Another day, another miracle drug.
Another day, another recanted clinical study that released preliminary results – just a little too preliminarily.
Relegating another miracle drug as another mistake in a long line of miscues and false starts that have come to define drug development for COVID-19 treatments.
We all remember the great hope that never was with hydroxychloroquine. But there are a slew of high profile drugs coming into the spotlight only to leave just as unceremoniously.
From where are these drugs coming?
Why are they touted as potential treatments?
To understand how these drugs come to be considered treatments, and why they either fall short or are inconsistently applied, we need to know: (1) how COVID-19 affects us and (2) how drug development works – and (3) how COVID-19 information disseminates.
COVID-19, or more formally, SARS CoV-2, is believed to behave like other coronaviruses. And infects human cells by attaching onto angiotensin-converting enzyme 2 (ACE-2) receptors on the outer membrane of cells.
The original coronavirus, SARS CoV, was first reported in China in 2002 or 2003. And spread to more than two dozen countries, including North America, South America, Europe, and Asia, before it was contained.
The acronym ACE may appear familiar because it is the same receptor that the class of anti-hypertensive medications called ACE inhibitors bind to when reducing a patient’s blood pressure.
The ACE-2 receptor is on many cells, including the cells of blood vessels; gastric, esophageal, and intestinal cells; and cardiac myocytes, or the heart muscle cells.
The wide distribution of this receptor explains why there are so many symptoms of COVID-19 which affect different parts of the body.
And of course, the ACE-2 receptor is in the cells lining the inside of lungs. Specifically, the alveolar type 2 pneumocytes, which are responsible for initiating lung repair and maintaining appropriate lung pressure.
SARS CoV-2 damages these lung cells by triggering a cascade of local inflammatory responses. The details of which are complex and involve a whole host of biochemicals. But the entire response derives from the accumulation of the biochemical angiotensin II, that begins when the virus attaches onto ACE-2 receptors.
Once enough of the angiotensin II builds up, the local inflammatory response initiates an even broader systemic inflammatory response and causes even more damage to the infected patient.
An inflammatory storm spreads throughout the lungs and instigates acute respiratory distress. Small blood clots form within blood vessels across the body. Patients develop nausea, vomiting, and diarrhea. And curious neurological deficits appear like loss of taste and smell.
All beginning with angiotensin II. A biochemical that has been extensively studied to treat hypertension.
Angiotensin II triggers several actions in the body. The most important being the narrowing of the blood vessels, stimulating the sympathetic nervous system (the fight or flight system), producing steroids in the kidneys, and assisting with cell repair.
At a microscopic level, angiotensin II induces cell growth, division, and migration for cells that line the inside of blood vessels and lungs – to assist with cell repair.
So clearly this biochemical does a lot. And affects quite a few regions throughout the body.
Most COVID-19 treatments focus on preventing the accumulation of this compound, or the inflammatory response triggered by it. By repurposing existing drugs as novel treatments against the virus. A tried-and-true process of drug development for other infectious diseases, including both bacterial and viral diseases.
Current approaches to COVID-19 treatment fall into two categories: (1) antivirals, which prevent the virus from multiplying; and (2) immune modulators, which help to reduce the inflammatory response triggered by the virus. Many drugs work at one specific part of the (1) reproductive or (2) inflammatory process. Some drugs work at different parts.
But the overarching logic for all potential treatment begins as follows. Since drug 1 reduces the spread of a similar virus, it should work for this virus. Since drug 2 reduces the inflammatory response triggered by similar biochemicals for other diseases or autoimmune conditions, it should work for this virus.
The logic is intuitive and fundamentally inductive. It begins with a premise, and seeks to apply that premise in a different context, in this case, COVID-19, and evaluates whether that premise holds in the different context. Sometimes its does, sometimes it does not.
That is the logic underlying scientific experimentation, and of clinical research.
But inductive logic can only work in generalized settings when it is vetted through deductive reasoning and proven to hold true in all contexts. Therefore, many clinical studies have rigorous controls and standards for evaluating drugs, and the data in drug studies.
Yet the drugs used to treat COVID-19 patients lack any consistent evaluation. Some treatments were initiated based upon anecdotal evidence, like hydroxychloroquine. Some were based on non-statistically significant studies. And a few were based on statistically significant studies, normally the gold standard for drug studies.
Which is understandable given the hectic pace of the pandemic. Desperate times calls for desperate measures. What is concerning is not how these drugs are selected. Rather, it is the disparity between the drugs that are used most often, and the drugs that have been vetted most thoroughly.
Many of the drugs, and drug combinations used to treat COVID-19 patients have questionable efficacy, or lack any clinical benefit.
As of the middle of February 2021, these are the most popular drug treatments trending across the internet: Remdesivir, Dexamethasone, Tocilizumab, ACE inhibitors, and Interferons.
Remdesivir was originally designed to treat Hepatitis C, and has been studied in Ebola. In November 2020, the World Health Organization issued a conditional recommendation against the use of the drug in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival.
Dexamethasone is a steroid that reduces inflammation by mimicking anti-inflammatory biochemicals produced naturally. It is normally used for the suppression of inflammatory and allergic disorders. And currently used for patients who are already in the hospital, and receiving oxygen or on mechanical ventilation. Of note, it is the first drug to be shown to improve survival in COVID-19.
Tocilizumab is indicated for the treatment of rheumatoid arthritis and has been shown to curtail the inflammatory response among severely ill COVID-19 patients. It has been studied extensively in numerous studies. But they often contradict one another, with varying outcomes largely based on the study design itself [studies cited below].
ACE inhibitors would seem to make sense. After all, angiotensin II is the main driver for the COVID-19 induced inflammatory response. Yet no study found any benefit from using these drugs. Including the largest study on ACE inhibitors, the BRACE CORONA trial.
Interferons have been used to regulate the body’s natural inflammatory responses and are broadly used for different infectious diseases and autoimmune conditions. Most preliminary studies on COVID-19 patients suggest little to no benefit in using this medication. Though only a limited number of studies have been conducted and the largest study is still ongoing. Which may eventually prove beneficial in limited context. But the data so far is not promising.
Five drugs, each trending on the internet as popular solutions for COVID-19. Three have little to no benefit. One is mired in a pile of conflicting studies. With only one proving beneficial for critically ill patients.
A concerning disparity that reveals the drug treatments considered popular are not necessarily the ones proven most effective.
We have the perception that clinical research is a sterile field, independent of public opinion and of media influence.
This is not true at all. During the pandemic, many purported drug treatments were determined more by general popularity than by scientific rigor. Demonstrating firsthand the impact of public perception on medicine and the role it plays in creating treatment options.
A study by Dr. Kacper Niburski from McGill University in Canada quantifies the influence of public perception on medicine during the pandemic. By examining the former president’s speeches and Twitter posts, and comparing internet searches, online purchases, and television airtime for mentions of hydroxychloroquine, chloroquine, azithromycin, and remdesivir following any discussion of those drugs by the former president.
It found that following any tweet that mentioned specific drugs, news networks devoted at least 2% of airtime to discuss the drugs in the following news cycle. And internet searches and online purchases of the drug increased following his press conferences and tweets.
Including when the former president’s promoted debunked drugs like hydroxychloroquine and azithromycin.
Interestingly, many prominent academic medical institutions used that very combination – hydroxychloroquine and azithromycin – during the early months of the pandemic. With many institutions changing their treatment regimen after September 2020, when the first studies came out proving that these two medications should not be used.
Until then, most hospital systems treating patients with COVID-19 used these treatments largely because they were told it would work – and formulated their judgments on the drug’s benefit through the recommendations from centralized healthcare authorities, including the World Health Organization and the Centers for Disease Control.
But this is how medicine works. It is heavily based upon intuition. Which physicians use every day in treating patients. Intuition is how we apply large scale clinical studies to individual patients.
But we cannot rely solely on intuition. Intuition is subject to bias. And bias can come from all sources, including non-clinical sources.
We have learned much about medicine during this pandemic. It has changed how we see medicine and how we perceive our own health. We are beginning to realize that our relationship with our health is largely subjective. Based upon intuition and inductive logic that fluctuates depending on the context.
How we see our health and healthcare at large depends more on the perceptions we hold than any objective metric or data point.
This is the reason miracle drugs came and went throughout the pandemic. The drugs never changed, only our perceptions of those drugs.
Recognizing that distinction may prove the most important lesson we learn during the pandemic.
Frequently cited Tocilizumab studies:
Preliminary results from the RECOVERY trial suggest that for every 25 patients treated with tocilizumab, one additional life would be saved, and for patients who were not on invasive mechanical ventilation, tocilizumab also significantly reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33% (11 February 2021).
A randomized controlled trial has found that, in patients with severe or critical COVID-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days and might increase mortality (Veiga et al, 20 January 2021).
Early results from the REMAP-CAP trial suggest that the mortality rate was 35.8% for patients receiving the current standard of care alone and 27.3%, on average, for patients given tocilizumab or sarilumab; (28.0% for tocilizumab, 22.2% for sarilumab) and NHS guidance has been updated to recommend both drugs are considered in the treatment of COVID-19 patients admitted to intensive care (7 January 2021).
In hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified (Salama et al. 17 December 2020).
Early findings from the REMAP-CAP trial have suggested that tocilizumab significantly improves outcomes for critically ill patients with severe COVID-19, potentially reducing mortality and time spent in intensive care (19 November 2020).
Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide (Stone et al, 21 October 2020).
Tocilizumab may reduce the need for mechanical and noninvasive ventilation or death by day 14 but not mortality by day 28 (Hermine et al, 20 October 2020).
For hospitalized adult patients with COVID-19 pneumonia and partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio of between 200-300mmHg, tocilizumab had no benefit on disease progression compared with standard care (Salvarani et al, 20 October 2020).
Patients who received tocilizumab were 44% less likely to progress to mechanical ventilation or death compared to patients who received placebo plus standard of care according to late-stage clinical data (18 September 2020).
All the drugs that have been evaluated in some capacity as a potential form of treatment for COVID-19 [Source: Royal Pharmaceutical Society]
Antiviral antibody cocktail
Other or multiple mechanisms:
Angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers
Ascorbic acid/vitamin C
Heatmaps showing opioid sub-epidemics by demography and urbanicity
Total number of deaths in each category from 1999 through 2016 are shown in the upper left corner of each plot. The colors indicate age-adjusted mortality rates per 100,000 people. (Synth Opioids OTM: synthetic opioids other than methadone. This category includes fentanyl and its analogs.)