Pfizer hikes price of COVID antiviral Paxlovid from $530 to nearly $1,400

A box of Paxlovid, the Pfizer antiviral drug.
Enlarge / A box of Paxlovid, the Pfizer antiviral drug.

Pfizer on Wednesday revealed that it raised the list price of a course of Paxlovid—its lifesaving antiviral drug used to reduce the risk of severe COVID-19 in those most vulnerable—to nearly $1,400, more than double the roughly $530 the US government has paid for the treatment in the emergency phase of the pandemic.

Pfizer CEO Albert Bourla had noted in an investor call at the beginning of the week that the company would increase the price of Paxlovid as it moves from government distribution to the commercial market at the end of this year. But, he did not announce the new list price then. Instead, the company revealed the more than twofold increase in a letter to pharmacies and clinics dated Wednesday. The Wall Street Journal was the first to report the list price of $1,390 after viewing the letter.

A Pfizer spokesperson told the Journal that “pricing for Paxlovid is based on the value it provides to patients, providers, and health care systems due to its important role in helping reduce COVID-19-related hospitalizations and deaths.”

A cost-effectiveness analysis last year determined the value of Paxlovid at between $563 and $906 per treatment course, according to nonprofit drug-pricing watchdog The Institute for Clinical and Economic Review.

The list price is not necessarily what people and insurers will pay for the drug. The cost will be negotiated with pharmacy benefit managers (PBMs), independent middle-managers who oversee prescription drug benefits and copays for health insurers, federal programs, and other payers. A person familiar with Pfizer’s pricing decision told the Journal that the company set the higher list price so that it can offer larger discounts and rebates to PBMs and insurers.

But these rebates and discounts, which are currently not transparent, aren’t always passed on from PBMs to insurers and other payers. Thus, they can add to the overall skyrocketing costs of health care in the US—which by far spends more on health care than any other high-income country despite having many of the worst health outcomes of any other high-income country.

For now, those covered by Medicare or Medicaid and those who are uninsured will continue to have free access to Paxlovid through 2024 via a government program. And the government and Pfizer will offer assistance programs to reduce the price for several years afterward. Without assistance, people who are uninsured would face the steeply increased list price.

Still, with assistance and rebates, doctors and other advocates say higher list prices will lead to lower use of the drug, which is already inequitably distributed globally and underused in the US, particularly in settings where it is most beneficial.

https://arstechnica.com/?p=1977187




Anti-viral drug backfires: COVID drug linked to viral mutations that spread

Anti-viral drug backfires: COVID drug linked to viral mutations that spread

With every new infection, the pandemic coronavirus gets new chances to mutate and adapt, creating opportunities for the virus to evolve new variants that are better at dodging our immune systems and making us sicker.

Anti-viral drugs, such as Paxlovid and remdesivir, aim to halt this incessant evolution in individual patients—shortening illnesses, snuffing out opportunities for mutation, and reducing transmission. But one antiviral appears to be backfiring—allowing SARS-CoV-2 more opportunities to mutate.

According to a new peer-reviewed study in the journal Nature, the anti-viral drug dubbed molnupiravir is linked to specific SARS-CoV-2 mutation signatures that happened to spring up in 2022 when the drug was introduced.

The study’s authors—led by researchers at the Francis Crick Institute in London and the University of Cambridge—scanned through more than 15 million SARS-CoV-2 genome sequences found in global databases. They picked out unique mutation signatures that closely linked to signatures seen in viruses from patients known to have been treated with molnupiravir. These suspected molnupiravir-linked mutation signatures also matched those seen in viruses examined in a clinical trial of molnupiravir. Overall, the signatures appeared in older people, who are most likely to have been treated with an antiviral, and people in countries where molnupiravir has often been used.

Beyond simply finding molnupiravir-linked mutations, the researchers noted concerning features of them. The researchers found evidence that some of the molnupiravir-linked mutations were under positive selection—that is, they increased in frequency, suggesting that they were advantageous to the virus in some way. They also noted that some viruses with molnupiravir-linked mutations were passed on from person to person in clusters, which suggested onward transmission of these drug-induced mutations.

The findings indicate that “molnupiravir results in new mutations, increasing the genetic diversity in the surviving viral population,” Theo Sanderson, lead author and postdoctoral researcher at the Francis Crick Institute, said in a statement.

For now, there is no evidence that molnupiravir has contributed to the development of any of the most significant SARS-CoV-2 variants, such as omicron. And the clusters of transmission seen in the data are small. Still, Sanderson says the study’s finding is important for weighing the risks and benefits of molnupiravir, highlighting the “possibility of persistent antiviral-induced mutations.”

https://arstechnica.com/?p=1971307




COVID rebounds: Immune responses may be reignited by cleanup of viral scraps

A box of Paxlovid, the Pfizer antiviral drug.
Enlarge / A box of Paxlovid, the Pfizer antiviral drug.

Pfizer’s antiviral pill Paxlovid is among the most treasured tools for hammering COVID-19; it can knock back the relative risk of hospitalization and death by 89 percent in unvaccinated patients at high risk of severe disease. But, as use of the convenient drug has grown in the US, so have troubling reports of rebound cases—people who took the pill early in their infection, began feeling better, and even tested negative but then slid back into symptoms and tested positive again days later.

It’s still unclear just how common the phenomenon is, but it certainly happens in some proportion of Paxlovid-treated patients. In May, the Centers for Disease Control and Prevention even issued a health alert over the rebound reports.

But, amid the rising awareness, it has also become clear that patients who have not been treated with Paxlovid can also rebound. In fact, in Pfizer’s clinical trials of Paxlovid, researchers noted that about 1 percent to 2 percent of both treatment and placebo groups had rebounds.

Together, this has raised a slew of questions: Are the rebounds reignited infections? Are people still infectious? Do they need to resume isolation? Are they again at risk of severe disease? Did their immune systems fail to mount an effective response? Is the virus mutating to become resistant to Paxlovid? Is omicron causing more rebounds than previous variants?

So far, there’s limited data and mostly only anecdotal reports. But a new, small pre-print study led by researchers at the National Institutes of Health offers some encouraging news about COVID rebounds. The study, which included data on seven rebounding patients—six of whom were treated with Paxlovid and one who was not—found no evidence of Paxlovid-resistant mutations, viral replication gone wild, or faltering immune responses.

Intact immune responses

Instead, a detailed look at their immune responses found that rebounds were associated with a surge in antibody and cellular immune responses specific against SARS-CoV-2. At the same time, rebounds were accompanied by downward trends in markers of innate (non-specific) immune responses, as well as levels of SARS-CoV-2 nucleocapsid bits in the blood.

Together, the findings suggest that the rebounds could be partly due to reignited immune response as the body works to clear cellular debris and viral scraps from a quickly smothered infection. Or, as the authors put it: “rebound symptoms may in fact be partially driven by the emerging immune response against residual viral antigens possibly shed from dying infected cells due to cytotoxicity and tissue repair throughout the respiratory tract.”

In further support of this, the authors—co-led by infectious disease experts Brian Epling and Joe Rocco—note that while three of four controls had a recoverable, live virus during their acute infection, only one of the seven rebounding patients had a live virus at the time of their rebound. And that one patient also had underlying immune suppression, which may explain the finding. Further, none of the rebounding patients developed severe disease.

The study is, again, very small and may not be generalizable to all rebound cases. The authors call for rebound studies with larger cohorts. But some elements of the findings are already backed up. For instance, other studies have also failed to identify Paxlovid-resistant mutations. And on Tuesday, the CDC published a study of more than 5,000 Paxlovid-treated patients, finding that less than 1 percent of patients had emergency visits or hospitalizations in the 5-to-15 rebound period after treatment.

For now, the NIH researchers find their new findings “encouraging.” As Epling wrote in a tweet on Tuesday, ” the findings suggest that “an appropriate immune response is developing, so rebound isn’t caused by people not developing an immune response to COVID while on Paxlovid.”

https://arstechnica.com/?p=1862113




Pfizer says its antiviral pill can cut 89% of COVID hospitalizations and deaths

Pfizer headquarters in Manhattan on November 19, 2020.
Enlarge / Pfizer headquarters in Manhattan on November 19, 2020.

An antiviral pill developed by Pfizer reduced COVID-19 hospitalizations and deaths by about 89 percent in a trial involving 774 newly infected people at risk of developing severe disease. That’s according to a press release posted Friday by the company; the full data has not yet been released, published, or peer-reviewed.

Still, Pfizer said the results looked promising enough that an independent data-monitoring committee recommended the trial end early. Pfizer said it now plans to submit its data as soon as possible to the Food and Drug Administration for an Emergency Use Authorization (EUA).

Pfizer’s oral antiviral—PF-07321332—is the second drug candidate to generate buzz as an easy-to-use and highly effective COVID-19 treatment. Last month, Merck announced that its oral antiviral treatment, molnupiravir, cut the risk of hospitalization and death from COVID-19 by roughly 50 percent in newly infected, at-risk people. Merck has applied for an EUA, and FDA advisers will review the application on November 30.

Advantages

Though health experts are happy to have as many effective drugs as possible to fight the devastating pandemic, Pfizer has not-so-subtly noted the advantages PF-07321332 has over molnupiravir. Beyond the better efficacy (89 percent vs. 50 percent), Pfizer pointed out in its press release that PF-07321332 “originated in Pfizer’s laboratories.” In fact, its development started with Pfizer’s work to find a treatment for SARS-CoV-1 after the 2002 SARS outbreak. Highlighting this fact seems to be a shot at Merck’s molnupiravir, which was born in an academic research lab at Emory University years ago. Merck only purchased rights to the drug in 2020 during late-stage development against COVID-19.

Pfizer also noted that PF-07321332 “did not demonstrate evidence of mutagenic DNA interactions,” another apparent jab at molnupiravir. PF-07321332 is a protease-inhibiting drug; it works by hindering a specific enzyme, called a protease, found in SARS-CoV-2 and other coronaviruses. The protease plays a critical role for the virus by snipping apart strings of proteins into smaller units that are functional—and vital to the virus’s ability to make infectious copies of itself. By inhibiting the protease, PF-07321332 prevents SARS-CoV-2 from replicating.

By contrast, molnupiravir thwarts SARS-CoV-2 by posing as a building block for the virus’s genetic code, which is in the form of RNA. When the virus’s RNA-dependent RNA polymerase—an enzyme that makes copies of SARS-CoV-2’s RNA code—incorporates the drug into new RNA strands, those strands are doomed, and the virus is unable to make viable copies of itself. Though early animal and human trial data suggest that molnupiravir is safe, there exists the theoretical possibility that the drug could also damage the human genetic code. For this reason, it’s unlikely that the drug will be used during pregnancy.

Limited data

For now, there’s only a small amount of data available to fully evaluate PF-07321332. According to Pfizer’s press release, 774 people newly diagnosed with SARS-CoV-2 and at high risk of developing severe COVID-19 were enrolled in a trial. Of those, 389 received PF-07321332 and an HIV antiviral drug called ritonavir within three days of developing symptoms, and 385 received a placebo and standard care. (Ritonavir helps slow the metabolism and breakdown of PF-07321332 in the body so it can be active for longer, Pfizer said.) After 28 days, only three PF-07321332-treated patients were hospitalized, and zero died. Meanwhile, 27 participants in the placebo group were hospitalized, and seven died. That works out to an 89 percent reduction in the risk of hospitalization and death.

Pfizer also looked at the drug’s effects in people treated within five days of COVID-19 symptom onset, rather than three. In that trial of 1,219 people, 607 received PF-07321332 and ritonavir within five days. Only six treated people were hospitalized, and none died. Among the 612 people in the placebo groups, 41 were hospitalized, and 10 died. That trial indicates about an 85 percent reduction in risk of hospitalization and death.

As for safety, Pfizer said that mild effects were reported about equally between the treated and placebo groups (19 percent vs. 21 percent). Also, more people receiving a placebo reported serious side effects (1.7 percent vs. 6.6 percent), and more dropped out of the trial (2.1 percent vs. 4.1 percent) than people treated with PF-07321332.

If PF-07321332 is granted authorization, Pfizer says it will offer the drug with tiered pricing based on countries’ income levels. But experts are already skeptical of equitable distribution of the drug based on the significant inequity in the distribution of Pfizer’s COVID-19 vaccine.

https://arstechnica.com/?p=1810678




Meet molnupiravir, Merck’s Thor-inspired pill that hammers COVID

A Merck sign stands in front of the company's building on October 2, 2013, in Summit, New Jersey.
Enlarge / A Merck sign stands in front of the company’s building on October 2, 2013, in Summit, New Jersey.

An oral antiviral drug appears to cut the risk of hospitalization and death from COVID-19 by roughly 50 percent in people newly diagnosed with the infection and at risk for severe disease, pharmaceutical company Merck announced Friday morning.

The drug-maker and its partner, Ridgeback Biotherapeutics, released top-line results of a Phase III trial, which the companies ended early given the positive results. The companies say they will apply for an Emergency Use Authorization from the US Food and Drug Administration as soon as possible.

The trial enrolled people who had newly tested positive for a SARS-CoV-2 infection and had onset of mild-to-moderate COVID-19 symptoms within just the past five days of starting the trial. The enrollees also had to have at least one risk factor for a poor outcome, such as having obesity, diabetes, heart disease, or being age 60 or above. While some participants received a placebo and standard care, others took an oral dose of the drug every 12 hours for five days.

After 29 days of follow-up, 53 out of 377 participants who received the placebo were hospitalized with COVID-19, and eight of those participants died. Among those who received the drug, only 28 of 385 were hospitalized and none of those patients died. Put another way, 7.3 percent of patients on the drug were either hospitalized or died compared with 14.1 percent in the placebo group.

Merck also highlighted that the trial was global and that the drug appeared to work equally well against varying SARS-CoV-2 variants, including delta, gamma, and mu. The drug-maker noted that it had viral genetic data to identify variants from 40 percent of participants.

The safety data was equally promising, with participants reporting similar numbers of drug-related adverse events between the placebo group than the drug group (11 percent and 12 percent, respectively). About 3.4 percent of people in the placebo group quit the study due to adverse events, while only 1.3 percent quit in the drug group.

Pharmaceutical mythology

The drug at the center of these seemingly smashing results is dubbed molnupiravir—a name inspired by that of Thor’s hammer, Mjölnir. The idea is that the drug will strike down SARS-CoV-2, like a mighty blow from the god of thunder. In an interview with Stat news, Merck’s head of research and development, Dean Li, said that the new data proves the drug’s mythological force. “Our prediction from our in vitro studies and now with this data is that molnupiravir is named after the right [thing]… this is a hammer against SARS-CoV-2 regardless of the variant.”

Molnupiravir is a small molecule that wallops the work of a viral RNA-dependent RNA polymerase, an enzyme critical for making copies of RNA viruses, such as SARS-CoV-2. The drug had been in the works for years before SARS-CoV-2 emerged and, in March of 2020, it was on the verge of entering clinical trials for use against influenza. At that point, Ridgeback partnered with the drug’s non-profit developers at Emory University to turn it against SARS-CoV-2. A few months later, in May, Ridgeback and Merck announced a collaboration to develop the drug, then called EIDD-2801, into a COVID-19 treatment.

Molnupiravir delivers a precise blow to viral RNA polymerase by posing as a building block for RNA. In the body, molnupiravir is forged into a deceptive ribonucleoside that the polymerase unwittingly incorporates into new strands of viral RNA instead of cytidine. This is essentially lethal. Researchers call the effect a “viral error catastrophe,” in which the rate of genetic mutations or errors exceeds a threshold compatible with the virus surviving.

These types of nucleoside decoy drugs raise concerns of creating problems for human enzymes, too. For this reason, pregnant people were carefully excluded from trials. However, so far, all the animal and clinical trials have suggested good safety results.

In early animal studies with other coronaviruses, namely SARS-CoV and MERS-CoV, molnupiravir improved lung function, lowered viral loads, and improved infection-related weight loss. Other early studies showed molnupiravir also worked to kill off SARS-CoV-2 infecting cells from human airways.

The new clinical data suggests that, when given early, molnupiravir can bash out the worst-case scenarios of COVID-19. Its easy-to-use oral pill is also an advantage worth noting. Remdesivir, another antiviral drug used against COVID-19, must be given intravenously. If molnupiravir gains FDA authorization, it would certainly be another useful tool against COVID-19. However, vaccines will remain the best tool for pounding out the pandemic, smashing down not only severe disease and hospitalization but infection and transmission as well.

https://arstechnica.com/?p=1800050