Sorrento Therapeutics, Inc. announced positive preliminary results from two Phase 2 studies designed to identify the hospitalized patient population suffering from COVID-19-induced pneumonia and respiratory depression likely to respond to treatment with oral Abivertinib. Abivertinib is a novel small molecule tyrosine kinase inhibitor (TKI) that selectively targets both mutant forms of the epidermal growth factor receptor (EGFR) as well as Bruton’s tyrosine kinase (BTK). Abivertinib irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor. Due to this effect, it has shown potent immunomodulatory activities in vitro with potent inhibition of key pro-inflammatory cytokine production, including IL-1 beta, IL-6 and TNF-alpha. These cytokines are associated with acute respiratory distress syndrome (ARDS), and with cytokine release syndrome (CRS) or cytokine storm, and COVID-19 disease progression with poor outcomes in patients.
The US study, entitled “A Phase 2, Double Blinded, Randomized Study of the Efficacy and Safety of STI-5656 (Abivertinib Maleate) With Standard of Care Versus Standard of Care in Subjects Hospitalized With COVID-19” (NCT04440007), recently completed enrollment (N=96 randomized 1:1). The Brazil study, entitled “A Phase 2, Randomized, Double-Blind, Placebo-controlled Study of the Safety and Efficacy of STI-5656 (Abivertinib Maleate) in Subjects Hospitalized Due to COVID-19” also completed enrollment (N=400, randomized 3:1 active vs. placebo). Both studies were designed to assess the potential clinical benefits of Abivertinib’s ability to reduce inflammatory cytokine storm associated with COVID-19-induced respiratory depression. It was also important to identify the potential patient population most likely to respond to treatment based upon severity of COVID-19 respiratory depression at baseline. In both studies the clinical status was assessed using a 9-point (0 to 8) categorical scale, where 3=hospitalized with no oxygen therapy, 4=hospitalized with oxygen by mask or nasal cannulae, 5=non-invasive ventilation or high flow oxygen, 6=intubation and mechanical ventilation, 7=additional organ support such as extracorporeal membrane oxygenation, and 8=death.
| Brazilian Protocol Design | U.S. Protocol Design |
| Mild, Moderate and Severe COVID-19 patients | Severe COVID-19 patients |
| Any hospitalized patient | ICU non-ventilated |
| N=400 randomized 3:1 (Abivertinib to placebo); stratified for COVID-19 severity at baseline | N=96 randomized 1:1 (Abivertinib to placebo) |
| 100 mg QD x 7 days | 100 mg QD x 14 days or discharge if sooner |
| All patients received standard of care treatment for COVID-19 | All patients received standard of care treatment for COVID-19 |
| Duration 65 days | Duration 94 days |
| Primary endpoint: % alive and discharged at one month |
Primary endpoint: % alive and free of respiratory failure at one month |
| NCT 04528667
ANVISA (Brazilian authority) under Process nº 25351.105670/2020-14, Reference n° 3380614/20-4 |
NCT 04440007 |
In the US Abivertinib study, most patients (57%) were sicker at baseline (category 5 clinical status) with patients in the Abivertinib group skewed to sicker or worse severity by clinical status (Abivertinib Group: 29/48: 60% vs. Control Placebo Group: 26/48: 38% for category 5, respectively) and by oxygenation status (P/F ratio 211 vs. 253, respectively). In the Brazil Abivertinib study, only 8% were in category 5, demonstrating a far less severely compromised population having been enrolled. In the US study, patients in category 5 showed a 20% improvement (78.3% survival vs. 58.3%) in the primary endpoint of avoiding death and respiratory failure at one month, and in the Brazil study, a 25% improvement (69.6% vs. 44.4%), respectively for Abivertinib vs. controls. In the US study, patients in category 5 treated with Abivertinib were discharged from the hospital 2 days sooner than those in the Control Group (8.6 vs. 10.6 days). Overall, in both studies patients who were in category 5, but not in category < 4, showed improvement with Abivertinib treatment. Based upon these preliminary results, a pivotal multi-country, multi-center pivotal Phase 3 study is being planned in 400 patients (randomized 1:1) on the At-Risk Hospitalized COVID-19 Patients requiring oxygen support via non-invasive ventilation or high flow oxygen at baseline (category 5 patients).
“Patients on non-invasive ventilation or high flow oxygen supplementation due to COVID-19-induced respiratory failure represent a sicker and at-risk population with few available treatment options,” stated Dr. Mike Royal, Chief Medical Officer of Sorrento Therapeutics. “Abivertinib has the potential to fill this unmet need and significantly reduce progression to intubation, mechanical ventilation and death.”