As the death toll inches closer to 150,000, researchers across the globe are racing against the clock to develop an effective treatment option for patients suffering from COVID-19. There are three main pathways to a treatment solution: adapt an already approved drug, push an experimental drug through a clinical trial, or create an entirely new drug or vaccine. Vaccines are a promising long-term solution, but they typically take 12 to 18 months to create. In the short-term, researchers have been having early success with experimental drugs.
Remdesivir
Remdesivir was recently given on a compassionate-use basis to 53 critically ill patients hospitalized in the U.S., Europe, Canada and Japan. Clinical improvement was observed in 68% of the patients treated, according to an analysis published in The New England Journal of Medicine. Each patient was given at least one dose of remdesivir and evaluated during a median follow-up of 18 days. According to the study results, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.
“In studying remdesivir, the question is not just whether it is safe and effective against COVID-19 but in which patients it shows activity, how long should they receive treatment and at what stage of their disease would treatment be most beneficial,” wrote Daniel O’Day, CEO of Gilead, the pharmaceutical manufacturer of remdesivir, in an open letter last week. “Many answers are needed, which is why we need multiple types of studies involving many types of patients. Some of these answers will start to emerge in the coming weeks as we receive the first data from the various clinical trials underway.”
Worldwide, there are seven clinical trials underway to determine if remdesivir is safe and effective against COVID-19. Gilead says it expects to share preliminary data from a study of remdesivir in severe patients at the end of April, and will work quickly to interpret the findings. Come May, initial data from a placebo-controlled NIAID trial, as well as data from a Gilead study of patients with moderate symptoms of COVID-19, will also be available.
Chloroquine
Chloroquine is an antimalarial drug used to treat and prevent malaria; however, it has been known to have potentially serious heart side effects. Now, scientists working on a clinical trial in Brazil have been forced to stop part of their study of chloroquine as a possible coronavirus treatment after heart rhythm problems developed in 25% of people given the higher of two doses being tested.
According to medRxiv, the Brazilian study initially planned to enroll 440 severly ill COVID-19 patients to test two doses of chloroquine— 450 mg twice a day for one day and then one a day for four more days, and 600 mg twice a day for 10 days. When 25% of patients in the latter 600 mg group developed heart rhythm problems—and trends suggested more deaths were occurring in that group—the scientists halted that part of the study.
There are other ongoing clinical trials for chloroquine, though. Washington University School of Medicine in St. Louis just announced a trial for patients hospitalized with COVID-19 that will investigate the effectiveness of different combinations of chloroquine and another antimalarial drug hydroxychloroquine, as well as the antibiotic azithromycin, which is used to treat many types of infections caused by bacteria.
Patients with confirmed cases of COVID-19 who enroll in the trial will be randomly assigned to one of four treatment groups: One group will receive chloroquine alone; a second group will receive hydroxychloroquine alone; a third group will receive chloroquine and azithromycin; and a fourth group will receive hydroxychloroquine and azithromycin. Given the side effects of the antimalarial drugs, the university’s infectious disease specialist Rachel Presti said the patients will be carefully screened for abnormal heart rhythms before being administered these drugs.
Hydroxychloroquine
Researchers from Intermountain Healthcare and University of Utah Health in Salt Lake City have also launched a clinical trial to test the effectiveness of hydroxychloroquine and azithromycin.
The first trial will enroll 300 patients hospitalized with suspected or confirmed COVID-19. They will be given either hydroxychloroquine or azithromycin to determine whether either drug affects the severity of COVID-19. In the second set of trials, 2,000 patients with confirmed COVID-19 who are being treated as outpatients will be given hydroxychloroquine or azithromycin to determine if either drug can prevent hospitalization. The trials will also determine whether hydroxychloroquine impacts viral shedding and prevents infection of household contacts as compared to placebo.
Thus far, study results for hydroxychloroquine have been inconclusive. For example, results from the first controlled study of hydroxychloroquine for treating COVID-19 showed no significant difference in outcomes between those who received the drug and those who received standard care. The study, led by a team at the Shanghai Public Health Clinical Center in China, involved 30 patients hospitalized with confirmed COVID-19 between February 6 and February 25. Half the patients were randomly assigned to receive 400 mg of hydroxychloroquine per day for 5 days in addition to standard care, while the other patients in the control group received just standard care. There was no placebo. The researchers concluded that disease progression was statistically similar, although there was evidence of a reduction in viral load.
On the contrary, initial results from a placebo-controlled trial of hydroxychloroquine at Renmin Hospital of Wuhan University in Wuhan, China indicate that patients hospitalized with mild COVID-19 recovered more quickly with addition of the drug than with placebo at the start of a standard treatment. In this trial, 62 patients at the hospital were randomized to receive either a placebo or 200 mg of hydroxychloroquine twice daily for five days, in addition to standard care for both groups. According to the results, the 31 patients given hydroxychloroquine reported a normal body temperature and cessation of cough much quicker when compared with the 31 patients given the placebo. A larger proportion of patients on hydroxychloroquine also demonstrated an improved chest CT, with 61% showing “significant improvement.”
Leronlimab
Leronlimab is a CCR5 antagonist with the potential for multiple therapeutic indications developed recently by CytoDyn, a late-stage biotechnology company. The FDA has approved the drug as an Emergency Investigational New Drug and provided the green light for trials. To date, more than 25 patients have been administered leronlimab in the clinical setting. The rate of response in mild-to-moderate patients under EIND has been very promising with the first five patients treated being removed from oxygen.
As of last week, 12 patients have been treated in the Phase 2 trial for mild-to-moderate COVID-19 indications but, because it is a double-blinded, placebo-controlled trial, results are not yet available. Yesterday, the FDA approved the CytoDyn to begin enrolling patients in a Phase 2b/3 study of the drug.
“We continue to coordinate around the clock with healthcare professionals across the country to deliver leronlimab to patients and we are in regular contact with the FDA to ensure they receive current patient data. We are planning to rapidly enroll 75 patients and report the results to the FDA as quickly as possible,” said Nader Pourhassan, president and CEO of CytoDyn.
EIDD-2801
The FDA has also approved and Investigational New Drug application for EIDD-2801, an oral broad-spectrum antiviral, from Ridgeback Biotherapeutics LP, enabling the company to initiate human clinical testing.
In animal models, EIDD-2801 has been proven to prevent the replication of SARS-CoV-2,a well as SARS-CoV and MERS-CoV. In addition to coronaviruses, EIDD-2801 has broad spectrum activity against a number of diseases of public health concern, including influenza, chikungunya, Ebola, and equine encephalitis.
“FDA's prompt approval of our IND allows us to initiate human testing for EIDD-2801 as quickly as possible," says George Painter, director of the Emory Institute for Drug Development (EIDD) and CEO of DRIVE. “We are grateful to our collaborators for helping us to assemble this application quickly, and to the FDA for expediting the process. An orally available antiviral medication would be a critical weapon for fighting COVID-19.”
Ivermectin
Researchers at Monash University have performed lab tests that indicate Ivermectinan, an anti-parasitic drug already approved by the FDA and available around the world, kills COVID-19 within 48 hours. During tests, a single dose of the drug stopped the SARS-CoV-2 virus from growing in cell culture.
Monash’s Kylie Wagstaff, who led the study, said the mechanism by which Ivermectin works on the virus is not known; however, it is likely, based on its action in other viruses like dengue, HIV and Zika, that it works to stop the virus “dampening down” the host cells’ ability to clear it.
Wagstaff said the next step is to determine the correct human dosage to ensure the doses shown to effectively treat the virus in vitro are safe for humans, as well.
“The use of Ivermectin to combat COVID-19 would depend on the results of further pre-clinical testing and ultimately clinical trials, with funding urgently required to keep progressing the work,” Wagstaff said.
Vaccines
Today, Sanofi and GSK, two of the largest vaccine developers in the world, agreed to collaborate to develop an adjuvanted vaccine for COVID-19. Sanofi will contribute its S-protein COVID-19 antigen, which is based on recombinant DNA technology. The technology has already produced an exact genetic match to proteins found on the surface of the virus. GSK will contribute its pandemic adjuvant technology, which has been proven to reduce the amount of vaccine protein required per dose, allowing more vaccine doses to be produced and distributed.
The companies plan to initiate phase I clinical trials in the second half of 2020 and, if successful and subject to regulatory considerations, aim to complete the development required for availability by the second half of 2021.
Photo credit: Intermountain Healthcare