Small Molecule and Great Potential: Oral Small Molecule COVID-19 Pharmaceutical Chemicals

Recently, MSD announced to initiate the Phase III clinical trial of its oral small molecule COVID-19 drug - Molnupiravir (MK-4482).

Recently, MSD announced to initiate the Phase III clinical trial of its oral small molecule COVID-19 drug - Molnupiravir (MK-4482). This global study, named MOVe-AHEAD, enrolled people aged no less than 18 years and living in the same family with SARS-CoV-2 infected people who were confirmed to have the symptoms by the laboratory, aiming to evaluate the effectiveness and safety of MK-4482 for the above-mentioned exposure population.

Representative of oral small molecule COVID-19 pharmaceutical chemicals -- Molnupiravir

Molnupiravir is a nucleoside analogue jointly developed by MSD and Ridgeback Biotherapeutics. After metabolism in vivo, the ester bond of this analogue is hydrolyzed to obtain ribonucleotide analogue NHC(β-D-N4-hydroxycytidine), which replace normal ribonucleotides during virus replication, thus preventing the replication of RNA virus.

In the first ten days of March this year, the Phase II clinical research results of Molnupiravir for mild and moderate COVID-19 patients show that Molnupiravir has an excellent curative effect. In this study, patients were divided into four groups: 800mg dose group, 400mg dose group, 200mg dose group and placebo group. The virus status of patients in different groups was detected on the first, third day and fifth day. The results showed that on the third day, only 1.9% of patients in 800mg dose group could be detected with the virus, while 16.7% in placebo group. On the fifth day, no virus was detected in 800mg and 400mg dose group, while the proportion in the placebo group was 11.1%. The results of comprehensive research showed that the drug could significantly reduce the infectivity.

Comparative advantage of oral small molecular pharmaceutical chemicals 

It is worth noting that Molnupiravir is a capsule, which can be obtained as soon as possible. Therefore, it is convenient for patients to take orally. In the early stage of COVID-19 infection, the virus replicates rapidly, but there is not enough time for the host's immune system to establish the immune defense. Therefore, the best treatment time based on blocking antiviral drugs is in the first few days of infection. The formulation design of Molnupiravir oral capsule has the potential of wide application. More and more potential people will be benefited from such design.

At present, the drugs under research/on the market for the treatment of COVID-19 are mainly pharmaceutical chemicals, macromolecular biological drugs and biological pharma products, mainly including RdRP inhibitors, protease inhibitors, neutralizing antibodies, macromolecular non-neutralizing antibody drugs, etc. These drugs can prevent viruses from entering cells, inhibit virus synthesis, reducing patients' inflammatory reactions and improving clinical benefits.

Among them, pharmaceutical chemicals with relatively low cost have clear and highly conservative targets, and have potential antiviral activity against various mutants. Theoretically, it can be used to treat the patients with mild, moderate and severe COVID-19. In particular, small molecule oral drugs, which are convenient for administration, are more suitable for the treatment of patients with mild and moderate diseases, and can play an important role in the early fight against SARS-CoV-2 infection. As the COVID-19 is likely to be as common as the influenza, pharmaceutical chemicals are expected to broaden the market application scenarios in the future by virtue of many advantages in administration methods, action targets, drug cost, etc. 

Oral small molecule COVID-19 pharmaceutical chemicals in the late stage of development worldwide

Up to now, there are 6 types of oral small molecule COVID-19 pharmaceutical chemicals in the late stage of development worldwide, including 1 type developed by domestic pharmaceutical companies and 5 developed by foreign companies. These small molecule drugs can be divided into four categories by the mechanism of action of drugs. Remdesivir of Gilead Sciences, MK-4482 of MSD/Ridgeback Biotherapeutics, AT-527 of Roche/Atea Pharmaceuticals are all RdRP inhibitors, baricitinib of Eli Lilly/Incyte is AAK1/JAK inhibitor, proxalutamide of Kintor Pharmaceuticals is AR antagonist, and PF-07321332 of Pfizer is 3CL protease inhibitor. 

Source: Public data compilation 

Among the six oral small molecule drugs listed in the above table, remdesivir, baricitinib, proxalutamide and MK-4428 have been approved for marketing/emergency authorization. The treatment needs for indications at different degrees of symptoms of COVID-19 infection are the focus of current and future clinical research of these drugs.