As the pandemic continues, there is an increasingly desperate need for a drug that will be effective against Covid-19 and not too unsafe in other respects.
On March 19, at one of his daily self-display sessions for TV and the press, ‘Dr.’ Trump promoted hydroxychloroquine – a drug used to treat malaria, lupus, and rheumatoid arthritis – as a remedy for the coronavirus. He did not permit his medical adviser, Dr. Fauci, to say a word. New French and Chinese studies have confirmed that hydroxychloroquine is indeed quite ineffective against Covid-19. It also causes heart complications. Nevertheless, the demand for hydroxychloroquine shot up, jeopardizing supply to the lupus sufferers whose lives really do depend on the drug. See here.
Why did Trump do it? Some suggested that his motive was to push up the value of stock he owns in companies that manufacture hydroxychloroquine. However, Philip Bump in The Washington Post argues that although Trump and his family do own some shares in one such company, the French firm Sanofi, they are worth $1,500 at most – mere ‘loose change’ for a billionaire.[2] Moreover, Trump has been equally willing to promote other drugs. The hype is best viewed as part of Trump’s effort to reassure the public and prepare the ground for an early end to the lockdown.
Remdesivir
It is widely believed that the most promising drug is remdesivir, the patent for which is owned by Gilead Sciences, an American company specializing in antiviral drugs. Originally developed to treat Ebola during the West African epidemic of 2014–16, it was no longer being manufactured when the current pandemic broke out, though the company still had a small inventory. Production has now resumed and is undergoing rapid expansion.[1]
A preliminary study was based on data for 53 patients with severe Covid-19 who received at least one dose of remdesivir over the period from January 25 to March 7. At follow-up 2—3 weeks later, two-thirds of the patients (36) showed improvement; almost half (25) had improved enough to be discharged; and only 7 had died – an impressively low death rate given the severity of these cases. Admittedly, this was not a properly organized clinical trial: it was very small and had no control group.[2]
An interim report of an ongoing clinical trial at a Chicago hospital, published on April 16, revealed even more encouraging results. At this hospital 125 people with Covid-19, including 113 with a severe form of the disease, received daily infusions of remdesivir. Nearly all made rapid recoveries in fever and respiratory symptoms and were discharged within a week. Equally encouraging results have been obtained in the UK. Results like these suggest that it may not be premature to speak of a ‘cure’ for Covid-19.
Six large clinical trials are now underway. In March Gilead Sciences started two transnational trials – one for severe and one for moderate cases. In addition, it is supplying remdesivir without charge for the other four trials: one in the US, one in Europe, and two in China’s Hubei Province.
‘Compassionate Use’
Prior to completion of clinical trials and approval by the US Food & Drug Administration (or by the corresponding regulatory agency in another country), an ‘investigational drug’ – which may be a new drug or, as in this instance, an old drug being put to new use – is not usually made available to treat patients, apart from those enrolled in the clinical trials. An exception is made for so-called ‘compassionate use’ – also known as ‘early access,’ ‘expanded access,’ ‘managed access,’ or ‘emergency access.’ The approval of the FDA must be sought in each individual case. The application is submitted either by the patient’s physician after obtaining the consent of the manufacturer or by the manufacturer at the physician’s request. Approval is subject to the following conditions:
- There is an immediate threat to the patient’s life.
- No comparable or satisfactory alternative treatment is available.
- The patient cannot be enrolled in a clinical trial of the drug.
- The potential benefit to the patient justifies the risks of treatment with the drug.
- Providing the drug will not interfere with clinical trials that could support development of the drug or marketing approval for it.
It is true that this system was not designed with pandemics in mind. Under normal circumstances applications for compassionate use are few and far between. Nevertheless, it provides a legal device that could be used to get timely help to a much larger number of people when an epidemic does occur.
Gilead Sciences began accepting physicians’ requests for compassionate use of remdesivir on January 25. As the existence of the drug was not widely known, the number of requests was initially manageable. However, on March 20 Trump talked on his show about remdesivir and drew attention to the option of compassionate use. The result was a sudden flood of new requests. On March 23, the company complained that it had been ‘overwhelmed’ by this flood and suspended intake of new requests except in cases where the patient was a pregnant woman or a child under the age of 18. The number of patients who had received the drug for ‘compassionate use’ by the end of March was ‘over 1,000.’
In an open letter published on March 28, Gilead Sciences CEO Daniel O’Day announced that the company was switching to a new program for receiving and processing requests for ‘compassionate use.’ It was going to build up a network of ‘active sites’ (or ‘study locations’) – hospitals, medical centers, and research centers participating in the program.[3] Requests could now be submitted in batches, but they had to come from one of these hospitals or centers. ‘While it will take some time to build a network of active sites,’ wrote O’Day, ‘this approach will ultimately accelerate emergency access for more people.’
Ultimately. One of those who did not get emergency access was Dr. Frank Gabrin, who on March 31 became America’s first Emergency Room physician to die of Covid-19. He worked at East Orange General Hospital in New Jersey. Although New Jersey is the state with the largest number of ‘active sites,’ this hospital is not one of them.
Profit-making Strategy
There is no need to accept the company’s public explanations at face value. Gilead Sciences is clearly very good at projecting a ‘caring’ image. However, had it really wanted to bring timely help to as many patients as possible, it could surely have hired and trained the additional staff needed to handle the increased flow of requests. The switch to the new program had the initial effect of halting the flow almost completely. The flow would then increase again, but only gradually, as the network of active sites expanded. This gives the company time. Ultimately – quite soon, in fact – clinical trials would be completed, the company would obtain FDA approval to start marketing the drug, and there would be no further need for any ‘compassionate use’ programs. What we have here is actually a cleverly designed profit-making strategy.
It was not because the drug was in short supply that Gilead Sciences slowed down the flow of requests for ‘compassionate use.’ In January 2020 the company had an inventory of 5,000 courses of remdesivir – enough to administer a ten-day course of treatment to 5,000 patients. But by late March over 30,000 courses were on hand. The company aimed to produce over 140,000 courses by the end of May, over 500,000 by October, over a million by December, and (if required) several million in 2021 (see here).
The size of the inventory was 30,000 courses in late March and must have reached about 50,000 by mid-April. The number needed for the clinical trials did not exceed 10,000.[4] Even allowing a couple of thousand courses for the expanded-access program, most of the inventory was being held back.
Why did Gilead Sciences hold back most of its accumulating inventory when so many people were in desperate need of the drug? The drug courses assigned for clinical trials and for ‘compassionate use’ at the present stage had to be provided free of charge, as the FDA had not yet given its approval to market remdesivir. Once it did, however, Gilead Sciences would be able to sell its accumulated stock while continuing to expand productive capacity.
The strategy paid off. On May 1 the FDA approved remdesivir ‘for emergency use’; full approval followed on October 22. The drug is being marketed under the brand name Veklury. A five-day course costs $3,120. Remdesivir brought Gilead Sciences revenues of $873 million in the third quarter of 2020, playing the decisive role in generating a quarterly net profit for the company of $360 million.
In the past companies in India and China have manufactured generic forms of expensive Western drugs for sale at lower prices, leading to conflicts over intellectual property rights between these countries and the United States. The same thing is set to happen with this drug. In February it was reported that BrightGene Bio-Medical Technology Company, based in Suzhou in China’s Jiangsu Province, had succeeded in producing a copy of remdesivir (here). The Wuhan Institute of Virology has also applied for a Chinese patent on the drug (here).
A Better Alternative?
Victoria C. Yan and Florian L. Muller of the University of Texas have argued (here and here) that another antiviral drug developed by Gilead Sciences and known as GS-441524 has significant advantages over remdesivir. While closely related to remdesivir, its simpler structure makes it easier to mass produce, only 3 steps being required as against 7 for remdesivir. It also spreads more evenly through different organs than remdesivir, which tends to concentrate in and may harm the liver and kidneys. There have been no trials on humans, but test-tube experimentation and the use of GS-441524 in treating cats suggest that it is very safe, so that it could be given in higher doses without risk of serious adverse effects.
Yan and Muller urge Gilead Sciences to ‘ditch remdesivir’ and focus on GS-441524. The company has shown no inclination to take their advice, probably because its patent on GS-441524 is due to expire much sooner than its patent on remdesivir. Perhaps GS-441524 would be a better alternative for patients, but almost certainly remdesivir will make more money for the shareholders of Gilead Sciences.
Notes
[1] Information is provided on the company’s website.
[2] Twenty-two patients were in the United States, 22 in Europe or Canada, and 9 in Japan. Jonathan Grein et al., ‘Compassionate Use of Remdesivir for Patients with Severe Covid-19,’ The New England Journal of Medicine, April 10.
[3] At the time of writing (April 16), 46 sites are active in the following countries: the United States (31), France (4), Germany (2), Italy (3), Spain (2), Switzerland (2), and the UK (2). In the US the states with the largest numbers of sites are New Jersey (8), California (7), New York (5), Florida (3), and Louisiana (3). See here.
[4] I am not in a position to calculate this figure exactly. The total number of participants in the six trials is 8,301. Some subgroups receive only a placebo; others receive courses of 5, 10, 15, or 20 days. Sizes are not given for all the subgroups.
