COVID-19 Therapeutic Opportunity

ST-001 nanoFenretinide may offer additional support in the battle against the COVID-19 pandemic

Fenretinide & nanoFenretinide Antiviral Activity

Published data makes the case for the use of fenretinide in treating COVID-19 (and by inference, SciTech’s lead oncology drug ST-001 nanoFenretinide). Fenretinide has recently demonstrated antiviral activity against MERS-CoV-2 (1), but also previously against Dengue, Zika (2), West Nile, HIV, and HCV viruses (3). This recorded antiviral activity, taken in conjunction with fenretinide’s known safety and tolerability profile, makes it an ideal candidate to repurpose for use in the prevention and/or treatment of early or late stage COVID-19 patients. Importantly, fenretinide has been shown to inhibit viral replication in infected cells and has demonstrated modes of action that may help suppress inflammation and the progression to cytokine storms that damage vital organs.

Fenretinide is the safer analogue of retinoic acid (vitamin A metabolite), for which the antiviral premise has been known for a long time. Fenretinide (also known as 4-HPR or N-(4-hydroxyphenyl) retinamide) was identified as one of 54 positive and usable hits in a recent high-throughput screen that assessed 1,247 drugs for inhibition of MERS-CoV-2. Initial screening parameters were set for >70% virus inhibition and >70% cell viability. Subsequent analysis indicated that fenretinide has a very promising dose-response curve for MERS-CoV-2. 

 

Summary of Fenretinide and nanoFenretinide Antiviral Activity

Fenretinide & nanoFenretinide Antiviral Mechanisms of Action (MOA)

Multiple investigations have demonstrated that fenretinide can act as an antiviral molecule through a variety of mechanisms of action (MOAs). These studies suggest that fenretinide might generate both direct and indirect effects in treating COVID-19. It acts on both RAR and RXR receptors, which is important because efficient, simultaneous and maximum pharmacological action on RAR and RXR pathways are demonstrably beneficial in viremia reduction. Indeed, 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia in several murine models (3). In the case of HIV, fenretinide treatment was shown to effectively inhibit HIV infection by re-directing the virus to the endocytic pathway (4).  Flavivirus replication is also directly inhibited by fenretinide (3). Overall, 4-HPR suppresses viral production and induces antiviral immune mechanisms.

 

Given below is a graphical depiction of ST-001 nanoFenretinide’s potential multiple mechanisms of action in the treatment of patients infected with COVID-19 (SARS-CoV-2).

 

A feature of fenretinide that has posed a major hurdle of clinical use of the molecule is its poor bioavailability. SciTech’s patented and differentiated drug delivery vehicle (SDV) overcomes this bioavailability hurdle and enables fenretinide to be distributed through the circulatory system in sufficient quantities and doses to reach the target cells and produce a therapeutic effect while maintaining low toxicity levels. ST-001 nanoFenretinide is the first therapeutic agent that can deliver a bolus amount of fenretinide by intravenous (IV) delivery. In the critical care setting of COVID-19, ST-001 will deliver therapeutic doses, fast, through routine IV administration.

 

SciTech recently evaluated ST-001 nanoFenretinide antiviral activity against SARS-CoV-2. ST-001 nanoFenretinide demonstrated inhibitory effects on SARS-CoV-2 virus replication in cell culture (blue highlighted entry in table above).

 

SciTech has submitted an expedited COVID-19 pre-IND application (PIND No. 150066) to the U.S. FDA that cross-references the company’s already FDA approved IND No. 135475 for nanoFenretinide treatment of a cancer indication cleared to enter the clinic (T-cell non-Hodgkin's lymphoma).

 

For additional information, download SciTech’s concept paper on ST-001 nanoFenretinide enhanced retinoid treatment of viral SARS (severe acute respiratory syndrome):

References

(1) Ko M, Chang SY, Byun SY, Choi I, d’Orengiani A-LPH d’Alexandry, Shum D, et al. Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19. bioRxiv. 2020 Mar 19;2020.02.25.965582. 
(2) Pitts JD, Li P-C, de Wispelaere M, Yang PL. Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus. Antiviral Res. 2017 Nov;147:124–30. 
(3) Carocci M, Hinshaw SM, Rodgers MA, Villareal VA, Burri DJ, Pilankatta R, et al. The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob Agents Chemother. 2015 Jan;59(1):85–95. 
(4) [Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]. - Abstract - Europe PMC [Internet]. [cited 2020 Apr 9]. Available from: https://europepmc.org/article/med/32164089.

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