Why is the rate of prescription of Paxlovid to new crown patients by British and American doctors so low?

Recently, according to a report by Airfinity, a London-based health analysis company, Paxlovid prescription rate is not high, only for about 0.5% of new crown patients in the UK and about 13% in the United States. This is due to concerns about "Paxlovid rebound" (relapse or increased virus concentrations when you feel well soon) and side effects, and the growing belief that the risk of coronavirus has decreased. Inadequate funding allocation, expensive medications, and having to take it immediately after infection hinder Paxlovid use.

Paxlovid is a combination of the oral antiviral drugs Nirmatrelvir and Ritonavir. According to a clinical trial sponsored by Pfizer, Paxlovid reduced the risk of hospitalization or death by 89% in high-risk people who took the drug within three days of the onset of COVID symptoms. However, on June 14, 2022, Paxlovid released the results of a phase II/III clinical trial (EPIC-SR), which was declared "unsuccessful" due to non-statistically significant risk related to hospitalization or death, the secondary endpoint.

On August 24, 2022, an article published in NEJM by Israel's largest medical institution noted that Paxlovid only played a clear role in high-risk patients aged 65 years or older, and there was no evidence of an effect in young people. Professor Jin Dongyan, a virology expert in the School of Biomedical Sciences at the Li Ka Shing School of Medicine of the University of Hong Kong, also said that Paxlovid patients have the best effect when taken within 72 hours after infection, and if there is severe disease, it is not of much value. The data show that the drug is more effective in the elderly over 65 years old and patients with underlying diseases, reducing mortality by 81%, but there is no significant benefit in the 40-64 age group.

In December 2021, U.S. regulators authorized Paxlovid for the first time and relaxed prescription restrictions to make it more widely available. But health officials were disappointed to say the drug was not being used as they expected, and that about 10 million Paxlovid courses had been delivered to the U.S., but only about 6.7 million had been used. Global regulators have revoked their authorization for coronavirus monoclonal antibodies, making Paxlovid one of the only tools to prevent deaths in high-risk groups.

Paxlovid's low prescription rate, where does it come from?

Davey Smith, an infectious disease doctor at UC San Diego, said: "There is widespread concern about the Paxlovid rebound phenomenon. Rebound cases by public figures such as U.S. President Joe Biden and former U.S. infectious disease chief Anthony Fauci have exacerbated that concern, having a chilling effect on patients seeking Paxlovid. In addition, Paxlovid cannot be taken with many other medications. Due to the inclusion of the CYP3A4 enzyme inhibitor ritonavir, Paxlovid interacts with many drugs and affects liver and kidney function, so it greatly limits its medication population and increases the risk of medication for people with underlying diseases and the elderly. In some people, Paxlovid makes certain foods taste bitter or metallic, both of which reinforce people's perception that Paxlovid is 'toxic.' ”

The researchers found that rebound often occurred even in people who did not take Paxlovid. Precise estimates of the incidence of rebound vary depending on the population studied and the definition of 'rebound'. But Smith said that regardless of whether people take Paxlovid or not, they usually experience a viral rebound (i.e., people test positive again) or a symptom rebound, but not at the same time. Symptom rebound tends to be very mild and remains far better than hospitalization or death.

Daniel Griffin, an infectious disease doctor at Columbia University, said: "Part of the underuse of this drug is due to misconceptions about Paxlovid and the spread of some misinformation. For example, COVID risk is perceived to be lower than it was early in the pandemic, making patients less likely to seek treatment and doctors less likely to prescribe medication in a timely manner. Paxlovid works by inhibiting viral replication, which mostly occurs early in the course of the disease. This means that the medication must be taken within the first five days of symptom onset, leaving a narrow window of time for people to receive treatment. This does not fit well with the 'let's wait and see' mentality of doctors treating COVID patients. ”

The person in charge of Boton Pharmaceutical said: "The actual effect of Paxlovid may not be as miraculous as everyone rumors, and now the Omicron severe disease rate is low, if the use of the drug can be improved, it means that the person's own constitution is okay, taking other relief drugs may also achieve the effect, for this, Pfizer also agrees." Relatively speaking, we have a detailed understanding of the synthetic equations, pharmacology and pathology reports of this drug, and we have a better understanding of the basic situation and background of this drug. ”

What is the difficulty of local production in Paxlovid in China?

Paxlovid's local production is mainly limited by production characteristics, localized production licenses and supply chain issues. In terms of production characteristics, according to Airfinity, the Paxlovid production process requires a large procurement of 38 different raw materials and reagents from global suppliers. Pfizer said that the production of Paxlovid (mainly nimatevir) is like building blocks, the key raw materials are in different regions, manufacturers in more than 20 locations in more than 10 countries, and its production cycle has been shortened from the initial 9 months to 7 months.

In terms of localized production license, China currently implements the MAH system (Drug Marketing Authorization Holder), and when production depends on when Pfizer obtains a localized production license. However, Pfizer CEO Bourla said that local production of Paxlovid in China began in the first half of this year, but local partners in China have not yet started production and are expected to start soon.

In terms of supply chain, many production steps of Paxlovid production chain involve Boc groups, namely di-tert-butyl dicarbonate (DIBOC), but the capacity of DIBOC is not high, because its upper raw material is tert-butanol sodium, which needs to be synthesized with tert-butanol and sodium metal, but most countries, including the United States, will encounter upstream supply chain bottlenecks, that is, there is not enough sodium metal. Sodium metal is extremely active, production needs to be carried out in a dry and low temperature environment, developed countries' production capacity gradually withdrawn, has been mainly concentrated in the country, while the state for new capacity approval is extremely strict, the industry has strong barriers.

In August 2022, Pfizer and Huahai Pharmaceutical signed a localized production agreement for Paxlovid, during which Huahai Pharmaceutical will provide preparation manufacturing services for Paxlovid. In October 2022, Ascletis disclosed that its wholly-owned subsidiary had entered into a licensing and supply agreement with Pfizer to manufacture and supply Ritonavir tablets for Pfizer in Chinese mainland. Ascletis is currently progressing well and is in normal production. Huahai Pharmaceutical said it is promoting the localization of Pfizer products to ensure the supply of products in the Chinese market.