Japan’s Shionogi & Co. is set to receive regulatory approval this February for a new antiviral drug to treat COVID-19 infection caused by the SARS-CoV-2 coronavirus. To that end, an application for its registration for conditional early approval will be sent in the next week or two.
- Shionogi & Co. did just that, by filing to the regulator.
The brand name of the new Japanese drug against COVID-19 is Xocova. The active ingredient is ensitrelvir. The code name is S-217622.
The new drug is expected to become available to Japanese patients in early March. At this stage, Shionogi & Co. can produce a batch of the drug for one million patients by the end of March. Production capacity will then be expanded to produce the medicine for 10 million patients.
- In late March, Shionogi & Co. agreed with the Japanese Ministry of Health, Labor and Welfare (MHLW) to supply ensitrelvir as soon as it is approved by the regulator. The first shipment will be 1 million therapeutic courses.
Oral Xocova (ensitrelvir), which has the same mechanism of action as Pfizer’s Paxlovid (nirmatrelvir + ritonavir), differs in that it only needs to be taken once a day, while the therapeutic effectiveness of ensitrelvir does not seem to be inferior to Paxlovid. As a reminder, nirmatrelvir is administered twice daily, together with the booster represented by ritonavir.
Shionogi & Co. is continuing talks with international partners to launch a large-scale clinical trial in late February that will open the way for Xocova to other countries, including the highly lucrative U.S. market. However, the first results of the trial won’t be available until the summer, so ensitrelvir, if confirmed safety and efficacy, won’t hit the international market until late this year, 2022.
The price of Xocova has not yet been determined, but Shionogi & Co. suggest that the cost of ensitrelvir for government procurement will be set at world-class levels (read, competitive with other oral COVID-19 drugs). However, for low- and middle-income countries, the price of Xocova will be only slightly higher than for flu medications.
- For reference: Pfizer has set out three levels of cost for a course of COVID-19 treatment with Paxlovid, which depend on the income level of countries — high, middle, or low. For example, the price of Paxlovid for U.S. patients is $530. For low-income countries, Paxlovid is given at cost. Roche together with Shionogi & Co. promotes Xofluza (baloxavir marboxil), which is enough to take in single dose to treat or prevent influenza and which price in the US is $170.
From a business perspective, Shionogi & Co. has a lot to fight for: Pfizer intends to make a whopping $22 billion on Paxlovid in 2022. The money could be even more, given that the U.S. pharmaceutical giant, first, has set the cost of a therapeutic course of Paxlovid at $529 for developed economies and, second, is ready to release 120 million courses of it this year.
Ensitrelvir works regardless of coronavirus mutations, including the Omicron variant. It remains to be seen whether Xocova is as effective as Paxlovid, which reduces the risk of hospitalization or death from COVID-19 by almost 90%.
- Ensitrelvir is claimed to successfully counteract the Omicron subvariants BA.4 and BA.5 with the same high antiviral activity as in the case of other coronavirus variants. In any case, this follows from in vitro testing.
The need for new drugs to fight coronavirus infection is extremely high, and there are a number of important reasons for this. First, treating COVID-19 at home reduces the burden on already overheated health care systems. Second, the oral route of administration is convenient for the patient, with tablets being easier and cheaper to make than injectable medications. Third, the drugs will help those who resist vaccination or cannot be vaccinated for medical reasons. Fourth, the wider the drug armamentarium, the lower the risk of virus mutations with the subsequent emergence of resistance to therapy. Fifth, new drugs against COVID-19 spur price competition and somehow solve the problem of unmet demand for such drugs due to insufficient production.
Xocova: Efficacy and Safety of COVID-19 Treatment With Ensitrelvir
The jRCT2031210350 phase 2/3 (randomized, double-blind, placebo-controlled, multicenter) clinical trial enrolled patients with COVID-19 infection that was mild to moderate in severity (symptoms must have manifested no later than 5 days before randomization) or asymptomatic.
Participants were given placebo or ensitrelvir (low- or high-dose) once daily for 5 days.
Phase 2a Results
The results of the the phase 2a study among 47 patients demonstrated that the use of ensitrelvir was statistically significantly superior to placebo (unless otherwise noted) in the following respects:
- A more rapid decline in viral titer and viral RNA.
- On day 4 (after the 3rd dose), the proportion of patients with a positive viral titer decreased by 60%–80% compared to the placebo group, meaning Xocova quickly spared patients from the viral shedding status when sick people infect healthy people.
- The median time to negative viral titer was approximately 2.5 days, a reduction of about 2 days compared to the control group.
- In the Xocova group, none of the subjects were hospitalized, whereas in the placebo group, 14.3% of patients were hospitalized (or received equivalent treatment).
- There was a trend toward an improvement in the overall score on the 12 symptom COVID-19 scale, although no statistically significant difference with placebo was recorded.
The safety profile of ensitrelvir was characterized by acceptable tolerability: none of the patients discontinued treatment.
Among the treatment-emergent adverse events (TEAEs), the most common were the following: nasopharyngitis (in 9.5%, 0%, and 0% of subjects in the high-dose S-217622, low-dose, and placebo group, respectively), headache (4.8%, 13.0%, 0%), rhinalgia (9.5%, 0%, 0%), high-density lipoprotein (HDL) cholesterol decreased (14, 3%, 52.2%, 8.3%), blood triglycerides increased (0%, 13.0%, 0%), aspartate aminotransferase (AST) increased (4.8%, 4.3%, 8.3%), blood bilirubin increased (0%, 8.7%, 0%), alanine aminotransferase (ALT) increased (4.8%, 0%, 8.3%).
Among treatment-related TEAEs, the following were noted: HDL cholesterol decreased (14.3%, 34.8%, 0%), blood triglycerides increased (0%, 8.7%, 0%).
Almost all TEAEs were manifested with a mild degree of severity.
Phase 2b Results
The results of the phase 2b study, which enrolled 428 patients infected primarily with the Omicron variant of the SARS-CoV-2 coronavirus, were generally not different from those collected in the phase 2a study. Ensitrelvir administration resulted in the following beneficial effects:
- A more rapid decline in viral titer and viral RNA.
- On day 4 of treatment, less than 10% of patients had a positive viral titer.
- There was a trend toward improvement in COVID-19 symptoms, according to the time-weighted average change in the total score of 12 COVID-19 symptoms between days 1–6 from the start of treatment, although no statistically significant difference with placebo was noted, but such a difference was registered for respiratory symptoms (stuffy or runny nose, sore throat, cough, shortness of breath).
No new safety concerns have been identified with ensitrelvir.
Data from 341 patients treated with either placebo or ensitrelvir at a low dose (375 mg loading dose followed by 125 mg) or high dose (750 mg loading dose followed by 250 mg), have shown the following results from the phase 2b clinical trial
The use of Xocova provided a rapid reduction in viral load. Thus, by day 4 (after the third dose) of therapy the viral titer decreased by a mean of 1.49 log10 TCID50/ml (amount of infectious agent infecting 50% of the cell culture) in the ensitrelvir subgroups — versus a decrease of 1.08 log10 TCID50/ml in the placebo group (p<0.0001). In other words, ensitrelvir compared to placebo accelerated the viral load drop by 2.5 times. Moreover, in the majority of subjects receiving ensitrelvir, the viral titer fell to undetectable values.
This was also true for the decrease in viral RNA levels (copies/ml): a statistically significant (p<0.0001) difference with the control group was observed by day 4 of treatment.
The time to the first negative viral titer test after treatment initiation was a median of 51 hours (95% CI: 44–62) and 62 hours (95% CI: 44–67) in the low- and high-dose ensitrelvir subgroups — versus 92 hours (95% CI: 84-110) in the placebo group (p<0.0001). Thus, administration of Xocova reduced the time of viral shedding when a sick person infected healthy ones by a median of 41 hours and 30 hours, or 1 to 2 days, relative to placebo. By the 4th day of treatment, about 10% remained infectious, compared with about half in the control group.
Xocova and placebo showed an identical degree of improvement in COVID-19 symptoms, although when it came to respiratory and feverish symptoms (stuffy or runny nose, sore throat, shortness of breath, cough, feeling hot or feverish), there was some tendency for them to resolve more quickly with ensitrelvir.
The main safety complaint about ensitrelvir was a decrease in high-density lipoprotein (HDL) cholesterol, experienced by 22% and 29% of subjects in the low-dose and high-dose subgroups of the drug.
Xocova: Ensitrelvir for Prevention of COVID-19
Shionogi & Co. has not yet run ensitrelvir through a clinical trial of its applicability in the task of preventing the development of COVID-19 infection. However, experiments in animal models indicate that Xocova is well suited to protect healthy individuals sharing or in contact with infected individuals from infection with SARS-CoV-2 coronavirus.
Thus, in Syrian hamsters treated with high doses of ensitrelvir, 4 days after inoculation with the highly pathogenic Delta variant, the level of coronavirus RNA in nasal turbinates and lung tissue was dramatically reduced (105-fold), and the viral titer dropped to undetectable. The same was true when infected with Alpha, Gamma, and Omicron variants. After 18 days, neutralizing antibodies against coronavirus were undetectable. In experiments with infection of healthy hamsters with sick ones, prophylactic doses of ensitrelvir resulted in a dramatic reduction of the viral load in the lungs after 6 days of contact between the animals. All this indicates that ensitrelvir administration provides sterile protection against SARS-CoV-2 infection and COVID-19 development.
In comparison, the protective efficacy of molnupiravir in some cases was not different from that of placebo.
It should be understood that in animal experiments, the prophylactic administration of an antiviral drug at the pre-infection or infection stages is a highly sensitive experimental method for detecting protective drug efficacy.
Xocova: Mechanism of Action of Ensitrelvir
Xocova (ensitrelvir) is an oral antiviral drug for the treatment of COVID-19 infection caused by the new coronavirus SARS-CoV-2.
The active ingredient in Xocova is ensitrelvir (S-217622), a slow-molecule non-peptidomimetic non-covalent orthosteric selective inhibitor of 3C-like protease (3CLpro), also known as main protease (Mpro), an enzyme necessary for coronavirus replication.
SARS-CoV-2, being an enveloped positive-sense (+) RNA virus, enters host cells by binding its S protein to angiotensin-converting enzyme 2 (ACE2) on the cells and then releasing genomic RNA (gRNA) into the cytoplasm after uncoating. The cell’s ribosomes then translate the gRNA into the two major polyproteins, pp1a and pp1ab. Proteases embedded in viral nonstructural proteins 3 (Nsp3) and 5 (Nsp5), papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro), respectively, cleave pp1a and pp1ab into 16 nonstructural proteins that assemble into replication–transcription complexes (RTCs). The latter produce new gRNAs and a set of subgenomic RNAs (sgRNAs) including open reading frames (ORFs) that encode structural viral proteins such as S protein, membrane (M), envelope (E), and nucleocapsid (N) proteins, as well as a number of accessory proteins. The newly created gRNAs are translated to produce additional nonstructural proteins, serve as a template for further RNA synthesis, or are packaged into new virions.
Inhibition of 3CLpro with ensitrelvir interrupts the life cycle of the virus, making it unable to replicate.
Since no significant mutations near the catalytic center of 3CLpro have been reported so far, it is safe to say that ensitrelvir will retain its high antiviral activity in all SARS-CoV-2 variants, current and future.
Thus, the in vitro antiviral activity of ensitrelvir assayed on Vero E6/TMPRSS2 cell lines infected with various SARS-CoV-2 variants was independent of mutations. For the original coronavirus and its variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) the EC50 (effective drug concentration required to suppress viral replication by 50%; the lower this value, the more effective, that is, at lower concentrations, the drug compound works) was 0.37, 0.33, 0.40, 0.50, 0.41, and 0.29 μmol.
- For the sake of clarity, it should be understood that in the context of the SARS-CoV-2 coronavirus, mutations leading to new variants are usually understood as spontaneous mutations in the S protein of the virus, which is used for adhesion and cell invasion. As a survival strategy, the coronavirus, by mutating the S protein on its surface, tries to increase proliferation, virulence, and infectivity, as well as to find new hosts. This is accomplished through a series of spontaneous mutations, occurring one after another under the pressure of host selection, regardless of the presence of any antiviral drug in the body. At the same time, mutations in viral enzymes, which have already evolutionized so that their function is maximized, are not selected for, and therefore do not spread to the entire coronavirus population. If artificial mutational pressure is applied, e.g. in the form of a pharmaceutical enzyme inhibitor, wild variants of the virus die out — new drug-resistant variants emerge. However, such variants are generally less infectious and less capable of spreading.
Ensitrelvir reduces viral RNA load at levels comparable to nirmatrelvir, molnipiravir by Merck & Co., and a number of monoclonal antibodies.
The mechanism of action of ensitrelvir is similar to that of nirmatrelvir developed by Pfizer. However, the latter is not as chemically optimal. Nirmatrelvir, first, is a peptidomimetic covalent inhibitor of 3CLpro and, second, requires the concomitant administration of ritonavir as a pharmacokinetic booster. A number of challenges are known to improve the target selectivity and pharmacokinetic profile of peptidomimetic covalent inhibitors because of their inherent natural reactivity properties, low oral bioavailability (due to low cellular permeability), low metabolic stability, and low stability in serum.   
Ensitrelvir, unlike Paxlovid, is not characterized by a wide range of drug interactions. Pfizer’s drug includes ritonavir (pharmacokinetic booster of nirmatrelvir), which inhibits cytochrome P450 3A4 (CYP3A4), a hepatic enzyme that metabolizes xenobiotics, i.e. deactivates drug compounds. Adding ritonavir at a low dose increases the bioavailability of nirmatrelvir, helping to slow down the metabolism of this molecule so that it retains its activity in the body for a longer period of time and at higher concentrations. Thus, first, co-administration of Paxlovid with other drugs whose clearance is highly dependent on CYP3A4 activity is contraindicated due to the fact that their concentrations may increase. Second, some drugs that are CYP3A4 inducers may decrease the concentration of ritonavir and nirmatrelvir, resulting in loss of therapeutic efficacy of Paxlovid.
A 5-day course of COVID-19 treatment with Xocova involves taking 5 pills of ensitrelvir. A similarly long course of treatment with Paxlovid requires 20 pills of nirmatrelvir and 10 pills of ritonavir.
Ensitrelvir was developed by Shionogi & Co. in collaboration with Hokkaido University.
Xocova: Expert Comments
The design of the ensitrelvir’s clinical trial is developed to be as close to the real patient population as possible. First, the age range of participants is set at 12–70 years. Second, there are no restrictions on vaccination status: both vaccinated and unvaccinated were invited. Third, there were no conditions that the patients were characterized by the presence of any risk factors potentially contributing to severe COVID-19: e.g., diabetes mellitus or a history of cardiovascular disease.
The only requirement is to start COVID-19 treatment no later than 5 days after the onset of its symptoms and signs. And this is obvious, because the mechanism of action of ensitrelvir implies suppression of coronavirus replication, and this is reasonable to do only at the initial stage of disease development, because further COVID-19 goes into a phase where it is not the virus itself that plays a decisive role, but the consequences it causes.
Remarkably, the majority (71%–88%) of participants in all phase 2a groups were vaccinated against SARS-CoV-2. Nevertheless, Shionogi & Co. believe that the positive effect of treatment is due to ensitrelvir and not to the vaccine.
Overall, the Xocova’s trial aimed to gather evidence that timely administration of ensitrelvir effectively suppressed the spread of the coronavirus and rapidly improved COVID-19 symptoms. And it succeeded.
The small sample size of subjects in the phase 2a study does not allow for unequivocal conclusions as to whether ensitrelvir can significantly reduce the risk of worsening the course of COVID-19 infection with further hospitalization. However, given the accumulated data, there are all the prerequisites for this.
Shionogi & Co. was originally scheduled to collect clinical data from 2,100 people in the phase 2b study before sending an application for Xocova to the regulator. But after the Olympics in Japan, COVID-19 cases dropped off sharply, so it was decided to limit the data to 400 patients in order to confirm safety and efficacy results as soon as possible for early conditional approval of ensitrelvir. The relevant data will be disclosed shortly. Shionogi & Co. will then initiate a local phase 3 clinical trial.
- Now, a Japanese pharma company is conducting a phase 3 study of Xocova in patients (n=1260) with mild-to-moderate symptoms of COVID-19 and a phase 2b study in patients (n=200–300) with only mild symptoms or asymptomatic.
If Xocova is approved, Shionogi & Co. will organize a clinical trial of the applicability of ensitrelvir, first, for the prevention of COVID-19 infection in healthy persons living together or in contact with infected individuals, and second, for use in the pediatric population.
Shionogi & Co. continues intensive discussions with the U.S. Food and Drug Administration (FDA) on the design features of a global phase 3 clinical trial of ensitrelvir.
- In mid-March, Shionogi & Co. agreed with The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, to conduct the US National Institute of Allergy and Infectious Diseases (NIAID) sponsored SCORPIO-HR (ACTIV-2d, NCT05305547) phase 3(randomized, double-blind, placebo-controlled, multicenter, international) clinical trial of ensitrelvir among adult non-hospitalized patients (n=1700) infected with SARS-CoV-2 coronavirus and at high risk for progression of COVID-19 infection to hospitalization or death. These risks include obesity, diabetes, cardiovascular disease or hypertension, chronic lung disease, Down’s syndrome, sickle cell disease, dementia, Parkinson’s disease, or immunodeficiency.
- An international SCORPIO-SR phase 3 clinical trial is planned that will test ensitrelvir in non-hospitalized patients with mild-to-moderate COVID-19.
Phase 2b part of S-217622, a novel 3C-like protease inhibitor as once daily oral treatment for SARS-CoV-2 infection in Japan and South Korea. ECCMID, April 24, 2022. [PDF]
Results from Ph1 and Ph2a studies of S-217622, a novel 3C-like protease inhibitor as once daily oral treatment for SARS-CoV-2 infection. ECCMID, April 24, 2022. [PDF]
Top-line results of the phase 2a part of the phase 2/3 trial of S-217622, the COVID-19 therapeutic drug. Shionogi & Co., February 7, 2022. [PDF]