Facing Omicron, Where is the Next 'Special Medicine'?

The COVID-19 outbreak started in early 2020 and has not completely disappeared. The new coronavirus is constantly mutating, among which Omicron has become the main epidemic strain in the world.

In more than two years, since the first known as "people's hope" Remdesivir, some new crown treatment drugs have appeared in the public eye one after another, but with the continuous mutation and evolution of the new crown virus, it has also made Treatment becomes more complicated. People's expectations for the "special medicine" for the new crown have not changed.

01 Current status of covid-19 drug development: racing with mutant strains

According to statistics from Guotai Junan Securities, as of March 28, 2022, more than 10 novel coronavirus therapeutic drugs have been approved worldwide. Mainly based on macromolecular biopharmaceutical neutralizing antibodies and small molecule oral drugs.

Among them, neutralizing antibodies are widely used in Europe and the United States, and the treatment cost is high. At this stage, the price of neutralizing antibodies for new crowns in the United States is generally more than 2,000 US dollars per course of treatment. Since neutralizing antibodies need to be injected, oral small-molecule drugs have attracted market attention due to their advantages of convenient administration and low cost.

However, the most important thing to face is that neutralizing antibodies mainly target the S protein to function, while the mutations generated by the Omicron strain are mainly located in the S protein, and the treatment of neutralizing antibodies can cause escape. Since the beginning of this year, the neutralizing antibody products of many pharmaceutical companies such as Eli Lilly, Regeneron, and GlaxoSmithKline have been suspended or restricted for regional use due to their ineffectiveness against mutant strains, bringing many uncertainties to future treatments.

New crown oral antiviral drugs generally function against viral enzyme structures (RdRp, 3CLpro, PLpro, etc.), and the probability of mutation at this position is low, so new crown oral drugs are less affected by new coronavirus mutations. A variety of covid-19 oral drugs have shown inhibitory activity against Omicron strains in vitro.

Therefore, the small molecule covid-19 oral drug has become the most promising drug against Omicron. So far, four anti-COVID-19 oral drugs have been approved for marketing/emergency use authorization worldwide. Only Pfizer's Paxlovid has been approved for marketing in China, and it has been included in medical insurance and used in the first-line clinical use in China. In addition, the three domestic oral drugs for COVID-19 under Junshi Bio, Real Bio, and Kintor Pharmaceutical have the fastest clinical progress.

From a macro perspective, most of the currently approved neutralizing antibodies, new crown oral drugs and other drugs are mainly aimed at mild patients and prevent the transformation of mild to severe. For those with mild symptoms, there are many options for treatment. However, there is still a lack of effective treatment methods for patients with moderate and severe new coronary pneumonia, which is a clinical problem that needs to be overcome urgently.

02Reduce the severity and mortality of the new crown, the top priority of prevention and control

On November 24, 2021, South Africa reported the first case of Omicron variant infection to WHO. Since then, the Omicron variant has infected about 90 million people in just 10 weeks, exceeding the number of reported cases of COVID-19 in all of 2020, and spreading 10 times faster than the original strain. Within 2 months, its original strain (21K, BA.1) gradually replaced Delta as the world's major epidemic strain, which attracted global attention.

Omicron also has a series of sub-variants, of which BA.2 has occupied the main popular position in at least 68 countries around the world, while at the same time, BA.4 and BA.5 have become the main variants in South Africa.

On the whole, most of the Omicron variant infection cases are asymptomatic or mild cases, and there is a trend towards influenza development. However, due to its strong infectivity, the harm to high-risk groups cannot be underestimated.

The latest research from the international authoritative medical journal "JAMA" shows that in Massachusetts, the new coronavirus variant Omicron has caused more excess deaths than Delta. And it took less time: Omicron lasted 8 weeks, Delta lasted 23 weeks.

At present, the main epidemic strain in my country is the Omicron BA.2 subtype. This strain spreads fast and has strong concealment, causing large-scale epidemics in Jilin, Shanghai, Hong Kong and other places.

On May 22, 2022, Professor Zhang Wenhong published the latest research and judgment on my country's new crown pneumonia in an academic exchange. The report pointed out that with the changes in the epidemic situation, Omicron has become the biggest challenge in my country's current prevention and control. The reproduction number (R0) of Omicron is 9.5. Since the neutralization titer of Omicron has escaped to a certain extent due to the mutation of the virus, the effect of existing antibody treatments and vaccines has been greatly reduced.

The report pointed out that vulnerable populations are the biggest challenge since the outbreak of Omicron. Omicron induces a certain degree of inflammatory response, but less so than the flu. However, if the patient is older and the underlying disease is severe, this inflammatory response may be fatal.

Since the outbreak of the new crown pneumonia, although there are prevention and control measures such as nucleic acid testing, new crown vaccines, and therapeutic drugs, in the face of the new crown virus that may not disappear in the short term, the task of reducing the severity and mortality of the new crown is expected to remain in the current prevention and control. in the center of.

03AI-assisted screening, some drug candidates emerged

According to data from authoritative academic institutions, although most COVID-19 patients have only mild to moderate symptoms, 15-20% of patients will still experience excessive inflammation caused by the production of a large number of cytokines, that is, "cytokine storm", which will eventually lead to Alveolar damage and respiratory failure.

Once a patient develops a cytokine storm, a ventilator is usually required. Solving the cytokine storm in patients is one of the effective means to treat severe new coronary pneumonia. There are mainly anti-cytokine antibodies or anti-cytokine receptor antibodies. There are only a handful of drugs in this part.

In cytokine therapy, only Eli Lilly/Incyte's JAK inhibitor Baricitinib and Roche's anti-inflammatory drug Tocilizumab have previously received emergency use authorization from the US FDA, Humanigen's Lenzilumab has submitted an NDA, and Tianjing Bio's Plonmarlimab , Kiniksa's Mavrilimumab and Shutaishen's BDB-001 are in clinical trials. On May 11 this year, baricitinib was officially approved by the FDA for the treatment of hospitalized adult patients with COVID-19 receiving supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). In addition, baricitinib has also been recommended by the World Health Organization (WHO) in the latest update of the new crown treatment guidelines for the treatment of severe patients with pneumonia and hypoxia.

In addition, it is worth noting that the team at the Fred Hutchinson Cancer Research Center (Fred Hutchinson Cancer Research Center) at the University of Washington has also achieved some cutting-edge research results on the way to find drugs for the treatment of moderate and severe new crowns.

The research team found that the N-terminus of the SARS-CoV-2 spike protein can promote the release of cytokines in immune cells. As early as last September, researchers at the Hutchinson Cancer Research Center used AI screening to find that this process is related to JAK1, EPHA7 , IRAK1, MAPK12 and MAP3K8 and other kinases are related, and the multi-kinase inhibitor Ponatinib was further screened to inhibit the occurrence of this inflammatory storm. One of the main targets of Ponitinib is Bcr-Abl.

Prior to this, there were also related studies on BCR-ABL inhibitors for the treatment of new crown drugs. For example: In June 2020, Dutch scientists published an article in the preprinted journal BioRxiv and found that Bcr-Abl inhibitors Imatinib and Ponatinib can bind to RBD with μM-level affinity, providing another explanation for their mechanism of action against the inflammatory storm of COVID-19; In February 2021, Dutch scientists published a review article in the journal Blood Advances on the immune regulation of hematologic tumor kinase inhibitors for COVID-19, pointing out the mechanism and potential therapeutic value of JAK inhibitors and BCR-ABL inhibitors in regulating inflammatory storms. 

Ponatinib is a novel orally active multi-target TKI developed and produced by Takeda Pharmaceuticals, which has previously been approved for chronic myeloid leukemia. Targets include BCR-ABL, VEGFR, PDGFR, FGFR, EPH, SRC family, KIT, RET, TIE2 and FLT3. It has been validated in BCR-ABL positive leukemia.

However, public information shows that Takeda Ponatinib was in short supply at that time, and there were no additional doses to conduct clinical trials for the treatment of COVID-19. It's worth noting that Ponatinib was not the only potential drug that Gujral's team screened.

Not long ago, on May 18, 2022, a preclinical study at the Hutchinson Cancer Research Center showed that Ponatinib's same-target drug orebatinib (Neric®, olverembatinib) can effectively inhibit the new coronavirus variant virus. The production of cytokine storm in human peripheral blood mononuclear cells (PBMCs) induced by SARS-CoV-2-Omicron, suggesting that orebatinib has the potential to treat novel coronavirus pneumonia (COVID-19) Especially the potential of moderate to severe patients.

The study was successfully published in EMBO Molecular Medicine, a top journal of the European Molecular Biology Organization. This study confirmed that SARS-CoV-2-Omicron variant NTD (Omicron-NTD) can also significantly stimulate a variety of cells released in PBMCs. Factors, including IL-1β, IL-6 and tumor necrosis factor (TNF-α). Compared to baricitinib and ponatinib, orebatinib showed more potent inhibition of Omicron-NTD-mediated cytokine release. Baricitinib itself has obtained dual certification in the treatment of severe new crowns, from emergency authorization to FDA official approval on the one hand, and the latest WHO guidelines on the other hand. This has also made the outside world have more expectations for the therapeutic potential of Orebatinib.

Orebatinib is an original class 1 new drug of Ascentage Pharma with global "best-in-class" potential and has been approved for marketing in China for the treatment of chronic myeloid leukemia with T315I mutation and resistance to any TKI (CML) chronic phase (CP) or accelerated phase (AP) adult patients, is the first and only third-generation BCR-ABL inhibitor approved for marketing in China.

The conclusion of this study is only a preclinical study, and the specific efficacy needs to be advanced to clinical trials. However, the use of AI to screen drug candidates has reduced the cost of trial and error for pharmaceutical companies. Omicron is still raging around the world. If pharmaceutical companies push the already-marketed drugs into clinical trials, they will undoubtedly have a certain advantage over those brand-new drug candidates.