The FDA has signed off on the emergency use of PerkinElmer’s (PKI -1.0%) EURORealTime SARS-CoV-2 molecular test for use during the COVID-19 pandemic. The nod is the third for the company.
https://seekingalpha.com/news/3583069-fda-oks-emergency-use-of-third-perkinelmer-covidminus-19-test
Monday, June 15, 2020
RECOVERY Hydroxychloroquine Trials: ‘The Marx Brothers do science’
LAST Friday, hard on the heels of the retraction by The Lancet of its now-notorious paper purporting
to show that hydroxychloroquine not only did not help Covid-19
patients, but actually made them worse, came the termination of the
hydroxychloroquine ‘arm’ of the UK’s RECOVERY (Randomised Evaluation of COVid-19 thERapY) clinical
trials. A huge embarrassment was conveniently overlain by news from
Oxford University that sorry, hydroxychloroquine really isn’t any good.
So even if The Lancet paper was fake, ‘a political hit job’ as one American doctor had it, Oxford’s clinical trial showed the same result.
Professor Martin Landray, MB ChB, PhD, FRCP, FHEA, FASN, FBPhS, FESC, Professor of Medicine and Epidemiology at Oxford, and deputy chief investigator of the RECOVERY trial, was interviewed by the increasingly astute France Soir. It began well: the trial termination was triggered by a request from the Medicines and Healthcare products Regulatory Agency who were bothered about safety (reasons not explained). In consequence the study was ‘unblinded’, that is, results were revealed. Finding no significant difference between treated and untreated patients, they called off the trial, with Oxford triumphantly announcing that hydroxychloroquine was no good for Covid-19, at least for hospitalised patients.
Since those following the issue already knew that no anti-viral was likely to help very sick late-stage Covid-19 patients, this wasn’t news. The trial design had already been savaged within days of launch; the results were no surprise. Internet sleuths also got to work on the very heavy doses of the drug that were given – 2400 mg in the first 24 hours, a ‘dose fit for a gorilla’ as one critic had it. Quizzed about this, Landray defended the dosage, twice, as being usual for other diseases such as amoebic dysentery. Say again? Hydroxychloroquine is used for lupus and arthritis as well as malaria, but dysentery? As a footnote in medical history, the older chloroquine was used half a century ago in attempts to control dysentery, but Professor Christian Perronne, head of infectious diseases at Garches, France, told France Soir that it had been abandoned before 1976. Was Landray confusing hydroxychloroquine with the hydroxyquinolines, which are used for dysentery? Perhaps all those post-nominals had induced some medical dyslexia.
Landray explained there was no approved dosing for Covid because it was a new disease. Well, yes, but the toxic dose won’t change depending on the illness. Asked whether the UK had a maximum dose for hydroxychloroquine, Landray wasn’t sure, but opined it would be much larger, say six to ten times the trial’s dose. That makes 24 whole grams. NICE says about 490 mg per day for a 75kg adult. In France 1800 mg in a day mandates hospitalisation as a poisoning. Twenty-four grams at one go would be almost certainly lethal, possibly even to a gorilla. So Landray has had notice of some hard questions on dose, which will no doubt be explained in the full report, not yet released.
Others were shocked by the overall mortality: about a quarter of patients had died after 28 days. These is very poor compared with hospitals and regions elsewhere. In New York and the Bouches-du-Rhône department of France, hospital mortality is around 13 per cent. At the University Hospital in Marseille it is 15.6 per cent for the sickest patients, those not just hospitalised, but in intensive care. Either the RECOVERY patients were very ill indeed, or something is badly wrong with the ‘standard of care’ in the 175 NHS hospitals involved.
RECOVERY was scattered over multiple hospitals, a network, and Prof Landray admitted that he did not treat any of the patients himself. Professor Didier Raoult, director of the University Hospital in Marseille, which has diagnosed more than 6,000 cases, described the mortality as ‘effroyable’ – appalling. Raoult published his hydroxychloroquine/azithromycin dual therapy in early March and has since used it in well over 3,000 patients with 18 deaths – about 0.5 per cent. He has, though, always been clear that ‘quand il est trop tard, il est trop tard’. Like other successful clinicians, he insists that early treatment is key. This is because, as Dr Harvey Risch of Yale explains: ‘Early outpatient illness is very different from later hospitalised florid disease, and the treatments differ.’ It is clear from world experience that the early infectious stage (‘just a mild illness’) is very different from the ‘inflammatory’ stage when patients start drowning in their own fluids. You can find a chart of the clinical course here.
What is killing patients is their own body’s immune response in overdrive. Treating this with anti-viral medications misses the target; the infection is no longer their really big problem.
In an interview on Tuesday, Raoult scathingly called RECOVERY ‘the Marx Brothers doing science’. He runs through the defects: lack of positive diagnosis, failure to discriminate different stages of the disease, the huge dosage, lack of virological follow-up, and the shocking mortality – which is when his simile ceases to be funny. The one upside is that no cardiac deaths occurred even with the thumping initial dose, showing that talk of the drug’s cardiac risk is massively overblown. But we did not need to experiment on more than 4,000 very ill people to find that. So more hard questions for RECOVERY’s report; we shall see.
Landray wrapped up his interview with France Soir: ‘We have demonstrated that this drug is no good for this disease whatever one wants to believe.’ Thousands of Professor Raoult’s patients, successfully treated with his hydroxychloroquine combination therapy, probably will go on wanting to believe something different. The cognitive dissonance needs resolving. A clue may lie in one of Landray’s papers published in February and entitled The Magic of Randomisation versus the Myth of Real-World Evidence which I first thought was irony. Only in today’s dreaming spires would it be possible for someone to call ‘real-world evidence’ a ‘myth’, revoking centuries of Oxford’s fabled reliance on primary sources. Rattling dice now determines the answer.
Professor Peter Horby, the chief investigator of the trial, doubled up: ‘The RECOVERY trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalised with COVID-19. Although it is disappointing that this treatment has been shown to be ineffective, it does allow us to focus care and research on more promising drugs.’
His first statement is broadly true, and may well follow from the evidence (though we havn’t seen it all yet). Hydroxychloroquine, not in combination with adjuncts potentially important to its anti-viral effect, isn’t likely to work in very ill hospitalised patients with late stage disease. But plenty of doctors using the drug successfully knew that already. Their goal was keeping patients out of hospital.
Horby’s second statement isn’t so qualified and open to easy misrepresentation, so let’s be accurate now: RECOVERY has shown nothing whatever about the effectiveness of hydroxychloroquine-based combinations in the clinically very different early-stage infections, before the ‘inflammatory’ stage has set in. Horby does however declare his future recommendations, ‘to focus . . . on more promising drugs’. Good to have that made clear, but is this ‘following the science’, or what some major sponsors wish to hear?
It is well that the hydroxychloroquine ‘arm’ of RECOVERY has been cancelled. It was always looking in the wrong place. Will Oxford’s PRINCIPLE trials, based in GP surgeries, looking to treat early-stage disease, start to take note of successful empirical experience around the world, and arrange a trial of the Marseille combination, or the related protocol with zinc supplementation pioneered by Dr Zelenko in New York? Or will Oxford’s latter-day denial of ‘real-world evidence’ continue to blind them to what successful clinicians elsewhere – and sometimes whole countries – are reporting?
With a destructive lockdown ongoing, and the worst deaths per million in the world after Belgium, the UK needs far better than clinical trials run by the Marx Brothers. Wake up, Oxford, and rediscover your empirical inheritance. With a trail of deadly failure behind us, taking an objective look at what others have already done is a pretty small ask.
Dr Edmund Fordham is a physicist, and not a physician. He is an experienced patient: a 23-year survivor of Stage 4 lymphoma, cured by a clinical trial in stem-cell transplantation. He was an Independent parliamentary candidate in the General Election.
Professor Martin Landray, MB ChB, PhD, FRCP, FHEA, FASN, FBPhS, FESC, Professor of Medicine and Epidemiology at Oxford, and deputy chief investigator of the RECOVERY trial, was interviewed by the increasingly astute France Soir. It began well: the trial termination was triggered by a request from the Medicines and Healthcare products Regulatory Agency who were bothered about safety (reasons not explained). In consequence the study was ‘unblinded’, that is, results were revealed. Finding no significant difference between treated and untreated patients, they called off the trial, with Oxford triumphantly announcing that hydroxychloroquine was no good for Covid-19, at least for hospitalised patients.
Since those following the issue already knew that no anti-viral was likely to help very sick late-stage Covid-19 patients, this wasn’t news. The trial design had already been savaged within days of launch; the results were no surprise. Internet sleuths also got to work on the very heavy doses of the drug that were given – 2400 mg in the first 24 hours, a ‘dose fit for a gorilla’ as one critic had it. Quizzed about this, Landray defended the dosage, twice, as being usual for other diseases such as amoebic dysentery. Say again? Hydroxychloroquine is used for lupus and arthritis as well as malaria, but dysentery? As a footnote in medical history, the older chloroquine was used half a century ago in attempts to control dysentery, but Professor Christian Perronne, head of infectious diseases at Garches, France, told France Soir that it had been abandoned before 1976. Was Landray confusing hydroxychloroquine with the hydroxyquinolines, which are used for dysentery? Perhaps all those post-nominals had induced some medical dyslexia.
Landray explained there was no approved dosing for Covid because it was a new disease. Well, yes, but the toxic dose won’t change depending on the illness. Asked whether the UK had a maximum dose for hydroxychloroquine, Landray wasn’t sure, but opined it would be much larger, say six to ten times the trial’s dose. That makes 24 whole grams. NICE says about 490 mg per day for a 75kg adult. In France 1800 mg in a day mandates hospitalisation as a poisoning. Twenty-four grams at one go would be almost certainly lethal, possibly even to a gorilla. So Landray has had notice of some hard questions on dose, which will no doubt be explained in the full report, not yet released.
Others were shocked by the overall mortality: about a quarter of patients had died after 28 days. These is very poor compared with hospitals and regions elsewhere. In New York and the Bouches-du-Rhône department of France, hospital mortality is around 13 per cent. At the University Hospital in Marseille it is 15.6 per cent for the sickest patients, those not just hospitalised, but in intensive care. Either the RECOVERY patients were very ill indeed, or something is badly wrong with the ‘standard of care’ in the 175 NHS hospitals involved.
RECOVERY was scattered over multiple hospitals, a network, and Prof Landray admitted that he did not treat any of the patients himself. Professor Didier Raoult, director of the University Hospital in Marseille, which has diagnosed more than 6,000 cases, described the mortality as ‘effroyable’ – appalling. Raoult published his hydroxychloroquine/azithromycin dual therapy in early March and has since used it in well over 3,000 patients with 18 deaths – about 0.5 per cent. He has, though, always been clear that ‘quand il est trop tard, il est trop tard’. Like other successful clinicians, he insists that early treatment is key. This is because, as Dr Harvey Risch of Yale explains: ‘Early outpatient illness is very different from later hospitalised florid disease, and the treatments differ.’ It is clear from world experience that the early infectious stage (‘just a mild illness’) is very different from the ‘inflammatory’ stage when patients start drowning in their own fluids. You can find a chart of the clinical course here.
What is killing patients is their own body’s immune response in overdrive. Treating this with anti-viral medications misses the target; the infection is no longer their really big problem.
In an interview on Tuesday, Raoult scathingly called RECOVERY ‘the Marx Brothers doing science’. He runs through the defects: lack of positive diagnosis, failure to discriminate different stages of the disease, the huge dosage, lack of virological follow-up, and the shocking mortality – which is when his simile ceases to be funny. The one upside is that no cardiac deaths occurred even with the thumping initial dose, showing that talk of the drug’s cardiac risk is massively overblown. But we did not need to experiment on more than 4,000 very ill people to find that. So more hard questions for RECOVERY’s report; we shall see.
Landray wrapped up his interview with France Soir: ‘We have demonstrated that this drug is no good for this disease whatever one wants to believe.’ Thousands of Professor Raoult’s patients, successfully treated with his hydroxychloroquine combination therapy, probably will go on wanting to believe something different. The cognitive dissonance needs resolving. A clue may lie in one of Landray’s papers published in February and entitled The Magic of Randomisation versus the Myth of Real-World Evidence which I first thought was irony. Only in today’s dreaming spires would it be possible for someone to call ‘real-world evidence’ a ‘myth’, revoking centuries of Oxford’s fabled reliance on primary sources. Rattling dice now determines the answer.
Professor Peter Horby, the chief investigator of the trial, doubled up: ‘The RECOVERY trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalised with COVID-19. Although it is disappointing that this treatment has been shown to be ineffective, it does allow us to focus care and research on more promising drugs.’
His first statement is broadly true, and may well follow from the evidence (though we havn’t seen it all yet). Hydroxychloroquine, not in combination with adjuncts potentially important to its anti-viral effect, isn’t likely to work in very ill hospitalised patients with late stage disease. But plenty of doctors using the drug successfully knew that already. Their goal was keeping patients out of hospital.
Horby’s second statement isn’t so qualified and open to easy misrepresentation, so let’s be accurate now: RECOVERY has shown nothing whatever about the effectiveness of hydroxychloroquine-based combinations in the clinically very different early-stage infections, before the ‘inflammatory’ stage has set in. Horby does however declare his future recommendations, ‘to focus . . . on more promising drugs’. Good to have that made clear, but is this ‘following the science’, or what some major sponsors wish to hear?
It is well that the hydroxychloroquine ‘arm’ of RECOVERY has been cancelled. It was always looking in the wrong place. Will Oxford’s PRINCIPLE trials, based in GP surgeries, looking to treat early-stage disease, start to take note of successful empirical experience around the world, and arrange a trial of the Marseille combination, or the related protocol with zinc supplementation pioneered by Dr Zelenko in New York? Or will Oxford’s latter-day denial of ‘real-world evidence’ continue to blind them to what successful clinicians elsewhere – and sometimes whole countries – are reporting?
With a destructive lockdown ongoing, and the worst deaths per million in the world after Belgium, the UK needs far better than clinical trials run by the Marx Brothers. Wake up, Oxford, and rediscover your empirical inheritance. With a trail of deadly failure behind us, taking an objective look at what others have already done is a pretty small ask.
Dr Edmund Fordham is a physicist, and not a physician. He is an experienced patient: a 23-year survivor of Stage 4 lymphoma, cured by a clinical trial in stem-cell transplantation. He was an Independent parliamentary candidate in the General Election.
The Marx Brothers do science
FDA revokes emergency use ruling for hydroxychloroquine
The Food and Drug Administration on Monday said it had withdrawn an
emergency approval for use of the malaria drug hydroxychloroquine as a
Covid-19 treatment.
Almost since the beginning of the novel coronavirus pandemic, President Trump and other world leaders have touted hydroxychloroquine as an effective treatment based on scattered anecdotes, not reliable scientific studies. But the FDA said Monday that the drug, along with chloroquine, is “unlikely to be effective in treating Covid-19,” and highlighted “serious side effects.”
The FDA’s withdrawal of the emergency use order, which Politico first reported, appears to formally close the door on U.S. officials’ willingness to use the drug to prevent or treat Covid-19, the disease caused by the novel coronavirus.
In recent weeks, an increasingly conclusive body of research showed
the drug was not effective at treating Covid-19 or at preventing the
respiratory disease from developing in individuals who’d been exposed to
the virus.
The controversy has pitted Trump and his high-profile allies against the country’s scientific establishment. Rick Bright, a prominent government scientist, has alleged he was ousted from his vaccine-development role after he opposed the initial emergency approval for hydroxychloroquine. At a March press conference, Trump said his belief in the drug was “just a feeling,” contradicting Tony Fauci, the country’s top infectious disease researcher, who told reporters minutes before there was no reliable evidence supporting hydroxychloroquine’s use.
Despite the lack of evidence supporting the drug’s use, Trump
continued to tout it as a promising tool to treat and prevent Covid-19,
even announcing last month that he had taken a regimen of
hydroxychloroquine as a safeguard.
Asked for comment, an FDA spokesman directed STAT to an online list of current emergency use authorizations for Covid-19 medical products. The list no longer includes hydroxychloroquine.
In a letter to Gary Disbrow, the acting director of the Biomedical Advanced Research and Development Authority, a top FDA official said the withdrawal of the hydroxychloroquine approval was based on recent science that showed the drug to be ineffective.
“Today’s request to revoke is based on new information, including clinical trial data results, that have led BARDA to conclude that this drug may not be effective to treat [Covid-19] and that the drug’s potential benefits for such use do not outweigh its known and potential risks,” wrote Denise Hinton, the FDA’s chief scientist.”
Almost since the beginning of the novel coronavirus pandemic, President Trump and other world leaders have touted hydroxychloroquine as an effective treatment based on scattered anecdotes, not reliable scientific studies. But the FDA said Monday that the drug, along with chloroquine, is “unlikely to be effective in treating Covid-19,” and highlighted “serious side effects.”
The FDA’s withdrawal of the emergency use order, which Politico first reported, appears to formally close the door on U.S. officials’ willingness to use the drug to prevent or treat Covid-19, the disease caused by the novel coronavirus.
The controversy has pitted Trump and his high-profile allies against the country’s scientific establishment. Rick Bright, a prominent government scientist, has alleged he was ousted from his vaccine-development role after he opposed the initial emergency approval for hydroxychloroquine. At a March press conference, Trump said his belief in the drug was “just a feeling,” contradicting Tony Fauci, the country’s top infectious disease researcher, who told reporters minutes before there was no reliable evidence supporting hydroxychloroquine’s use.
Asked for comment, an FDA spokesman directed STAT to an online list of current emergency use authorizations for Covid-19 medical products. The list no longer includes hydroxychloroquine.
In a letter to Gary Disbrow, the acting director of the Biomedical Advanced Research and Development Authority, a top FDA official said the withdrawal of the hydroxychloroquine approval was based on recent science that showed the drug to be ineffective.
“Today’s request to revoke is based on new information, including clinical trial data results, that have led BARDA to conclude that this drug may not be effective to treat [Covid-19] and that the drug’s potential benefits for such use do not outweigh its known and potential risks,” wrote Denise Hinton, the FDA’s chief scientist.”
FDA revokes emergency use ruling for hydroxychloroquine, the drug touted by Trump as a Covid-19 therapy
Novavax raises $200 million to advance vaccine candidates
Novavax (NVAX +8.7%) raises ~$200 million from the direct sale of ~4.4M shares of Series A convertible preferred stock to RA Capital (~$45.57/share).
The capital will help fund the advancement of its COVID-19 vaccine candidate and flu vaccine NanoFlu.
Closing date was June 12.
https://seekingalpha.com/news/3583051-novavax-raises-200-million-to-advance-vaccine-candidatesBayer Starts Phase III Study for Finerenone in Heart Failure Patients
Bayer AG said Monday that it is starting a phase III study for
Finerenone for the treatment of patients who suffer from heart failure.
The FINEARTS-HF study’s main goal is to show Finerenone’s superiority over a placebo regarding cardiovascular death and hospitalization or emergency treatment for heart failure, the German pharmaceutical company said.
The study involves 5,500 patients with a left ventricular ejection fraction of at least 40%from 34 countries.
Finerenone is also being studied in two long-term trials in patients with chronic kidney disease and type 2 diabetes.
https://www.marketscreener.com/BAYER-AG-436063/news/Bayer-Starts-Phase-III-Study-for-Finerenone-in-Heart-Failure-Patients-30772556/
The FINEARTS-HF study’s main goal is to show Finerenone’s superiority over a placebo regarding cardiovascular death and hospitalization or emergency treatment for heart failure, the German pharmaceutical company said.
The study involves 5,500 patients with a left ventricular ejection fraction of at least 40%from 34 countries.
Finerenone is also being studied in two long-term trials in patients with chronic kidney disease and type 2 diabetes.
https://www.marketscreener.com/BAYER-AG-436063/news/Bayer-Starts-Phase-III-Study-for-Finerenone-in-Heart-Failure-Patients-30772556/
Catalent Agrees to Manufacture AstraZeneca Covid-19 Vaccine Candidate
Catalent Inc. said it will provide vial filling and packaging
capacity to AstraZeneca PLC at Catalent’s manufacturing facility in
Anagni, Italy, and prepare for large-scale commercial supply of the
University of Oxford’s Covid-19 vaccine candidate, AZD1222.
Catalent shares were up 11% to $77 premarket.
The agreement accelerates the rapid scale-up of capacity over the coming months to support the dedicated production of AZD1222, the provider of advanced delivery technologies, development, and manufacturing solutions for drugs.
Catalent said it will prepare the facility to enable manufacturing schedules and supply hundreds of millions of doses of the vaccine candidate from August 2020, and potentially through to March 2022 if the product is approved by regulatory agencies.
https://www.marketscreener.com/ASTRAZENECA-PLC-4000930/news/AstraZeneca-Catalent-in-Agreement-with-AstraZeneca-to-Manufacture-Covid-19-Vaccine-Candidate-30771704/
Catalent shares were up 11% to $77 premarket.
The agreement accelerates the rapid scale-up of capacity over the coming months to support the dedicated production of AZD1222, the provider of advanced delivery technologies, development, and manufacturing solutions for drugs.
Catalent said it will prepare the facility to enable manufacturing schedules and supply hundreds of millions of doses of the vaccine candidate from August 2020, and potentially through to March 2022 if the product is approved by regulatory agencies.
https://www.marketscreener.com/ASTRAZENECA-PLC-4000930/news/AstraZeneca-Catalent-in-Agreement-with-AstraZeneca-to-Manufacture-Covid-19-Vaccine-Candidate-30771704/
Dosing underway in mid-stage study of Immunic’s IMU-838 in COVID-19
Immunic (IMUX -1.6%) announces the start of dosing in a Phase 2 clinical trial, CALVID-1, evaluating IMU-838 plus standard-of-care treatment in COVID-19 patients. Topline data should be available later this year.
The company says IMU-838 is
an orally available, next-generation immune modulator that dampens the
immune response by inhibiting an enzyme called dihydroorotate
dehydrogenase (DHODH) that plays a key role in intracellular metabolism
of activated immune cells.
https://seekingalpha.com/news/3583016-dosing-underway-in-mid-stage-study-of-immunics-imuminus-838-in-covidminus-19
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