molnupiravir

Nirmatrelvir and Molnupiravir and Post–COVID-19 Condition in Older Patients

Posted by

0


While the COVID-19 pandemic appears to be winding down, its effects are still felt by the millions of people worldwide experiencing post–COVID-19 condition (PCC, or long COVID).1 The antiviral drug nirmatrelvir (marketed as Paxlovid [Pfizer], in combination with ritonavir) and molnupiravir (Lagevrio [Merck]) are recommended as first- and second-line treatments for acute illness in patients with specific risk factors (eg, diabetes).2 However, there are still no US Food and Drug Administration–approved drugs for the treatment or prevention of PCC. Recent studies among US veterans (mostly male) suggest that nirmatrelvir and molnupiravir reduce the risk of some sequelae of COVID-19.3,4 We performed a cohort study of the 2 drugs in PCC in older patients who were Medicare enrollees.

Methods

The cohort came from Medicare enrollees aged 65 years or older diagnosed with COVID-19 between January and September 2022. COVID-19 was identified with an outpatient International Statistical Classification of Diseases, Tenth Revision, Clinical Modification code of U07.1. In January 2022, free home COVID-19 tests became available and not all positive self-tests were captured in Medicare data. Therefore, we also considered the prescription of nirmatrelvir or molnupiravir to be indicative of COVID-19 because no other indications existed. Following previous work,5 we identified PCC based on the World Health Organization (WHO) consensus clinical definition.6 Any new occurrence (not present prior to COVID-19 diagnosis) of the 11 symptoms between 4 to 12 weeks after infection was considered as PCC. We used an extended Cox regression with propensity score adjustment to examine the 2 drugs and the incidence of PCC. We included age, sex, race, geographic region, dual eligibility, low-income subsidy, and 51 chronic comorbidities as covariates as included in the Medicare data (eMethods, eTable in Supplement 1). This study was declared not human participant research by the Office of Human Research Protection at the National Institutes of Health. Statistical analyses were conducted using SAS version 7.15 (SAS Institute Inc) and a 2-sided significance at P < .05. This study followed the STROBE reporting guideline.

Results

Overall, among 3 975 690 outpatients with COVID-19, 57% remained in our study after exclusion. Among them, 19.5% received nirmatrelvir and 2.6% received molnupiravir. PCC incidence among patients receiving nirmatrelvir was 11.8%, 13.7% for molnupiravir, and 14.5% for neither, absolute risk reduction was 2.7% for nirmatrelvir, 0.8% for molnupiravir, with hazard ratios (HRs) of 0.87 (95% CI, 0.86-0.88; P < .001) for nirmatrelvir and 0.92 (95% CI, 0.90-0.94; P < .001) for molnupiravir, compared with no treatment (Table 1). Sensitivity analysis of only patients with the COVID-19 code showed a similar pattern but smaller effect sizes (nirmatrelvir: HR, 0.93 [95% CI, 0.92-0.94; P < .001], molnupiravir: HR, 0.96 [95% CI, 0.93-0.99; P = .001]). In an interaction analysis, we found significantly smaller effect sizes in females than males (HRs for nirmatrelvir: 0.89 vs 0.84; molnupiravir: 0.95 vs 0.88). Female sex; Asian, Black, and Hispanic races; and indicators of low income were associated with increased risk of PCC. The most common symptoms in PCC were fatigue (29.9%), dyspnea (22.4%), and cough (21%) (Table 2).

Discussion

Consistent with the findings of Xie et al,3,4 we found that nirmatrelvir and molnupiravir were associated with a small reduction in incidence of PCC. Our effect sizes are smaller than those of Xie et al3,4 (absolute risk reduction, nirmatrelvir 4.5%; molnupiravir 3.0%) but our sample size is 8-fold larger. We also have a more balanced sex ratio (female 59% vs 14%), which is important because PCC is more common in females. The smaller effect sizes in females may explain our overall smaller effect sizes. We used the WHO consensus definition based on symptoms rather than disease diagnosis (eg, ischemic heart disease), which is more akin to how PCC is identified clinically. Limitations of our study include not incorporating vaccination status because of incomplete data, use of prescription of the drugs as evidence of COVID-19, and restriction to patients 65 years or older. The current approved use of the 2 drugs is for the prevention of severe acute COVID-19. Our findings suggest that they may also have a role in preventing PCC.

Molnupiravir Heavily Used Despite Concerns; ‘Tranq Dope’ Use Rising in U.S.

Posted by

0


INVESTIGATIVE ROUNDUP over an image of two people looking at computer screens.

Welcome to the latest edition of Investigative Roundup, highlighting some of the best investigative reporting on healthcare each week.

Molnupiravir Heavily Used, Despite Concerns

Merck’s COVID antiviral molnupiravir is being heavily used despite concerns and a preference for Pfizer’s nirmatrelvir/ritonavir (Paxlovid), according to the Wall Street Journal.

According to data from IQVIA, more than 74,700 prescriptions for molnupiravir have been filled through February 25, which is not far behind the 79,150 prescriptions filled for Paxlovid through that time. Both drugs were authorized in December.

That’s despite federal guidelines recommending Paxlovid over molnupiravir. Paxlovid showed 90% efficacy against hospitalization and death in its clinical trial, compared with 30% for molnupiravir.

Physicians have also raised concerns about molnupiravir’s mechanism of action, which involves introducing errors into the virus’ genetic code. There was some evidence from clinical trials of a higher frequency of mutations in the virus, which could result in new variants. And lab data have suggested it may cause birth defects, WSJ reported.

Prescribers say they use molnupiravir because it has been available when Paxlovid has not been. “It comes down to what’s available,” said Ryan Laughlin, DO, a family physician in Knoxville, Iowa, who wrote about 10 prescriptions for nursing-home residents because Paxlovid wasn’t available. Ali Khan, MD, a chief medical officer at Oak Street Health, which runs about 100 primary care clinics across the U.S., said, “In a lot of our markets, the thing that we can actually get our hands on is molnupiravir.”

‘Tranq Dope’ Use Rising in U.S.

Xylazine, a veterinary tranquilizer, is increasingly turning up in overdose deaths, STAT News reported.

A recent paper showed that xylazine was found in 6.7% of overdose deaths in 2020, up from 0.36% in 2015. Researchers from the University of California Los Angeles analyzed data from medical examiners and coroners in 10 cities and states, and also embedded themselves with communities in Philadelphia, where the problem was particularly prevalent.

Joseph Friedman, an MD/PhD student who studies addiction at UCLA and is an author on the paper, said the number of contaminants in the drug supply “is just spiraling out of control. … People are not buying what they think they’re buying, or they don’t know what they’re buying.”

Opioids containing xylazine are known as “tranq dope,” and the sedative is added in order to extend the high of the opioid, according to STAT. CDC has only issued one small report on the drug in 2019, so the researchers took a deeper look to get a sense of how widespread the problem is in the U.S.

The study turned up wide regional variation, with the drug being more prevalent in the Northeast compared with the West. In Philadelphia, xylazine was found in 1 in 5 overdose deaths.

The researchers noted, however, that fentanyl was also found in nearly every xylazine-involved death, suggesting it’s not just the tranquilizer that’s problematic. However, the sedative can increase the risk of fatal overdose, given that it amplifies the respiratory depression effect of opioids. It may also make it harder to reverse overdoses with naloxone, they warned.

Schools and COVID: Less Is More?

The Lewis-Palmer school district in Monument, Colorado, brought students back into classrooms in fall 2020, with fewer COVID protocols than most districts — and officials argue that their learners flourished because of that approach, according to the Washington Post.

Elementary school students didn’t have to wear masks in the classroom; just in the hallways. There was no push for social distancing. There was a virtual option, but 85% of students in the district chose to return to the classroom.

Yet no children were hospitalized with COVID, school administrators said. Two school system employees were admitted, but officials said it wasn’t possible to track exactly where they’d picked up the virus.

And, students made educational gains above state averages, administrators told the Post. Reading proficiency for third and fifth graders in the district, for instance, increased by much larger percentage points compared with state-wide data, the Post reported.

But the district had strong consensus from the public in returning to classrooms from the start, with the majority of teachers believing they could do so safely, and the majority of parents saying they’d be very likely to send their kids back to school.

The district also didn’t shy away from pulling back when necessary. Its middle and high schools shut down during a surge in November 2020, and switched to virtual learning through winter break. They re-opened to a hybrid schedule in January 2021, only resuming full-time in-person instruction in March 2021. The district also quarantined entire classrooms when someone in the room tested positive for COVID.

With Molnupiravir, Timing Is Everything

Posted by

0


In a phase 2 trial, molnupiravir was not effective for patients with COVID-19 requiring inpatient care.

In December 2021, the nucleoside analog molnupiravir received EUA for outpatient treatment of COVID-19 based on a phase 3 study (MOVe-OUT) showing it reduced hospitalization and death by 30% (N Engl J Med 2021 Dec 16 [e-pub]). Researchers now report phase 2 results of a companion study (MOVe-IN) assessing molnupiravir’s efficacy in patients ill enough to require hospitalization but without critical illness or severe respiratory failure. This international trial compared 200, 400, or 800 mg of molnupiravir or placebo twice daily for 5 days in individuals with COVID-19 for ≤10 days; those with immunosuppression, COVID-19 vaccination, or thrombocytopenia were excluded, but treatment with remdesivir, glucocorticoids, or both was permitted.

Among 304 individuals enrolled between October 2020 and January 2021, 218 received molnupiravir and 75 placebo. There were no apparent dose-ranging clinical or laboratory safety concerns identified, and the incidence of adverse events was comparable among all groups. Median time to recovery (9 days), 29-day recovery rate, and all-cause mortality also were comparable across all groups. Sub-group analysis showed no indication of efficacy for those with symptoms for ≤5 days. Further, rates of reduction of nasopharyngeal SARS-CoV-2 viral load did not appear to differ by group.

COMMENT

While this study’s small sample size is a limitation, the results show no apparent benefit of molnupiravir once a patient is sick enough to need hospitalization for COVID-19. Given that relatively few individuals with mild symptoms will progress to severe disease — and that molnupiravir’s mechanism of action promotes viral mutagenicity with the potential to induce variants of concern — I will use this agent cautiously and only for high-risk non-hospitalized patients.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Posted by

0


Abstract

BACKGROUND

New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

METHODS

We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.

RESULTS

A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.

CONCLUSIONS

Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.

FDA issues EUA for Merck’s COVID-19 antiviral molnupiravir

Posted by

0


The FDA has issued an emergency use authorization for molnupiravir — now the second oral antiviral treatment available for COVID-19.

The drug is authorized for the treatment of mild-to-moderate COVID-19 in adults who test positive for SARS-CoV-2, and who are at high risk for progression to severe disease. It is not authorized for use in patients aged younger than 18 years because it may affect bone and cartilage growth, the agency said.

Source: Adobe Stock.

FDA’s Antimicrobial Drugs Advisory Committee endorsed a recommendation for granting an EUA in a split 13-10 vote on Nov. 30. The recommendation extended to individuals with COVID-19 who are at high risk for serious illness.

“The EUA for molnupiravir is a sign of progress, since it ushers in an era of oral antivirals that can be used by individuals at increased risk of severe disease (elderly and/or immunocompromised patients) when first diagnosed with SARS-CoV-2,” Kenneth H. Mayer, MD, the medical research director of Fenway Health and codirector of the Fenway Institute, told Healio. “This may become similar to how drugs like Tamiflu are used for patients who develop influenza.”

On Wednesday, the FDA granted an EUA for Pfizer’s Paxlovid, an antiviral that was also developed for the treatment of adults who are at risk for severe COVID-19, but it can also be used to treat pediatric patients aged 12 years and older weighing at least 40 kg, or about 88 pounds.

Molnupiravir, which was developed by Merck in collaboration with Ridgeback Biotherapeutics, reduces the risk for hospitalization or death from COVID-19 among high-risk patients, according to phase 3 data. Merck and Ridgeback Biotherapeutics submitted an EUA application on Oct. 11. Since then, Merck has begun manufacturing capsule pills of molnupiravir. The company expects to have 10 million treatment courses produced by the end of the year. With the EUA, the drug may be available to patients within weeks.

“We’re hopeful that we can make a meaningful impact on the pandemic through the development of an effective oral antiviral COVID-19 medicine, pending regulatory discussions,” a Merck spokesperson told Healio.

The drug’s authorization was supported by a phase 3, double-blind, randomized, placebo-controlled trial called MOVe-OUT. The study included patients aged 18 years or older with a chronic medical condition or an increased risk for SARS-CoV-2 infection who had not received a vaccine. Among the 709 participants who received molnupiravir, 6.8% were hospitalized or died during a 1-month period vs. 9.7% of the 699 people who received a placebo. Results of the trial, published in The New England Journal of Medicine, showed that the rate of hospitalization or death through day 29 was approximately 31% lower with molnupiravir than with placebo (HR = 0.69; 95% CI, 0.48 to 1.01).

In comparison, Pfizer’s investigational oral antiviral, Paxlovid, reduced the risk for COVID-19-related hospitalization and death by almost 90% among patients who received the antiviral within days of experiencing symptoms, Healio previously reported.

Of the participants who received molnupiravir, one died during the follow-up period compared with nine people who received placebo. According to the FDA, adverse events included diarrhea, nausea and dizziness.

The drug’s safety and efficacy continue to be evaluated, the agency said.

Reference:

Bernal AJ, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2116044.