Hydroxychloroquine: How a WWII-era drug became Donald Trump's calling card in coronavirus war
Since March, US President Donald Trump has been hyping hydroxychloroquine (HCQ) as a potential therapy against coronavirus which remains to be approved.
On April 5, Trump yet again seemed to pressurize Americans into taking the drug. "I’ll tell you what: What do you have to lose? In some cases, they’re in bad shape. What do you have to lose? It’s been out there for a long time, and I hope they use it," he said during a briefing. He also went on to say, "I may take it. And I’ll have to ask my doctors about that, but I may take it."
A Reuters report alleges that Trump "personally pressed federal health officials" to make drugs chloroquine and hydroxychloroquine available to treat the novel coronavirus. "In a series of conversations last month, President Trump personally instructed top officials at the Centers for Disease Control (CDC), the Food and Drug Administration (FDA) and the National Institutes of Health to focus on the two drugs as potential therapies, said two sources familiar with the president," claims the report.
It adds, "Rarely, if ever, has a U.S. president lobbied regulators and health officials to focus their efforts on specific unproven drugs."
Top US adviser on COVID-19, Dr Anthony S Fauci, the National Institute of Allergy and Infectious Diseases (NIAID) Director, has also repeatedly cautioned that there is no scientific evidence currently available to support the use of hydroxychloroquine to treat COVID-19.
What is this drug currently used for?
Hydroxychloroquine is in a class of drugs called antimalarials. It was used originally to treat malaria, especially in patients who could not tolerate the similar compound chloroquine. These are both US FDA approved antimalarial drugs. Also known as hydroxychloroquine sulfate, it is available in the US by prescription only. It is sold under the brand name Plaquenil and it is also sold as a generic medicine.
Hydroxychloroquine is also used to treat discoid or systemic lupus erythematosus and rheumatoid arthritis in patients whose symptoms have not improved with other treatments.
The FDA recently issued an Emergency Use Authorization (EUA) to permit the emergency use of hydroxychloroquine sulfate to treat adults and adolescents, who weigh 50 kg or more and are hospitalized with COVID-19 and for whom a clinical trial is not available, or participation isn't feasible.
What is its history?
Chloroquine was originally developed in 1934 at the pharmaceutical company Bayer.
According to an article, chloroquine was developed from quinine, an active compound in cinchona bark, whose medicinal properties had long been known among the natives of South America in the tropical parts of the Andes. "It doesn’t seem to have been used by them as a malaria treatment per se, but rather was known as a treatment for shivering, brought on by either low temperatures or by malaria itself," says an article in Science Translational Medicine.
Antimalarial drugs were discovered shortly before World War 2. Their production was industrialized during the war because malaria was a leading cause of disease among soldiers. According to one account, by the 1940s, quinine, or rather its derivative chloroquine, was recognized for its anti-malarial properties and found use among troops fighting in the Pacific during WW-II.
However, it was noted that this compound had significant toxicities. "In 1945, a modification of this compound via hydroxylation led to the development of HCQ, which was found to be less toxic and remains in use, without change, to this day," writes Dr Bergman, clinical associate professor of medicine, Drexel University College of Medicine in Philadelphia, and chief of the Section of Rheumatology at Taylor Hospital in Ridley Park, PA.
The American Chemical Society says that in 1950, chemists Alexander R Surrey and Henry F Hammer at the Sterling–Winthrop Research Institute published a synthesis of hydroxychloroquine. The parent company, Sterling Drug, obtained a US patent on the compound and its method of preparation the same year.
"Atabrine (quinacrine), the first antimalarial widely used, had numerous side effects including yellowing of the skin. Aggressive research efforts to develop an alternative led to field testing of one of its derivative compounds, chloroquine, by the US Army in 1943. Continued chemical modification would create hydroxychloroquine, introduced in 1955," says the Cleveland Clinic Journal of Medicine.
What are pharma companies doing?
In his April 5 briefing, Trump said that the US is getting the drug from multiple locations and countries. Trump also said that the US itself has "millions and millions of doses of it; 29 million to be exact."
"And we’ve got millions of doses that are being made here and many millions of doses that are made elsewhere that are being shipped here, and it will be arriving," he added.
Meanwhile, two manufacturers namely Mylan and Teva Pharmaceuticals had ramped up their production of hydroxychloroquine in March itself.
"Mylan has restarted production of hydroxychloroquine sulfate tablets at its West Virginia manufacturing facility in the US to meet the potential for increased demand resulting from potential effectiveness of the product in treating COVID-19," said a statement. The company expects to begin supplying products by mid-April. "With the active pharmaceutical ingredient that we currently have available, we will be able to ramp up manufacturing to provide 50 million tablets to potentially treat a total of more than 1.5 million patients.
The potential use of this medicine for COVID-19 related treatment is pending additional FDA and other regulatory body guidance," it said.
Teva Pharmaceutical announced on March 19 that it will donate over 6 million doses of hydroxychloroquine sulfate tablets through wholesalers to hospitals across the US "to meet the urgent demand for the medicine as an investigational target to treat COVID-19. "Additional production of hydroxychloroquine sulfate tablets is also being assessed and subsequently ramped up with materials that are being sent to Teva from our ingredient supplier.
Teva will ship 6 million tablets through wholesalers to hospitals by March 31, and more than 10 million within a month," said a statement.
On March 29, the US Department of Health and Human Services (HHS) issued a statement saying that it has accepted 30 million doses of hydroxychloroquine sulfate donated by Sandoz, the Novartis generics and biosimilars division, and one million doses of chloroquine phosphate donated by Bayer Pharmaceuticals, for possible use in treating patients hospitalized with COVID-19 or for use in clinical trials.
"These and other companies may donate additional doses, and companies have ramped up production to provide additional supplies of the medication to the commercial market," it said.
India is one of the largest producers of hydroxychloroquine, with drugmakers Zydus Cadila and IPCA Laboratories among the biggest manufacturers. "Ipca’s shares jumped to touch a record high on March 20 after Trump endorsed the drug the day before, urging FDA to expand its use as an experimental therapy against this coronavirus," says a March 23 BloombergQuint report.
According to the report, in a March 21 securities filing, Ipca Laboratories said, "The US FDA has made an exception to the import alert for three of its facilities, allowing it to supply tablets as well as raw materials for making chloroquine phosphate and hydroxychloroquine sulfate." The report states that three plants of Ipca laboratories have been under a US import alert since FDA inspectors visited them in 2014.
According to the FDA, import alerts inform the FDA's field staff and the public that the agency has enough evidence to allow for "Detention Without Physical Examination (DWPE) of products that appear to be in violation of the FDA's laws and regulations."
Another BloombergQuint report said that as per Morgan Stanley, hydroxychloroquine sulfate formulations gross sales in the US stand at $220 million by volume. "Cadila is the largest player with 32% share, followed by Prasco (18%), Sandoz (13%), Dr Reddy’s Laboratories Ltd. (10%), Teva (10%) and Sun Pharmaceutical Industries Ltd. (7%), according to Morgan Stanely," it says.
Trump, meanwhile, said that he has spoken with India's Prime Minister Narendra Modi regarding the drug. "They make large amounts of hydroxychloroquine — very large amounts, frankly...And I said I’d appreciate it if they would release the amounts that we ordered. And they are giving it serious consideration," he said. However, India’s Directorate General of Foreign Trade (DGFT) said in an order that it is banning the export of hydroxychloroquine, as well as formulations made with the drug.
Data compiled by Bloomberg Intelligence shows 47% of the US's supply of the drug last year came from India makers.
What does science say?
The World Health Organization (WHO) has rolled out extensive trials, evaluating several potential drugs, including hydroxychloroquine.
In guidance on therapeutic options for COVID-10, CDC said that hydroxychloroquine is currently under investigation in clinical trials for the treatment of patients with mild, moderate, and severe COVID-19. It said based upon limited in-vitro and "anecdotal data," chloroquine or hydroxychloroquine are currently recommended for the treatment of hospitalized COVID-19 patients in several countries.
"Although optimal dosing and duration of hydroxychloroquine for COVID-19 treatment are unknown, some US clinicians have reported anecdotally different hydroxychloroquine dosing," it said. An HHS statement repeats anecdotal reports suggesting that these drugs may offer some benefit in the treatment of hospitalized COVID-19 patients. "Clinical trials are needed to provide scientific evidence that these treatments are effective," it adds.
The American College of Cardiology has warned that hydroxychloroquine or chloroquine therapy should occur in the context of a clinical trial or registry until sufficient evidence is available for use in clinical practice. An article in The Lancet warns hydroxychloroquine can have dangerous side-effects if the dose is not carefully controlled.
A small study published in a French medical journal has said that hydroxychloroquine does not appear to help the immune system clear the coronavirus from the body. The study comes on the heels of two others, one in France and the other in China that reported some benefits in the combination of hydroxychloroquine and azithromycin for COVID-19 patients who did not have severe symptoms of the virus.
Another pre-print study found that hydroxychloroquine and chloroquine may be deadly when combined with a common diabetes drug. "We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice. While our observations in mice may not translate to toxicity in humans, the reports that chloroquine or HCQ has anti-COVID-19 activity, the use of chloroquine resulting in toxicity and at least one death, and the recent EUA for HCQ by FDA prompted our report," says the team.