Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Abstract

The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.

Keywords: ABC294640; dihydroceramide desaturase; glucosylceramide synthase; opaganib; sphingolipid; sphingosine kinase.

Figure 1

Multitargeting of sphingolipid metabolism by opaganib. Opaganib (aka ABC294640; Yeliva^®; 3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)-1-adamantanecarboxamide, hydrochloride salt) inhibits SK2 decreasing S1P synthesis, DES1 elevating dihydroceramides, and GCS reducing hexosylceramides.

Figure 2

Model for the therapeutic activity of opaganib against Covid-19. Sphingolipids regulate the ability of SARS-CoV-2 to replicate and thereby cause Covid-19. Firstly, pro-autophagic dihydroceramide levels are normally maintained at low levels by DES1. Inhibition of DES1 by opaganib elevates dihydroceramides and promotes autophagy which suppresses viral replication. Secondly, hexosylceramides are necessary for the endocytosis of virus bound to ACE2. Inhibition of GCS by opaganib reduces hexosylceramides thereby impairing the ability of the virus to enter target cells. Thirdly, SK2 regulates several signaling pathways, as well as the viral replication complex, that are required for viral replication. Inhibition of SK2 by opaganib therefore has multifaceted suppressive effects on viral infection and replication. Furthermore, opaganib suppression of inflammation and thrombosis mediated by SK2 may protect against multi-organ dysfunction in Covid-19 patients.