Candidates: Combination of Plaquenil® (hydroxychloroquine sulfate) and Zithromax® or Z-Pak (azithromycin); monotherapies Chloroquine phosphate (formerly Aralen®); Chloroquine hydrochloride (formerly Aralen Hydrochloride®); Zithromax (azithromycin); Zmax (azithromycin extended release)
Type: Plaquenil and the chloroquine treatments are antimalarial drugs; plaquanil has also been approved by the FDA for lupus erythematosus and rheumatoid arthritis. Chloroquine, for extraintestinal amebiasis. Zithromax and Zmax are antibacterials indicated for adults with acute bacterial sinusitis, and community-acquired pneumonia. Zithromax is also indicated for acute bacterial exacerbations of chronic obstructive pulmonary disease.
Status: The National Institute of Allergy and Infectious Diseases (NIAID) said May 14 it has begun assessing hydroxychloroquine and azithromycin in a Phase IIb clinical trial (A5395; NCT04358068) being conducted by the NIAID-funded AIDS Clinical Trials Group (ACTG). Teva Pharmaceuticals is donating medications for the study, which will enroll approximately 2,000 adults at participating ACTG sites nationwide. The principal aim of the study is to determine whether hydroxychloroquine and azithromycin can prevent hospitalization and death due to COVID-19. Additionally, investigators will evaluate the safety and tolerability of the experimental treatment for people with SARS-CoV-2 infection.
The FDA on April 24 issued an advisory to healthcare professionals cautioning against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. The agency cited reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT prolonging medicines—as well as increased use of these medicines through outpatient prescriptions. “Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19,” the FDA said. “We will continue to investigate risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate publicly when we have more information.”
The advisory capped a week in which demand for hydroxychloroquine plummeted 62%, to 198,500 tablets from 462,850 tablets the week ending April 17, according to Vizient, a group purchasing organization for about 3,000 U.S. hospitals and health care facilities.
The FDA’s advisory followed weeks of actions and statements about the antimalarial drugs ranging from cautious to positive by federal officials as high as President Donald Trump. Some prominent supporters of Trump have advocated for hydroxychloroquine over other widely-discussed potential COVID-19 treatments, notably Gilead Sciences’ remdesivir, Politico reported May 2.
The heightened caution followed publication April 23 of a preprint study in medRxiv in which researchers in South Carolina and Virginia concluded: “Hydroxychloroquine use with or without co-administration of azithromycin did not improve mortality or reduce the need for mechanical ventilation in hospitalized patients.”
The researchers conducted a retrospective analysis of data from 368 patients (men whose median age was over 65 years) hospitalized with confirmed SARS-CoV-2 infection in all U.S. Veterans Health Administration medical centers until April 11. The analysis showed rates of death in the hydroxychloroquine (HC), HC + azithromycin (AZ), and no HC groups were 27.8%, 22.1%, and 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.
Also in April, a team of Brazilian investigators published preliminary findings in JAMA Network Open from a study of 81 patients with severe SARS-CoV-2 recommending against the higher of two dosages of chloroquine diphosphate (CQ): “The 600 mg dosage of should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir,” the Brazilian researchers concluded.
Eleven patients died by the sixth day of treatment with 600 mg CQ twice daily for 10 days after developing heart arrhythmias, leading researchers to halt that portion of the Phase II trial (CloroCOVID19; NCT04323527). The study also assessed a lower dosage (450 mg twice daily on day 1 and once daily for 4 days). Overall, lethality until day 13 was 39% in the high-dosage group (16 of 41 patients) and 15% in the low-dosage group (6 of 40 patients).
“Hydroxychloroquine has several serious known side effects and should be used with caution. Not everyone can take this medicine. To date, there is insufficient clinical evidence to draw any conclusion over the safety and efficacy of hydroxychloroquine in the management of COVID-19 patients.”
Novartis, whose Sandoz generics and biosimilars division markets a generic version of hydroxychloroquine, has launched a Phase III trial (NCT04358081) designed to assess hydroxychloroquine in hospitalized patients with COVID-19, after reaching agreement with the FDA April 20 to initiate a randomized, double-blind, placebo controlled study, set to recruit approximately 440 patients and use hydroxychloroquine donated by Sandoz.
Earlier in April, Sanofi said it would donate 100 million doses of Plaquenil across 50 countries, adding that it had doubled its incremental production capacity—in addition to production for current indications—across its eight hydroxychloroquine manufacturing sites worldwide, and was on track to quadruple production by the summer.
On April 4, Trump said the U.S. government will place 29 million doses of hydroxychloroquine into the Strategic National Stockpile to allow for use by COVID-19 patients—one of several statements that promoted use of that drug, alone and in combination with Zithromax (“I just hope that hydroxychloroquine wins, coupled with, perhaps, the Z-Pak”)—despite concerns expressed by Anthony Fauci, MD, Director of the NIH’s National Institute of Allergy and Infectious Diseases, that more data was needed on the safety and efficacy of the drugs.
Trump’s remarks came five days after the FDA on March 28 issued an emergency use authorization allowing healthcare providers to make available chloroquine phosphate or hydroxychloroquine sulfate to “patients for whom a clinical trial is not available, or participation is not feasible,” adding “FDA encourages the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of these products in treating COVID-19.”
The University of Oxford plans to recruit 40,000 participants for a double-blind, randomized, trial assessing chloroquine phosphate or hydroxychloroquine sulfate compared with placebo (NCT04303507). The Population Research Institute is recuirting 1,500 participants for an open-label, parallel group, randomized controlled trial (NCT04324463).
Two other clinical trials are now recruiting healthcare workers as patients to assess hydroxychloroquine. One is an up-to-440-patient randomized study (NCT04331834) by the Barcelona Institute for Global Health; the other is an up-to-360 patient no-randomized study (NCT04333225) by Baylor Research Institute. Two other trials are being conducted in Australia, where the government of Prime Minister Scott Morrison on April 2 exempted hydroxychloroquine from the nation’s register of therapeutic goods, conditioned on the drug being imported, manufactured, or supplied via contract or arrangement with the health department.
Sanofi has offered French authorities “millions of doses” of Plaquenil, enough to treat up to 300,000 people. Sanofi obtained FDA approval for both Plaquenil (in 1955) and Aralen (in 1949), though the company has discontinued marketing brand-name Aralen. Pfizer gained FDA approval for Zithromax in 1991. All three drugs are marketed as generics by numerous companies worldwide. Among generic manufacturers, Mylan said in March it would restart production of hydroxychloroquine sulfate tablets at its West Virginia manufacturing facility while Teva Pharmaceutical Industries committed to donating more than 10 million doses by this month.
The combination of hydroxychloroquine and azithromycin has gained public attention for successful results in some studies. Notably, a study in press March 17 in the journal International Journal of Antimicrobial Agents was a 42-patient study in which 26 patients completed treatment with hydroxychloroquine, six with hydroxychloroquine and azithromycin, and 16 patients served as a control group receiving symptomatic treatment and antibiotics (six halted hydroxychloroquine treatment early).
According to the study, “100% of patients treated with hydroxychloroquine and azithromycin combination were virologicaly cured comparing with 57.1% in patients treated with hydroxychloroquine only, and 12.5% in the control group.” The study’s corresponding author, Professor Didier Raoult, MD, PhD, of l’Institut Hospitalo-Universitaire (IHU) Méditerranée Infection in Marseille—who discussed the results in a YouTube video posted March 17—has been appointed by the French government to research possible COVID-19 treatments. On April 9, French President Emmanuel Macron unexpectedly flew to Marseille and spent more than three hours meeting with Raoult. While Prof. Christine Rouzioux, MD, PharmD, PhD, of Paris Descartes University told BFM TV said the meeting sent a message of support to Raoult, aides to the French president said it showed instead his willingness to listen to a broad range of scientific opinions.
A Chinese research team published positive results for hydroxychloroquine in COVID-19 patients, concluding March 18 in Cell Discovery that: “HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. In combination with its anti-inflammatory function, we predict that the drug has a good potential to combat the disease. This possibility awaits confirmation by clinical trials.”
Another Chinese team concluded that chloroquine and Gilead Sciences’ Remdesivir were “highly effective in the control of 2019-nCoV infection in vitro,” according to a study published February 4 in the Nature-owned journal Cell Research that added: “They should be assessed in human patients suffering from the novel coronavirus disease.” Another Chinese team reported March 4 in Clinical Infectious Diseases that “Hydroxychloroquine was found to be more potent than chloroquine.”
However, neither the French nor Chinese studies were randomized clinical trials. The French investigators also acknowledged the “small sample size” in their conclusion—as cited by critics, along with the side effects of hydroxychloroquine. Critics also cite the death of a man after he and his wife ingested fish tank cleaner containing chloroquine phosphate; the death was disclosed March 23 by healthcare provider Banner Health, which added that his wife was in critical condition at a Banner hospital. Supporters of chloroquine phosphate have countered that the couple ingested a far higher dose than a doctor would have prescribed.
Other clinical trials of hydroxychloroquine for COVID-19 are underway in China vs. placebo (NCT04261517) and vs. AbbVie’s Kaletra (NCT04307693). While the ‘1517 study showed positive preliminary outcomes, its sample size was small (N=30, randomized 1:1 to treatment or placebo), and virological clearance rate was for placebo patients (93.3%) vs. hydroxychloroquine (86.7%). Radiological progression showed on 5 hydroxychloroquine patients (33.3) vs. 7 placebo patients (46.7%). A multi-nation trial comparing chloroquine with Kaletra in up to 3,040 patients (NCT04304053) was recruiting patients as of March 24.
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
Hydroxychloroquine, Azithromycin, Sanofi, Donald Trump, National Institute of Allergy and Infectious Diseases, Clinical trial, Malaria
World news – GB – Sanofi, Pfizer, and various manufacturers