Japan's COVID‐19 treatment strategy: An examination of approved oral medications

This study scrutinizes Japan's coronavirus disease 2019 (COVID‐19) medication policy, focusing on three approved oral drugs: molnupiravir, nirmatrelvir, and ensitrelvir. The study highlights a potential bias favoring domestic drugs, suggesting politics may influence clinical decisions, as shown in the previous Japan polio vaccine policy. Regulatory processes rooted in international cooperation and scientific evidence, prioritizing patient health over nationalistic priorities, are essential.

In Japan, there are three oral medications approved for coronavirus disease 2019 (COVID‐19) treatment as of May 2023: molnupiravir (Lagevrio), approved on December 24, 2021; nirmatrelvir (Paxlovid), approved on February 10, 2022; and ensitrelvir fumaric acid (Xocoba), approved on November 22, 2022. ¹ Among these, ensitrelvir was the first domestically developed medication and has received an emergency approval. Notably, the government procured one million prescriptions of this drug prior to approval, ¹ triggering concerns about its underlying scientific validity for regulatory endorsement. Such policy invites scrutiny, raising speculation that the driving force may be oriented toward expanding the market for Japanese companies rather than for the public's health.

The classification of the severity of COVID‐19 in Japan is divided into four stages: mild, moderate I, moderate II, and severe, based on oxygen levels in the blood. ² Mild and moderate I refer to situations where independent breathing and systemic inflammation are possible without oxygen supplementation. ² Table 1 shows the detailed profiles of each drug. Molnupiravir is an RNA polymerase inhibitor for patients with mild (high‐risk) to moderate I. A consent form is not required when prescribing. Ensitrelvir is a protease inhibitor indicated for patients with mild to moderate I. There are many contraindications for concomitant use, and written consent is required due to teratogenicity or other adverse effects. Nirmatrelvir, like ensitrelvir, is a protease inhibitor and is also indicated for high‐risk patients with mild to moderate I. Numerous contraindications exist for concomitant use, and a consent form due to adverse effects is required.

TABLE 1.

Profiles of oral COVID‐19 drugs approved in Japan.

	Molnupiravir	Ensitrelvir	Nirmatrelvir
Manufacturing company	MSD K.K.	SHIONOGI & CO., LTD.	Pfizer
Price	1 tablet of 200 mg 2357.80 yen	1 tablet of 125 mg 7407.40 yen	1 sheet (Nirmatrelvir 600 mg/Ritonavir 200 mg) 19805.50 yen
Mechanism	RNA polymerase inhibitor	Protease inhibitor	Protease inhibitor
Indication	Mild (high‐risk) to moderate I	Mild to moderate I	Mild (high‐risk) to moderate I
Contraindications	Pregnant	Concomitant drugs metabolized by CPY3A (e.g., antihypertensive drugs, some psychotropic drugs). Patients with renal or hepatic dysfunction receiving colchicine.	Concomitant drugs metabolized by CPY3A (e.g., antihypertensive drugs, some psychotropic drugs). Patients with renal or hepatic dysfunction receiving colchicine.
Patient written consent form	Not required	Required Emergency approval Adverse effects Teratogenicity	Required Special approval Side effects
Number of prescriptions (March 31, 2022–September 15, 2022)	484,839	N/A	41,179
Number of prescriptions (January 15, 2023–March 31, 2023)	N/A	22,785	11,629

Abbreviations: COVID‐19, coronavirus disease 2019; N/A, not applicable.

Of these, nirmatrelvir has been reported to reduce the risk of hospitalization and death by 89%, whereas such an effect was not confirmed in a systematic review for molnupiravir. ³ , ⁴ Furthermore, reports suggest that nirmatrelvir may also effectively prevent post‐acute sequelae. ³ Ensitrelvir has been reported to shorten the time to selected symptom resolution by ~24 h. ⁵ However, in an analysis limited to the Japanese population, the difference was only 6.3 h, and no statistically significant difference has been reported. ⁵ Moreover, because it is administered mainly in mild cases, to the best of our knowledge, the drug's effectiveness in reducing the risk of hospitalization or death has not yet been clarified.

According to a 2023 report from the United States Centers for Disease Control and Prevention (CDC), most people infected with COVID‐19 exhibit mild symptoms and can self‐treat at home with over‐the‐counter medications like acetaminophen and ibuprofen ⁶ ; thus, the crucial point in prescriptions is to prevent severe disease. However, in Japan, not only is molnupiravir the most frequently prescribed drug, probably due to no requirement of a consent form and scarce contraindications for concomitant use, but ensitrelvir, whose effectiveness is not clearly established, is also being widely prescribed. Additionally, although caution must be exercised in interpretation due to a temporal discrepancy, since the initiation of its prescription, as shown in Table 1, ensitrelvir has been reported to have been prescribed at a rate twice that of nirmatrelvir from January 15 to March 31, 2023, and, furthermore, the recording of prescriptions for molnupiravir has been discontinued. This suggests that the domestically developed drug is preferred in Japan over clinical evidence. Actually, although nirmatrelvir has numerous contraindications for the concomitant use of other drugs, the same is true for ensitrelvir. In addition, the efficacy of ensitrelvir is controversial because the protocol of the pivotal clinical trial for regulatory approval prohibits the co‐administration of any medication other than acetaminophen. In actual clinical settings, it is common to use cough suppressants and expectorants to treat patients with COVID‐19, further obscuring ensitrelvir's effectiveness.

Indeed, Japan has a history of prioritizing domestic manufacturers for political rather than scientific reasons, as demonstrated in the historical course of the implementation of polio vaccines. The Japanese government continued to use the oral polio vaccine exclusively manufactured by a Japanese company until 2012 without importing foreign companies' inactivated polio vaccines, and after eradicating the wild poliovirus in 1981, more than 80 cases of vaccine‐associated paralytic poliomyelitis occurred. ⁷ Similar scenarios favoring domestic companies have also been reported in other countries; for instance, in China, the introduction of the mRNA vaccine, which has proven effective in Western countries, was delayed due to the prioritization of domestically developed vaccines for COVID‐19. ⁸ Certainly, using domestically produce drugs and vaccines may stabilize the supply chain and prevent shortages or price hikes caused by sudden surges in demand in other countries. ⁹ However, in clinical practice, the decision on which drug to prescribe should be based on scientific evidence of its effectiveness and safety and put the patient first rather than the political situation of a country.

There have been efforts to gain approval for ensitrelvir in markets such as Taiwan and South Korea. However, with the rise of the Omicron variant, which has a lower fatality rate, the world is moving toward relaxed restrictions. The primary objective of future COVID‐19 strategies should be to prevent severe disease for high‐risk patients. As many past examples have demonstrated, a political bias toward domestically developed drugs could potentially compromise the populace's health. It is necessary to critically review the approval and regulatory process from the perspective of international cooperation to provide affordable and valuable prescriptions to those who need them the most.

FUNDING INFORMATION

No funding was received for this work.

CONFLICT OF INTEREST STATEMENT

T.T. receives personal fees from MNES Inc., and Bionics Co., Ltd. outside the submitted work. No other authors reported conflicts of interest.

Higuchi Y, Kaneda Y, Tanimoto T. Japan's COVID‐19 treatment strategy: An examination of approved oral medications. Clin Transl Sci. 2023;16:2075‐2077. doi: 10.1111/cts.13628