All patients initially required mechanical ventilation, and all recovered and survived with narsoplimab treatment. A manuscript detailing the results of the study has been accepted for publication in the peer-reviewed journal Immunobiology.
Rationale for the use of narsoplimab for treatment of COVID-19 patients with ARDS
In COVID-19, ARDS and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. MASP-2, the lectin pathway’s effector enzyme and the target for narsoplimab, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) – the virus responsible for COVID-19 – resulting in complement activation and lung injury. Numerous articles have been published detailing and further confirming specific aspects of the central role of endothelial injury, activation of the complement system and the lectin pathway and thrombosis development in COVID-19.
Narsoplimab also has been evaluated in patients in hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), another often-lethal thrombotic disorder associated with endothelial damage. In its pivotal HSCT-TMA trial, narsoplimab-treated patients demonstrated marked improvement in laboratory and clinical endpoints and unexpected survival. With FDA’s Breakthrough Therapy designation, submission of a rolling Biologics Licensing Application for narsoplimab is underway in this indication.
In addition to its inhibitory effect on lectin pathway activation, narsoplimab has been shown to block microvascular injury-associated thrombus formation as well as MASP-2-mediated activation of thrombin, kallikrein and factor XII. These unique anticoagulant effects may provide therapeutic benefits in both HSCT-TMA and COVID-19. Importantly, narsoplimab leaves the complement system’s classical pathway and adaptive immune response fully intact, and does not appear to increase infection risk.
Study Origin
The study was initiated in response to a request from treating physicians at the Papa Giovanni XXIII Hospital in Bergamo, Italy. The principal investigator, Alessandro Rambaldi, MD, Professor of Hematology at the University of Milan and Head of the Department of Hematology and Oncology at Papa Giovanni, was a lead investigator in the pivotal trial for narsoplimab in HSCT-TMA. Given the clinical and pathologic similarities between COVID-19 and HSCT-TMA, Professor Rambaldi requested that narsoplimab be made available under compassionate use for patients at his hospital in Bergamo, the initial epicenter of the COVID-19 pandemic in Europe.
“The patients that we treated with narsoplimab were critically ill, and the uniformly successful outcomes were truly impressive,” said Professor Rambaldi. “Also of importance in this terribly sick population studied, the drug was well tolerated, showing no adverse effects. The pathophysiology of COVID-19 appears to be consistent with that of stem cell transplant-associated TMA, and the mechanism of the lectin pathway inhibitor narsoplimab looks to be well suited to treat the often-lethal manifestations of both disorders. The outcomes in these six patients provide further evidence of the potential role of narsoplimab in treating diseases caused by endothelial damage.”
Study Results
In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab. The median age of the patients was 57 years (range 47 – 63 years), 83 percent were men, and all had comorbidities. At baseline, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer and aspartate aminotransferase (AST) – all markers of endothelial/cellular damage and/or inflammation – were significantly elevated. Narsoplimab treatment was begun within 48 hours of initiation of mechanical ventilation. Dosing occurred twice weekly for two to four weeks.
- All narsoplimab-treated patients recovered, survived and were discharged from the hospital
- Narsoplimab treatment was associated with rapid and sustained reduction across all assessed markers of endothelial/cellular damage and/or inflammation – CEC, IL-6, IL-8, CRP, LDH, D-dimer and AST
- Temporal patterns of laboratory markers were consistent with the observed clinical improvement
- In particular, CEC counts appear to be a reliable tool to evaluate endothelial damage and treatment response in this disease
- The temporal improvement of IL-6 and IL-8 with narsoplimab treatment suggests that lectin pathway activation may precede cytokine elevation in COVID-19 and that lectin pathway inhibition has a beneficial effect on the cytokine storm described in patients with COVID-19 infection
- The courses of two patients (one requiring intubation and the other on CPAP) were further complicated by massive bilateral pulmonary thromboses, and both patients recovered with narsoplimab, possibly benefitting from the drug’s anticoagulant effects
- Narsoplimab was well tolerated in the study and no adverse drug reactions were reported
- Two control groups with similar entry criteria and baseline characteristics were used for retrospective comparison, both showing substantial mortality rates at 32 percent and 53 percent
“We are excited by the results in Bergamo,” stated Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros. “The work at Papa Giovanni, for the first time, puts many of the COVID-19 pieces together – endothelial injury and the pathophysiology of COVID-19, complement activation and clinical evidence of the potential therapeutic role of the lectin pathway inhibitor narsoplimab in treating this disease. We look forward to being able to make narsoplimab broadly available to hospitalized COVID-19 patients.”
U.S. Government Support
Discussions are progressing between Omeros and offices in the Department of Health and Human Services, including the Biomedical Advanced Research and Development Authority (BARDA), along with the National Institutes of Health Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program regarding potential funding to accelerate large-scale manufacturing to enable broader availability of narsoplimab for COVID-19 patients and for other COVID-19-related programmatic activities.
Source: Company Press Release