The outbreak of coronavirus across the New York area in early March touched off a round-the-clock, all-hands-on-deck effort by Mount Sinai Health System researchers and clinicians to uncover therapies for critically ill patients amid a welter of insufficient, unsubstantiated, and, at times, misleading information from countries around the world. “There was tremendous pressure on us because people were dying all around and we had so little knowledge about what to do or what to tell families in those early days,” acknowledges Judith Aberg, MD, Chief of Infectious Diseases and the Dr. George Baehr Professor of Clinical Medicine at the Icahn School of Medicine at Mount Sinai.
To bring scientifically promising trials to the large inpatient COVID-19 population, Mount Sinai grew its dedicated COVID-19 clinical trials team from around 20 people at the outset to more than 150 doctors, nurses, lab personnel, pharmacists, clinical research coordinators, and more, from nearly every division and department. “We ramped up very quickly with an incredible multidisciplinary effort,” says Linda Rogers, MD, Associate Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine), who as Medical Director, Clinical Trials Office, Icahn School of Medicine, helped to plan and coordinate much of that effort. “And within the space of weeks we had in place the protocols, processes, and training that under normal circumstances would have taken months.”
Indeed, by the third week of March this specialized team began playing a prominent national role in an onrush of COVID-19-related studies, from remdesivir and convalescent plasma to gimsilumab and sarilumab. Besieged by pharmaceutical companies in search of academic medical partners for clinical trials on new or repurposed drugs, Mount Sinai formed a COVID-19 Scientific Review Committee to determine which agents to put its research muscle behind. “We saw early on the importance of being selective, so a process was developed within our Division of Infectious Diseases that brought together pulmonary critical care physicians, infectious disease specialists, molecular biologists, immunologists, and many others to vet each proposal and decide what our priorities should be,” explains Dr. Rogers, who is widely known for her research in the field of asthma.
Among the early choices was remdesivir, an antiviral initially developed to treat SARS and MERS—other coronaviruses that infect humans much like SARS-CoV-2, the virus that causes COVID-19—as well as Ebola and other types of viruses. Considered to be one of the most promising therapies against COVID-19, remdesivir was granted an emergency use authorization by the U.S. Food and Drug Administration (FDA) on May 1, clearing the way for doctors to prescribe it for the most severe cases of COVID-19. With Dr. Aberg as Principal Investigator, Mount Sinai became one of the top-enrolling remdesivir sites in the country.
Researchers at Mount Sinai have also played a pivotal role in scrutinizing convalescent plasma, transfused from people who have recovered from COVID-19 to those with the disease. In a study of 39 patients hospitalized at The Mount Sinai Hospital, the research team reported that patients who received convalescent plasma demonstrated improved survival and that these patients were more likely than the control group to remain the same or show improvements in their supplemental oxygen requirements.
Mount Sinai also developed and clinically deployed an enzyme-linked immunosorbent assay test (ELISA) to titrate SARS-CoV-2-specific antibodies in serum, giving clinicians the unique ability to refer for blood collection only those convalescent donors with the highest plasma antibody levels. These plasma units are being sent to our partner, Emergent Biosolutions, to manufacture hyperimmune globulin, a highly concentrated antibody product. Under the leadership of Dr. Aberg, the Health System is now partnering with the National Institutes of Health in placebo-controlled trials of COVID-19 patients—trials that Dr. Aberg feels are critically needed to determine if SARS-CoV-2 hyperimmune globulin confers a true benefit.
Mount Sinai also participated in investigations of several other therapies for the treatment of acute respiratory distress syndrome associated with SARS-CoV-2 infection. One such therapy was gimsilumab (Roivant Sciences), a human monoclonal antibody that targets granulocyte-macrophage colony stimulating factor, the pro-inflammatory cytokine found to be upregulated in the serum of COVID-19 patients. What most impresses Kusum Mathews, MD, Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine), about gimsilumab is its ability to regulate the “cytokine storm” and the overactivation of inflammatory myeloid cells that infiltrate and damage delicate tissues of the lung. The Mount Sinai site, for which Dr. Mathews is lead investigator, was a top-enrolling site nationally, and is expected to jump from phase 2 directly to the FDA for emergency use authorization.
Other investigators in our division, including Charles A. Powell, MD, MBA; Stacey-Ann Brown, MD, MPH; and Hooman Poor, MD, have all been seeking therapeutic options for the most critically ill patients with COVID-19 failing other therapies and supportive care. Dr. Powell, the Janice and Coleman Rabin Professor and Chief of the Catherine and Henry J. Gaisman Division of Pulmonary, Critical Care and Sleep Medicine, led the Mount Sinai effort for two studies investigating the effect of complement inhibition in treating the hyperinflammatory state ongoing in critically ill COVID-19 patients via targeting of complement component C5a in an expanded access program for eculizumab (Soliris®, Alexion) and a clinical trial of ravulizumab (Ultomiris®, Alexion). Dr. Brown, an Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine), along with Principal Investigator Keren Osman, MD, Associate Professor of Medicine (Hematology and Medical Oncology) and the Medical Director of the Cellular Therapy Service, investigated the role of mesenchymal stem cells (Remestemcel-L®, Mesoblast) in critically ill COVID-19 patients requiring mechanical ventilation. Finally, Dr. Poor, Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) and a key frontline critical care provider for COVID-19 patients in intensive care, developed an investigator-initiated study to investigate the role of thrombolysis with tissue plasminogen activator (tPA) in critically ill patients with COVID-19 with evidence of a hypercoagulable state.
“We were pushed exponentially to develop therapies that could benefit our patients,” notes Dr. Mathews, whose experience as a pulmonologist and critical care attending physician led to major roles with several important studies. “Our knowledge is now broader and we are more standardized in the use of supportive care and adjunct therapies like steroids, oxygen, and anticoagulation. The information we continue to gather is giving us a clearer picture of what works and what doesn’t.”
For now, the consensus among Mount Sinai’s clinical leaders is that no one therapy is likely to offer a magic bullet against the ravages of coronavirus. “I think the jury is out on whether blocking any single point in the inflammatory pathway is really the key,” says Dr. Rogers. “It is more likely to be a combination of therapeutic modalities depending on the manifestations and needs of the patient—and that is why there is so much important work that we and others in the field still need to do.”
Judith Aberg, MD
Chief of Infectious Diseases and Dr. George Baehr Professor of Clinical Medicine
Linda Rogers, MD
Associate Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine)
Hooman Poor, MD
Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine, and Cardiology