Narsoplimab Significantly Improves Outcomes in HSCT-TMA

Treatment with narsoplimab (OMS721) led to complete responses, improved laboratory markers, and encouraging 100-day survival rates in patients diagnosed with hematopoietic stem cell transplant-thrombotic microangiopathy.

Treatment with narsoplimab (OMS721) led to complete responses (CRs), improved laboratory markers, and encouraging 100-day survival rates in patients diagnosed with hematopoietic stem cell transplant (HSCT)-thrombotic microangiopathy (TMA), according to results of a pivotal, phase 2 trial (NCT02222545) that were virtually presented during the 2020 European Hematology Association Congress.

Findings showed that, in the entire population (n = 28), the CR rate with narsoplimab was 54% (95% CI, 34%-72%). For patients treated per protocol (4 weeks or more of dosing; n = 23), the CR rate was 65% (95% CI, 43%-84%).

“Most narsoplimab-treated patients achieved a complete response with a significant improvement in laboratory markers and in clinical status,” lead study author Alessandro Rambaldi, MD, a professor in the Department of Oncology and Hematology-Oncology at the University of Milan, and head of the Hematology and Bone Marrow Transplant Unit at ASST Papa Giovanni XXIII in Bergamo, Italy, stated in a virtual presentation during the meeting. “100-day survival was similarly impressive across all groups.”

HSCT-TMA is a rare, but often fatal, complication, Rambaldi explained, adding that transplant can cause marked endothelial injury through conditioning regimens, toxicities associated with immunosuppressive drugs, and infection. Endothelial injury therefore causes “endothelial injury syndromes,” which involves HSCT-TMA, graft-versus-host disease, diffuse alveolar hemorrhage, veno-occlusive disease, capillary leak syndrome, and idiopathic pneumonia syndrome. Moreover, endothelial injury activates the lectin pathway of complement.

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

“Blocking by narsoplimab the lectin pathway activation could mitigate endothelial injury and improve endothelial injury syndromes,” he said.

Previously, the FDA had granted narsoplimab breakthrough therapy designation for the treatment of patients with high-risk TA-TMA, as well as an orphan drug designation for TA-TMA therapy and complement-mediated TMA prevention.

In the single-arm, open-label, phase 2 trial, which was later converted to a pivotal trial following the breakthrough designation status and recommendations from the FDA, patients with HSCT-TMA were treated with once-weekly narsoplimab for at least 4 weeks, and could be given longer if necessary.

To be eligible for enrollment, patients must have been at least 18 years old at screening and had persistent HSCT-TMA, which was defined as having all of the following characteristics for at least 2 weeks following modification or discontinuation of calcineurin inhibitors: a decreased platelet count of below 150,000 per uL, evidence of microangiopathic hemolysis (presence of schistocytes, serum lactate dehydrogenase [LDH] greater than the upper limit of normal, or haptoglobin lower than the lower limit of normal), and renal dysfunction with doubling of serum creatinine compared with pretransplant levels.

Those who had prior eculizumab (Soliris) therapy within 3 months prior to screening, had a positive direct Coombs test, or active systemic bacterial or fungal infection that requires antimicrobial therapy were excluded from enrolling on the trial.

The primary end points were improvement in TMA laboratory markers of platelet count and LDH levels, as well as improvement in clinical status, and safety and tolerability. Secondary end points were survival and change from baseline in laboratory markers.

If a patient’s baseline platelet count was 20,000 per uL or less, an improvement was defined as triple baseline and absolute count of higher than 30,000 uL, as well as freedom from platelet transfusion. If the baseline level was more than 20,000 per uL, an improvement was noted if there was an increase in counts by at least 50% and an absolute count of more than 75,000 per uL and freedom from platelet transfusion. Additionally, LDH levels needed to be lower than 1.5 uL.

The clinical status end point was organ-specific, Rambaldi explained. For example, in the blood, the criteria for improvement in clinical outcome was transfusion independence. Improvement in renal function was defined as a higher than 40% reduction of creatinine, normalization of creatinine and reduction of creatinine of higher than 20%, or discontinuation of renal replacement therapy. Pulmonary status was improved with extubation and discontinuation of ventilator support, or discontinuation of noninvasive mechanical ventilation from continuous positive pressure ventilation. For gastrointestinal (GI) status, an improvement was noted through the GI measures in the Mount Sinai Acute GVHD International Consortium. Finally, an improvement in neurological status was limited to stroke, posterior reversible encephalopathy syndrome, seizures, and weakness.

Baseline characteristics showed that the mean age was 48 years, and 71% (n = 20) were male. Most patients (96%) had malignant underlying disease and had undergone transplant for such, with risk factors including: presence of GVHD (64%), significant infection (75%), noninfectious pulmonary complications (14%), and neurological signs (50%). The study population was considered to be one of high-risk, as 93% of patients had multiple risk factors for poor outcomes.

Additional results showed that treatment with narsoplimab led to a rapid increase in platelet counts in most patients and reached the threshold above 20,000 per uL, and transfusion independence was then defined at about 30,000 per uL (P = .001).

A similar trend was confirmed in LDH change from baseline over time in all patients, as most patients experienced a trend in downward LDH levels (P = .008). Similarly, an improvement in haptoglobin change from baseline was also observed in most patients following narsoplimab treatment (P <.001).

Moreover, 100-day survival rates following an HSCT-TMA diagnosis were also measured. In all treated patients, patients treated per protocol, and treatment responders (n = 15), the rates were 68%, 83%, and 93%, respectively.

Regarding safety, narsoplimab was well tolerated, with the most commonly reported adverse effects (AEs) defined as nausea (25%), vomiting (32.1%), diarrhea (28.6%), hypokalemia (25%), neutropenia (25%), and pyrexia (25%). These AEs are comparable with what are typically seen in a posttransplant patient population, Rambaldi added. Moreover, 21% of patients died on trial due to transplant-related causes.

Based on these data, Rambaldi noted that a rolling biologics license application for narsoplimab has been initiated with the FDA as a treatment for patients with HSCT-TMA, with a completion date targeted for the third quarter of 2020. A European marketing authorization application is also being prepared for narsoplimab in a similar indication.

Narsoplimab is also being explored in phase 3 trials for other lectin pathway-associated diseases, including IgA nephropathy (NCT03608033).


Rambaldi A. Smith M, Whitaker S, et al. Narsoplimab (OMS721) for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S262.