As of this writing, no drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of COVID-19, although several have received emergency use authorization and many others are being used off-label during the pandemic. In addition to searching for novel therapies, David Fajgenbaum, MD, MBA, MSc, FCPP, and colleagues are pursuing whether repurposing available drugs may pay off as effective treatments to combat the pandemic. Dr. Fajgenbaum is Director of the Center for Cytokine Storm Treatment and Laboratory at the University of Pennsylvania, Philadelphia.
David Fajgenbaum, MD, MBA, MSc, FCPP
Dr. Fajgenbaum and his team have done extensive research and identified a number of candidate drugs for clinical trials in outpatients and inpatients with COVID-19.1 Because of the heterogeneity of COVID-19, it is difficult to tease out exactly where a specific drug might fit in the disease spectrum. It appears that the route of administration of a drug and the timing during the course of disease affect response.
Potential Treatments
Repurposed drugs identified by the CORONA Project as potential outpatient treatments include colchicine, inhaled budesonide, arbidol, fluvoxamine, and nitazoxanide. Promising candidates for inpatient treatment include dexamethasone (for patients on oxygen), tocilizumab, baricitinib, heparin, intravenous immunoglobulin, bromhexine, inhaled interferon beta, a recombinant cytokine gene-derived protein known by the proprietary name Novaferon, remdesivir, colchicine, and calcifediol. Up-to-date information on the candidates for further study are listed in the CORONA database and can be found at www.CDCN.org/CORONA.
“I got into this area [of repurposing available drugs] because of my personal experience. As a young medical student, I suffered from cytokine storm and developed multiorgan failure. This happened several times, and no treatments were effective. I was in a race to find a drug that would save my life,” he told listeners at the recent AACR Virtual Meeting: COVID-19 and Cancer. His diagnosis was eventually pinned down as idiopathic multicentric Castleman disease, and he did identify a drug that could be repurposed to keep his disease at bay—an mTOR inhibitor—which is now in clinical trials for the treatment of idiopathic multicentric Castleman disease. (Dr. Fajgenbaum’s journey is the subject of his national bestselling book, Chasing My Cure; for more information, visit www.ChasingMyCure.com.)
Castleman disease and COVID-19 share some characteristics. “Patients with both diseases can experience cytokine storm,2 downstream acute systemic inflammatory symptoms, multiorgan failure, and many of the immune cells that become activated are shared by these conditions,” he explained.
The cause of organ dysfunction can be challenging to identify. “Response to therapy can distinguish and infer if there is organ dysfunction that is primarily due to excessive inflammation vs a pathogen. Given the improvement in outcomes with immunosuppressive treatments, severe COVID-19 should fall into the category of cytokine storm,” Dr. Fajgenbaum noted. Other hallmarks of severe COVID-19 and cytokine storm include inappropriate cytokine signaling and immune dysregulation.
The goal of drug repurposing for COVID-19 is to identify effective agents that will save lives and eventually gain FDA approval. Candidates for randomized controlled trials can be identified through biologic investigation, artificial intelligence mining of the literature to identify drug targets and existing agents, and high throughput drug screening.
“Sometimes observational data from off-label prescribing can lead to clinical trials and randomized controlled trials of an agent. There was no concerted framework or database to collect all the data on drugs being given off-label for COVID-19, so we developed the CORONA Project to extract data on all drugs given to patients with COVID-19,” he explained.
Dr. Fajgenbaum recruited 90 volunteers who have reviewed more than 29,000 papers with a total of more than 270,000 patients treated for COVID-19 with more than 400 different drugs. All the data are available at www.CDCN.org/CORONA.
The first report in May 2020 included 9,052 patients. “We were really surprised by our findings,” he said. Despite recommendations to not use corticosteroids, the report showed that corticosteroids remained the number three drug class given to patients with COVID-19. Type 1 interferons were the second most frequently used drug class, but this was primarily outside the United States. Unproven antivirals such as lopinavir/ritonavir were the most frequently administered drug class.
“Finally, no matter how hard we tried, it was impossible to evaluate efficacy and compare drugs outside of a randomized controlled trial, mainly because COVID-19 has such a heterogeneous course of illness,” Dr. Fajgenbaum stated. The ideal treatment for COVID-19 depends on the course and severity of the disease. Treatments early in the disease course should target the virus directly, supplement a component of the immune response, or boost the immune response to fight the virus. This concept led to the extensive use of interferon outside the United States.
Severe inflammation has been documented in patients with severe COVID-19 who are ventilated.3 Therefore, treatments for patients with more severe disease later in the disease course should focus on suppressing the immune response or mitigating sequelae of the cytokine storm.
“It has become clear that if you give intravenous interferon beta at the wrong time, that will worsen the outcome, but if it is given at the right time via the right mode [early and nasally], it can improve outcomes,” Dr. Fajgenbaum told listeners. “A similar observation has been made with corticosteroids like dexamethasone.”
A patient with too weak or too strong an immune response will have a poor outcome; treatments can help to boost, supplement, or suppress the immune response. Corticosteroids should be reserved for patients with a strong immune response, whereas type 1 interferon may be most effective for those with a weak immune response.
Perhaps an aspect of the immune system can be replaced by a monoclonal antibody, Dr. Fajgenbaum suggested. Antivirals are also being studied. Based on present knowledge, dexamethasone, tocilizumab, and heparin should be given only to hospitalized patients. “Colchicine, used to treat gout, may be of benefit in outpatients and inpatients, making it one of the only drugs that can be used in both settings,” he said.
Future Directions
The CORONA database will expand to integrate preclinical and further clinical trial data through a system known as STORM (Systematic Tracker Of Repurposed new Medicines). The researchers will continue to investigate the inflammatory response to search for actionable candidates. The staff of the CORONA Project will be enlarged by eight people, and the investigators will continue to advocate for drug repurposing for COVID-19 and beyond.
“Drug repurposing is like teaching an old dog to do new tricks,” he said. “We are advocating for repurposing beyond COVID-19.”
During the discussion following his presentation, Dr. -Fajgenbaum said there are two axes to consider—the timing within the disease course and the severity of the disease. “This accounts for why some drugs don’t work early, and some don’t work late. Many variables can have an impact when these drugs are helpful or harmful. It is complicated,” he noted.
DISCLOSURE: Dr. Fajgenbaum reported no conflicts of interest.
REFERENCES
1. Fajgenbaum D: Storming the castle: Repurposing treatments for COVID-19. AACR Virtual Meeting: COVID-19 and Cancer. Abstract S5-03. Presented February 4, 2021.
2. Fajgenbaum DC, June CH: Cytokine storm. N Engl J Med 383:2255-2273, 2020.
3. Haberman R, Axelrad J, Chen A, et al: COVID-19 in immune-mediated inflammatory diseases: Case series from New York. N Engl J Med 383:85-88, 2020.
