Five Israeli teams fighting for a COVID-19 cure

When Israel launched its mass vaccination campaign, there were many who believed there would no longer be a need for medication, Prof. Eli Schwartz, founder of the Center for Travel Medicine and Tropical Disease at Sheba Medical Center in Tel Hashomer, told The Jerusalem Post.

“Now we know that this was an illusion,” he said. “Even in Israel, not everyone is taking the vaccine. There is quite a big population of youngsters under the age of 16 for whom it will be at least months until we have a vaccine.”

Prof. Shlomo Maayan, head of the Infectious Disease Division at Barzilai Medical Center, explained to the Post that there are three reasons the vaccines will not mean the end of COVID. First, even the most effective vaccines – Pfizer and Moderna – are only around 95% effective. That means that there is still a one-in-1,000 chance of getting the virus.

Moreover, the virus continually mutates, which means that at various points a mutation may come about that renders the vaccines less effective or even noneffective, as was shown in the case of the South African mutation.

Finally, the global population is massive, and it will take a long time, probably several years, for everyone who wants to be inoculated to be jabbed.

Even in Israel, there is no expectation of 100% recovery from the pandemic.

As such, teams of medical professionals and scientists are striving to develop novel treatments and drugs to help solve the crisis and keep people out of hospitals.

Almost daily, there is an announcement of a breakthrough medication – many of them being tested in Israel.

Despite all of the excitement around them, Prof. Yaakov Nahmias, director of the Grass Center for Bioengineering at the Hebrew University of Jerusalem, said that these press releases “need to be taken with a grain of salt” and put into perspective.

“SARS-CoV-2 infects a lot of people. A few people develop symptoms. Of the few that develop symptoms, such as viral pneumonia, only a fraction actually requires any type of assistance,” Nahmias explained. “The majority of patients with COVID-19 would essentially get better even if we do nothing.”

And as researchers learn and test more, opinions about various breakthrough treatments can start to change.

“There is a plethora of drugs that are being used [during the pandemic],” said Maayan. “Some of the drugs we started using a year ago we are still using, and some have been phased out.”

For example, Gilead’s remdesivir, which was originally touted for its believed ability to hinder the virus’s ability to reproduce, was later discovered to be only modestly effective.

The same is true with hydroxychloroquine, which is traditionally used to prevent or treat malaria. At the beginning of the pandemic, the drug was given emergency use authorization by the Food and Drug Administration. That authorization was later revoked, after reports of serious heart rhythm problems and other safety issues, including blood and lymph system disorders, kidney injuries and liver problems and failure.

In contrast, monoclonal antibodies – laboratory-made proteins that mimic the immune system’s ability to fight off harmful antigens, including viruses, and that became well-known last year when former US president Donald Trump received them immediately upon being diagnosed with COVID-19 – continue to be used by hospitals worldwide to help ward off serious infection.

“The idea is to do a proper study,” Maayan said. “If you do not have a proper study, you don’t have a control group, then even if the initial impression is good, it is not really good enough.”

He said there will not be one magical drug. Rather, like the protocol for treating AIDS, there will be a cocktail of drugs.

“The cocktail approach seems to be building up as more data accumulate,” he said.

Here are five Israeli companies and people and their treatments to watch for:

Sheba’s Schwartz, a tropical disease expert, recently told the Post that he has new proof that ivermectin, which has been used to fight parasites in third-world countries, could help reduce the length of infection for people who contract coronavirus.

Last week, he completed a double-blind, placebo-controlled study of 100 people with mild-to-moderate cases of COVID-19 that tested whether ivermectin could shorten the viral shedding period, allowing them to test negative for coronavirus and leave isolation in only a few days.

According to his still unpublished data, Schwartz said, the drug was shown to help “cure” people of the virus within just six days. Moreover, the chances of testing negative for coronavirus were three times higher for the group that received ivermectin than the placebo, he said.

“From a public health point of view, the majority of patients with corona are mild cases, and 90% of these people are isolated outside of the hospital,” Schwartz said. “If you have any kind of drug that can shorten the duration of the infectiousness of these patients, that would be dramatic, as then they will not infect others.”

Moreover, instead of isolating for a minimum of 10 days and maybe more, this period could be shortened, benefiting the economy.

Schwartz’s study did not focus on whether ivermectin could prevent deterioration and hospitalization, but he said that the results indicate it is likely to have an effect.

He met this week with the Health Ministry, and is also preparing the data for submission for peer review and review by the FDA.

Since April, there have been many trials and analyses suggesting the effectiveness of ivermectin against the novel coronavirus. But only a handful have been conducted effectively as double-blind, placebo-controlled tests such as Schwartz’s, which led the National Institutes of Health to say last week that there is still insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19.

However, Schwartz said that because ivermectin is already FDA-approved for other indications and its safety is well known, once those studies are completed it is likely to achieve authorization. He said he hopes his new study will “be a cornerstone to get this permission.”

Tel Aviv-headquartered RedHill Biopharma, a specialty biopharmaceutical company primarily focused on gastrointestinal and infectious diseases, is now in the midst of late-stage clinical trials for two coronavirus treatments on hundreds of patients. The first focuses on early-stage cases and the second on treating hospitalized serious disease.

“Together, we can treat the full spectrum of coronavirus patients,” said the company’s chief operating officer, Gideon Raday.

“RedHill is unique, even relative to the world’s largest pharmaceutical companies, in that it is rapidly advancing not one but two Phase III-stage, orally administered, novel molecules for the treatment of COVID-19: RHB-107 for outpatient use and Opaganib for hospitalized patients,” explained CEO Dror Ben-Asher. “With these two promising and complementary shots on goal across the disease severity spectrum, RedHill is positioned at the very forefront of COVID-19 therapeutic research, aiming to address both existing and emerging mutations.”

On Wednesday, the company announced that it had dosed its first patient in the United States with RHB-107 as part of a Phase II/III trial. The drug is administered orally and aimed at patients with symptomatic COVID-19 but who do not require hospital care. Patients are given the treatment once a day.

A release explained that RHB-107 is a “potent inhibitor of serine proteases, that targets human cell factors involved in preparing the spike protein for viral entry into target cells and is therefore expected to be effective against emerging viral variants with mutations in the spike protein.”

In other words, Raday explained, the drug prevents the entrance of the virus into a person’s cells, stopping infection.

The treatment has already demonstrated a strong ability to stop the viral replication of the novel coronavirus in in-vitro and preclinical trials. The company also completed Phase I and II studies of the drug for different indications, demonstrating its safety in around 200 patients.

“The ability to treat patients early in the course of COVID-19 disease, with an oral therapy designed to be used outside the hospital, and with a compound expected to be effective against emerging viral variants, has the potential to be a game changer in managing this disease,” said one of RedHill’s medical directors, Terry F. Plasse.

The new study is a multicenter, randomized, double-blind, placebo-controlled trial. More than 300 patients are expected to be tested in two parts.

At the same time, RedHill announced in late January that it was continuing with a Phase II/III study of Opaganib in patients with severe COVID-19.

The drug, which like RHB-107 is orally administered, targets the human host cell component sphingosine kinase-2 (SK2), which is involved in both viral replication inside the cell and downstream inflammatory/immune responses. In earlier tests, it demonstrated antiviral, anti-inflammatory, and antithrombotic activity.

“Opaganib is expected to maintain its activity irrespective of the worrisome mutations in SARS-CoV-2 spike protein,” said Mark L. Levitt, also one of RedHill’s medical directors. “These mutations underscore the potential of SARS-CoV-2... to potentially impact vaccine effectiveness. This is an important advantage of Opaganib in the face of the growing multitude of viral strains, and provides the promise of a much-needed treatment option to help get patients off oxygen and out of hospital.”

In the past, Opaganib has also shown anticancer activity and has the potential to target multiple oncology, viral, inflammatory and gastrointestinal indications. It received Orphan Drug Designation from the FDA for the treatment of cholangiocarcinoma and is being evaluated in a Phase IIa study in advanced cholangiocarcinoma and in a Phase II study in prostate cancer.

Raday said that it was also previously tested in the treatment of Ebola, which is currently on the rise again.

Nineteen out of 21 COVID-19 patients in severe and critical condition were able to leave the hospital within a week after being administered an innovative treatment developed by researchers at Hadassah-University Medical Center.

Allocetra, the brainchild of Prof. Dror Mevorach – director of Hadassah’s internal medicine and coronavirus departments – is meant to treat a wide range of cases in which there is an overreaction of the immune system, which leads to an increase in the secretion of proteins by cells of the immune system called cytokines, and causes a cytokine storm.

A cytokine storm is when the immune system essentially goes into overdrive and begins attacking healthy cells.

Mevorach has been researching the mechanism of how “dying cells” are handled in the body for 20 years, discovering that the body responds to these cells by down-regulating inflammation.

“I collect white blood cells from healthy donors. After engineering them to be in a dying state, I infuse them into the patients with COVID-19, patients who are in severe or critical condition, who are in the cytokine storm phase of the disease,” Mevorach explained. “Soon after I infuse them, they interact with the master regulator of the storm, called the macrophage. They reprogram the macrophage to be much more relaxed.”

In other words, these white blood cells, administered through the vein, calm the storm.

The drug itself was developed with the Enlivex Company. In addition to being used against COVID-19, it has been successfully tested on sepsis and bone marrow transplant patients.

“One of the best things that we see is that we were able to significantly shorten the time at the hospital for these patients,” Mevorach said. “We could significantly reduce the burden on Israelis hospitals and those in other countries.”

He said that the company is preparing to embark on a double-blind clinical trial which he hopes will lead to the rapid authorization of the drug within six months. He also plans to present the data to the FDA and the European Medicines Agency.

Since Tel Aviv’s Sourasky Medical Center announced earlier this month that it managed to “cure” 29 out of 30 moderate-to-severe COVID-19 patients who were administered a treatment developed by the hospital, it has received international attention.

The patients, who were part of a Phase I trial, recovered from the disease and were released within three to five days, according to Prof. Nadir Arber, whose lab developed the treatment.

Since then, another five patients have received it, showing the same results.

The patients were given Arber’s EXO-CD24 COVID-19 treatment, which is based on CD24-enriched exosomes and is meant to fight the cytokine storm.

Exosomes are responsible for cell-to-cell communication. In this case, they deliver the CD24 protein to the lungs, which helps calm down the immune system.

Arber said that a cytokine storm develops in between 5% and 7% of COVID-19 patients within five to seven days.

“This protein is located on the surface of cells and has a well-known and important role in regulating the immune system,” explained Dr. Shiran Shapira, who works in Arber’s lab.

Arber said that in all cases that oxygen levels increased, respiratory rates and cytokines in the blood decreased. And, subjectively, the patients said they felt better. The primary end point of the Phase I study was safety.

“We are now sure about the safety,” he said. “We have a good feeling about efficacy.”

Arber has been researching exosomes for the better part of two decades. He said it took about six months from the time the idea of using this treatment in the battle against COVID-19 was raised until it was first tested in humans.

“Me and my team have been at the hospital every day, including Friday and Saturday, for the last six months,” he said. “We are now full of excitement and hope that we can find a cure for this pandemic.”

The treatment is inhaled once a day for a few minutes at a time for five days. It directly targets the lungs, the site of the storm, as opposed to other treatments that could be given systemically and hence cause severe side effects, Arber explained.

The hospital is now moving forward with additional clinical trials.

The largest hospital in Greece is hoping to take part in the next trial, following a meeting between Greek Prime Minister Kyriakos Mitsotakis and Prime Minister Benjamin Netanyahu earlier this month.

During a press conference with the Greek leader, Netanyahu held up a vial of Arber’s treatment and called it a “miracle drug.”

Arber said that other leading hospitals from Brazil, the Czech Republic and other places around the world have also reached out.

“This is an innovative treatment that can be produced quickly and efficiently at a low cost,” Arber explained. “Even if the vaccines do what they are supposed to, and even if no new mutations are produced, then still, in one way or another, coronavirus will remain with us.”

He said he does not know how long it will take, but “my drug can be produced rapidly, efficiently and reliably, and at a low cost.”

Finally, Hebrew University’s Nahmias believes he could downgrade COVID-19’s severity into nothing worse than a common cold, by using the FDA-approved drug Fenofibrate.

His technology, licensed by Tissue Dynamics, a drug development company, permits rapid discovery of new therapeutics.

“Viruses are parasites,” Nahmias explained. “They cannot replicate by themselves. They have to get inside a human cell and hijack their machinery to replicate.”

Nahmias research with collaborators at Mount Sinai Hospital demonstrated that the novel coronavirus prevents the burning of fat in lung cells, resulting in large amounts of fat accumulating inside lung cells – a condition the virus needs to reproduce. Fenofibrate, according to his published data, reversed that effect and eliminated virus replication in less than five days of treatment.

“By understanding how the SARS-CoV-2 controls our metabolism, we can wrestle back control from the virus and deprive it of the very resources it needs to survive,” Nahmias said, noting that it also may help explain why patients with high blood sugar and cholesterol levels are often at a particularly high risk to develop COVID-19.

Nahmias, working with Sourasky and Hadassah medical centers, gathered and evaluated retrospective data on over 20,000 patients. This data showed the several dozen COVID-19 patients who were taking fibrates were protected from the virus, confirming his laboratory results

“We looked at 20,000 patients; out of them, we screened out all patients who didn’t have blood measurements, were not hospitalized, or were not over 18 years old,” he explained. “We ended up with around 3,000 patients. And when you look at the population that took fibrates and compared it to a... population that did not take fibrates, you see something very interesting.

“Even though the risk factors for the fibrates group are slightly higher, all the main indicators are down,” he continued. “Patients that took fibrates were five days less in the hospital, had ICU admission rates drop from 44% to 7%. And their survival rate increased to about 100%.

“Within four to five days, for these patients, the pneumonia was gone,” he said. “Inflammation disappeared incredibly fast.”

Now, together with Abbott, the pharmaceutical company producing fenofibrate, he is involved in Phase III, placebo-controlled, double-blind studies that are already taking place in clinical centers in Israel, South America, the United States and Europe.

“It will take several months,” he told the Post. “But at the end, we will know if we have a drug that can deal with coronavirus.”