Although considered eccentric toward the end, Howard Hughes was incredibly rich and put that capital to work in many interesting and important ways, including what has become one of the largest private funding organizations for biological medical research in the United States if not the world. With a total endowment of $22.6 billion, the Howard Hughes Medical Institute (HHMI) spends about $1 million per investigator per year, totaling around $825 million. HHMI has put scientific talent and capital to work in pursuit of answers to COVID-19. A HHMI principal investigator heading this prominent team based at Johns Hopkins previously investigated the topic of how to respond to hyperinflammatory immune responses in cancer patients before COVID-19 appeared. They recently summarized some ongoing studies targeting the deadly, economically cataclysmic pathogen. One important study area centers on the body’s potentially destructive response to SARS-CoV-2. One of the most dangerous aspects of the virus is how some people respond: immune system in overdrive. Until a vaccine is certain, an approach to address this deadly condition must be pursued. Can alpha blockers be a pathway to saving more lives from the deadly pathogen?
The Study: Now Recruiting Participants
Now with Howard Hughes Medical Investigator, Bert Vogelstein and team will test a treatment targeting the overactive immune response. Based out of the prestigious Johns Hopkins University School of Medicine (ranked second nationwide for research) the study team now seeks participants ranging in age from 45 to 85 at Johns Hopkins Hospital—patients who have COVID-19 but who are not on a ventilator or in the ICU reports HHMI’s website. This team was already investigating ways to counter hyperinflammatory immune responses before COVID-19 ever emerged.
The study team’s hypothesis: a common type of prescription drug known as an alpha blocker can potentially disrupt inflammatory cycles prior to occurring. This is premised upon preclinical research via mouse studies and what they position as a recent analysis of medical claims data. After all, the novel coronavirus isn’t deadly for most but upon certain conditions it becomes very lethal. One such condition involves acute respiratory distress syndrome and associated cytokine storm. Hence, the goal to identify a compelling treatment for this patient segment. What follows are some key points to this study.
Hyperactive Immune Response
Not unique to COVID-19 as autoimmune disorder and cancer patients receiving immunotherapy can experience similar symptoms—referred to as macrophage activation syndrome, cytokine release syndrome or “cytokine storms.” As the virus penetrates and replicates in the respiratory area macrophages respond with alert messages via various proteins known as cytokines. As sort of a collective response, other immune cells join the fight to create an inflammatory response that in normal conditions, helps the human body combat the invading and replicating pathogen. However when the human body’s macrophages releases additional signaling molecules known as catecholamines an intensification and amplification of this response initiates a runaway feedback loop of more and more cytokines. As described by the Howard Hughes Medical Institute news release this creates a big problem “like a snowball getting bigger as it barrels down a hill.” As HHMI rheumatologist Maximillian Konig acknowledged, “It seems that once this process starts, there’s this inability to properly switch it off.”
The Preclinical Study
This team was involved with various studies as to how to stop runaway inflammation prior to COVID-19. In fact the team drove a study published in the journal Nature in 2018 on the topic. In this study, they gave mice with bacterial infections an alpha blocker which evidenced the reduction in cytokine storm activity not to mention reduced mouse mortality. The study team concluded that the treatment didn’t interrupt other important elements of the animals’ immune response.
Use of Alpha Blockers
The HHMI team, led by Vogelstein recently posited in the Journal of Clinical Investigation the importance of testing alpha blockers to combat the COVID-19 pandemic for those patients at risk of deadly cytokine storms. In a nutshell, they positioned that medications that target catecholamine-associated inflammation could possibly help prevent cytokine storm syndrome associated with SARS-CoV-2, the virus behind COVID-19, as well as other diseases. For this study, they will use Prazosin.
The Johns Hopkins team poured through medical claims data in their quest for an alpha blocker-based clinical trial. They studied the health records of patients that were hospitalized for pneumonia and acute respiratory distress syndrome. Seeking to better understand any correlation with use of alpha blockers and improved outcomes, they came tom the conclusion that in fact there was a positive association—uploading their report in a preprint server called arRxiv. Importantly, Susan Athey, a collaborator from Stanford University (ranked 4th nationwide for research) commented that on its own this wasn’t enough evidence but it bolstered the case for a clinical trial to investigate.
This study is sponsored by Johns Hopkins University with collaborator Fast Grants, an organization set up to accelerate scientific grants since the advent of the COVID-19 pandemic.
As discussed a core issue involves the enhancement of inflammatory injury via catecholamines via the augmentation of the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells requiring alpha-1 adrenergic receptor (⍺1-AR ) signaling. The ⍺1-AR antagonist Prazosin prevents cytokine storm and markedly increases survival following inflammatory stimuli in preclinical models. Moreover, the study team showed that in a retrospective study of outcomes of in acute respiratory distress syndrome or pneumonia, patients who were taking ⍺1-AR antagonists had significantly lower probability of needing invasive mechanical ventilation and dying in the hospital compared to non-users.
Hence, in this study, the investigators will treat COVID-19 patients with increase doses of Prazosin, an alpha blocker. Marketed under the trade name Minipresss reports Chetan Bettegowda, a neurosurgeon at Johns Hopkins who is helping to design and run the trials. The team will evaluate whether patients who receive the treatment .
The investigators will enroll patients with positive SARS-CoV-2 testing who are hospitalized (but not requiring more than 4 liters/minute of supplemental oxygen by nasal cannula). Those patients meeting the eligibility criteria and offering informed consent will be randomized in a 1:1 ration to receive either prazosin or standard of care. Participants randomized to the study drug will receive prazosin for 28 days and all patients will be followed for a total of 60 days to collect and analyze outcomes.
The Phase II study commenced May 2020 and runs through the end of the year. A total of 220 patients are sought.
Johns Hopkins Files Patent associated with Research
Interestingly, Johns Hopkins filed a patent based on their arguments. Patent filers included core investigational team members: Bert Vogelstein, Kenneth W. Kinzler, Verena Staedtke, Ren-Yuan Bai, Nickolas Papadopoulos, Shibin Zhou and Maximillian F. Konig. Of course, Johns Hopkins University is the assignee and controls any terms associated with the licensing or associated equity or royalty payments associated with the invention and in accordance with the university’s conflict of interest policies. Professor Konig stands out as declaring he would not assert patent rights from the filing for treatment related to COVID-19—clearly indicating his commitment what he considers a public good for a pandemic situation.
Chetan Bettegowda, MD, Jennison and Novak Families Professor of Neurosurgery, Professor of Neurosurgery
Call to Action: With support from HHMI and Fast Grants, the team at Johns Hopkins University pursues an interesting potential strategy to possibly offer more protection to at risk COIVD-19 patients. TrialSite News will follow this study and report on results has they are disclosed. Potential biopharma sponsors could be interested in the commercial aspects of the patent filings by Johns Hopkins.