The ‘very, very bad look’ of remdesivir, the first FDA-approved COVID-19 drug

Authors: By Jon CohenKai KupferschmidtOct. 28, 2020 , 7:05 PM

October was a good month for Gilead Sciences, the giant manufacturer of antivirals headquartered in Foster City, California. On 8 October, the company inked an agreement to supply the European Union with its drug remdesivir as a treatment for COVID-19—a deal potentially worth more than $1 billion. Two weeks later, on 22 October, the U.S. Food and Drug Administration (FDA) approved remdesivir for use against the pandemic coronavirus SARS-CoV-2 in the United States—the first drug to receive that status. The EU and U.S. decisions pave the way for Gilead’s drug into two major markets, both with soaring COVID-19 cases.

But both decisions baffled scientists who have closely watched the clinical trials of remdesivir unfold over the past 6 months—and who have many questions about remdesivir’s worth. At best, one large, well-designed study found remdesivir modestly reduced the time to recover from COVID-19 in hospitalized patients with severe illness. A few smaller studies found no impact of treatment on the disease whatsoever. Then, on 15 October—in this month’s decidedly unfavorable news for Gilead—the fourth and largest controlled study delivered what some believed was a coup de grâce: The World Health Organization’s (WHO’s) Solidarity trial showed that remdesivir does not reduce mortality or the time COVID-19 patients take to recover.

Science has learned that both FDA’s decision and the EU deal came about under unusual circumstances that gave the company important advantages. FDA never consulted a group of outside experts that it has at the ready to weigh in on complicated antiviral drug issues. That group, the Antimicrobial Drugs Advisory Committee (AMDAC), mixes infectious disease clinicians with biostatisticians, pharmacists, and a consumer representative to review all available data on experimental treatments and make recommendations to FDA about drug approvals—yet it has not convened once during the pandemic.

For More Information: https://www.sciencemag.org/news/2020/10/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug

Peer-reviewed data shows remdesivir for COVID-19 improves time to recovery

Authors:  Beigel, et al. Remdesivir for the Treatment of COVID-19 – A Preliminary Report. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2007764 (2020).  

What

The investigational antiviral remdesivir is superior to the standard of care for the treatment of COVID-19, according to a report published today in the New England Journal of Medicine. The preliminary analysis is based on data from the Adaptive COVID-19 Treatment Trial (ACTT), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The randomized, controlled trial enrolled hospitalized adults with COVID-19 with evidence of lower respiratory tract involvement (generally moderate to severe disease). Investigators found that remdesivir was most beneficial for hospitalized patients with severe disease who required supplemental oxygen. Findings about benefits in other patient subgroups were less conclusive in this preliminary analysis.

The study began on Feb. 21, 2020 and enrolled 1,063 participants in 10 countries in 58 days. Patients provided informed consent to participate in the trial and were randomly assigned to receive local standard care and a 10-day course of the antiviral remdesivir intravenously, developed by Gilead Sciences, Inc., or local standard care and a placebo. The trial was double-blind, meaning neither investigators nor participants knew who was receiving remdesivir or placebo.

The trial closed to enrollment on April 19, 2020. On April 27, 2020 (while participant follow-up was still ongoing), an independent data and safety monitoring board overseeing the trial reviewed data and shared their preliminary analysis with NIAID. NIAID quickly made the primary results of the study public due to the implications for both patients currently in the study and for public health. The report published today in the New England Journal of Medicine describes the preliminary results of the trial.

For More Information: https://www.nih.gov/news-events/news-releases/peer-reviewed-data-shows-remdesivir-covid-19-improves-time-recovery

Remdesivir for the Treatment of Covid-19 — Final Report

Authors: John H. Beigel, M.D., Kay M. Tomashek, M.D., M.P.H., Lori E. Dodd, Ph.D., Aneesh K. Mehta, M.D., Barry S. Zingman, M.D., Andre C. Kalil, M.D., M.P.H., Elizabeth Hohmann, M.D., Helen Y. Chu, M.D., M.P.H., Annie Luetkemeyer, M.D., Susan Kline, M.D., M.P.H., Diego Lopez de Castilla, M.D., M.P.H., Robert W. Finberg, M.D., et al., for the ACTT-1 Study Group Members*

Abstract

BACKGROUND

Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.

METHODS

We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

RESULTS

A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).

CONCLUSIONS

Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705. opens in new tab.)

For More Information: https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

Alert — EU looking into new side effects of Vaccine…

Authors: By citizenfreepress.com

Three new conditions reported by people after vaccination with shots from Pfizer and Moderna are being studied to assess if they may be possible side effects, Europe’s drug regulator said on Wednesday.

Erythema multiforme, a form of allergic skin reaction; glomerulonephritis or kidney inflammation; and nephrotic syndrome, a renal disorder characterised by heavy urinary protein losses, are being studied by the safety committee of the European Medicines Agency (EMA), according to the regulator.

Last month, the EMA found a possible link between heart inflammation and the mRNA vaccines.

For More Information: https://www.dailyadvent.com/news/8222b115dc20c18b06116efcab52ea12-Alert–EU-looking-into-new-side-effects-of-Vaccine

How Will the Coronavirus Evolve?

Authors: By Dhruv Khullar


In 1988, Richard Lenski, a thirty-one-year-old biologist at UC Irvine, started an experiment. He divided a population of a common bacterium, E. coli, into twelve flasks. Each flask was kept at thirty-seven degrees Celsius, and contained an identical cocktail of water, glucose, and other nutrients. Each day, as the bacteria replicated, Lenski transferred several drops of each cocktail to a new flask, and every so often he stored samples away in a freezer. His goal was to understand the mechanics of evolution. How quickly, effectively, creatively, and consistently do microorganisms improve their reproductive fitness?

Lenski’s flasks produced about six new generations of E. coli a day; the bacteria woke up as babies and went to bed as great-great-great-grandparents. In this way, Lenski and his team have studied more than seventy thousand generations of E. coli over thirty-three years. Compared with their distant ancestors, the latest versions of the bacterium reproduce seventy per cent faster; it once took them an hour to double their ranks, but now they can do it in less than forty minutes. Different populations have taken different paths to enhanced fitness, but, after decades, most have arrived at reproduction rates within a few percentage points of one another.

Lenski’s Long-Term Evolution Experiment, or L.T.E.E., as it’s called, has yielded fundamental insights into the mutational capabilities of microorganisms. For his work, Lenski, now in his sixties and at Michigan State University, has received a MacArthur “genius” grant and a Guggenheim Fellowship. “I’m not sure I can tell you how it’s affected my thinking, because I’m not sure I can conceive of being in this field without this experiment existing,” Michael Baym, an evolutionary biologist at Harvard Medical School, recently told Discover.

Three of the experiment’s key findings are especially relevant today. The first is that, in general, there were diminishing returns to mutation over time: the bacteria made many of their most reproductively advantageous moves early on. A second finding, however, was that the bacteria never stopped getting fitter. Seventy thousand generations in, they’re still finding new ways to improve, albeit at a somewhat slower rate. “I had sort of imagined that things would have flatlined,” Lenski told me recently, when we spoke over Zoom. “But there seem to be endless possibilities for tinkering and progress. If there is a hard limit, it’s so, so far away that it’s impractical to consider on an experimental timescale—maybe even a geological timescale.”

For More Information: https://www.newyorker.com/science/annals-of-medicine/how-will-the-coronavirus-evolve

Use of adenovirus type-5 vectored vaccines: a cautionary tale

Authors: The Lancet

We are writing to express concern about the use of a recombinant adenovirus type-5 (Ad5) vector for a COVID-19 phase 1 vaccine study,1 and subsequent advanced trials. Over a decade ago, we completed the Step and Phambili phase 2b studies that evaluated an Ad5 vectored HIV-1 vaccine administered in three immunizations for efficacy against HIV-1 acquisition.23 Both international studies found an increased risk of HIV-1 acquisition among vaccinated men.24 The Step trial found that men who were Ad5 seropositive and uncircumcised on entry into the trial were at elevated risk of HIV-1 acquisition during the first 18 months of follow-up.5 The hazard ratios were particularly high among men who were uncircumcised and Ad5 seropositive, and who reported unprotected insertive anal sex with a partner who was HIV-1 seropositive or had unknown serostatus at baseline, suggesting the potential for increased risk of penile acquisition of HIV-1. Importantly for considering the potential use of Ad5 vectors for COVID-19 infection, a similar increased risk of HIV infection was also observed in heterosexual men who enrolled in the Phambili study.4 This effect appeared to persist over time. Both studies involved an Ad5 construct that did not have the HIV-1 envelope. In another HIV study, done only in men who were Ad5 seronegative and circumcised, a DNA prime followed by an Ad5 vector were used, in which both constructs contained the HIV-1 envelope.6 No increased risk of HIV infection was noted. A consensus conference about Ad5 vectors held in 2013 and sponsored by the National Institutes of Health indicated the most probable explanation for these differences related to the potential counterbalancing effects of envelope immune responses in mitigating the effects of the Ad5 vector on HIV-1 acquisition.7 The conclusion of this consensus conference warned that non-HIV vaccine trials that used similar vectors in areas of high HIV prevalence could lead to an increased risk of HIV-1 acquisition in the vaccinated population. The increased risk of HIV-1 acquisition appeared to be limited to men; a similar increase in risk was not seen in women in the Phambili trial.4Several follow-up studies suggested the potential mechanism for this increased susceptibility to HIV infection among men. The vaccine was highly immunogenic in the induction of HIV-specific CD4 and CD8 T cells; however, there was no difference in the frequency of T-cell responses after vaccination in men who did and did not later become infected with HIV in the Step Study.8 These findings suggest that immune responses induced by the HIV-specific vaccine were not the mechanism of increased acquisition. Participants with high frequencies of preimmunisation Ad5-specific T cells were associated with a decreased magnitude of HIV-specific CD4 responses and recipients of the vaccine had a decreased breadth of HIV-specific CD8 responses,9 suggesting that pre-existing Ad5 immunity might dampen desired vaccine-induced responses. 

For More Information: https://www.thelancet.com/journals/lancet/home

From adenoviruses to RNA: the pros and cons of different COVID vaccine technologies

Authors: Joel Abrams

The World Health Organisation lists about 180 COVID-19 vaccines being developed around the world.

Each vaccine aims to use a slightly different approach to prepare your immune system to recognise and fight SARS-CoV-2, the virus that causes COVID-19.

However, we can group these technologies into five main types. Some technology is tried and trusted. Some technology has never before been used in a commercial vaccine for humans.

As we outline in our recent paper, each technology has its pros and cons.

1. DNA/RNA-based

DNA and RNA vaccines use fragments of genetic material made in the lab. These fragments code for a part of the virus (such as its spike protein). After the vaccine is injected, your body uses instructions in the DNA/RNA to make copies of this virus part (or antigen). Your body recognises these and mounts an immune response, ready to protect you the next time you encounter the virus.

Pros

  • these vaccines can be quickly designed based on genetic sequencing alone
  • they can be easily manufactured, meaning they can potentially be produced cheaply
  • the DNA/RNA fragments do not cause COVID-19.

Cons

  • there are no approved DNA/RNA vaccines for medical use in humans, hence their alternative name: next-generation vaccines. So they are likely to face considerable regulatory hurdles before being approved for use
  • as they only allow a fragment of the virus to be made, they may prompt a poor protective immune response, meaning multiple boosters may be needed
  • there’s a theoretical probability vaccine DNA can integrate into your genome.

The speed at which these vaccines can be designed, needing only the genetic sequence of the virus, is why these vaccines were among the first to enter clinical trials.

An RNA vaccine, mRNA-1273, being developed by Moderna and the US National Institute of Allergy and Infectious Diseases, advanced to clinical testing just two months after the virus was sequenced.

2. Virus vectors

These vaccines use a virus, often weakened and incapable of causing disease itself, to deliver a virus antigen into the body. The virus’ ability to infect cells, express large amount of antigen and in turn trigger a strong immune response make these vaccines promising.

Examples of viruses used as vectors include vaccinia virus (used in the first ever vaccine, against smallpox) and adenovirus (a common cold virus).

Pros

  • highly specific delivery of antigens to target cells and high expression of antigen after vaccination
  • often a single dose is enough to stimulate long-term protection.

Cons

  • people may have existing levels of immune protection to the virus vector, reducing the effectiveness of the vaccine. In other words, the body raises an immune response to the vector rather than to the antigen.

For More Information: https://theconversation.com/from-adenoviruses-to-rna-the-pros-and-cons-of-different-covid-vaccine-technologies-145454

Here’s Why Viral Vector Vaccines Don’t Alter DNA

— It’s pretty simple — they can’t

Authors: by Veronica Hackethal, MD, MSc, Enterprise & Investigative Writer, MedPage Today March 12, 2021

Adenoviral vector vaccines have been in development for decades, but very few have been approved for use in humans. What does the history of adenoviral vector vaccine development tell us about their safety and their potential to alter DNA?

How Do Adenoviral Vector Vaccines Work?

Essentially, these types of vaccines act like delivery shuttles. They use an adenovirus — which has been engineered to be incapable of replicating and causing disease — to deliver the genes for making the antigen; in this case, that’s the SARS-CoV-2 spike protein. That in turn elicits an immune response and provides protection against the coronavirus.

Adenoviruses are basically common cold viruses that can cause illnesses ranging from cold-like symptoms to bronchitis, gastroenteritis, and conjunctivitis.

“I think people are unfortunately familiar with adenoviruses … [A]t far too many points, you know, you’ve had the sniffle. You’ve had the cough. You felt crummy. If it’s a cold it’s often adenovirus,” Daniel Griffin, MD, PhD, said on a recent episode of MedPage Today‘s “Track the Vax” podcast. Griffin is chief of infectious disease at ProHEALTH Care, an Optum unit.

Humans are infected with multiple different types of adenoviruses throughout their lifetimes. Most serotypes cause mild illness, although adenovirus serotype 7 has been associated with more severe illness. Older adults and people who are immunocompromised or have pre-existing respiratory or cardiac disease may have worse illness.

Precisely because adenoviruses are so common, one problem with using them in vaccines is that people may already have antibodies to them, overwhelming them before they can do their assigned work. Researchers get around that issue by using adenoviruses that humans are unlikely to have encountered before.

Currently, five adenovirus vector vaccines for COVID-19 are in use worldwide.

Each works on the same basic principle, although delivery platforms differ. The AstraZeneca/Oxford vaccine uses the ChAdOx1 platform, which is based on a modified version of a chimpanzee adenovirus.

The Johnson & Johnson vaccine uses a proprietary AdVac platform, made up of a recombinant human adenovirus (adv26). It’s the same platform used in the company’s Ebola virus vaccine (which is approved in Europe) and its investigational Zika, RSV, and HIV vaccines.

Russia’s Sputnik V uses recombinant human adenoviruses Ad26 and Ad5 for the first and second doses, respectively. Finally, China’s CanSino vaccine uses the recombinant human adenovirus Ad5.

For More Information: https://www.medpagetoday.com/special-reports/exclusives/91604

More Dangerous Side Effects Potentially Linked To mRNA Vaccines, EU Warns

Authors: BY TYLER DURDEN

As shares of MRNA-vaccine purveyors Moderna and BioNTech tumbled on Wednesday, Reuters reported that the EMA, the EU’s medicines regulator, is looking into new potential side effects from the still-experimental MRNA jabs, including suspicious skin reactions and kidney ailments.

According to Reuters, three new conditions have been reported by a small number of people after vaccination with jabs from Pfizer and Moderna. The ailments include Erythema multiforme, a form of allergic skin reaction; glomerulonephritis, or kidney inflammation; and nephrotic syndrome, a renal disorder that leads to heavy urinary protein losses. All of the cases are being studied by the EMA to determine whether the vaccines might be linked to the conditions.

This isn’t the first time regulators have raised issues with an MRNA vaccine. As we reported a few months ago, the FDA determined that one side effect of the jabs in a small number of male patients with certain complications included heart inflammation. Still, the FDA, CDC and WHO have insisted that the risks posed by the jabs are far outweighed by their benefits to society.

The finding comes as Israeli health authorities have found that a small number of patients still managed to get infected with the virus even after their third dose of the vaccine.

For More Information: https://www.zerohedge.com/covid-19/new-side-effects-potentially-linked-mrna-vaccines-eu-warns