Radiation emerges as an intriguing — and divisive — treatment for Covid-19

Back in 2013, toxicologist Edward Calabrese and a colleague at the University of Massachusetts, Amherst, were combing over a cache of century-old data on low-dose radiation therapy, hunting for evidence on the scientific idea that small doses of certain poisons might actually be beneficial. They found small amounts of radiation were surprisingly successful in combating pneumonia. Again and again, doctors reported symptoms subsided within hours of a single X-ray.

Hardly anyone took notice. Calabrese’s ideas had sometimes been brushed off by his peers as too out-there, and the idea of low-dose radiation as therapy had long been dismissed in favor of more modern treatments. The paper only gained a smattering of citations.

That all changed when Covid-19 snowballed into a crisis, fueling fresh interest in anything that might ease the devastating cases of pneumonia in some patients. At least 52,000 of the more than 135,000 deaths due to Covid-19 in the U.S. have involved pneumonia, according to federal health data.

“Back in February, I started getting just dozens and dozens and dozens of emails from radiation oncologists —people who treat cancer patients with targeted radiation. And they had come across our paper and they thought that this might be a vehicle by which they could help suffering and dying Covid patients perhaps survive,” he said. “Clinical trials are now going on across the country.”

There are at least a dozen trials worldwide testing low-dose radiation therapy, or LDRT, as a treatment for pneumonia related to Covid-19, some spurred by the same historical data Calabrese and colleagues scoured years ago. The theory: Targeted radiation to the lungs will halt the out-of-control inflammation responsible for the devastating pneumonia that bookends the course of some Covid-19 patients.

But the revived interest in radiotherapy has sparked a debate among physicians and researchers, who are divided on whether the idea is even ready for test-driving in clinical trials. With little known about the way LDRT works on inflamed lungs, some experts say it might exacerbate respiratory damage, while introducing the additional risk of cancer. Others say patients participating in the trials may suffer by missing out on more promising treatments.

On the other side, though, are experts who say there’s a clear and urgent need for Covid-19 treatments that work, particularly for cases that become severe. Antibiotics can help treat cases of pneumonia from bacterial infections, but not those caused by viruses. Those experts argue compelling historical data gives LDRT a promising head start.

“It seems to be such an almost emotional topic,” said Dörthe Schaue, a radiation oncologist at UCLA, on the debate raging over LDRT. “You get two extremes on the spectrum and the truth is probably somewhere in the middle, where you have to consider all the pluses and minuses.”

The new wave of low-dose radiation trials are registered at academic centers and hospitals around the world, including in Italy, Spain, Iran, India, and the U.S. The studies are recruiting anywhere from five to 106 Covid-19 patients with pneumonia, and half require participants to be at least 40 years of age.

Arnab Chakravarti, chair of Ohio State’s radiation and oncology department, is spearheading two of the four LDRT trials in the U.S. The first trial, PREVENT, will enroll around 100 oxygen-dependent Covid-19 patients at up to 20 hospitals around the country. The second trial, VENTED, is limited to Ohio State, where it will recruit 24 critically-ill patients who require ventilator support. Unlike PREVENT, VENTED is open to participants as young as 18.

Chakravarti hypothesizes that LDRT will tamp down the unchecked inflammation that ultimately overwhelms the lungs of some Covid-19 patients. In these individuals, immune cells overreact to the virus and secrete a dangerous excess of proinflammatory cytokines, known as a “cytokine storm.”

“The severe illness and death that we see from Covid-19 pneumonia appear to be mostly due to the inflammatory response to the infection in the lung tissues,” said radiation oncologist David Kozono, who is launching a LDRT trial at Brigham and Women’s Hospital. “The idea is that low-dose lung radiation has the potential to reduce this inflammatory response.”

Some experts have theorized that small amounts of radiation might flip a switch on these immune cells so that they release soothing, anti-inflammatory cytokines instead, though this is just one among many proposed mechanisms.

“The history of the utilization of ultra-low-dose radiation for viral pneumonia actually dates back to the 1920s and ’30s and ’40s — just post the Spanish flu pandemic in 1918,” Chakravarti noted. He said literature from that era indicates that LDRT was effective in 75 to 90% of influenza-induced viral pneumonia cases, though the therapy “fell out of favor” after the development of antiviral therapies and vaccines.

Beyond historical data, Chakravarti said that his hypothesis is staked in recent evidence from an interim analysis of a clinical trial at Emory testing low-dose radiation in ten patients with Covid-19. All of the first five patients, averaging 90 years of age, were alive two weeks after treatment, and researchers reported three patients were weaned off oxygen within 24 hours of receiving radiation.

SOURCE 

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Why many medicines are so costly

Question:  How much do drug companies spend on research and development to bring a new medicine to market?

Findings:  In this study, which included 63 of 355 new therapeutic drugs and biologic agents approved by the US Food and Drug Administration between 2009 and 2018, the estimated median capitalized research and development cost per product was $985 million, counting expenditures on failed trials. Data were mainly accessible for smaller firms, products in certain therapeutic areas, orphan drugs, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018.

Meaning:  This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data; differences from previous studies may reflect the spectrum of products analyzed and the restricted availability of data in the public domain.

Abstract

Importance:  The mean cost of developing a new drug has been the subject of debate, with recent estimates ranging from $314 million to $2.8 billion.

Objective:  To estimate the research and development investment required to bring a new therapeutic agent to market, using publicly available data.

Design and Setting:  Data were analyzed on new therapeutic agents approved by the US Food and Drug Administration (FDA) between 2009 and 2018 to estimate the research and development expenditure required to bring a new medicine to market. Data were accessed from the US Securities and Exchange Commission, Drugs@FDA database, and ClinicalTrials.gov, alongside published data on clinical trial success rates.

Exposures:  Conduct of preclinical and clinical studies of new therapeutic agents.

Main Outcomes and Measures:  Median and mean research and development spending on new therapeutic agents approved by the FDA, capitalized at a real cost of capital rate (the required rate of return for an investor) of 10.5% per year, with bootstrapped CIs. All amounts were reported in 2018 US dollars.

Results:  The FDA approved 355 new drugs and biologics over the study period. Research and development expenditures were available for 63 (18%) products, developed by 47 different companies. After accounting for the costs of failed trials, the median capitalized research and development investment to bring a new drug to market was estimated at $985.3 million (95% CI, $683.6 million-$1228.9 million), and the mean investment was estimated at $1335.9 million (95% CI, $1042.5 million-$1637.5 million) in the base case analysis. Median estimates by therapeutic area (for areas with ≥5 drugs) ranged from $765.9 million (95% CI, $323.0 million-$1473.5 million) for nervous system agents to $2771.6 million (95% CI, $2051.8 million-$5366.2 million) for antineoplastic and immunomodulating agents. Data were mainly accessible for smaller firms, orphan drugs, products in certain therapeutic areas, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018. Results varied in sensitivity analyses using different estimates of clinical trial success rates, preclinical expenditures, and cost of capital.

Conclusions and Relevance:  This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data. Differences from previous studies may reflect the spectrum of products analyzed, the restricted availability of data in the public domain, and differences in underlying assumptions in the cost calculations.

SOURCE 

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If there is a second wave of Covid, the Swedish approach will have been right all along

Not going into lockdown was described as “a mad experiment” at the time, but Sweden can look to the winter with less trepidation than most

There have been times during this pandemic that I’ve felt as if my memory is playing tricks on me. I’m sure I remember scientists telling us that a second wave was inevitable. I could have sworn I saw a graph at the press briefings showing a scary bell curve of infections in the spring and an even scarier one in the winter. I’m sure I heard experts explaining that the only way COVID-19 would disappear would be when herd immunity was achieved, either through natural antibodies or vaccination.

Official documents reassure me that I am not going mad. The minutes from a Sage meeting in March say: “Sage was unanimous that measures seeking to completely suppress the spread of Covid-19 will cause a second peak.” As far as I can tell, this is still their view. Suppressing a wintry virus during the sunniest spring on record could turn out to be no great achievement. The worst may be yet to come.

One country can look to the winter with less trepidation than most. Last week, a study suggested that 30 per cent of Swedes have built up immunity to the virus. It would help explain why Covid-19 has been fizzling out in Sweden. If a measure of herd immunity also helps them avoid the second wave, Sweden’s take-it-on-the-chin approach will be vindicated.

Not going into lockdown was described as “a mad experiment” by Marcus Carlsson of Lund University in March. Dr Cecilia Söderberg-Nauclér of Sweden’s Karolinska Institute accused the government of “leading us to catastrophe”, and predicted that the healthcare system would collapse unless a lockdown was introduced. Every model predicted an exponential rise in infections.

With half of humanity living under lockdown, photos of Swedes socialising in bars and restaurants seemed like communiqués from another dimension. Aside from a ban on gatherings of more than 50 people, life carried on as normal. Children aged under 16 went to school. No one wore a mask. This, surely, was the calm before a terrible storm.

The catastrophe never arrived. As in most other European countries, Sweden saw a peak in Covid-19 deaths in the first half of April followed by a steady decline. Shown on a graph, the pattern of mortality is indistinguishable from that of many countries that locked down. Its daily death toll rarely exceeded double figures and has been below 30 since mid-June. As in Britain, half the deaths were in care homes and two-thirds of those who died were aged 80 or over.

Once it became clear that their apocalyptic prophecy had failed, critics of the Swedish approach turned to post hoc rationalisation. They cited low population density and a high rate of single person households as the explanation for Sweden’s lucky escape. Some claimed that social distancing was a natural part of Swedish culture or that Swedes did not talk enough for virus droplets to be transmitted. Some of this was true and much of it was nonsense, but none of it had been mentioned in March when Sweden was said to be doomed.

It is now considered gauche to compare Sweden to Britain, Italy, Spain or any other country that had a higher death rate. You are only allowed to compare it to its immediate neighbours where the death rate is lower. Mention the UK or, heaven forbid, Belgium (which locked down a week before the UK and has the highest COVID-19 death rate in the world) and you will be told that they should have locked down sooner. The proposition becomes unfalsifiable. Heads they win, tails you lose.

The goalposts have shifted. The purpose of lockdowns is no longer to protect health systems, but to prevent death at any cost. New Zealand has managed to eradicate the virus for the time being, but only by kissing goodbye to its biggest export industry – tourism – which sustains ten per cent of its economy and fourteen per cent of its workforce. Isolated from the rest of the world, it is a prisoner to a vaccine that may never be found.

Australia thought it had beaten the virus, but parts of Victoria are back under lockdown after new cases were found. There have been resurgences in the United States, Israel and South Africa, to name but three. Winning the battle against the first wave may prove to be like the invasion of Iraq, merely a prelude to a long war of attrition that wastes more money and lives.

 If there is hope of avoiding a second wave, it lies in contact tracing, but the NHS Test and Trace remains unproven in summer, let alone winter, and businesses will still be faced with crippling social distancing rules and – worst of all – the public’s fear of going out. For all the talk of ‘Super Saturday’, only five per cent of us went to the pub last weekend. A recent survey found that only 21 per cent of us would be comfortable eating in a restaurant.

And what of the costs? Sweden will not be unscathed by the global recession. Its GDP is expected to decline by 5.3 per cent this year. But GDP is expected to fall by 8.7 per cent in the Eurozone, by 9.7 per cent in Britain and by more than 10 per cent in Italy, France and Spain. Sweden has not put its children’s education on hold. It has not put its citizens under soul-sapping house arrest. If a vaccine goes into production by autumn, the Swedes will look reckless. But that is not going to happen - and winter is coming.

SOURCE 

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For more blog postings from me, see  TONGUE-TIED, EDUCATION WATCH INTERNATIONAL, GREENIE WATCH,  POLITICAL CORRECTNESS WATCH, AUSTRALIAN POLITICS, and Paralipomena (Occasionally updated), A Coral reef compendium and an IQ compendium. (Both updated as news items come in).  GUN WATCH is now mainly put together by Dean Weingarten. I also put up occasional updates on my Personal blog and each day I gather together my most substantial current writings on THE PSYCHOLOGIST.

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