Virus World

Scores of Covid vaccines are in development. Four companies have manufactured the majority of doses. But that doesn't mean they are the best. P fizer/BioNTech. Moderna. Johnson & Johnson. AstraZeneca. These are the marquee names that spring to mind when you think of the vaccine companies at the forefront of the global fight against Covid-19. And for good reason: together they have manufactured the majority of the estimated 7 billion-plus Covid vaccine doses administered to date around the world.  But as regulators in the U.S., Europe, and around the world mull the most responsible way to expand vaccine eligibility to an even larger share of their populations — including to younger children, as the Food and Drug Administration (FDA) and Centers for Disease Control (CDC) have done this month by greenlighting Pfizer’s vaccine for kids 5 to 11 years of age — it’s time to confront an uncomfortable reality: The global health community still doesn’t know which of the hundreds of Covid vaccines currently in clinical and preclinical development are truly “the best.” That’s a shortcoming governments and the global health system need to address if they are to ensure that the next pandemic doesn’t knock the world on its heels to the extent the novel coronavirus has done.  Of the 128 Covid vaccines currently being clinically tested (21 of which have been cleared for use in general populations), Pfizer, Moderna, J&J, and AstraZeneca manufacture just four, according to the latest World Health Organization (WHO) data. Russia’s Sputnik V jab is being distributed in 39 countries with dozens of other markets potentially on the horizon; Sinovac and Sinopharm, both of China, have delivered nearly half of the world’s vaccine doses to date; Bharat Biotech in India won WHO emergency use approval for its Covid shot earlier this month. These are just a handful of the other companies with vaccines that are being given to people in many low- and middle-income countries. Another 194 candidates are in preclinical development in labs or being tested in animals.

These companies and their products are largely unknown outside of the life sciences industry, some academic institutions, and government-backed public health centers. But just because massive, globally established pharmaceutical companies and universities have fueled the world’s vaccine supply to date doesn’t mean they have created the best ones. Other vaccines may prove to be more effective, or safer, or more appropriate for a certain coronavirus variant or among certain age groups in the coming years as the march of SARS-CoV-2, the virus that causes Covid-19, is slowed and it becomes endemic. To be clear, I am not denigrating the safety and effectiveness of the most common and widely used Covid-19 vaccines. But as with so many other facets of public health, the pandemic has turned a glaring light on a long-festering problem: There is no unifying framework for what makes a vaccine “best.” This shortcoming inevitably leads to R&D and manufacturing imbalances down the line as dominant pharmaceutical players leverage their access to institutions and capital to leapfrog the vaccines-that-might-have-been.  The first essential step in addressing this failure is establishing a working definition of what constitutes “best” in vaccine development. Key data points to consider will include safety and effectiveness across coronavirus variants; short-, medium-, and long-term immunity; safety; and overall real-world health outcomes.

Should the level of neutralizing antibodies produced by a vaccine and their staying power be the metric by which it is judged? Should one vaccine be prioritized in certain geographic locations over another because different demographics respond to various jabs in different ways? Those questions need answers. Randomized clinical trials, the gold standard for sniffing out effective medicines, conducted early in the development process must be paired with monitoring real-world evidence for an evolving virus, like the data being collected in the 427 ongoing observational Covid-19 studies the WHO has tracked so far. Head-to-head clinical trials that compare one vaccine directly against another have their uses as well, but don’t address the underlying dilemma of defining exactly which qualities you’re looking for in a vaccine. And with hundreds of vaccine candidates, it’s simply implausible to conduct head-to-head studies of all of them. The focus, then, must be on ensuring that the vaccines most likely to be best are supported early. That requires a level of consensus on critical issues such as proper endpoints and goals, whether a vaccine is keeping people out of the hospital or preventing breakthrough infections, as well as more consistency in clinical trial enrollment, such as whether or not a study assesses a jab in children ages 5 to 12 rather than ages 5 to 11.  Beyond those clinical fundamentals, vaccines for Covid-19 or future infectious disease threats cannot reach their full potential without adequate investment and funding mechanisms guided by science.

The vaccines that have been granted approvals or authorizations to date have been the best funded, either through government programs such as Operation Warp Speed or private funding, while other candidates have stalled for lack of access to capital that can facilitate a quick manufacturing ramp-up to meet the moment’s need. If the same kind of global emergency were to emerge again, the system for advancing vaccine candidates currently in place would be no better — and perhaps would be even worse — without gargantuan ad hoc measures like Operation Warp Speed at play. By default, the current pandemic response has revealed a system where finance is a proxy for “best,” as if it was a betting market, rather than letting science guide resource allocation. There is currently no set of mutually recognized guidelines by which to rationalize investment in global vaccines, even though the U.S. will accept WHO “recognition” of a vaccine as sufficient for immunized travelers wishing to come into the country. But there is no prospect of the European Union, the United Kingdom, the U.S., and countries around the world working together “next time.” This is not a sustainable dynamic if we are to prevent, or at the very least mitigate, the public health catastrophes of tomorrow. Global health experts at the WHO and beyond had been warning that the world is fundamentally unprepared for such a calamitous event years before Covid-19 reared its head. And there has been a common theme in critiques of the existing vaccine infrastructure: There must be a mutual recognition around the world of rationalizing investment in vaccines of the future to outsmart yet-unknown pathogenic foes. Some of the world’s leading health organizations, such as the Coalition for Epidemic Preparedness Innovations (CEPI) and think tanks such as the Peterson Institute for International Economics, have already proposed common-sense improvements to the vaccine discovery, development, and evaluation process that can also make a tangible difference in manufacturing and distributing vaccines down the line. These are “portfolio” approaches meant to take a vaccine through its full life cycle, from discovery to real-world deployment. For instance, Peterson’s Reinhilde Veugelers, a professor in the department of management, strategy, and innovation at KU Leuven in Belgium, penned a report in March on the level of public and private investment necessary for both discovering and identifying the best vaccines in future pandemics and making sure they are effectively distributed across the globe.

“Because of the high risks associated with research projects, and the high social cost of failure, we need multiple vaccine candidates and technologies simultaneously. Public resources should especially support (or at least not bias against) the early stage, riskiest projects, which offer the greatest promises for big breakthroughs. Risks can be managed by diversifying and staging grants,” she writes. Veugelers goes on to note that this portfolio approach, which will almost inevitably mean government support for programs that will eventually fail, necessitates proactive investment at both the cheaper, early developmental stages and the far costlier long-term prospect of mass vaccine production and distribution. GAVI, the International Vaccine Institute, and CEPI laid out concrete steps on how to make sure promising vaccines are effectively distributed in an unpredictable pandemic environment in an article in the journal Nature Medicine:

• Standardize labeling of vaccines so they can be interchanged across countries and regions;
• Use date of production rather than expiration so shelf life can be tracked;
• Adopt three-dimensional bar coding to allow critical information to be updated;
• Employ standard indemnification and liability language that provides protection for manufacturers;
• Create no-fault compensation mechanism for serious adverse events related to vaccine administration;
• Harmonize regulations.

Pharmaceutical innovation requires constant reinvention and the ability to adapt to shifting circumstances while carrying forth the lessons learned from previous shortcomings. The world faces a tough set of choices on how to change existing structures of pandemic preparedness and vaccine development if it is to ward off the next worldwide threat. And that conversation must begin with the acknowledgment that the status quo cannot ensure a different, better outcome in the coming years and decades.

Mike Rea is a biopharmaceutical industry and innovation expert, a senior fellow at the Milken Institute’s FasterCures center, and the CEO of IDEA Pharma and Protodigm

The Food and Drug Administration held no advisory meeting on antiviral, and the European Union signed contract without knowing of failed trial. 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. The European Union, meanwhile, decided to settle on the remdesivir pricing exactly 1 week before the disappointing Solidarity trial results came out. It was unaware of those results, although Gilead, having donated remdesivir to the trial, was informed of the data on 23 September and knew the trial was a bust. “This is a very, very bad look for the FDA, and the dealings between Gilead and EU make it another layer of badness,” says Eric Topol, a cardiologist at the Scripps Research Translational Institute who objected to remdesivir’s FDA approval. FDA has no obligation to convene outside panels for its decisions, stresses AMDAC member David Hardy, an HIV/AIDS scientist of the University of California, Los Angeles. Yet the agency often does so for tricky drug approvals and Hardy is “amazed” the agency didn’t consult the panel in this case. “This sets the standard for the first COVID-19 antiviral,” he says. “When it comes to the point of giving pharmaceutical companies exclusive marketing rights in this area, that really is something that’s very, very important. And there does need to be more than just governmental input.”

FDA did not respond to Science’s request to discuss why it opted against convening the committee, noting only that it is “at the discretion” of division directors. But FDA’s inaction stands in sharp contrast to its handling of potential COVID-19 vaccines. Last week, the agency convened an advisory group to discuss the mere possibility of such a vaccine passing regulatory muster. As to the EU agreement, Gilead confirmed to Science that WHO in “late September” provided the company with a manuscript about the study results, but a spokesperson for the European Commission, the EU executive arm, said these weren’t revealed during its negotiations. The company has aggressively called into question the validity of the Solidarity data, in part because the study was carried out in vastly different countries around the world with different health care standards. In a 15 October statement, Gilead went so far as to say “it is unclear if any conclusive findings can be drawn from the study results.” That criticism has angered investigators in the Solidarity study, including Marie-Paule Kieny, director of research at the French medical research agency INSERM and a former WHO officer. “It’s appalling to see how Gilead tries to badmouth the Solidarity trial,” Kieny says. “Pretending the trial has no value because it is in low-income countries is just prejudice.”...

Published in Science (Oct. 28, 2020):

https://doi.org/10.1126/science.abf4549

A rundown of the science that goes into the decision-making process and what it tells us about when results could be available. In a U.S. pandemic response dominated by missteps, the effort to develop vaccines to prevent Covid-19 has so far been a triumph. Vaccines against the coronavirus that causes the disease are now racing through giant clinical trials as a result. It’s a terrible irony, then, that the Trump administration’s statements have resulted in an erosion of public trust, with the percent of Americans who tell pollsters they would take a Covid-19 vaccine dropping and experts worrying the president could compel the Food and Drug Administration to approve a vaccine before one is ready. (Spoiler: No vaccine will likely be ready by Election Day.)  “When the the president comes out and says, ‘by a very special day, we might have a vaccine,’ the whole thing blows up,” Ashish Jha, the dean of the Brown School of Public Health, said at a session focused on Covid-19 at the STAT Health Tech Summit. “In some ways, we’ve got to get the politicians to shut up and let the scientists talk about this and drive this process.”  The process of deciding when a vaccine appears to be safe and effective isn’t as straightforward as the general public might believe. But it’s important to understand it if we are to have confidence in these critical tools for helping to curb the pandemic. Here, then, is a rundown of the science that goes into the decision-making process, what it tells us about when results could realistically be available, and when vaccines could start to be administered. This story is based on interviews as well as on documents the drug makers have released detailing their clinical trial plans. 

When will vaccine makers have enough data?

A clinical trial is typically sponsored by a company making a vaccine candidate or an academic institution, or a partnership of both. But it is actually monitored by what is known as a data and safety monitoring board, or DSMB, a group of independent experts hired to make sure volunteers in the study are safe. In many studies, the DSMB has the ability to recommend stopping a study not only if a treatment is unsafe, but also if it is so clearly effective that continuing just wouldn’t be ethical.  In the case of the vaccine trials, the studies being run by Moderna, AstraZeneca, and Johnson & Johnson with the National Institutes of Health share a common DSMB. The study being run by Pfizer and its partner BioNTech has its own. The DSMBs will conduct what’s called an interim analysis after a certain number of people have been infected with Covid-19 and shown symptoms. Each of these cases is considered an “event,” and each vaccine maker has set a different number of events as a threshold to conduct an interim analysis as part of their trial protocols. The study being run by Pfizer and its partner BioNTech, frontrunners in the race for a vaccine, is conducting its first interim analysis after 32 events, and would consider the vaccine effective if 26 people in the placebo group and six in its vaccine group had Covid. A study of Moderna’s vaccine, another frontrunner, is waiting until there are 53 cases of Covid. In the case of Pfizer and BioNTech, an interim analysis could happen in October.  Should a vaccine be approved, potentially for millions of people, after its efficacy has been shown based on 32 cases of Covid-19? 

Some experts say no. Eric Topol, the director of the Scripps Research Translational Institute, has been fervently saying that all the trials should continue beyond even their designed ends — when there are about 150 cases of Covid — saying that even the 150 number “may make statistical sense, but it defies common sense.” This could be particularly true if efficacy is limited, given that all the vaccines frequently cause side effects like fever. Others say that while making a decision based on an interim analysis is fine, the first Pfizer analysis, in particular, seems to set a relatively low bar for efficacy given the small number of events. The numbers are in line with past vaccine studies. Prevnar 13 was approved to prevent pneumonia in adults based on a study of 84,000 people that detected 139 cases of pneumonia, 90 of them in the placebo group.  But there’s also a precedent for keeping such studies going to collect more safety data. Researchers studying RotaTeq, a vaccine to prevent a virus that causes childhood diarrhea, collected data from 70,000 patients to rule out a potential side effect which had been seen with a previous vaccine....

This use of adaptive clinical trials is letting researchers work faster and collaborate better to find solutions for the Covid-19 pandemic. Viruses like SARS-CoV-2 can circle the globe with astonishing speed by taking advantage of human networks. The global medical research community couldn’t immediately contain it because it had no comparable network for defense — but we are moving quickly to create one. Employing adaptive clinical trials will help. The initial response to Covid-19, driven by the best intentions, was to stand up more than 1,000 clinical studies. Many were small, uncontrolled, and unlikely to yield reliable information. This is one reason vaccines and definitive cures continue to elude us. Even so, researchers have scored some remarkable wins. Less than a month after the first Covid-19 cases surfaced in late December, a research team sequenced the virus. Since then, other teams have identified cellular proteins that bind to it, shared data in open-access journals, and kicked off at least two dozen credible Phase 3 trials for vaccines, antivirals, and other treatments. 

More milestones will follow as we expand research networks and exploit major innovations in clinical trial design. One advance in particular — an iterative, long-duration study known as an adaptive platform trial — is helping researchers up their game. The use of adaptive clinical trials allows them to simultaneously test multiple interventions against a single, shared control arm, add and eliminate treatments as the trial progresses, and update the study design as the treatment landscape changes. In contrast, each traditional standalone Phase 3 trial must recruit patients to its own control group and test just one hypothesis. Even designing in techniques such as subset analysis and adaptation, these are extravagant undertakings that can’t match the supple efficiency and productivity of well-managed adaptive platform studies.

The adaptive clinical trials approach has already led to a series of high-value, actionable research results:

• In April, data from an adaptive platform study called the Adaptive Covid-19 Treatment Trial, or ACTT, from the National Institutes of Health, validated the clinical benefits of remdesivir, an antiviral agent, in patients hospitalized with Covid-19.
• A few weeks later, the similarly-designed Randomised Evaluation of Covid-19 Therapy (RECOVERY) trial in the United Kingdom demonstrated the benefits of dexamethasone, a widely used steroid.
• RECOVERY further showed that the malaria drug hydroxychloroquine provides little help for people with Covid-19, an invaluable contribution in the face of public confusion and pressure to use the medicine. It also showed that a combination of HIV treatments, lopinavir and ritonavir, was ineffective in treating the disease....

Imagine how the Covid-19 picture might look today if initiatives like these had been staged in advance — anticipating an inevitable pandemic — and networked into a globe-spanning adaptive platform ecosystem. Such an uber-program would allow researchers on every continent to pool knowledge, data, analytics, materials, and other resources, and adding and deleting trial arms based on interim rea..douts, real-world data, and insights from the field. Adaptive platform trials are not new. The methodology was already gaining traction in oncology and other areas before Covid-19 struck. They’re a subset of master protocol trials that Janet Woodcock, the Food and Drug Administration’s long-serving director for drug evaluation and research, and Lisa LaVange explored in a review article in the New England Journal of Medicine in 2017. This May, the FDA’s updated guidance on Covid-19 drug development recognized the potential of these trial designs, and the agency is likely to issue further recommendations....

INOVIO Pharmaceuticals, Inc. (NASDAQ:INO) today announced that the U.S. Food and Drug Administration has accepted the company's Investigational New Drug (IND) application for INO-4800, its DNA vaccine candidate designed to prevent COVID-19 infection, paving the way for Phase 1 clinical testing of INO-4800 in healthy volunteers beginning this week. The first dosing is planned for today.

Dr. J. Joseph Kim, INOVIO's President and CEO, said, "This is a significant step forward in the global fight against COVID-19. Without a new safe and effective vaccine, the COVID-19 pandemic is likely to continue to threaten lives and livelihoods. It also demonstrates the power of our DNA medicines platform to rapidly develop and advance a vaccine for COVID-19 into Phase 1 clinical testing. Our dedicated team of staff, partners and funders have been mobilized since the genetic sequence of the virus became available in early January and continues to work around the clock to ensure that we are rapidly advancing INO-4800 through this Phase 1 study towards planned efficacy trials."

Richard Hatchett, CEO of the Coalition for Epidemic Preparedness Innovations (CEPI), said, "This development is an important step forward in the world's search for a COVID-19 vaccine. INOVIO's DNA vaccine platform was one of the first technologies selected by CEPI to develop a vaccine candidate against COVID-19. We are pleased to see the rapid advancement of their vaccine candidate into clinical safety testing. Producing a COVID-19 vaccine within the next 12 to 18 months is not only a scientific challenge; it will also require new levels of collaboration and investment across industry and government. There is still a long road ahead before we have a safe, effective, and globally accessible vaccine ready for broader use, but today we have reached an important milestone on that journey."

The Phase 1 study of INO-4800 will enroll up to 40 healthy adult volunteers in Philadelphia, PA (at the Perelman School of Medicine at the University of Pennsylvania) and Kansas City, MO (at the Center for Pharmaceutical Research), where screening of potential participants has already begun. Study supplies of INO-4800 arrived at the sites last week. Each participant will receive two doses of INO-4800 four weeks apart, and the initial immune responses and safety data from the study are expected by late summer. Preclinical data, which have been shared with global regulatory authorities and submitted as part of the IND, have shown promising immune response results across multiple animal models. Additional preclinical trials, including challenge studies, will continue in parallel with the Phase 1 clinical trial.

President Donald Trump has touted the drug as a treatment but scientists still don't know for sure that it is effective in patients. A number of clinical trials aim to find out. On March 16, SpaceX founder Elon Musk tweeted that the anti-malaria drug chloroquine was “maybe worth considering” as a treatment for COVID-19. He got 13,000 retweets. By March 19, President Donald Trump was touting chloroquine at a press conference. He even announced that the Food and Drug Administration had fast-tracked its approval for COVID-19. The FDA denied that this was the case a short time later. While some of the hype has been fuelled by a document generated outside the scientific literature, chloroquine’s potential in treating COVID-19 is gaining traction in the medical community. The drug has a long track record in medicine, having been used since the 1940s as an antimalarial. The modern drug is made from the bark of the Cinchona plant, which was taken as an herbal remedy by indigenous Peruvians four centuries ago to treat fever. And there are some early indications it could work against SARS-CoV-2 infections.

For instance, a study in France published on March 20 in the International Journal of Antimicrobial Agents described the treatment of 42 patients hospitalized with COVID-19, 26 of whom received a version of chloroquine called hydroxychloroquine and 16 of whom received routine care. Of the 20 patients who took the antimalarial and completed the study, six also received azithromycin, an antibiotic. All six of these patients were free of SARS-CoV-2 by the fifth day post-treatment, while seven of 14 patients who took hydroxychloroquine alone were negative for the virus, and two of 16 control patients were no longer infected. Small-scale experiments in which chloroquine has been given to COVID-19 patients in China and Australia have also shown encouraging results as far as shortening the course of the disease. A small trial of 1,500 people would be a pragmatic step towards verifying the drug’s efficacy, says Jeremy Rossman, a virologist at the University of Kent, who praises the approach. 

A number of other chloroquine experiments on humans are in the works. According to clinicaltrials.gov, researchers at the University of Oxford plan to give it as a prophylactic to 10,000 health care workers and others at high risk of contracting SARS-CoV-2. In Norway, doctors expect to begin administering the drug to hospitalized patients. And in Thailand, clinicians are preparing for a clinical trial comparing various combinations of antivirals, including chloroquine.

In a review of several trials, the World Health Organization found that Gilead’s drug did not improve survival rates for patients nor did it help them recover. The World Health Organization on Thursday recommended against using the antiviral remdesivir, a drug that had generated intense interest as a treatment for Covid-19.  An expert panel “concluded that remdesivir has no meaningful effect on mortality or on other important outcomes for patients, such as the need for mechanical ventilation or time to clinical improvement,” the W.H.O. announced. The panel published its review in the journal The BMJ. The report did not rule out the use of the drug altogether as a Covid treatment, but said evidence was lacking to recommend its use. Gilead Sciences, manufacturer of remdesivir, whose trade name is Veklury, said in a statement that its drug “is recognized as a standard of care for the treatment of hospitalized patients with Covid-19 in guidelines from numerous credible national organizations, including the U.S. National Institutes of Health and Infectious Diseases Society of America, Japan, U.K., and Germany.” It added that there are “multiple randomized, controlled studies published in peer-reviewed journals that demonstrate the clinical benefits of Veklury.” The potential utility of remdesivir had been the subject of debate and skepticism for months, and especially in recent weeks, after the Food and Drug Administration approved it as the first treatment for Covid-19 in late October. One large study, sponsored by the National Institutes of Health, found that the drug reduced recovery time in hospitalized patients from 15 to 11 days. Two other trials the agency considered, sponsored by Gilead, did not include placebo controls, which are considered critical to judging effectiveness.

President Trump was administered remdesivir along with other treatments last month when he was hospitalized with Covid. Since at least March, when the pandemic began spreading from China to Europe to the United States, drug companies and researchers have been working on the fly, and practicing doctors have experimented with any treatment that looks promising, including steroids. In September, the W.H.O. expert panel strongly recommended the use of steroids for patients in critical condition. For the new analysis, the panel reviewed evidence from four trials, including one conducted by the N.I.H. and another sponsored by the W.H.O. and recently posted to a preprint server, which included some 5,000 patients, the largest to date. The paper has not been peer-reviewed or published in a scientific journal.  The results from that trial “brought into question some of the benefit that had been seen earlier, in the N.I.H. study,” said Dr. Bram Rochwerg, an associate professor of medicine at McMaster University in Hamilton, Ontario, and a co-chair of the W.H.O. panel. Dr. Rochwerg said that the panel “made explicit in the document that trials of remdesivir should continue, and there may be specific populations that could benefit.” But the drug is expensive and administered intravenously, he noted. Using it could divert resources that could be deployed more effectively, Dr. Rochwerg said.  Remdesivir has been authorized for emergency use since the spring in the United States, and in October, Gilead reported that it had generated $873 million in revenue thus far this year. The drug’s widely adopted use for Covid symptoms had baffled some experts well before the F.D.A. approval.....

W.H.O. revised guidelines available at:

http://press.psprings.co.uk/bmj/november/remdesivir.pdf

Roche is paying Atea Pharmaceuticals $350 million upfront for the ex-U.S. rights to COVID-19 antiviral AT-527. The oral direct-acting antiviral is set to enter a phase 3 trial in non-hospitalized patients early next year, giving Roche and Atea a shot at establishing it as the go-to early treatment for COVID-19. Atea put its COVID-19 program on the map in May when it raised $215 million in a round led by Bain Capital Life Sciences. Up to that point, Atea was perhaps best known for being set up by Jean-Pierre Sommadossi, co-founder of Sovaldi developer Pharmasset. 

Reflecting Sommadossi’s background, Atea initially studied its oral purine nucleotide prodrug AT-527 in hepatitis C, before the pandemic and in vitro evidence of efficacy in coronaviruses persuaded it to target SARS-CoV-2. A phase 2 trial of 190 hospitalized patients with moderate COVID-19 got started in May and is due to wrap up around the end of the year, according to ClinicalTrials.gov.  “AT-527 is expected to be ideally suited to combat COVID-19 as it inhibits viral replication by interfering with viral RNA polymerase, a key component in the replication machinery of RNA viruses,” Sommadossi said in a statement. The phase 2 results will provide a clearer picture of whether AT-527 is efficacious in COVID-19, but Roche has already seen enough to bet $350 million and commit to milestones and royalties. The outlay secures Roche ex-U.S. rights to AT-527. Atea will retain responsibility for distributing the drug in the U.S., although it has an option to ask for the support of Roche’s Genentech. 

While AT-527 is currently in development in hospitalized patients, Roche centered its discussion of the value of the drug on its potential role in non-hospitalized patients. As an oral small molecule, AT-527 has several potential advantages over anti-SARS-CoV-2 antibodies outside of hospital settings. AT-527 stands to be cheaper, easier to administer and manufactured at larger quantities.  Atea and Roche plan to start a phase 3 trial in non-hospitalized patients in the first quarter of 2021. By then, the U.S. and other countries may have begun vaccinating their populations against the novel coronavirus, thereby beginning the process of bringing the pandemic under control. However, with the rollout of immunization programs taking time and vaccines likely to only offer partial protection, Atea and Roche are betting there will remain a need for treatments for some time.   Roche foresees AT-527 being used to treat patients early, perhaps even in post-exposure prophylactic settings. Widespread access to an effective early treatment could stop some cases from progressing to severe COVID-19, thereby improving patient outcomes and reducing the burden on healthcare systems.  The deal opens up another front in Roche’s response to the pandemic. In August, Roche secured the ex-U.S. rights to Regeneron’s REGN-COV2, securing itself a leading spot in the race to bring COVID-19 antibody therapies to market. The deals position Roche to apply its development and manufacturing muscle to drugs with the potential to defang SARS-CoV-2.

'Human challenge trials' to test the effectiveness of possible Covid vaccines may be held in London. The UK could be the first country in the world to carry out Covid "challenge trials" - where healthy volunteers are deliberately infected with coronavirus to test possible vaccines. It is understood the studies - first reported by the Financial Times - would be conducted in London. The UK government said it was holding discussions about developing a vaccine through such "human challenge studies" No contracts have yet been signed, the BBC understands. Alastair Fraser-Urquhart, an 18-year old university student, is planning on volunteering for the trial if it is given the green light to go ahead. He helps run the advocacy group, 1Day Sooner. He told the BBC Radio 4 Today programme: "I think the challenge trial has the potential to save thousands of lives and really bring the world out of the pandemic sooner. It is just something that made instant sense to me." Speaking on the same programme, Prof Peter Horby of Oxford University, said he thought the trial was a good idea that had the real potential to advance science and get a better understanding of the disease. He said: "We now know the risk in a healthy young adult with no underlying conditions is extremely low. "We suspected this before, but we really did not have the strength of evidence to go forward with challenging people with the virus - but now I think there is clear data. "The second thing that has changed is there are now some treatments that have been shown to have a benefit, so in the likely event that a a challenged person does becomes unwell, there are drugs that can be given very early to help control the disease." 

Prof Horby said it is likely volunteers would be observed very closely and their immune systems would be monitored to see how they respond to the virus There are - perhaps surprisingly - lots of young, healthy people ready to volunteer for coronavirus challenge trials. It would be a way of finding out, almost immediately, whether a vaccine works. And it could help speed the selection of the promising coronavirus vaccines. The health of the volunteers would be monitored round the clock at a clinical research facility in London. I understand that no contracts for the study, which would be government funded, have yet been signed, but the hope is they could begin in January. What's been holding things up are ethical considerations - challenge studies have been used to test vaccines for flu, cholera and typhoid, but in each case there was an effective treatment to prevent volunteers from falling ill. With coronavirus, there would be an added level of risk - but it's one that volunteers say they are willing to take. A government spokesman said discussions around challenge trials were ongoing as part of the overall consideration of potential avenues for coronavirus research. Work to find a coronavirus vaccine is under way at breakneck speed around the globe. There are currently 36 vaccines in clinical trials, including one being developed by the University of Oxford that is already in an advanced stage of testing A successful vaccine would provide some protection against the virus by training people's immune systems to fight it so they should not become sick. This would allow lockdowns to be lifted more safely, and social distancing to be relaxed...

Given the accelerated rate at which trial information and findings are emerging, an urgent need exists to track clinical trials, avoid unnecessary duplication of efforts, and understand what trials are being done and where. In response, we have developed a COVID-19 clinical trials registry to collate all trials.

Data are pulled from the International Clinical Trials Registry Platform, including those from the Chinese Clinical Trial Registry, ClinicalTrials.gov, Clinical Research Information Service - Republic of Korea, EU Clinical Trials Register, ISRCTN, Iranian Registry of Clinical Trials, Japan Primary Registries Network, and German Clinical Trials Register. Both automated and manual searches are done to ensure minimisation of duplicated entries and for appropriateness to the research questions. Identified studies are then manually reviewed by two separate reviewers before being entered into the registry.

Concurrently, we have developed artificial intelligence (AI)-based methods for data searches to identify potential clinical studies not captured in trial registries. These methods provide estimates of the likelihood of importance of a study being included in our database, such that the study can then be reviewed manually for inclusion. Use of AI-based methods saves 50–80% of the time required to manually review all entries without loss of accuracy.  Finally, we will use content aggregator services, such as LitCovid, to ensure our data acquisition strategy is complete. With this three-step process, the probability of missing important publications is greatly diminished and so the resulting data are representative of global COVID-19 research efforts.

Published in The Lancet (April 24, 2020)

https://doi.org/10.1016/S2589-7500(20)30086-8

Clinical Trial Registry Site:

https://www.covid-trials.org/

A drug combo already used against HIV. A malaria treatment first tested during World War II. A new antiviral whose promise against Ebola fizzled last year. Could any of these drugs hold the key to saving coronavirus disease 2019 (COVID-19) patients from serious harm or death? On Friday, the World Health Organization (WHO) announced a large global trial, called SOLIDARITY, to find out whether any can treat infections with the new coronavirus for the dangerous respiratory disease. It’s an unprecedented effort—an all-out, coordinated push to collect robust scientific data rapidly during a pandemic. The study, which could include many thousands of patients in dozens of countries, has been designed to be as simple as possible so that even hospitals overwhelmed by an onslaught of COVID-19 patients can participate.

With about 15% of COVID-19 patients suffering from severe disease and hospitals being overwhelmed, treatments are desperately needed. So rather than coming up with compounds from scratch that may take years to develop and test, researchers and public health agencies are looking to repurpose drugs already approved for other diseases and known to be largely safe. They’re also looking at unapproved drugs that have performed well in animal studies with the other two deadly coronaviruses, which cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Drugs that slow or kill the novel coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could save the lives of severely ill patients, but might also be given prophylactically to protect health care workers and others at high risk of infection. Treatments may also reduce the time patients spend in intensive care units, freeing critical hospital beds. 

Scientists have suggested dozens of existing compounds for testing, but WHO is focusing on what it says are the four most promising therapies: an experimental antiviral compound called remdesivir; the malaria medications chloroquine and hydroxychloroquine; a combination of two HIV drugs, lopinavir and ritonavir; and that same combination plus interferon-beta, an immune system messenger that can help cripple viruses. Some data on their use in COVID-19 patients have already emerged—the HIV combo failed in a small study in China—but WHO believes a large trial with a greater variety of patients is warranted.

Michelle Moorhouse, MB BCh, from Wits Reproductive Health and HIVInstitute, like many other physicians, started to notice that the numbers on the scale kept going up for her patients who were taking integrase inhibitors. Speaking from the podium here at the International AIDS Society (IAS) 2019 Conference on HIV Science, Moorhouse explained that "a real flurry" of reports started coming in about tenofovir alafenamide and dolutegravir being associated with weight gain.

Dolutegravir and tenofovir alafenamide can lead to weight gain, especially in women, according to new data that are changing the way researchers look at their study populations.  So the ADVANCE team worked with researchers from the New Antiretroviral and Monitoring Strategies in HIV Infected Adults in Low-income countries (NAMSAL) trial NCT02777229) to pull together all the weight-gain data accrued from their combined cohort of 1666 participants.  And they found a consistent story.

In the NAMSAL trial, weight gain was higher in the dolutegravir group than in the efavirenz group (5 kg vs 3 kg; P ≤ .001), and the mean increase in body mass index was greater in the dolutegravir group (1.7 vs 1.2 kg/m2; P ≤ .001). In the ADVANCE trial, weight gain was even more pronounced, but the pattern was the same: participants in the dolutegravir plus Descovy group gained more weight over 96 weeks than those in the dolutegravir plus Truvada group (8 kg vs 5 kg).