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.
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 Mpro 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
About Sorrento Therapeutics, Inc.
Sorrento is a clinical and commercial stage biopharmaceutical company developing new therapies to treat cancer, pain (non-opioid treatments), autoimmune disease and COVID-19. Sorrento's multimodal, multipronged approach to fighting cancer is made possible by its extensive immuno-oncology platforms, including key assets such as fully human antibodies (“G-MAB™ library”), immuno-cellular therapies (“DAR-T™”), antibody-drug conjugates (“ADCs”), and oncolytic virus (“Seprehvec™”). Sorrento is also developing potential antiviral therapies and vaccines against coronaviruses, including Abivertinib, COVISHIELD™ and COVI-MSC™; and diagnostic test solutions, including COVIMARK™.
Sorrento's commitment to life-enhancing therapies for patients is also demonstrated by our effort to advance a first-in-class (TRPV1 agonist) non-opioid pain management small molecule, resiniferatoxin (“RTX”), and SP-102 (10 mg, dexamethasone sodium phosphate viscous gel) (SEMDEXA™), a novel, viscous gel formulation of a widely used corticosteroid for epidural injections to treat lumbosacral radicular pain, or sciatica, and to commercialize ZTlido® (lidocaine topical system) 1.8% for the treatment of postherpetic neuralgia (PHN). RTX has been cleared for a Phase II trial for intractable pain associated with cancer and a Phase II trial in osteoarthritis patients. Positive final results from the Phase III Pivotal Trial C.L.E.A.R. Program for SEMDEXA™, its novel, non-opioid product for the treatment of lumbosacral radicular pain (sciatica), were announced in
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Source: Sorrento Therapeutics, Inc.