Plitidepsin is derived from Aplidium albicans, a marine organism that typically attaches itself to hard surfaces, such as reefs.

The search for better medical treatments for COVID-19 has led a team of scientists from the Icahn School of Medicine at Mount Sinai, with colleagues in San Francisco, to plitidepsin—a promising small molecule drug derived from a sea organism. When tested in human lung cells, plitidepsin was particularly effective in stopping the replication of SARS-CoV-2, the virus that causes COVID-19. In fact, in pre-clinical trials, plitidepsin was 28-fold more effective than remdesivir—the only antiviral drug currently approved by the U.S. Food and Drug Association (FDA) to treat COVID-19.

Kris M. White, PhD

The research team from Mount Sinai and the University of California at San Francisco recently published their work in Science, revealing one of the most promising efforts to date in identifying an already approved drug that could be successfully repurposed to fight COVID-19. Plitidepsin is approved in Australia—under the name Aplidin—as a treatment for multiple myeloma, a cancer that forms in a group of white blood cells.

One of plitidepsin’s strengths is that it inhibits eEF1A, a host protein within human cells that every variant of SARS-CoV-2 needs to survive. Viruses hijack a human’s cellular machinery in order to thrive and create more copies of themselves, but plitidepsin works by blocking an important pathway that would be used by SARS-CoV-2, its variants, and potentially other respiratory diseases such as respiratory syncytial virus and influenza. In a separate preliminary study in bioRxiv, the research team, and a group of colleagues in England, showed that plitidepsin was effective against b.1.1.7, the newly identified British variant of SARS-CoV-2.

“Aplidin is quite unique in its potency,” says one of the study’s corresponding authors, Kris M. White, PhD, Assistant Professor of Microbiology, and a member of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine. “It is likely going to be able to work against any variant of SARS-CoV-2 and other coronaviruses, including new pandemics that might happen in the future. eEF1A appears to be a broadly used protein for viruses because it has an important role in protein production, making it important for the host cell and also extremely important for the virus. Now we’re looking to test plitidepsin against these other viruses as well.”

Corresponding study author Adolfo García-Sastre, PhD, Professor of Microbiology and Director of the Emerging Pathogens Institute at the Icahn School of Medicine, says, “The ongoing pandemic created the immediate need for us to find antiviral therapeutics that could be moved into the clinic. This led us to screen clinically approved drugs with established data and safety profiles. We found that plitidepsin was a very promising therapeutic candidate.”

Adolfo García-Sastre, PhD

The decision to pursue plitidepsin resulted from research the team conducted last spring, when they identified 332 different host proteins that SARS-CoV-2 interacted with. The scientists looked to see which ones had FDA-approved drugs that targeted the host protein for cancer or other diseases and began following a trail that ultimately led them to Aplidin. Within a week after publishing their work in Nature, the researchers were contacted by PharmaMar, the drug’s small Madrid-based manufacturer.

In October, PharmaMar released the results of a phase 1,2 clinical trial of Aplidin for use against COVID-19, which showed the drug was safe and effective in helping hospitalized patients recover from the disease. By day seven after taking Aplidin, the patients’ viral load was reduced by 50 percent, and by day 15, viral load was reduced by 70 percent. More than 80 percent of patients had been discharged from the hospital on or before day 15.

The results of the clinical trial also confirmed the tolerability of Aplidin for patients with COVID-19. Tolerability had already been observed in studies of approximately 1,300 cancer patients who actually received higher doses of Aplidin than the COVID-19 patients. PharmaMar is currently establishing phase 3 clinical trials.

“The data has shown that it’s worth trying the drug in a phase 3 clinical trial,” says Dr. White. “There’s a good chance we might see efficacy and that it will be well tolerated by the patients at certain doses.” Like remdesivir, plitidepsin would be given intravenously in a hospital setting.

The researchers have proposed that the drug be tested for use alongside remdesivir and also dexamethasone, an anti-inflammatory authorized for use in severely ill COVID-19 patients. As with other antiviral drugs, plitidepsin would work only if given early in the disease cycle, in the active viral replication stage of COVID-19.

A new study published in the journal Nature by researchers at Mount Sinai in collaboration with two other labs at Rockefeller University and co-investigators from the California Institute of Technology and Weill Cornell Medicine describes for the first time a persistence of SARS-CoV-2 in the intestines long after clinical resolution.

The study, entitled “Evolution of antibody immunity to SARS-Cov-2” and published online January 18, 2021, suggests that the memory B cell response to SARS-Cov-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

Saurabh Mehandru, MD

The authors studied intestinal biopsies obtained from asymptomatic individuals four months after the onset of COVID-19.

Minami Tokuyama, a medical student at the Icahn School of Medicine at Mount Sinai, and other members of the Mehandru Lab at the School of Medicine discovered that SARS-CoV-2 antigens persisted in the lining cells (epithelium) of the intestines long after (3-4 months post infection) resolution of clinical symptoms. The presence of such sanctuary sites could potentially enable continued maturation of the antibody response as was independently discovered by the Nussenzweig Lab at Rockefeller University.

“This finding is significant because it suggests that the memory B cell response does not wane after six months, providing reassurance that those who have previously been infected with the virus will likely mount a vigorous response if they are exposed a second time,” says study author Saurabh Mehandru, MD, Associate Professor of Gastroenterology at the Icahn School of Medicine and Director of the Mehandru Lab.

“Additionally, the presence of viral sanctuaries within the body needs to be better understood in COVID-19 patients with chronic symptoms, or ‘long haulers,’ which could help in identifying novel opportunities for the treatment of this group of patients,” says Dr. Mehandru.

Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

Building on treatment protocols developed at the height of the COVID-19 pandemic, Mount Sinai Heart has launched the global FREEDOM COVID Anticoagulation Trial to determine the most effective dosage and regimen of anticoagulant therapy in improving the survival rate of hospitalized COVID-19 patients.

“While vaccines are being used and clinical trials are underway, there is an urgent need to determine how to best treat the next hundreds of thousands of COVID-19 patients around the world,” says Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital, and principal investigator of the FREEDOM trial. “This is a coordinated international effort, launched as an investigator-led trial to speed up the process.”

In March 2020, during the early days of the pandemic, Dr. Fuster closely observed patients with blood clots in their legs who had been admitted with COVID-19. After hearing from colleagues in China of other cases of small, pervasive, and unusual clotting that had triggered myocardial infarctions, strokes, and pulmonary embolisms, he initiated decisive action. “We became one of the first medical centers in the world to treat all COVID-19 patients with anticoagulant medications,” says Dr. Fuster, a pioneer in the study of atherothrombotic disease. “It was a decision that we believe saved many lives.”

That early protocol—based largely on intuition, Dr. Fuster says—led to groundbreaking research and insights by Mount Sinai into the role of anticoagulation in the management of COVID-19-infected patients. That work includes a study published in August 2020 in Journal of the American College of Cardiology that showed a 50 percent higher chance of survival compared to patients given no anticoagulant. The analysis was conducted by the Mount Sinai COVID Informatics Center.

Dr. Fuster says, “While our study was observational, it helped us design the large-scale FREEDOM COVID Anticoagulation Trial in partnership with more than 100 sites in 14 countries in order to reach 3,600 patients.”  The prospective study will be randomized to investigate the effectiveness and safety of the anticoagulants enoxaparin and apixaban in patients age 18 and older who have been hospitalized with confirmed COVID-19, but are not in an ICU or intubated. The trial is currently enrolling and set for completion in June 2021.

Clotting in organs including the lungs, brain, and heart can be a complication of COVID-19, autopsies have shown. And anticoagulation therapies are associated with better outcomes in hospitalized patients with the virus. The FREEDOM clinical trial will evaluate different regimens.

The FREEDOM trial is based on months of clinical observation and pathology work conducted as deaths from the COVID-19 pandemic mounted globally in spring 2020 and thromboembolism emerged as an important disease manifestation. Autopsy studies at Mount Sinai demonstrated a high incidence of macrothrombi and microthrombi, prompting the suggestion that in-hospital use of blood thinners could be beneficial to COVID-19 patients. To help clarify the pivotal questions of anticoagulant choice, dosing, and treatment duration, Mount Sinai began an observational study in May 2020 of 4,389 COVID-19-positive patients who were admitted to five hospitals in the Mount Sinai Health System.

“In this observational study, anticoagulation was associated with improved outcomes, and bleeding rates appeared to be low,” says corresponding author Anu Lala, MD, Assistant Professor of Medicine (Cardiology), and Director of Heart Failure Research at the Icahn School of Medicine at Mount Sinai. “As a clinician who has treated COVID-19 patients on the front lines, the importance of having answers as to what the best treatment for these patients entails is immeasurable. Ultimately, clinical trials are what will inform those answers.”

Researchers looked at six different anticoagulant regimens, including oral and intravenous dosing. They found that both therapeutic and prophylactic doses of anticoagulants were associated with significantly improved in-hospital survival, and with a 30 percent reduced risk of admission to an ICU or intubation. The researchers used a hazard score to estimate risk of death, which took relevant risk factors into account before evaluating the effectiveness of anticoagulation, including age, ethnicity, pre-existing conditions, and whether the patient was already on blood thinners.

Separately, the researchers looked at autopsy results of 26 COVID-19 patients and found that 11 of them (42 percent) had blood clots—pulmonary, brain, and/or heart—that were never suspected in the clinical setting. These findings suggest that treating COVID-19 patients with anticoagulants as a preventive measure may be associated with improved survival.

Researchers were further encouraged by the finding that overall rates of major bleeding were low (3 percent or less), though slightly higher in the therapeutic group compared to the prophylactic and no-blood-thinner groups. This suggested to the team that clinicians should evaluate COVID-19 patients on an individual basis, weighing the risks and benefits of anticoagulant therapy.

“These observational analyses were done with the highest level of statistical rigor and provide important insights into the association of anticoagulation with critical in-hospital outcomes of mortality and intubation,” says first author Girish Nadkarni, MD, Co-Founder and Co-Director of the Mount Sinai COVID Informatics Center, and Clinical Director of the Hasso Plattner Institute for Digital Health at Mount Sinai.

The study also provided a strong rationale for the FREEDOM Trial, says co-author Zahi Fayad, PhD, Professor of Medicine (Cardiology), and Diagnostic, Molecular and Interventional Radiology, and Director of Mount Sinai’s BioMedical Engineering and Imaging Institute. “This work highlights the need to better understand the disease from a diagnostic and therapeutic point of view and the importance of conducting properly designed diagnostic and interventional studies.”

The panel on the left shows the host cell with an ACE2 receptor, which is the binding target for the SARS-CoV-2 virus spike protein that mediates entry into the cell. An antibody competes for binding with the ACE2 receptor and blocks (or neutralizes) this interaction. The panel on the right shows that even when an individual mutation (highlighted in red) disrupts or reduces the binding affinity of antibodies to one area of the spike protein, the body’s immune response to infection or vaccination typically generates a spectrum of antibodies that target different areas of the virus.

A new variant of SARS-CoV-2, the virus that causes COVID-19, appeared in Great Britain in greater frequency in December and has been reported in New York State. The new variant appears to spread more rapidly than older ones and has a distinct set of genetic changes, or mutations. This prompted renewed vigilance among scientists throughout the world who carefully monitor mutations of the virus within their own countries and share their data on public repositories. The genetic codes of 250,000 virus samples from all over the world have already been shared, according to the World Health Organization. Moreover, another new SARS-CoV-2 variant that appears to spread more quickly, but that is different from the English one, has been found in patients with COVID-19 in South Africa.

The Mount Sinai Health System’s Pathogen Surveillance Program continually studies the evolution of SARS-CoV-2 variants through genetic sequencing, a technique that allows them to examine the genetic composition of the virus and identify changes in its genetic code. The team’s work has yielded a series of firsts. Last spring, they reported that the first wave of SARS-CoV-2 in New York City started with several independent introductions of viruses that could be traced back to Europe. These studies also provided evidence for untracked community transmissions of the virus in February and March of 2020.

Mount Sinai Today recently discussed the latest SARS-CoV-2 variants with two leaders of Mount Sinai’s Pathogen Surveillance Program: Viviana Simon, MD, PhD, Professor of Microbiology, and Medicine (Infectious Diseases); and Harm van Bakel, PhD, Assistant Professor of Genetics and Genomic Sciences.

Has Mount Sinai’s Pathogen Surveillance team found this new UK variant in New York City?

Harm van Bakel, PhD

Dr. van Bakel: Although the UK variant has now been detected in New York State, in Saratoga Springs, we have not yet encountered it in our ongoing surveillance of patients cared for by the Mount Sinai Health System. Considering that New York City is a major hub for international travel we fully expect this to change as we continue to generate more data.

This new variant of SARS-CoV-2 from the United Kingdom has a set of distinct mutations—23 to be precise. Does that make it particularly noteworthy?

Dr. van Bakel: SARS-CoV-2 is a virus that tends to mutate slowly and the multiple mutations in this UK variant do make it different. Usually about one to two mutations occur each month. Mutations occur randomly and most of them do not change anything for the virus. But sometimes an occasional mutation makes it more transmissible or potentially less susceptible to existing immunity.

Viviana Simon, MD, PhD

Dr. Simon: There is some emerging evidence that the UK variant, termed B.1.1.7, is more transmissible, although that data is still being worked on. Importantly, there is no evidence that this variant is more deadly. One of the mutations in the UK variant is located within the receptor binding domain (RBD) of the virus’s spike protein, so that has created some concern. The RBD is an area of the virus that attracts a strong immune response from the human body. It is the area where the spike meets the cell receptor and where many neutralizing antibodies bind to prevent the virus from entering the cell.

Dr. van Bakel: A few months ago another variant arose in Danish mink farms that carried a different mutation in the RBD. We have also occasionally seen other RBD mutations as part of our surveillance efforts in New York City during the past few months. When this happens, the worry is that these variants can reduce the effectiveness of existing immunity, but we have not seen any evidence of that yet. There is also always a concern that the viruses become more infectious when they jump from humans to animals such as mink and back into humans. But thus far, we have not seen anything that points to this.

What can we say about this variant so far?

Dr. Simon: It is really important to note that there is no data suggesting that the UK variant is more dangerous or lethal. We are actively doing surveillance on this British variant. We are also looking at other variants that we know are in our city and in Mount Sinai’s patient populations. Starting in September, we began to notice a slow increase in diversity of SARS-CoV-2 detected in the patients seeking care at the Mount Sinai Health System. This is not surprising because SARS-CoV-2 is an RNA virus, and like other RNA viruses, such as influenza and HIV, the more people are infected, the more viral diversity is observed. SARS-CoV-2 does mutate more slowly than influenza viruses or HIV and the majority of these mutations are meaningless insofar as the properties of the virus remain unchanged.

Dr. van Bakel: We are waiting for functional data on the UK variant to tell us if there are differences with regard to how antibodies neutralize it. These data will come from already ongoing controlled experiments using sera from COVID-19 survivors as well as from vaccine recipients. Some genetic changes can render the virus more transmissible. For example, most of the SARS-CoV-2 variants circulating globally over the past 10 months carry a D614G mutation in the spike protein. Studies in animal models have shown that this mutation allows improved transmission compared to the original viral variant first reported in China. Similar studies are needed to determine if this is also the case for the distinct mutations seen in the UK variant.

Is there any evidence that the newly authorized COVID-19 vaccines will not work against this variant?

Dr. Simon:  We believe all of the new vaccines will be effective against this B.1.1.7 variant, as well as other variants, because the vaccines entice the immune system to make antibodies against different regions of the spike protein, and not only the sections of the RBD that are mutated. The immune responses developed upon vaccination will offer protection, even if we find out the RBD of the viral variants has been slightly changed.

Dr. van Bakel: Wearing face masks, maintaining social distancing, and observing all of the measures that have been put in place to protect oneself, as well as others, are still the most effective ways in controlling the spread of the virus until vaccines are more broadly available. Adhering to these guidelines will be effective regardless of the variant that is circulating.

Dr. Simon: Hope is on the horizon. We have highly protective vaccines, which will be delivered to as many people as possible in the coming weeks and months. Since the case numbers in our area remain worrisome, we really need to be careful and follow the guidelines that work for all SARS-CoV-2 variants.