Molnupiravir supplies dominate in times of Paxlovid scarcity

Despite the US government committed to buying 20m Paxlovid doses, deliveries have been slow compared to Merck’s molnupiravir write Andrew Hillman and Manasi Vaidya. 

Despite the early and sustained enthusiasm for Pfizer’s oral antiviral Paxlovid, lagging supply has meant that most places in the US have higher demand than availability for the drug, as per an analysis of antiviral allocations.

Data gleaned from the US Department of Health and Human Services (HHS) indicates most states that experienced a surge in cases due to the Omicron variant have been heavily reliant on the antiviral molnupiravir, while supplies of Pfizer’s Paxlovid and GlaxoSmithKline and Vir Biotechnology’s monoclonal antibody (mAb) Xevudy (sotrovimab) trickle by.

While an authorized antiviral, molnupiravir—co-developed by Merck and Ridgeback Biotherapeutics—is not the preferred therapeutic for Covid-19 infected individuals unless a patient has a contraindication to other therapeutics. A lower efficacy than Paxlovid, inherent safety concerns, and a consequently divided FDA Advisory Committee meeting meant that molnupiravir moved down the treatment schematic for COVID-19. However, in times of shortage, iremained the only option for several states.

Molnupiravir and Paxlovid were authorized by the FDA on consecutive days in the last few weeks of December. But in terms of availability, Vermont, for example, had an 11-to-1 ratio of molnupiravir to Paxlovid supplies, while Georgia and Texas had 10-to-1 and 8.8-to-1 proportions, respectively, of the two antivirals.

This analysis is based on allocation data from a Therapeutic Locator dashboard run by the HHS, which clinicians, pharmacists, and patients have used to find therapeutics, and weekly distribution reports released by the agency. An analysis of this data has shown that providers from some states continued to receive fewer antiviral shipments than the national average despite a growing need for therapeutics, while others ended up with a surplus. This disparity is even more apparent when the supplies of the individual oral antivirals are probed more closely.

For example, on January 24, providers in Utah were reporting availability of molnupiravir above the national average while Utah’s availability of Paxlovid – six courses per 100,000 people – was the third lowest among all states. In fact, Utah’s ratio of 20 available courses of Molnupiravir for every course of Paxlovid was the highest in the US. Then, in the next round of distribution supplied by the HHS between January 24 and January 30, Utah received the lowest per-capita allocation of Paxlovid of any state.

Availability has risen faster for Molnupiravir than for Paxlovid

Available courses per 100,000 people

The supply of these antivirals has been closely scrutinized, as many places experienced surges in Covid-19 cases due to the Omicron variant. An analysis of the data on the HHS allocations and Covid-19 infection rates provided by the Centers for Disease Control and Prevention (CDC) has revealed an uneven supply across states. The HHS did not respond to a request for comment, but its distribution strategies are based on “current cases and hospitalizations, current utilization rates, and the activity of each product against currently circulating SARS-CoV-2 variants.”

Paxlovid favored but molnupiravir delivered

The US government has committed to buying 20 million courses of Paxlovid as per deals announced in the last few months. In contrast, Merck and Ridgeback were obligated to supply the government with close to one-third of that, or 3.1 million courses of the rival drug molnupiravir, which the companies recently fulfilled.

Still, while over 1.5 million courses of molnupiravir have been supplied to providers, only a little more than 364,000 Paxlovid courses have been distributed.

When asked about the distribution of their respective antivirals, Merck did not respond to a request for comment. A Pfizer spokesperson referred to the US government, which oversees arranging deliveries.

Apart from the oral antivirals, the HHS has been allocating monoclonal antibodies (mAbs) like Xevudy, Regeneron Pharmaceuticals’ REGEN-COV cocktail of casirivimab and imdevimab, and Eli Lilly’s mAb combination of bamlanivimab and etesevimab.

News reports on decreased efficacy seen with both antibody cocktails started to pour in at the beginning of December. Regeneron finally stated on December 16 that its cocktail has diminished potency against Omicron, while Eli Lilly spokespersons made similar statements to the press around the same time. Interestingly, despite this lack of efficacy, mAb allocations continued and since December 27, 213,000 courses of REGEN-COV and 173,000 courses of the Lilly cocktail were distributed, based on Public Health Emergency Declarations (PHE) data.

The FDA limited the use of these mAbs due to their lacking efficacy only on January 24. The elimination of two therapeutics from the armamentarium exacerbated the demand for antivirals during the peak surges.

Even prior to receiving an EUA, experts had raised concerns regarding molnupiravir’s safety. Moreover, updated efficacy data indicated that molnupiravir, also known as Lagevrio in the UK, reduced the hospitalization risk by 31% in comparison to 88% with Paxlovid in a separate study. This dimmed the enthusiasm for molnupiravir in recent times, while Paxlovid’s efficacy raised expectations for a scenario where eligible Covid-19 -infected individuals would immediately be treated easily and in an effective manner.

Patient guidelines as per the National Institutes of Health (NIH) have listed Paxlovid, sotrovimab, Gilead Sciences’ Veklury, and then molnupiravir in order of preference, and in the absence of any drug-drug interactions. “Molnupiravir has become the drug of last resort when you go down the priority list and are not able to access others,” says Dr Luis Ostrosky, an infectious disease physician at the University of Texas Health Sciences Center at Houston.

Triaging therapeutics

An unpredictable and limited supply has made matching patients with the right therapeutic even more challenging. Hospitals have had to produce their own systems to ensure equitable distribution in times of shortage.

Allocation decisions were made by a team including infectious disease physicians, critical care physicians, pharmacists, and medical ethicists which designs the criteria for a decision-making process, says Northwestern Memorial Hospital infectious diseases clinical pharmacist Justin Moore, PharmD.

States like Indiana have set up a system where providers refer patients to a Covid-19 therapeutic “triage center,” and pharmacists can decide on the best treatment there, says Michael Ganio, the director of pharmacy practice at American Society of Health Systems Pharmacists.

This, Ganio says, “is effective, rather than the provider evaluating that the patient needs Paxlovid, and then needing to find a site with that therapeutic.”

Drug-drug interactions play a role in treatment choice

Apart from availability, each drug’s pharmacokinetics influences its use in people with Covid-19. Once the surge of cases started a few months ago, it was a scramble to design criteria to identify high-risk individuals and then consider the nuances for each agent to select the right patient, says Moore.

“The people that are [getting these antivirals] are high risk, so they're either immunocompromised at baseline …. [and] on certain medications, or unvaccinated with multiple comorbidities,” says Moore. Risk factors include diabetes, hypertension, certain arrhythmias, and liver or lung disease, so these patients would likely have been on other medications, says Moore.

Paxlovid consists of two drugs: ritonavir and nirmatrelvir. The ritonavir component of Paxlovid causes certain drug levels to be increased, increasing risk of toxicity. The list of medications that are said to be contraindicated for Paxlovid includes antibiotics and blood pressure medications. Molnupiravir, on the other hand, is known for embryo-fetal toxicity and is contraindicated for use in pregnant individuals and women of child-bearing age not using contraceptive methods right before or during treatment.

Often pharmacists also need to make individual adjustments based on the patient’s profile. For example, dose adjustments would be needed if a patient’s kidney function is impaired, and there are nuances to which agent might work best for a particular patient.

Prior to the EUAs being granted, Ganio had talked about the potential benefits of pharmacists being able to prescribe oral antivirals to eligible patients owing to recent legislative changes in the PREP Act. However, language in the antiviral EUAs does not provide this prescribing power to pharmacists. These treatments need to be administered within five days of infection, and letting a pharmacist make the determination on patient eligibility to dispense the medication would make the process more efficient, he added.