A Race For Better 3CL Inhibitors to Cure COVID-19: Copies vs. Innovators

Disclaimer: This post is not medical advice and is for informational purposes only. All the information contained here is related to research and development and is not intended for clinical use. Never attempt to take any medications without consulting with your medical doctor. 

The global COVID-19 pandemic is far from over with high numbers of daily new cases across the world and rising dynamics in some regions, like Japan, where more than 200,000 new daily cases were reported recently. The ongoing pandemics and the emergence of novel variants such as Omicron dictates urgent need for suitable oral medicines for treating COVID-19 at scale.

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Developed by Pfizer, Paxlovid™ is the latest COVID-19 treatment making headlines. In December, the Food and Drug Administration (FDA) granted Paxlovid™ an emergency use authorization for certain adults and pediatric patients at high risk for severe disease, after clinical trial results demonstrating 89% reduction in the risk of hospitalization and death for patients with certain risk factors. Paxlovid is also cheaper than many other COVID-19 drugs, and it is expected to work against the Omicron variant. 

Paxlovid™ is an antiviral therapy consisting of two different generic medications packaged together to offer a three-pill dose. Two of the pills are nirmatrelvir, the inhibitor of 3C-like protease, a key enzyme that is required in order for the coronavirus to make functional virus particles. Nirmatrelvir disrupts the ability of SARS-CoV-2 virus, released from the infected cells, to enter uninfected cells in the body, thereby stopping the infection. The third pill is ritonavir, a drug that was once used to treat HIV/AIDS, but is serving as a “booster” in the composition of Paxlovid™. The role of ritonavir is to shut down nirmatrelvir’s metabolism in the liver, so that it doesn’t get removed from the body too quickly -- before the therapeutic effect is achieved. 

While Paxlovid is not the only pill available to treat COVID-19 -- for example, the FDA also granted an emergency authorization to molnupiravir (Lagevrio) developed by Merck -- it is currently the most efficacious. Molnupiravir, for instance, has only a 30% reduction in the risk for hospitalization and death from COVID-19. Orally prescribed Paxlovid is also more convenient compared to another well-known COVID-19 drug, remdesivir, which is administered by intravenous injection.

With all the apparent benefits, Paxlovid is still not a perfect remedy against the COVID-19 pandemic. After Paxlovid entered markets in late 2021, researchers noticed a puzzling trend. In some people taking the drug and getting cured rapidly, symptoms and detectable virus reappeared days later -- as was the case with President Joe Biden. The strange phenomenon, dubbed ‘Paxlovid rebound’, was found to be surprisingly common in people who take Paxlovid as a treatment. According to one study, more than one-quarter of the Paxlovid recipients rebounded, based on levels of SARS-CoV-2, compared with just one of the 25 untreated people. Moreover, people with Paxlovid rebound had high levels of virus for several days, as if they had new acute infections. 

Another unpleasant issue with Paxlovid is the so-called ‘Paxlovid mouth’. About 5.6% of people who took Paxlovid to treat COVID-19 infection reported dysgeusia, which is a change in the taste in one's mouth. Some people reported a bitter or metallic taste shortly after taking their first set of pills, while others reported much worse taste characteristics. The reason for “Paxlovid mouth” is likely ritonavir, a part of the drug that is used to boost levels of antiviral medicines. Ritonavir has a known association with dysgeusia. Fortunately, the bad taste goes away upon discontinuation of the treatment. Considering the benefits Paxlovid provides, this side effect seems to be an acceptable trade-off, but its absence would have made the whole treatment approach a more pleasant one. 

Finally, there is an increasing concern about resistance mutations in SARS-CoV-2’s protease with a potential to render Paxlovid less efficient/inefficient, and some circulating variants of the coronavirus already have them. 

Yet, Paxlovid so far remains the lead treatment for COVID-19 and the mechanism on which it works – inhibiting the 3CL Protease – remains one of the most promising avenues of treatment for COVID-19 and related variants.   

The Promise of 3CL Protease Inhibitors

Similar to other coronaviruses, the SARS-CoV-2 RNA genome encodes four major structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). In addition, the virus genome encodes sixteen non-structural proteins required during various steps of the virus replication cycle. These proteins interact with the host cellular machinery of our body, utilizing it for replication to keep infecting more cells. In theory, any SARS-CoV-2 encoded protein may represent a valid therapeutic target. However, a lot of practical efforts were directed towards targeting 3CL protease (3CLpro, also known as main protease), one of the non-structural coronavirus proteins. Because of its essential role in processing the polyproteins that are translated from the viral RNA and essential for viral replication, and absence of human homologue, 3CLpro is one of the most intriguing drug targets for antiviral drug discovery. The inhibitors of 3CLpro are also most likely less toxic to cells of our body. 

Viral protease has been investigated as a drug target for decades resulting in several approved drugs for human immunodeficiency viruses (HIV) and hepatitis C virus (HCV). (6) Saquinavir was the first approved protease inhibitor for HIV, which started an era for this new class of antiviral drugs with approval in 1995. A considerable part of the drug discovery efforts to tackle the SARS outbreak in 2003 and the MERS outbreak in 2012 was dedicated to the development of potent 3CLpro inhibitors. The then-generated knowledge is important during the ongoing COVID-19 pandemics, since 3CLpro of SARS-CoV-2 shows 99% homology and 96% identity to that of SARS-CoV-1. 

Since the beginning of the coronavirus pandemic, several potential anti-SARS-CoV-2 drugs targeting viral proteases have been under investigation in clinical trials, including Kaletra (a fixed-dose combination of lopinavir and ritonavir used for HIV treatment), and more recently -- Paxlovid. Both drugs were previously known which allowed for their relatively quick debuts against rapidly spreading COVID-19. Lopinavir/ritonavir (Kaletra) is a well-known antiretroviral medication for the treatment and prevention of HIV/AIDS, approved as a single medication for use in the United States in 2000, and it is even included in the World Health Organization's List of Essential Medicines. It was repurposed against SARS-CoV-2 based on similarities in the mechanism of action. Paxlovid’s component Nirmatrelvir belongs to a group of compounds previously shown to specifically inhibit the coronavirus protease 3CL and successfully tested against SARS and Feline coronaviruses.

Another representative of 3CL protease-focused drugs is S-217622 by Japanese pharmaceutical giant Shionogi. High hopes were placed on this drug candidate, and it was considered to be the next “magic drug.” Unlike Pfizer’s Paxlovid, S-217622 is expected to get rid of the dependence on P450 enzyme inhibitors, such as ritonavir, achieve single-agent treatment of COVID-19, and expand the scope of the applicable patient population. But regulatory turbulence hit the project, and the application of S-217622 failed to obtain the support of the expert panel of Japan’s Ministry of Health, Labour and Welfare (MHLW). The basis of the expert group was that while S-217622 managed to reduce viral load and improved respiratory symptoms, it failed to improve systemic symptoms. 

Interestingly, in July Shionogi further pushed submission of materials for the new drug marketing authorization application of S-217622 in China’s Center for Drug Evaluation of the National Medical Products Administration. The company responsible for submitting the new drug application is Ping An-Shionogi Co., Ltd., which was jointly funded by Shionogi and China’s Ping An.

"Mee-too" drugs are heading to clinical trials in China

With a huge potential market for coronavirus oral drugs and delayed launch of Shionogi’s small molecule, there is an interesting trend emerging in China, a country still experiencing massive lockdowns due to COVID-19 threats. Most Chinese companies decided to play it safe and focus on essentially copying Paxlovid with minor modifications - a technique called Patent Busting. Apparently, this strategy can increase the chances of successful approval because Pfizer managed to do it. Some examples include:

FB2001 by Frontier Biotechnologies

In July, Frontier Biotechnologies announced the latest progress in the research on aerosol inhalation drug delivery of FB2001, a new anti-coronavirus drug under development. Both the aerosol inhalation and intranasal administration of FB2001 showed strong antiviral effects on Omicron strain-infected mice, which could significantly reduce the viral load in the lungs of mice. Frontiers is advancing a Phase II/III clinical study evaluating the efficacy and safety of FB2001 in hospitalized patients with COVID-19.

SIM0417 by Simcere Pharma 

In May, Simcere announced that SIM0417, a new coronavirus drug candidate targeting 3CL protease was approved for clinical trials by the National Medical Products Administration (NMPA) and was intended to be used in patients who have been exposed to potential coronavirus infection. This is the first clinical trial of post-exposure prophylaxis of COVID-19 in China.

RAY1216 by Zhongsheng Pharmaceutical

In May, Zhongsheng Pharmaceutical announced that its holding Zhongsheng Ruichuang was granted regulatory authorization by NMPA for the clinical trial of its oral anti-coronavirus 3CL protease inhibitor RAY1216 in a form of tablets. 

QLS1128 by Qilu Pharmaceutical 

Qilu Pharmaceutical recently registered a clinical trial for COVID-19 (ClinicalTrials.gov registration number: NCT05458076) to evaluate the safety, tolerability and pharmacokinetics of QLS1128 extended-release tablets combined with ritonavir in healthy subjects study. According to the combination regimen and indications, QLS1128 is likely to be a 3CL protease inhibitor.

ASC11 by Ascletis 

In April, Ascletis announced the results of ASC11 anti-COVID-19 cell experiments: the antiviral activity of ASC11 was substantially higher than that of nelmatevir, S-217622, PBI-0451, and EDP-7. Importantly, ASC11 remains active against different variants of the new coronavirus.

Here is a table adapted from a report by Guotai Junan Securities, the China's largest investment bank, summarizing several 3CL protease-focused candidates going to clinical studies or already there:

A novel approach to target 3CL protease 

In May, clinical stage biotech Insilico Medicine announced the nomination of a novel preclinical drug candidate ISM036-076 targeting 3CL protease for the treatment of pneumonia caused by the new coronavirus. Preclinical studies have shown that the compound has good in vivo efficacy even at low doses without the need for combination with CYP3A4/Pgp inhibitors such as ritonavir (and all the side effect issues the latter might entail). 

According to this report about 3CL drug candidates in China, ISM036-076 may be a second-generation 3CL protease inhibitor molecule that solves the pain point of Paxlovid. The drug candidate is a novel non-peptide structure generated by the company’s artificial intelligence platform Chemistry42, a generative chemistry component of its end-to-end artificial intelligence (AI)-based platform Pharma.AI; it possesses a new mechanism of action for this target, irreversible covalent binding. Compared with Pfizer's nirmatrelvir, it can achieve good in vivo efficacy without combining with ritonavir. It also retains the potential to form a cocktail in combination with RdRp inhibitors (Remdesivir, etc.). At the same time, Insilico Medicine’s drug candidate exhibits strong broad-spectrum anti-coronavirus activity, which appears to be efficient not only against the new coronavirus, but also against other types of coronaviruses, including SARS, and MERS, a property that can significantly expand the product value space. The antiviral activity of ISM036-076 was shown to be better than that of Nirmatrelvir. The synthetic route is short, and it only takes two steps from the raw material to the preparation of the compound. In terms of safety, the risk of off-target side effects was shown to be low, and the results of studies on teratogenicity and mutagenesis are negative, with a high therapeutic index and good safety. 

According to Insilico Medicine, which is headquartered in Hong Kong but has offices and labs across the globe, the molecule designed by Chemistry42, possesses distinct pharmacophores from existing 3CL protease inhibitors and binds to the target protein in a unique, irreversible, covalent binding mode as demonstrated by a co-crystal structure. 

Notably, Insilico Medicine’s AI platform has a track record of rapid drug candidate nominations in other therapeutic areas, including fibrosis, inflammation, and oncology. Its fibrosis candidate recently succeeded in the Phase 0 microdose trial and entered Phase I clinical trials in New Zealand and China. Their SARS-CoV-2 program is yet to be tested in humans, but the company states that it is committed to progress the molecule as fast as possible into clinical trials evaluating its usage in COVID-19 treatment.

It seems that while most Chinese drug discovery companies are focused on copying Paxlovid, Insilico Medicine appears to be the only company in the Asian region which started with this validated target (3CL protease) but designed a completely novel molecule with a new mechanism of action on this target, performing preclinical experiments to demonstrate that it works in vivo in many models and in all available coronavirus strains. It would be interesting to see how the molecule performs in the future clinical trials.