Sorrento Therapeutics, Inc. released unblinded Phase 1b study data of its oral main viral protease (Mpro) inhibitor, OVYDSO™ (STI-1558) in COVID patients. This Phase 1b safety, PK and efficacy study in healthy volunteers and COVID patients was conducted in China. The study (MPR-COV-101CN) is entitled: “A Randomized, Double-Blind, Placebo-Controlled, Phase I Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Single and Multiple Oral Doses of STI-1558 in Healthy Volunteers and COVID Patients”.

In the SAD portion of the study, four dose-escalation cohorts (single oral dose of 300, 600, 1200, and 2000 mg STI-1558 or placebo) were conducted with eight subjects in each cohort – randomized 3:1. In the MAD portion of the study, three dose-escalation cohorts with daily dose of 300 mg BID, 600 mg BID or 800 mg BID for consecutive 7.5 days (total 15 doses) were conducted with eight participants infected with SARS-CoV-2 in each dose cohort – randomized 3:1 (active:placebo), and in the 600 mg BID dose cohort, an additional 16 participants infected with SARS-CoV-2 (10:6, active:placebo) were added as a cohort extension. The topline safety, PK and efficacy data from the SAD and MAD portions of the study are now available. Overall, STI-1558 was well-tolerated at these doses, with most subjects in both the SAD and MAD portions of the study reporting no AEs.

There was no dose limiting toxicity during the study. There were no severe or serious AEs, no premature discontinuations of STI-1558 due to an AE, and no deaths. Most AEs were mild, transient, unrelated and required no medical treatment.

A total of 12 subjects reported an AE in the SAD portion of the study, with one AE of elevated blood thyroid-stimulating hormone (TSH) deemed related to STI-1558 in the 2000 mg cohort. No headaches were seen in this study. In the MAD portion of the study in COVID-19 patients, 20 subjects from a total of 46 subjects reported AEs, with only four subjects experiencing STI-1558-related events.

These four AEs included two subjects with mild or moderate liver enzyme elevation (ALT/AST) without bilirubin elevation in the 300 BID and 800 BID cohorts, one subject with mild hyperuricemia in the 600 mg BID cohort and one subject with mild rash in the 800 mg BID cohort. Antiviral activity was evaluated in the MAD portion of the study in participants infected with SARS-CoV2 (300 mg BID, 600 mg BID and 800 mg BID daily for 7.5 days). The viral RNA load in participants infected with SARS-CoV2 was measured by quantitative PCR.

The viral RNA load (log10 copies/ml) was significantly reduced in COVID-19 patients (n=29) treated with STI-1558 on Days 2, 4 and 6 post-treatment in comparison with placebo, indicating the strong antiviral activity of STI-1558 in COVID-19 patients. Notably the significant reduction of viral RNA (Log10 copies/ml) can be seen as early as day 2 after being treated with STI-1558 at the likely therapeutic dose of 600 mg BID (1.5 log lower than placebo, p=0.036). These data demonstrate early antiviral activity of STI-1558 in COVID-19 patients.

The PK profiles in the China trial were similar to the Australian trial and the linear and semi-log PK plots for doses of 300 mg, 600 mg, 1200 mg and 2000 mg are proportional in the SAD portion of study in healthy volunteers with AUC of 11.4 h* µg/mL, 24.0 h* µg /mL, 60.1 h* µg /mL and 84.4 h* µg /mL, respectively, and the T1/2 is from 21.4 h to 24.5 h. In the MAD portion of the study in COVID-19 patients, after 7.5 days of treatment (total of 15 doses), no accumulation was seen in all three MAD dose cohorts. The trough concentrations (Ctrough) in 300 mg BID, 600 mg BID and 800 mg BID cohorts were 265 ng/mL, 431 ng/mL and 518 ng/mL, respectively, similar to the trough concentrations in the Australian trial in healthy volunteers (190 ng/mL, 354 ng/mL and 418 ng/mL). These Ctrough values are significantly above the EC90 value for viral inhibition in preclinical models.

Based on the safety and PK profiles and significant antiviral efficacy in COVID-19 patients, a 600 mg twice-daily dose for 5 days has been selected as a recommended dose for Phase 3 studies for the standalone treatment of COVID-19. After communication with the regulatory agency, a Phase 3 protocol was submitted to China NMPA. The Phase 3 trial (MPR-COV-301CN) is entitled: “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study to Assess the Efficacy and Safety of STI-1558 for Treatment of Mild and Moderate Symptomatic Adults Infected with SARS-CoV-2”.

Once cleared by NMPA, the study, which plans to enroll 1200 COVID-19 patients, will be subsequently commenced.