Ascentage Pharma, a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, announced that a new preclinical study, conducted by the researchers from Fred Hutchinson Cancer Research Center, Seattle, suggests the therapeutic potential of olverembatinib (HQP1351) in inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron-mediated cytokine release. Results from this study were published in the journal EMBO Molecular Medicine. Olverembatinib is approved in China for tyrosine kinase inhibitor (TKI)-resistant chronic phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation.
Globally, more than 516 million cases of COVID-19 have been confirmed including more than six million deaths, reported to the World Health Organization (WHO). As the pandemic enters its third year, the Omicron variant have been driving an increase in cases primarily among people who are unvaccinated, and it is even causing infections in some vaccinated people. It is therefore critical that we develop therapeutic strategies for the patients predisposed to covid-19 related complications.
Dr. Taran Gujral, systems biologist at the Fred Hutchinson Cancer Research Center, University of Washington, is the corresponding author of this paper titled Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release in human peripheral blood mononuclear cells.
Although most patients with COVID-19 only develop mild to moderate symptoms, 15-20% of patients still face hyper-inflammation induced by a massive release of cytokine also known as ‘cytokine storm’, which ultimately leads to alveolar damage and respiratory failure. Therefore, it has become an imperative to identify alternative therapies that can effectively inhibit the cytokine release in patients with moderate to severe COVID-19.
Dr. Gujral’s research team found that the N-terminus domain (NTD) of the SARS-CoV-2 virus’ spike protein can mediate the release of inflammatory cytokines in monocytes and PBMCs. Using a machine-learning-based screening platform, Dr. Gujral’s team had previously established that several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K3, are essential for the SARS-CoV-2-mediated cytokine release, and identified ponatinib as a potent inhibitor of SARS-Cov-2-NTD mediated cytokine release.
In the current study, Dr. Gujral’s team observed that the NTD of the SARS-CoV-2-Omicron variant can also promote the release of various cytokines, including IL-1β, IL-6, and the tumor necrosis factor (TNF-α), in PBMCs. Interestingly, olverembatinib treatment showed the highest suppression of the Omicron-NTD-mediated cytokine release, in a comparison between olverembatinib, ponatinib, and baricitinib (a drug approved by the FDA and recommended by the WHO for the treatment of COVID-19).
Olverembatinib inhibited a panel of the Omicron-NTD-mediated cytokines tested (GM-CSF, IL-1β, IL-10, IL-6, IL-8, CCL-2, and TNF-α), with a EC50 (concentration required to inhibit 50% of the Omicron-NTD-mediated cytokine release) between 7.7 and 56 nM, demonstrating a wider range of concentrations than that of baricitinib. Interestingly, treatment with olverembatinib completely shuts dow Omicron-NTD mediated cytokine storm in PBMCs from all 9 COVID-19 patients.
This study concluded that the NTD of SARS-CoV-2 and many of its variants can stimulate multiple kinases (JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8), leading to the hyper-inflammation induced by massive cytokine production. Olverembatinib blocks the activity of several kinases essential for cytokine signalling, thereby dampening the Omicron-NTD-mediated cytokine release and reducing inflammations. This indicates that agents targeting multiple kinases essential for SARS-CoV-2 and variant mediated cytokine release, such as olverembatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.
Olverembatinib is a novel drug developed by Ascentage Pharma and has recently received approval in China for the treatment of adult patients with tyrosine kinase inhibitor (TKI)-resistant chronic phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation. Currently, olverembatinib is being evaluated in multiple clinical studies for the treatment of CML, acute lymphocytic leukemia (ALL), and gastrointestinal stromal tumor (GIST) in the US and China.
Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma, said, “Olverembatinib is a drug candidate we have studied for many years. As the world’s second third-generation BCR-ABL TKI entering clinical development in the US, and one of the few China-developed novel drug candidates positioned for the global market from the very beginning, olverembatinib has demonstrated excellent efficacy and safety, leading to the approval for the treatment of drug-resistant CML in China last year. Furthermore, olverembatinib has also generated encouraging clinical results in other cancer indications.
The publication of this preclinical study in the EMBO Molecular Medicine is very important as the study revealed olverembatinib’s potential as an alternative treatment for COVID-19. We look forward to soon following up with clinical studies in efforts to develop a safe and effective treatment option for patients with COVID-19 around the world.”