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Global trial eliminates drugs, pivots to new ones

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Science‘s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation

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COVID-19 patients in Mar del Plata, Argentina, one of 30 countries taking part in Solidarity.

PHOTO: NATACHA PISARENKO/AP IMAGES

When U.S. patients began to fall sick with COVID-19 earlier this year, Louis Staudt and Wyndham Wilson had an idea for how to help them. The two doctors at the National Cancer Institute had shown that acalabrutinib, a drug they helped develop for some types of lymphomas, has the side effect of dampening part of the immune response. Given the damage the immune reaction to SARS-CoV-2 creates in severely sick patients, acalabrutinib might have a positive effect, Staudt and Wilson reasoned.

Now, their idea is about to be tested in one of the world’s largest studies of COVID-19 therapies: the Solidarity trial, organized by the World Health Organization (WHO). That’s not because the drug holds so much promise—the evidence it might work is scant—but because Solidarity researchers have crossed more promising drugs off their list and are ready to try something new.

On 15 October, WHO released Solidarity’s preliminary results for drugs that had raised earlier hopes—and they’re a disappointment. The trial confirmed previous studies showing the antimalarial drug hydroxychloroquine and the HIV drugs lopinavir and ritonavir don’t reduce mortality. It also dashed hopes for the much-touted antiviral remdesivir (given to U.S. President Donald Trump) and for interferon beta, part of the body’s natural defense against viruses. “The take-home from this is that the cavalry is not coming,” says Ilan Schwartz, an infectious disease researcher at the University of Alberta, Edmonton.

But the results also demonstrated the power of the trial itself, which has enrolled more than 11,000 patients in 30 countries, to quickly sort through available drugs. “It’s disappointing that none of the four have come out and shown a difference in mortality, but it does show why you need big trials,” says Jeremy Farrar, director of the Wellcome Trust. WHO now plans to use this machinery, which enlists 2000 patients every month, to test additional “repurposed” drugs such as acalabrutinib, as well as therapies designed for COVID-19.

Nothing particularly promising

Designed in a hurry in March, Solidarity initially included the four seemingly promising treatments. But WHO decided to drop hydroxychloroquine and ritonavir/lopinavir from the study after the United Kingdom’s large Recovery trial showed in June that they did not increase survival, and continued with remdesivir and interferon beta. Now, the WHO study has delivered its verdict, which is under review at The New England Journal of Medicine (NEJM) and released as a preprint on medRxiv.

An earlier, U.S. trial in more than 1000 patients published in NEJM on 8 October indicated that remdesivir shortened the median recovery time for survivors from 15 days to 10 days, although it did not reduce mortality. Two smaller trials found few significant benefits. The U.S. Food and Drug Administration granted the drug an emergency use authorization (EUA) in May for severe COVID-19 patients and later expanded it to include all patients.

Now, the Solidarity trial is reporting that 11% of 2743 hospitalized patients who received the drug died, versus 11.2% in a control group—a difference that could have arisen by chance. When the researchers pooled their data with those from the three other trials, they found a slight reduction in mortality that wasn’t statistically significant either. “This absolutely excludes the suggestion that remdesivir can prevent a substantial fraction of all deaths,” the researchers write. The study also did not find that the drug delayed the need for ventilation or that it sped up recovery, although recovery time was harder to analyze because patients on study drugs had to stay in the hospital longer to complete their course.

Jason Pogue, a researcher at the University of Michigan College of Pharmacy, says he had hoped for a mortality benefit based on some suggestive data in a subset of patients in the U.S. trial. Now, Pogue says, “If your question to me is whether I think it still deserves an EUA status, I actually don’t.”

But the drug’s manufacturer, Gilead Sciences, which agreed to the study design and donated the drug, is casting doubt on the results. The study was not placebo-controlled; to keep it simple, patients in the control group just received the standard of care in their country. There was also “significant heterogeneity in trial adoption, implementation, controls and patient populations,” Gilead says in a statement.

But the lack of a placebo is less of a concern when looking at “hard” outcomes such as mortality, Schwartz says. “For an endpoint like death the fact that the trial is unblinded is going to have a meager if any effect,” he says. And Pogue says the diversity in patient populations is one of Solidarity’s strengths: “I actually think that makes the study more robust [and] more reflective of everybody.”

Solidarity’s results for interferon beta are even more disappointing, says cardiologist Eric Topol, who heads the Scripps Research Translational Institute. Mortality among 2050 people who received that drug (either alone or in combination with lopinavir/ritonavir) was 11.9%, versus 10.5% in the control group. Prior studies have suggested interferon can only help if given early in the course of disease, however. “So I think that’s still an open question,” Topol says.

Solidarity has now dropped interferon beta from the study. The remdesivir arm will continue “to get more precise evidence,” says John-Arne Røttingen, CEO of the Research Council of Norway, who heads the executive group of Solidarity’s steering committee. But the treatment landscape now looks bleak, Schwartz says: “There’s really not a lot out there that looks to be particularly promising.”

Hopes for new drugs

The hopes for acalabrutinib rest on assumptions about its mechanism of action and experience in 19 very ill COVID-19 patients treated off-label so far. Five of those died, Staudt and colleagues reported in June in Science Immunology, but most patients’ oxygen levels quickly improved. (The authors included instructions for mixing acalabrutinib with degassed Coca-Cola because it needs to be dissolved in acid: “Do not use other sodas, Diet Coke or Coke Zero,” they warned.)

Solidarity picked acalabrutinib in part because it’s plentiful. “This is a drug that is easy to synthesize and we have in stock,” says José Baselga, head of oncology at the manufacturer, AstraZeneca, which is running its own phase II trials in COVID-19 patients. Solidarity plans to start to give it to patients in the next few days.

Acalabrutinib might suppress damaging immune responses in much the same way as tocilizumab, a drug for rheumatoid arthritis and other autoimmune diseases that inhibits the signaling molecule interleukin-6 (IL-6). Tocilizumab has been tested against COVID-19 with mixed results and is now part of the Recovery trial, which might produce a definitive answer soon. Acalabrutinib inhibits a different enzyme, however: Bruton’s tyrosine kinase (BTK). Staudt believes BTK sits at the center of the pathway that triggers immune cells in the lung to induce a so-called cytokine storm in COVID-19 patients. IL-6 inhibitors essentially cut off a branch of this response, he says, whereas “BTK inhibitors are cutting down the entire tree.”

Acalabrutinib may be one of the last repurposed drugs to be tested in large numbers of hospitalized COVID-19 patients. Targeted therapies such as monoclonal antibodies and new antivirals are seen as more promising, and some are starting to become available for large-scale testing. The Recovery trial now includes a combination of two monoclonal antibodies from Regeneron (another experimental therapy given to Trump). Another phase III trial in the United States, now on hold after it was paused on 13 October over a safety concern, is testing an antibody cocktail from Eli Lilly.

Solidarity, which is still expanding to new countries, could yield definitive results about any new therapy within a few months. It and Recovery “have set the standard of the scale that’s required in order to give you clear answers,” Farrar says.

Its global scope has another advantage, says Ana Maria Henao Restrepo, who heads WHO’s Research and Development Group. When the more than 1300 participating doctors see the results in NEJM, they will think: “I’ve contributed to that and I understand why that drug works or doesn’t work. I know, I trust it,” she says. “That is different from some Northern Hemisphere group publishing, and they say: ‘Somewhere in a rich country they did a trial and now we all have to believe the results.’”

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Too bright to breed

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Night light from coastal cities overpowers natural signals for coral spawning from neighboring reefs.

PHOTO: NOKURO/ALAMY STOCK PHOTO

Most coral species reproduce through broadcast spawning. For such a strategy to be successful, coordination has had to evolve such that gametes across clones are released simultaneously. Over millennia, lunar cycles have facilitated this coordination, but the recent development of bright artificial light has led to an overpowering of these natural signals. Ayalon et al. tested for the direct impact of different kinds of artificial light on different species of corals. The authors found that multiple lighting types, including cold and warm light-emitting diode (LED) lamps, led to loss of synchrony and spawning failure. Further, coastal maps of artificial lighting globally suggest that it threatens to interfere with coral reproduction worldwide and that the deployment of LED lights, the blue light of which penetrates deeper into the water column, is likely to make the situation even worse.

Curr. Biol. 10.1016/j.cub.2020.10.039 (2020).

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SpaceX launches Starlink app and provides pricing and service info to early beta testers

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SpaceX has debuted an official app for its Starlink satellite broadband internet service, for both iOS and Android devices. The Starlink app allows users to manage their connection – but to take part you’ll have to be part of the official beta program, and the initial public rollout of that is only just about to begin, according to emails SpaceX sent to potential beta testers this week.

The Starlink app provides guidance on how to install the Starlink receiver dish, as well as connection status (including signal quality), a device overview for seeing what’s connected to your network, and a speed test tool. It’s similar to other mobile apps for managing home wifi connections and routers. Meanwhile, the emails to potential testers that CNBC obtained detail what users can expect in terms of pricing, speeds and latency.

The initial Starlink public beta test is called the “Better than Nothing Beta Program,” SpaceX confirms in their app description, and will be rolled out across the U.S. and Canada before the end of the year – which matches up with earlier stated timelines. As per the name, SpaceX is hoping to set expectations for early customers, with speeds users can expect ranging from between 50Mb/s to 150Mb/s, and latency of 20ms to 40ms according to the customer emails, with some periods including no connectivity at all. Even with expectations set low, if those values prove accurate, it should be a big improvement for users in some hard-to-reach areas where service is currently costly, unreliable and operating at roughly dial-up equivalent speeds.

Image Credits: SpaceX

In terms of pricing, SpaceX says in the emails that the cost for participants in this beta program will be $99 per moth, plus a one-time cost of $499 initially to pay for the hardware, which includes the mounting kit and receiver dish, as well as a router with wifi networking capabilities.

The goal eventually is offer reliably, low-latency broadband that provides consistent connection by handing off connectivity between a large constellation of small satellites circling the globe in low Earth orbit. Already, SpaceX has nearly 1,000 of those launched, but it hopes to launch many thousands more before it reaches global coverage and offers general availability of its services.

SpaceX has already announced some initial commercial partnerships and pilot programs for Starlink, too, including a team-up with Microsoft to connect that company’s mobile Azure data centers, and a project with an East Texas school board to connect the local community.

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Erratum for the Report “Meta-analysis reveals declines in terrestrial but increases in freshwater insect abundances” by R. Van Klink, D. E. Bowler, K. B. Gongalsky, A. B. Swengel, A. Gentile, J. M. Chase

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S. Rennie, J. Adamson, R. Anderson, C. Andrews, J. Bater, N. Bayfield, K. Beaton, D. Beaumont, S. Benham, V. Bowmaker, C. Britt, R. Brooker, D. Brooks, J. Brunt, G. Common, R. Cooper, S. Corbett, N. Critchley, P. Dennis, J. Dick, B. Dodd, N. Dodd, N. Donovan, J. Easter, M. Flexen, A. Gardiner, D. Hamilton, P. Hargreaves, M. Hatton-Ellis, M. Howe, J. Kahl, M. Lane, S. Langan, D. Lloyd, B. McCarney, Y. McElarney, C. McKenna, S. McMillan, F. Milne, L. Milne, M. Morecroft, M. Murphy, A. Nelson, H. Nicholson, D. Pallett, D. Parry, I. Pearce, G. Pozsgai, A. Riley, R. Rose, S. Schafer, T. Scott, L. Sherrin, C. Shortall, R. Smith, P. Smith, R. Tait, C. Taylor, M. Taylor, M. Thurlow, A. Turner, K. Tyson, H. Watson, M. Whittaker, I. Woiwod, C. Wood, UK Environmental Change Network (ECN) Moth Data: 1992-2015, NERC Environmental Information Data Centre (2018); .

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