Exploring the Potential of rNAPc2 as a Novel Therapeutic Approach in COVID-19: Insights from an International Phase 2b Trial


The global battle against the COVID-19 pandemic has been marked by continuous research and development of various therapeutic interventions.

Among these, rNAPc2, a novel tissue factor (TF) inhibitor, emerged as a candidate for investigation in the fight against severe cases of the disease.

This article delves into the comprehensive analysis of the findings from an international randomized phase 2b trial, known as ASPEN-COVID-19, which aimed to evaluate the safety and efficacy of rNAPc2 in hospitalized COVID-19 patients.

The Study Design and Rationale

The ASPEN-COVID-19 trial was meticulously designed in a time when efficacious treatments for COVID-19 had yet to be established. The trial enrolled hospitalized patients and compared the effects of rNAPc2 with those of heparin, a commonly used anticoagulant.

The primary endpoint was the change in D-dimer levels from baseline to day 8 or pre-day 8 discharge, offering insights into the thrombotic and coagulation activity in these patients. Notably, as the trial unfolded, the landscape of COVID-19 treatment evolved with the introduction of therapies like dexamethasone, remdesivir, and SARS-CoV-2 vaccines, potentially influencing the D-dimer levels and complicating the interpretation of the trial’s outcomes.

Safety and Tolerability of rNAPc2

One of the pivotal findings of the ASPEN-COVID-19 trial was the favorable safety profile of rNAPc2. The trial results indicated that treatment with rNAPc2 did not lead to an increased risk of bleeding or adverse events when compared with heparin. This observation underscores the importance of exploring novel therapeutic avenues that carry minimal safety concerns for severely ill patients.

D-Dimer Levels: An Enigmatic Biomarker

However, the trial’s assessment of the primary efficacy endpoint—change in D-dimer levels—revealed intriguing and complex results. Although the trial did not detect a significant difference in D-dimer level changes between rNAPc2 and heparin-treated groups, the interpretation of these findings must consider the multifaceted nature of D-dimer levels in COVID-19.

While traditionally elevated D-dimer levels signify hypercoagulability and hyperfibrinolysis, COVID-19 presents a unique scenario with paradoxical evidence of impaired fibrinolysis.

This conundrum has challenged the use of D-dimer as a straightforward therapeutic biomarker in COVID-19 treatment trials.

Disease Severity: A Key Factor

The study’s design also took into account the evolving understanding of COVID-19’s varying impacts on patients of different disease severities. Emerging evidence highlighted that the effects of anticoagulation might differ based on disease severity. Notably, therapeutic anticoagulation with heparin demonstrated benefits in non-critically ill patients, while critically ill patients did not experience the same advantages.

The ASPEN-COVID-19 trial also assessed the effects of rNAPc2 based on disease severity. Among non-severe patients, both rNAPc2 and heparin led to reduced D-dimer levels, with rNAPc2 showing a trend towards greater reduction.

This observation hints at the possibility that rNAPc2, like heparin, could be more effective in less severe cases of COVID-19.

Mechanistic Insights and Future Considerations

Interestingly, the trial delved into the potential mechanisms underlying the observed differences in outcomes. While heparin led to a greater reduction in IL-6, a key inflammatory mediator, compared to rNAPc2, this may be attributed to the diverse pathways through which these agents influence inflammation.

Heparin’s ability to target multiple coagulation mechanisms converging on thrombin generation could explain its more efficient inhibition of IL-6 levels. The findings underscore the intricate interplay between inflammation and coagulation in COVID-19 pathogenesis.

Future Prospects of rNAPc2

While the ASPEN-COVID-19 trial was a phase 2b study and not designed to definitively establish rNAPc2’s clinical utility, the results provide a solid foundation for further investigation. The trial indicated that rNAPc2’s safety and tolerability profiles are promising, and the potential benefit of the drug in less severe COVID-19 cases warrants deeper exploration.

The study also raises the question of whether combination therapy involving both rNAPc2 and heparin could provide synergistic benefits, given their different mechanisms of action.

Broader Implications Beyond COVID-19

Furthermore, the trial results stimulate consideration of rNAPc2’s applicability beyond COVID-19. Conditions characterized by TF-driven pathophysiology, such as cancer-associated thrombosis and cytokine storms related to oncological therapies, may offer avenues for rNAPc2 intervention. The persistence of thrombotic risk in COVID-19 patients treated with rNAPc2 or heparin underscores the complexity of the disease and suggests the possibility of using these agents in combination for enhanced therapeutic effects.


The ASPEN-COVID-19 trial’s outcomes shed light on the safety and potential efficacy of rNAPc2 in the treatment of severe COVID-19 cases. The trial’s nuanced findings emphasize the importance of considering disease severity, the multifaceted nature of D-dimer levels, and the intricate interplay between coagulation and inflammation.

While this phase 2b trial provides a stepping stone for further investigations, it also invites exploration of rNAPc2’s potential in broader contexts beyond COVID-19.

As the global medical community continues to unravel the complexities of COVID-19 pathogenesis, rNAPc2 stands as a promising candidate for addressing the intricate coagulation and inflammation dynamics in the disease.

reference link : https://www.ahajournals.org/doi/10.1161/ATVBAHA.122.318748#d1e1505


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