Sorrento Releases Positive Topline Results from the Phase I Study Completed in Australia and Preliminary Results from a Phase Ib Study in China with STI-1558, an Oral M(pro) Inhibitor as a Standalone Treatment for COVID-19 without the Need for Ritonavir B
- Topline safety and pharmacokinetic (PK) data from the Phase I single ascending dose (SAD)/multiple ascending dose (MAD) study of STI-1558 in 58 healthy volunteers in
Australiaare now available. The SAD portion of the study evaluated doses from 300 mg to 2,000 mg and the MAD portion evaluated 300 mg, 600 mg or 800 mg BID (twice a day daily) for 7.5 days.
- Overall, STI-1558 was well-tolerated at these doses with most subjects reporting no adverse events (AEs). There was no dose limiting toxicity during the study. There were no severe or serious AEs, no premature discontinuation of STI-1558 due to an AE, and no deaths. Most AEs were mild and unrelated. The PK profile was dose proportional; the mean AUC (h*µg/mL) in the SAD 300 mg, 600 mg, 1200 mg and 2000 mg cohorts was 14.3, 29.2, 43.8 and 93.3, respectively. In the MAD cohorts (300 mg BID, 600 mg BID and 800 mg BID), no accumulation was seen and trough concentrations (Ctrough) were 225 ng/mL, 475 ng/mL and 506 ng/mL, respectively. Even the lowest dose produced trough levels significantly above the EC90 value for viral inhibition of STI-1558. These data confirm adequate blood levels were achieved without the need for Ritonavir.
- A similar Phase I/Ib SAD/MAD study has been fully enrolled in
Chinain both healthy subjects and patients infected with SARS-CoV-2. The PK profile in Chinawas similar to that seen in Australia. Preliminary safety and efficacy data found that the safety profile was comparable between healthy uninfected subjects and infected subjects and that STI-1558 resulted in a dramatic rapid reduction in viral load.
- Phase II/III protocols of STI-1558 600 mg BID for 5 days as a standalone treatment of COVID-19 have been submitted to various regulatory agencies including the
US FDA, Mexico COFEPRIS and China.
- Testing to date has demonstrated that the antiviral activity of STI-1558 on the Mpro protein is not impacted by the spike mutations of emerging variants NMPA.
The Phase I safety and PK study (MPR-COV-101AU) is entitled: “A Randomized, Double-Blind, Placebo-Controlled, Phase I Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of STI-1558 in Healthy Volunteers”. In the SAD portion of the study, 4 dose-escalation cohorts (single oral dose of 300 mg, 600 mg, 1200 mg, and 2000 mg STI-1558 or placebo) were conducted with 8 subjects in each cohort-randomized 3:1 (active:placebo, except for cohort 2 for the fasted and fed dosing, with 10 subjects randomized 4:1). In the MAD portion of the study, 3 dose-escalation cohorts with daily doses of 300 mg BID, 600 mg BID or 800 mg BID for 7.5 days (total 15 doses) were conducted with 8 subjects in each dose cohort randomized 3:1 (active:placebo). Subjects remained at the facility for the entire treatment period.
Topline safety and PK data from the SAD and MAD portions of the study are now available. Overall, there were no changes in vital signs, physical examinations, or ECGs resulting from study participation. STI-1558 was well-tolerated at the doses studied, with most subjects reporting no AEs. There was no dose limiting toxicity and no severe or serious adverse events (AEs), premature discontinuation of STI-1558 due to an AE, or deaths. Most AEs were mild and unrelated.
A total of 11 subjects reported an AE in the SAD part of the study, with 3 AEs of headache deemed related to STI-1558 (one moderate severity in the 600 mg cohort and two mild cases in the 1200 mg cohort), possibly due to restricted caffeine intake. In the MAD part of the study, 13 subjects reported AEs, with only two subjects experiencing related events of mild or moderate liver enzyme elevation (ALT/AST) without bilirubin elevation in the highest dose cohort, 800 mg BID, which is 33% higher for 50% longer than the planned treatment regimen for Phase II, 600 mg BID for 5 days. The liver enzyme elevations occurred late (≥ 5 days) in study treatment and resolved without the need for any treatment.
The PK plots for SAD doses of 300 mg, 600 mg, 1200 mg and 2000 mg displayed dose proportionality with AUC (h*µg/mL) of 14.3, 29.2, 43.8 and 93.3, respectively. Trough levels (Ctrough) during the MAD dosing were 225 ng/mL, 475 ng/mL and 506 ng/mL, respectively, which are significantly above the EC90 value predicted for viral inhibition by various preclinical models. Observed half lives during the SAD/MAD dosing support BID dosing. These data demonstrate that STI-1558 can be a potential treatment for COVID-19 without the need for Ritonavir boosting. Additionally, in preclinical studies, STI-1558 is neither a CYP3A4 inhibitor nor inducer, which suggests a low risk of CYP3A4 related drug-drug interactions. Based upon the safety and PK profiles, a 600 mg BID dose for 5 days has been selected as the recommended dose for Phase II/III studies to treat mild-to-moderate COVID-19 in outpatients.
The enrollment of a Phase I trial in participants infected with SARS-CoV-2 was completed in
“The unblinded safety and PK data in the
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 next-generation tyrosine kinase inhibitors (“TKIs”), 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 STI-1558, COVISHIELD™ and COVIDROPS™, 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 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.