The rapid development of vaccines is essential for sustained resistance to new coronaviruses. However, challenges also persist, such as the continued emergence of new variants. Therefore, the development of antiviral therapies is also an important way to address the ongoing threat of COVID-19. Pfizer's Paxlovid neo-coronavirus oral drug was first launched in late 2021, until February this year, when the Chinese State Food and Drug Administration (SFDA) made a big splash when it published the import registration of the drug on its official website and included it in the health insurance payment system for a short period of time.

It is worth mentioning that for the pre-clinical development of drugs against new crowns, Medicilon has already established a comprehensive mRNA vaccine bioassay technology platform on the one hand; on the other hand, for active pharmaceutical ingredients or candidate compounds with drug-forming properties, Medicilon can provide professional pre-prescription services to lead the compounds into late stage development. Medici's pre-prescription research team has extensive experience in the development of a wide range of compounds, helping our clients to successfully advance their compounds into early screening.

The global outbreak of COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has been a global pandemic for over 3 years. As the disease progresses, patients with COVID-19 exhibit a wide range of symptoms. Common mild to moderate symptoms include fever, dry cough, fatigue, loss of sense of smell and diarrhoea. In severe and critical cases, patients may develop pulmonary symptoms such as acute respiratory distress syndrome. Patients with pre-existing conditions such as hypertension, obesity and diabetes will show a higher risk of disease progression and lower survival rates. Men infected with COVID-19 are less immune and have a higher mortality rate compared to women. This may be attributed to gender-determining gene expression, chromosomes and/or hormones. When COVID-19 progresses to a severe stage, plasma levels of inflammation-related factors, including IL-1, IL-6, IL-7, G-CSF, IP-10, MCP1, MIP1α and TNFα, are significantly elevated, resulting in a cytokine storm. Studies have shown that cytokine storms are directly associated with poor prognosis in cases of lung injury, multi-organ failure and severe COVID-19.

Progress in the development of new crown oral drugs

Vaccines and oral neocon therapeutics are an important approach against neoconviruses and a powerful weapon in reducing mortality from neocon infection. The main validated targets are the 3CL protease (3CLpro) and RNA polymerase (RdRp). 3CL protease inhibitors such as Pfizer's Paxlovid and Shionogi's S-217622 are popular.

Palo Verde Paxlovid

Paxlovid is an oral small molecule neo-coronavirus treatment from Pfizer, administered in a combination package of two tablets of Nirmatrelvir (PF-07321332) and one tablet of Ritonavir. Oral administration of Paxlovid reduces hospitalisation and mortality by ~90%.

Nirmatrelvir (PF-07321332) is a 3CL proteinase (3CLpro) inhibitor that inhibits the SARS-CoV-2 protein to stop viral replication. Ritonavir, a cytochrome CYP3A4 inhibitor, reduces the metabolism of PF-07321332 and allows PF-07321332 to remain in the body longer at higher concentrations, increasing its therapeutic concentration.

Paxlovid can be used for the treatment of adults with mild and common forms with high risk factors for progression to severe disease within 5 days of onset and adolescents over 12 years of age weighing more than 40kg (the National Health Council has changed the indication population to adults only). In adults, the five relevant indicators are: progressive worsening of hypoxaemic live respiratory distress, worsening of tissue oxygenation indicators or progressive elevation of lactate, and significant progression of pulmonary pathology on chest imaging. For children, there are six indicators such as increased respiratory rate, poor mental response, drowsiness, and the presence of underlying disease.

Paxlovid's rapid advance

13 Mar 2020, Dafydd R Owen et al. launch protease inhibitor project

22 July 2020, First synthesis of Nirmatrelvir (PF-07321332)

23 Mar 2021 Initiation of phase I clinical trial

September 2, 2021 Initiation of Phase II/III clinical trial

9 December 2021, completion of Phase III clinical trial

22 December 2021, FDA emergency approval

February 11, 2022, NMPA emergency approval

March 9, 2022 Commercial agreement signed

15 March 2022 NMPA adds it to the Novel Coronavirus Pneumonia Treatment Protocol (Trial Version 9)

Late on 16 March 2022, 20,000 boxes arrive at Pudong Airport

18 March 2022, two hours to complete customs clearance

20 March 2022 - Arrived in Changchun and immediately sent to the front line of the epidemic

On 22 March 2022, the National Health Insurance Bureau included Pfizer's New Crown oral drug in the scope of health insurance payment

3CL Protease

SARS-CoV-2 produces two polyproteins, pp1a and pp1ab, which are processed by two virus-encoded cysteine proteases, the main proteases being 3CLpro and papain-like protease. Mutagenesis experiments with other coronaviruses have shown that the activity of 3CLpro is essential for viral replication. 3CLpro proteolytically processes the viral p1a/p1ab protein at more than 10 junctions to produce a range of non-structural proteins essential for viral replication and transcription, including RdRp, decapping enzymes and 3CLpro itself. The essential functional importance of proteases in viral replication has led to the clinical success of protease inhibitors in the fight against a wide range of viruses. This makes 3CLpro an attractive target for antiviral drugs.

Nirmatrelvir (PF-07321332)

Nirmatrelvir (PF-07321332) is a 3CLpro inhibitor with potent in vitro antiviral activity against SARS-CoV-2 and other coronaviruses. The binding mechanism of PF-07321332 to coronavirus 3CLpro was demonstrated by docking and molecular dynamics simulations. Investigation of the dynamic behaviour of ligand-protein interactions revealed that PF-07321332 showed stronger binding through interaction with the catalytic binary residues His41-Cys145 of 3CLpro. This study will help to develop and optimise compounds with greater specificity against coronavirus disease.

Dafydd R Owen et al. reported the discovery and characterisation of PF-07321332, which targets the major proteases involved in the multiprotein cleavage of viral replication. PF-07321332 is an orally bioavailable inhibitor of the major SARS-CoV-2 protease with in vitro antiviral activity and excellent off-target selectivity and in vivo safety. PF-07321332 can be administered orally, has good selectivity and safety profile, and prevents infection in mouse models. PF-07321332 also inhibits other coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-COV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), and may be an arsenal against future viral threats.

PF-07321332 effectively reduces SARS-CoV-2 MA10 viral load in the lungs of mice. Researchers evaluated the in vivo antiviral effects of PF-07321332 in a mouse SARS-CoV-2 MA10 model. Intranasal infection of BALB/c mice with SARS-CoV-2 MA10 resulted in approximately 10% weight loss in 10-week-old mice. After infection with SARS-CoV-2 MA10, mice treated with PF-07321332 (at 300 and 1000 mg/kg twice daily) lost weight compared to control mice. Mice were executed 4 days after infection and lung virus titres were assessed by CCID50 assay. The control animals were strongly infected in the lungs (mean titer log10 4.93±0.140 CCID50/mL SARS-CoV-2 MA10), whereas the virus was significantly reduced in mice treated with PF-07321332 (mean virus titer log10 3.53±0.187 and 1000 mg/kg PF-07321332 treated groups respectively). 3.53±0.187 and log10 3.02± 0.423 CCID50/mL, respectively).

Summary and outlook

Paxlovid, a new oral treatment for NCCP, has performed well in clinical studies, reducing the risk of hospitalisation or death in patients with NCCP by ~90%, while being less resistant and effective against mutant strains, and is considered to be a treatment that could change the current epidemic control strategy. Paxlovid has been conditionally approved for import registration in China as a drug that could change the control strategy for the new coronary pneumonia epidemic.

The new coronavirus pneumonia outbreak caused by Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) poses an unprecedented threat to human health and is a wake-up call to the world. In addition to vaccines, antiviral therapy is an important part of the healthcare response to the ongoing threat of new coronavirus pneumonia. For active pharmaceutical ingredients or candidate compounds with drug-forming properties, Medicilon can provide expert pre-prescription services to lead compounds into late-stage development. Medici's pre-prescription research team has extensive experience in the development of a wide range of compounds, helping clients to successfully advance their compounds through early screening.

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