In parallel to vaccine research, there’s an urgent need for effective treatments for the respiratory disease caused by the SARS-CoV-2 coronavirus.
By Abigail Klein Leichman, ISRAEL21c
Scientists across the globe are working on vaccines to prevent Covid-19 infection.
But in the meanwhile, and even after initial vaccines are approved, there is an urgent need for effective treatments for the respiratory disease caused by the SARS-CoV-2 coronavirus.
Most potential treatments target the life-threatening lung inflammation typical of serious Covid-19 cases. It’s caused by a phenomenon called a “cytokine storm.”
Cytokines are proteins that trigger inflammation as a natural response to infection. In response to a virus overload, in this case in the lungs, the immune system activates a storm of cytokines. Too many cytokines lead to too much inflammation, which can damage the lungs and cause respiratory distress.
Israeli hospitals were among the first anywhere to use dexamethasone, a steroid drug, to stop cytokines storms and reduce lung inflammation in severely ill Covid-19 patients. However, steroids can suppress the immune response too strongly.
Additionally, an Israeli hospital is among the first to do a randomized, double-blind, placebo-controlled clinical trial of ivermectin, a drug to treat parasitic infections in people and animals, to see if it can shorten the duration of the disease if given to Covid-19 patients immediately after diagnosis.
Israelis are also formulating novel therapeutics of their own.
Below we summarize 13 potential Israeli treatments using a variety of approaches – such as placenta-derived cells, peptides, blood plasma of recovered patients, and the cannabis compound CBD.
There is plenty of room for more than one treatment.
“We believe humanity needs a toolbox of different solutions for Covid-19,” says Immanuel Lerner, CEO of Pepticom, one of the companies detailed below.
On June 11, Pluristem Therapeutics of Haifa announced a multicenter Phase 2 US Food and Drug Administration (FDA) efficacy and safety study of its PLX-PAD cells for treating severe Covid-19 complicated by acute respiratory distress syndrome (ARDS).
PLX, an injected regenerative placenta-derived cell therapy, stimulates the immune system’s natural regulatory T cells and M2 macrophages, possibly preventing or reversing a cytokine storm. PLX cells potentially reduce the incidence and/or severity of Covid-19 pneumonia and pneumonitis.
Pluristem has treated Covid-19 patients under compassionate use programs in the United States and Israel. Initial data from 18 patients showed that 75% were off mechanical ventilation within 28 days.
“PLX cells are available off-the-shelf and once commercialized, can be manufactured in large-scale quantities, offering a key advantage in addressing a global pandemic,” the company said.
Jerusalem-based Silkim Pharma recently submitted Coronzot, its novel treatment for Covid-19 patients with moderate to severe symptoms, to the FDA’s Investigational New Drug (IND) program.
IND designation would give Silkim permission to start human clinical trials and to ship Coronzot across state lines before a marketing application has been approved.
Coronzot’s novel mechanism targets a pivotal factor in cytokine storms. It removes an inflammatory overaccumulation of labile iron and replaces it with a minute amount of gallium or zinc.
This not only suppresses the storm but also inhibits viral proteins that attack the lungs and heart. Gallium inhibits virus replication and promotes apoptosis (self-destruction) of already invaded cells. Zinc helps suppress inflammatory reactions and enzymes that enable coronavirus replication.
The company is actively engaged in the FDA process. “We look forward to finalizing the IND and then moving towards conducting clinical studies of Coronzot for Covid-19,” said Silkim Pharma CEO Dror Chevion.
RedHill Biopharma, based in Raleigh, North Carolina and Tel Aviv, is “moving rapidly to advance our development program with opaganib for Covid-19,” according to a June 10 statement by Dr. Mark L. Levitt, RedHill medical director.
RedHill acquired opaganib from US-based Apogee Biotechnology, which developed this oral drug to fight cancer, inflammation and viruses.
RedHill has seen encouraging preliminary findings from six Israeli Covid-19 patients given opaganib under compassionate use to reduce lung inflammation. All were weaned from supplemental oxygen and discharged from the hospital without having to receive mechanical ventilation.
RedHill plans a multi-center, randomized, double-blind, parallel-arm, placebo-controlled Phase 2/3 clinical study on 270 US patients with severe Covid-19 pneumonia.
“We are expanding the development program to Russia and additional European countries, in parallel with the US clinical study, in order to accelerate the collection of robust data on the potential efficacy of opaganib against Covid-19,” said Levitt.
The company is working with government agencies worldwide to allow more patients access to the investigational drug through clinical studies and compassionate use programs.
InnoCan Pharma Israel and Tel Aviv University tech-transfer company Ramot are collaborating to develop a new CBD-loaded exosome technology to fight lung inflammation.
Exosomes, small particles created from stem cells, can act as “homing missiles” targeting specific damaged organs and facilitating cell-to-cell communication.
Combining the cell-healing properties of exosomes with the anti-inflammatory properties of the cannabis-derived compound CBD is expected to have a strong synergetic effect. The treatment is administrated by inhalation.
Stero Biotechs of Bnei Brak has started a small clinical trial at Rabin Medical Center in Petah Tikva on the tolerability, safety and efficacy of a CBD-enhanced steroid treatment for hospitalized Covid-19 patients.
“Steroid treatment is usually the first or second line of treatment for hospitalized patients. CBD enhances the therapeutic effect of steroid treatment and treats the bio-mechanism affected by the virus,” the company explained.
Eybna and CannaSoul
Two Israeli cannabis R&D firms, Eybna Technologies and CannaSoul Analytics, are developing a proprietary terpene formulation for modulating cytokine storms.
Terpenes are organic compounds found in cannabis and other plants. Studies suggest they can be effective antiviral agents.
CannaSoul’s Cytokine Storm Assay (from its Myplant-Bio subsidiary) will aid in optimizing and customizing Eybna’s novel NT-VRL inhaled formulation for treatment and prevention of viral infections in high-risk populations and actively ill patients.
“The FDA considers this assay as a good predictor for cytokine storm response and immunotoxicity, and it is commonly required in the development of biological treatments,” according to CannaSoul Chairman and CSO Prof. Dedi Meiri.
“The NT-VRL formulation intended to be used via inhalation,” said Eybna CEO Nadav Eyal. “This delivery method dramatically increases the terpenes’ bioavailability by directly contacting the infected cells in the respiratory system.”
CannaSoul aims to identify other cannabis molecules capable of suppressing a cytokine storm in response to Covid-19 without completely suppressing the immune system. It is also studying how cannabis molecules could modulate the ACE2 receptor, which allows the virus to inject its genetic expression into human cells.
Based in Rehovot, Kamada has begun supplying its experimental plasma-derived Hyperimmune IgG therapy for compassionate use in severe Covid-19 cases in Israel.
The treatment is based on plasma donated by recovered Israeli Covid-19 patients. One critically ill patient at Hadassah Medical Center showed initial improvement after having the experimental IgG therapy but ultimately did not survive.
During the third quarter of this year, Kamada expects to start a Phase 1/2 clinical study in hospitalized Covid-19 patients in Israel and hold a pre-IND meeting with the FDA to expand clinical development in the United States in partnership with Kedrion Biopharma.
Kedrion is collecting plasma from recovered American Covid-19 patients at 23 FDA-approved centers across the United States. This will be used by Kamada to manufacture additional batches of the product.
“To the best of our knowledge, Kamada is the first company globally to complete manufacturing of a plasma-derived IgG product for the treatment of Covid-19,” said Kamada CEO Amir London.
Israel Institute for Biological Research
The government-run Israel Institute for Biological Research (IIBR) announced in May that analogues of two drugs for Gaucher’s disease proved effective against SARS-CoV-2.
This drug cocktail is made up of the FDA-approved Cerdelga and an analogue of a second drug in advanced stages of the approval process.
The IIBR study on cell cultures demonstrated that the two-drug treatment significantly reduced the replication capacity of the coronavirus and the destruction of the infected cell. This potential treatment is currently being tested in animals infected with the coronavirus.
The IIRB also isolated several key coronavirus antibodies that successfully neutralized aggressive coronavirus in lab tests. These could form the basis of a future treatment following further testing.
Based in Jerusalem, Pepticom computationally designs novel peptide drug candidates using artificial intelligence. The company raised $5 million last year.
Three months ago, Pepticom began implementing its proprietary AI technology on various coronavirus proteins to identify novel peptides that inhibit interaction between the spike protein of SARS-Cov-2 and the ACE2 receptor – thereby stopping the virus from entering the cell.
CEO Immanuel Lerner says three such proteins have already been identified and are being validated in the lab.
“Using AI is a fast way to find these peptides, which are less expensive and easier to produce than antibodies,” Lerner tells ISRAEL21c. “Many parties are interested in looking at our results and finding ways to develop this further.”
In April, Bonus BioGroup initiated a preclinical study of MesenCure, its unique drug for treating acute and life-threatening respiratory distress in coronavirus and pneumonia patients.
MesenCure consists of activated mesenchymal stromal (stem) cells from healthy adult donors. The activation of these MSCs is intended to boost their ability to reduce lung inflammation, promote regeneration of the diseased lung tissue, and alleviate respiratory and other symptoms in the lungs.
The development of MesenCure relies on more than a decade of related experience and technologies that Bonus BioGroup has used in developing its lead product, a tissue-engineered bone graft also based on MSCs.
“With the current coronavirus outbreak, Bonus BioGroup has started tissue culture studies into the potential of these MSCs, further activated, to alleviate inflammation, including in the lungs, and possibly attenuate the cytokine storm in COVID-19 patients,” the company explained.
The preclinical study in several animal models is expected to be completed in the third quarter of 2020. The company said preliminary results indicate that “following the treatment with MesenCure, the microscopic appearance of the treated lungs was similar to a healthy lung, and a significant improvement in additional related parameters was achieved.”
Bonus BioGroup presented these results to 1,800 scientists, physicians, and public opinion leaders at the virtual conference of the International Society for Cell & Gene Therapy in May.
Technion-Israel Institute of Technology Prof. Marcelle Machluf developed a drug-delivery technology that uses reconstructed mesenchymal stem cells as nano-vesicles to transport medicine directly to a target.
NanoGhost is the startup she established to commercialize the technology, which has proven successful in treating pancreatic, lung, breast, prostate, and brain cancer in mice. The NanoGhost technology has been patented in the United States and Europe, with additional patents pending in India and China.
Now, Machluf is adapting her technology to create decoy NanoGhosts that attract and entrap the coronavirus, making for a less severe infection. She explains it in the video below.
Enlivex Therapeutics of Ness Ziona is developing Allocetra, a novel immunotherapy medication to treat organ dysfunction and acute multiple organ failure associated with sepsis and Covid-19, as well as solid tumors.
Allocetra rebalances a severely unbalanced immune system by engaging with the immune system’s own regulation mechanisms. It is designed to restore safe immune balance following a cytokine storm.
Enlivex is starting to recruit Covid-19 patients in Israel and in the United States to test the potential effect of Allocetra on moderate to severe cases. A patent from the Japan Patent Office is expected during the third quarter of 2020.
Weizmann Institute of Science
Organic chemist Nir London of the Weizmann Institute of Science in Rehovot is co-leading a collaborative project to identify small molecules that can bind to and inhibit a protease enzyme that the SARS-CoV-2 virus needs to reproduce.
London and his research team had previously developed an advanced method for identifying potential inhibitors for numerous proteins.
“So far, we have made close to 800 compounds and tested more than 650 and keep getting closer to sufficiently potent inhibitors,” London tells ISRAEL21c.
These inhibitors will be further investigated for their potential as a starting point for new drugs against the coronavirus.
London is working with researchers from Oxford University, Memorial Sloan Kettering Cancer Center, University of British Columbia, and Californian-based biotech company.
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