Narsoplimab Elicits High Response Rate, Improves Organ Function in HSCT-TMA

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Partner | Cancer Centers | <b>City of Hope</b>

Treatment with narsoplimab denoted high response rates and a significant improvement in laboratory thrombotic microangiopathy markers, translating to favorable overall survival in patients with hematopoietic stem cell transplantation–associated thrombotic microangiopathy.

Treatment with narsoplimab (OMS721) denoted high response rates and a significant improvement in laboratory thrombotic microangiopathy (TMA) markers, translating to favorable overall survival (OS) in patients with hematopoietic stem cell transplantation–associated TMA (HSCT-TMA), according to findings from a phase 2 study (NCT02222545) published in the Journal of Clinical Oncology.1

The results showed that the response rate was 61% (n = 17; 95% CI, 41%-79%) for the efficacy-evaluable population (n = 28). Additionally, improvement in organ function occurred in 74% of efficacy-evaluable patients.

Moreover, the 100-day survival after HSCT-TMA diagnosis was 68% (n = 19; 95% CI, 48%-84%) and 94% (n = 16; 95% CI, 71%-100%) in the evaluable population and responders (n = 17), respectively, and the median OS was 274 days (95% CI, 95% CI, 103-not estimable) in the evaluable population.

“In this prospective study, improvement in all response criteria following narsoplimab treatment indicates clinically relevant resolution of HSCT-TMA pathophysiology. Data across patient subgroups suggest broad treatment potential of narsoplimab for HSCT-TMA,” Samer K. Khaled, MD, of City of Hope, and coauthors wrote in the study publication.

HSCT-TMA is a serious complication associated with high mortality for which there is no approved treatment. HSCT-TMA develops from endothelial injury, which activates the lectin pathway of complement.

Narsoplimab is a monoclonal antibody that inhibits MASP-2, which is the effector enzyme of the lectin pathway, representing a potential novel approach for the treatment of HSCT-TMA. The agent’s mechanism served as the basis for its evaluation in adults with HSCT-TMA.

The agent received breakthrough therapy and orphan drug designations from the FDA for the treatment of patients with HSCT-TMA, but the FDA subsequently issued a complete response letter (CRL) requesting more information prior to approval.2 In January 2022, the developer of the agent, Omeros announced that they had submitted their response to the agency’s CRL.

In this single-arm, open-label, pivotal trial, patients with persistent HSCT-TMA received intravenous narsoplimab once weekly for 4 to 8 weeks. Patients were classified as having persistent HSCT-TMA if they had a platelet count under 150 x 109/L; evidence of microangiopathic hemolysis; and kidney dysfunction for at least 2 weeks after modification or discontinuation of their calcineurin inhibitor or at least 30 days after transplant.

Response rate served as the primary efficacy end point of the study and required clinical improvement in laboratory TMA markers including platelet count and lactate dehydrogenase (LDH), and organ function or freedom from transfusion. Safety was also evaluated as a primary objective. Key secondary end points included overall and 100-day survival, change from baseline in laboratory markers, and time to hematologic response.

Efficacy-evaluable patients included those who received at least one dose of narsoplimab, and safety-evaluable patients included those who received any amount of narsoplimab.

All patients had undergone allogeneic HSCT. The median age was 48 years (range, 22-68) and 71% of patients were male. There were no significant differences in baseline weight or body mass index between patients who received the weight-based dose of 4 mg/kg (n = 24) and those who received a fixed dose of 370 mg (n = 4).

All but 1 patient had a hematologic malignancy. Most patients had several baseline risk factors for poor outcomes, including significant infections, kidney dysfunction, GVHD, neurologic dysfunction, multiple organ TMA involvement, and pulmonary dysfunction.

Additional results demonstrated that components of the primary end point were similarly improved. Specifically, an improvement in laboratory TMA markers occurred in 61% (n = 17) of patients and improvement in organ function occurred in 74% (n = 20/27) of patients. Freedom from transfusion was achieved by 48% (n = 12/25) of patients

Regarding secondary end points, the median time to hematologic response was 36 days (range, 7-228) from first narsoplimab dose. The mean time-weighted average change from baseline in laboratory markers was as follows for platelet count (29.5 x 109/L; 95% CI, 13.5-45.6; P < .001), LDH (–111.9 U/L; 95% CI, –190.7 to –33.1; P = .007), hemoglobin (0.38 g/dL; 95% CI, –0.17-0.92; P = .164), haptoglobin (67.7 mg/dL; 95% CI, 40.2-95.2; P < .001), and creatinine (–0.18 mg/dL; 95% CI, –0.43-0.07; P = .156).

In a post-hoc subgroup analysis, the response rate for patients under age 65 and those age 65 or older was 58% and 75%, respectively. Response rates for patients with GVHD, significant infections, and multiple organ TMA involvement were 63%, 63%, and 64%, respectively. Response rates for patients with kidney, pulmonary, or gastrointestinal dysfunctions were 57%, 40%, and 100%, respectively.

In terms of safety, narsoplimab was well tolerated, and adverse effects (AEs) were consistent with those seen in this population, with no concerning safety signals or patient withdrawal due to an AE.

The most frequent treatment-emergent AEs were pyrexia, diarrhea, vomiting, nausea, neutropenia, fatigue, and hypokalemia.

The most common type of AE was infection in 71% of patients, including grade 2 or higher infection in 61% of patients. The most common grade 2 or higher infections were cytomegalovirus, lower respiratory tract infection, pneumonia, neutropenic sepsis, Klebsiella pneumoniae infection, septic shock, and staphylococcal bacteremia.


  1. Khaled SK, Claes K, Goh YT, et al. Narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, for the treatment of adult hematopoietic stem-cell transplantation–associated thrombotic microangiopathy. J Clin Oncol. 2022;40(22):2447-2457. doi:10.1200/JCO.21.02389
  2. Omeros confirms submission of response to FDA regarding the BLA for narsoplimab in the treatment of HSCT-TMA. News release. Omeros; January 19, 2022. Accessed September 20, 2022.