

Regarding safety, there were no unexpected adverse events (AEs) and narsoplimab was found to be well tolerated, Khaled said. The most commonly reported AEs were nausea (25.0%), vomiting (32.1%), diarrhea (32.1%), hypokalemia (21.4%), neutropenia (25.0%), and pyrexia (35.7%).

“The observed adverse events are comparable to these typically seen in the posttransplant population,” Khaled said.

Six patients died on study, all of which were common in HSCT and included neutropenic sepsis, septic shock, acute myeloid leukemia, TMA, and GVHD.

Narsoplimab is also being evaluated in phase 3 trials for other lectin pathway–associated conditions with endothelial injury, including IgA nephropathy (NCT03608033) and atypical hemolytic uremic syndrome (NCT03205995).


  1. Khaled SK, Boelens JJ, Cairo MS, et al. Narsoplimab (OMS721), a Masp-2 Inhibitor, for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 26.
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