Sorrento Therapeutics Announces First Subject Dosed in a Phase I Clinical Study of STI-1558, an Oral Mpro Inhibitor as a Standalone Treatment and Prevention of COVID-19 Without Co-Administration of Ritonavir Booster

• STI-1558, an oral SARS-CoV-2 main protease inhibitor, is specifically designed as a standalone treatment and prevention of COVID-19 without the co-administration of ritonavir as a booster for CYP3A4 inhibition.
• STI-1558 is also a Cathepsin L inhibitor, which may block effective viral entry into host cells without accelerating viral mutations and could work in conjunction with protease inhibition to further protect against COVID-19.
• STI-1558 showed good oral bioavailability of up to 85% in dogs and monkeys with a sufficient plasma exposure, suggesting that no CYP3A4 inhibitor co-administration is needed.
• No significant safety findings to date in GLP repeat-dose toxicology studies in rats and dogs at daily doses up to 2000 mg/kg and 300 mg/kg, respectively.

Excerpt from the Press Release:

SAN DIEGO, June 03, 2022 (GLOBE NEWSWIRE) — Sorrento Therapeutics, Inc. (Nasdaq: SRNE, “Sorrento”) today announced the first subject was dosed in a Phase I clinical study (NCT05364840) of its oral main viral protease (M^pro) inhibitor, STI-1558.

The world has been experiencing repeated waves of infection of SARS-CoV-2 and its continually emerging variants. Current vaccines and EUA-approved antibodies offer diminished protection against transmission and infection by Omicron variants. Oral antiviral drugs with broad-spectrum antiviral activities and limited potential for drug-drug interaction risks are still urgently needed. EUA-cleared Nirmatrelvir (Paxlovid) has demonstrated encouraging data in preventing disease progression; however, in order to achieve therapeutic blood level, it requires the co-administration or “boosting” with Ritonavir, a strong inhibitor of cytochrome P450 (CYP) 3A4 (“CYP3A4″). This means it blocks the liver from metabolizing drugs that utilize this enzyme for metabolism and clearance, resulting in the potential for significant drug-drug interactions, which can limit its use, especially in at-risk patients on multiple medications.

STI-1558 is a potent M^pro inhibitor with an IC₅₀ value of 2.7 nM and has demonstrated potent antiviral activity against all COVID-19 variants studied, including Omicron, with an IC₉₀ value between 14 nM and 41 nM (an IC₅₀/IC₉₀ is the concentration of drug need to produce a 50%/90% inhibition of activity) in vitro following infection of human bronchial epithelial cells. It is also a Cathepsin L inhibitor, which may block effective viral entry into host cells. In preclinical studies, STI-1558 showed an oral antiviral activity against SARS-CoV-2 in a humanized transgenic mice model. In these preclinical studies, STI-1558 protected virus infected mice from weight loss, viral replication in lungs, as well as associated lung pathology. STI-1558 possesses excellent off-target selectivity, is metabolically stable in human liver microsomes, and has demonstrated oral bioavailability of up to 85% in dogs and monkeys. In GLP repeat-dose toxicology studies in rats and dogs, there have been no significant safety findings to date, including blood chemistry, hematology and histopathology at daily doses of up to 2000 mg/kg and 300 mg/kg, respectively. Based on the safety and pharmacokinetic modeling, Sorrento expects the human efficacious dose to be between 300 mg and 600 mg BID without the need for a Ritonavir-boost.

The Phase I study will be conducted in Australia will evaluate the safety, tolerability, and pharmacokinetics of STI-1558 in single ascending doses (SAD) followed by multiple ascending doses (MAD) compared to placebo in healthy volunteers. A global pivotal Phase II/III trial will be initiated as soon as possible following the successful completion of the Phase I. “We are excited to reach the milestone of advancing STI-1558 to the clinical stage.

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