Virus World

The first-of-its-kind treatment, Paxlovid, has been found to be highly protective against severe illness. It could be available within a few days.  The Food and Drug Administration on Wednesday authorized the first pill for Covid-19, offering a highly effective defense against severe illness that will arrive as the country endures another major surge of the pandemic. The drug, developed by Pfizer and known as Paxlovid, is authorized for Covid patients age 12 and over who are vulnerable to becoming severely ill because they are older or have medical conditions such as obesity or diabetes. Tens of millions of Americans — including both vaccinated and unvaccinated people — will be eligible if they get infected with the virus. The treatment could be available within a few days. Pfizer’s laboratory studies indicate that its pills are likely to work against the Omicron variant, which has rapidly become the dominant form of new cases in the United States. A clinical trial indicated that Paxlovid is highly effective when taken soon after people start feeling sick. In a final analysis of a key study conducted while the Delta variant was surging, Pfizer’s drug reduced the risk of hospitalization or death by 88 percent when given to high-risk unvaccinated adults within five days of the start of their symptoms. Paxlovid appears to be substantially more effective than a similar antiviral pill from Merck, known as molnupiravir, that is still awaiting authorization by the F.D.A. In a clinical trial, Merck’s drug reduced risk of hospitalization and death for high-risk patients by 30 percent.

Pfizer said Tuesday it signed a licensing agreement to allow broader global access to its experimental Covid-19 pill.  The agreement with the Medicines Patent Pool, a United Nations-backed public health organization, would allow generic manufacturers to make the pill widely available in 95 low- and middle-income countries covering 53% of the world's population, the company said. The pill, known as PF-07321332 or Paxlovid, is to be given in combination with an older antiviral drug called ritonavir.  Earlier this month Pfizer announced topline results from its trial saying that an interim analysis -- done before the trial was scheduled to end -- showed an 89% reduction in the risk of hospitalization or death from Covid-19 among people given the drug within the first three days of symptom onset.  "Pfizer will not receive royalties on sales in low-income countries and will further waive royalties on sales in all countries covered by the agreement while COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization," Pfizer said in the statement. The Medicines Patent Pool, founded by Unitaid 10 years ago, facilitates rapid access to medicines for people in low- and middle-income-countries.

The study will now assess the tolerability and safety of multiple ascending doses of PF-07321332, an oral antiviral agent against SARS-CoV-2. The study will now assess the tolerability and safety of multiple ascending doses of PF-07321332, Pfizer’s investigational oral antiviral agent against SARS-CoV-2. Pfizer is progressing its novel oral antiviral candidate against SARS-CoV-2 into multiple ascending doses after completing the dosing of single ascending doses in a Phase I study in healthy adults. The trial is evaluating the safety and tolerability of PF-07321332, a SARS-CoV2-3CL protease inhibitor, which demonstrated potent in vitro antiviral activity against SARS-CoV-2 and other coronaviruses. SARS-CoV-2 is the virus that causes COVID-19. 

“Tackling the COVID-19 pandemic requires both prevention via vaccine and targeted treatment for those who contract the virus. Given the way that SARS-CoV-2 is mutating and the continued global impact of COVID-19, it appears likely that it will be critical to have access to therapeutic options both now and beyond the pandemic,” stated Dr Mikael Dolsten, Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer. “We have designed PF-07321332 as a potential oral therapy that could be prescribed at the first sign of infection, without requiring that patients are hospitalised or in critical care. At the same time, Pfizer’s intravenous antiviral candidate is a potential novel treatment option for hospitalised patients. Together, the two have the potential to create an end-to-end treatment paradigm that complements vaccination in cases where disease still occurs.”

Protease inhibitors such as PF-07321332 bind to a viral enzyme, called a protease, which is vital for the virus to successfully replicate in human cells. Through their interaction with the enzyme, this class of medicines prevent the virus from replicating. Protease inhibitors have been used to treat various other viral pathogens, including HIV and hepatitis C virus, both alone and in combination with other antivirals. Currently marketed protease inhibitors are not generally associated with toxicity and as such, this class of molecules may potentially provide well-tolerated treatments against COVID-19.  The Phase I trial is a randomised, double-blind, sponsor-open, placebo-controlled, single- and multiple-dose escalation study in healthy adults evaluating the safety, tolerability and pharmacokinetics of PF-07321332. Pfizer is also investigating an intravenously administered investigational protease inhibitor, PF-07304814, in a Phase Ib multi-dose trial in hospitalised patients with COVID-19.

Pfizer Press Release (March 23, 2021):

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-initiates-phase-1-study-novel-oral-antiviral 

Paxlovid, Pfizer’s pill to treat Covid-19, retained its 89% efficacy at preventing hospitalization and death in the full results of a study of 2,246 high-risk patients, the company said Tuesday.  In early November, Pfizer had released interim results from the first 1,219 patients in the study. But another oral antiviral targeting Covid, from Merck and Ridgeback Biotherapeutics, had seen estimates of its efficacy at preventing hospitalization drop from 50% to 30% between an interim result and a final one. A panel of experts advising the Food and Drug Administration on Nov. 30 recommended 13-11 that the Merck pill, molnupiravir, should be authorized for emergency use. The FDA has not announced a decision. The oral medicines are seen as important because they could be much easier to deliver to infected people than existing drugs like monoclonal antibodies, which must be infused intravenously or injected.  Experts contacted by STAT breathed a sigh of relief that the Pfizer results held up, though all emphasized the need to more fully examine the data, which were shared in a press release, not a scientific publication. “The protection from hospitalization is obviously fantastic,” said Andrew Pekosz, vice chair of microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health. “That number was a great number. The fact that it was conserved in that final analysis really points to this being a really important weapon in our arsenal to fight Covid-19 particularly as we see more variants that are going to be chipping at that efficacy number.”

Pfizer also reported results from a second study in adults with Covid at normal risk of developing severe disease, a group that included vaccinated people. That study failed to meet its main goal, of increasing the sustained alleviation of self-reported symptoms, at an interim analysis; the study is continuing. But Pfizer said that there was a decrease in hospitalization in that group, too, although numbers were small. In the study of high-risk patients, called EPIC-HR, 5 of 697 patients who received a five-day course of Paxlovid were hospitalized or died, compared to 44 of 682 who received a placebo. There were no deaths in the Paxlovid group and 9 in the placebo group. Adverse events occurred at similar rates between the placebo and Paxlovid groups, and patients on Paxlovid were less likely to have a severe problem or to stop taking the drug due to a perceived side effect. Patients in the study were considered high risk because they were not vaccinated and had at least one characteristic or underlying medical condition that increased their risk of Covid-19. These could include being over 65, being overweight, or having cardiovascular disease. The study of patients who were at lower risk, called EPIC-SR, showed that 2 of 333 patients who received a five-day course of Paxlovid were hospitalized compared to 8 of 329 who received placebo. The results were similar in a second analysis, Pfizer said, but barely missed statistical significance. Rates of adverse events were similar between the drug and placebo. Eric Topol, director and founder of the Scripps Research Translational Institute, said that despite this trial failing to succeed on its main goal of reducing symptoms, he was encouraged by the consistency between the results. “It all fits together,” he said. Céline Gounder, a clinical assistant professor of medicine and infectious diseases at the NYU Grossman School of Medicine and Bellevue Hospital, said that she was encouraged the efficacy was similar whether the treatment was given within three days of symptom onset or five. “It means you have a bigger window in order to get a diagnosis and get someone a drug,” Gounder said. “How impactful it will be will be determined by whether people are able to access it in time. The fact that you have a week of business days, that, to me, is really important.”

Paxlovid, if authorized, would be given as two pills of Paxlovid plus one of ritonavir, another antiviral, twice daily for five days. Ritonavir can interact with many other medicines, which could add logistical hurdles for its use. One big worry, Topol said, was supply of the drug. Pfizer says that it will have 200,000 courses of the medicine available this year and 80 million available next year. But he worried that may not be enough given the waves of Covid that could hit around the world. Annaliesa Anderson, a Pfizer senior vice president who played a leading role in the treatment’s development, said the company is working to ramp up production, just as it did with the Covid vaccine it developed with BioNTech, looking for ways it can work with partners to speed up production. “We’re doing what we can,” she said. Anderson said that Pfizer has “great confidence” that Paxlovid will remain potent against the Omicron variant based on in vitro data showing the pill inhibits a key protease enzyme in Omicron. However, she noted, antiviral assays for the new variant have not yet been developed. She also portrayed the development of the antiviral as, in some ways, bittersweet. Anderson said that a high point in its development had been when Covid vaccines proved effective, and some people asked if an antiviral was necessary. (It was, she said, because vaccines won’t work for everyone and not everyone will have access.) A low point was when other medicines against Covid failed, because she worried that no oral medicines would prove effective. “We all spent a lot of time developing this antiviral,” she said, “and we hoped we wouldn’t need it.” Information about how well the study represented people of different backgrounds and ethnicities was not immediately available. Those who were pregnant or breastfeeding were excluded from the trials.

Drugmaker Pfizer said Friday its experimental pill designed to fight coronavirus reduced the risk of hospitalization and death for high-risk patients taking part in a trial of the drug.  The company hopes it can eventually offer the pill, given in combination with an older antiviral drug called ritonavir, to people to take at home before they get sick enough to go to the hospital. A so-called interim analysis -- done before the trial was scheduled to end -- showed an 89% reduction in the risk of hospitalization or death from Covid-19 if patients got it soon enough, the company said.  Pfizer released the results in a news release and did not provide scientists to discuss the data ahead of release. The data has not been peer reviewed or published. The company says it will share more specifics in a peer-reviewed paper and in its submission to the US Food and Drug Administration.  On CNN New Day on Friday, Pfizer CEO Albert Bourla said the company planned to submit data to regulators as soon as possible, maybe before Thanksgiving. The company has been testing the drug in adults with Covid-19 who are considered at high risk of progressing to severe illness. The volunteers have been randomly given either the pill combination or a placebo within three days or five days of their symptoms starting. The pill, called Paxlovid and its experimental name, PF-07321332, is what's known as a protease inhibitor. It's designed to stop the virus from multiplying. Giving it along with ritonavir slows its breakdown in the body, the company said. Pfizer said 0.8% of patients who got the drug combination within three days were hospitalized within four weeks -- three out of 389 patients -- compared to 7% of patients who got placebos, or 27 out of 385. And seven of those who got placebos died, Pfizer said. No one who got the treatment died within a month.