Through our Tuesday TouchPoints series, we are sharing a diverse set of content we hope will be helpful to those managing through volatility, working from home, or just connecting.
By HPA Advisor Derrell Porter, M.D.
Globally as of June 15, 2020, there are over 7.9M cases of COVID-19 and 434,000 COVID-19 deaths in 188 countries/regions, with over 2.1M cases and 115,000 deaths in the US. Unfortunately, the U.S. leads the world on both dimensions. The healthcare industry is under a microscope, and biopharmaceutical leaders are charged with innovating a solution to the crisis.
We recently connected with HPA Advisor and biopharmaceutical expert Derrell Porter, M.D., to help us better understand the virus and the outlook for resolution. Derrell is CEO/Founder of Cellevolve Bio, a novel commercialization-focused cell therapy company, and formerly CCO at Atara Biotherapeutics, an off the shelf cell therapy company, following executive roles at Gilead Sciences, AbbVie and Amgen. He holds not only an M.D. from the University of Pennsylvania School of Medicine, but also an MBA from The Wharton School, and a B.S. in Psychobiology from UCLA – so he can seamlessly bridge the medical and business topics.
Given the broader dialogue happening around racial injustice in the U.S., our conversation also turned to the intersection of race and health. As a biopharmaceutical expert and Black man, Derrell graciously agreed to share his thoughts on those issues alongside our technical questions about the pandemic.
First things first: on a basic level, what is COVID-19/the coronavirus?
The global pandemic of novel coronavirus disease 2019, or COVID-19, is caused by a virus now called SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2. It is now commonly referred to as “coronavirus.” It is believed to have begun in Wuhan, China, in December 2019, and has spread worldwide since.
So it began in China, but where did it actually come from?
Based on its genetic proximity (it is a betacoronavirus), it likely originated from bat-derived coronaviruses with spread via an unknown intermediate mammal host to humans. However, it must be said that is still unclear where it originated, and new research suggestsi we may know less than we originally thought.
Regardless, it is generally believed that we will increasingly experience viral outbreaks that are a result of spread from animals to humans, with increasing population growth, human encroachment into natural habitats, and the growth of industrial farming.
Obviously we’re in uncharted territory, with many countries just starting to emerge from quarantine, and the global economy reeling – but haven’t we dealt with coronaviruses before? What makes this one different?
This coronavirus is similar to two prior coronavirus epidemics – SARS (2003) and MERS (2012). The first SARS epidemic was caused by severe acute respiratory syndrome coronavirus #1 or SARS-CoV-1. MERS is short for Middle East respiratory syndrome and was caused by a different coronavirus, MERS-CoV. The key difference between these three is the speed of their spread, generally driven by two metrics – the serial interval and R0.
R0, which measures the transmissibility of a virus, turns out to be similar across the three viruses. The serial interval, which is usually measured in days, is very different. This is the interval from illness onset in a primary case to illness in a secondary case. The shorter the interval, the quicker the disease can spread, because you do not have much time to act on protective measures, such as quarantining the infected individual to prevent additional infections. For MERS, this number was around 13 days, for SARS, around 8-9, and for COVID-19, as low as 2.5.
It makes sense then that COVID-19 has spread so much further than the others did. What does this virus actually do to the human body?
COVID-19 mainly attacks the lungs, and this occurs in three stages. National Geographic actually puts it wellii:
For most patients, COVID-19 begins and ends in their lungs, because like the flu, coronaviruses are respiratory diseases. It typically attacks the lungs in three phases: viral replication, immune hyper-reactivity, and pulmonary destruction. Fortunately, the majority of patients (80+%) do not go through all three phases, and most cases are mild.
- Viral Replication: This virus appears to prefer a specific type of lung cell – cilia cells, the ones with small hair like batons that clear out debris. SARS-CoV-2 loves to infect and kill these cells, which are then sloughed off and fill patients’ airways with debris and fluid. That is when patients typically develop pneumonia in both lungs.
- Immune Hyper-reactivity: This is when phase two kicks in – the immune system goes into hyperdrive. Normally, the immune system is tightly regulated and confined. However, sometimes it goes haywire and kills anything in its way, including healthy tissue.
- Pulmonary Destruction: Then, a select number of patients get MORE debris in their lungs and their pneumonia worsens. This is the third phase, where lung damage continues to respiratory failure and death. Even if death doesn’t occur, some patients survive with permanent lung damage, giving their lungs “a honeycomb-like appearance.”
Although the lungs are the main organs impacted by this virus, we are learning more every day. Recently, there have been a number of case studiesiii , most notably in children, of a multi-system inflammatory syndrome related to coronavirus that affects the cardiovascular system and leads to something resembling toxic shock (called PIMS-TS – pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2). It may have something to do with aberrant development of acquired immunity, since most cases are negative for the virus but positive for antibodies.
Given the severity of this disease, and as the global death tolls rises, there’s obviously a lot of buzz about different treatments for and vaccinations against it. Can you give us an informed picture of the current outlook for COVID-19 therapeutics?
Therapeutics for COVID-19 fall into two main categories:
- Treatments for the disease COVID-19. I will simply call these “treatments.” These can vary in their impact, from minimizing the symptoms to shortening hospital stays to improving mortality. Some, called antivirals, target the virus itself. Others target the body’s response to the infection. More on those later.
- Vaccines prevent you from developing COVID-19 in the first place, if you are exposed to it. Vaccines are the “holy grail” in epidemics and pandemics because they allow for vaccinating entire populations. This is why you’ve been hearing that “we will not get back to normal until we have a vaccine.”
According to BIO, there are over 548 unique pharmaceuticals in various phases of development for this diseaseiv, comprised of over 140 vaccines and 400+ antivirals or treatments, and that number is growing by the week. For example, there were just over 100 in development during the week of March 8, which then grew to just shy of 300 during the week of April 5th, and is now over 500.
Those are some encouragingly large numbers, but what steps do these pharmaceuticals have to go through in order to be approved and put into use?
In order to generate all of the data required and to gain regulatory approval by the two main bodies- the FDA in the U.S. and EMA (European Medicines Agency) in Europe – every therapeutic has to go through a few well chronicled steps:
- Pre-clinical research – Usually animal studies or laboratory experiments. This is the “R” in Research & Development, or R&D.
- Clinical development – This when the therapeutic is tested in humans and is the “D” in R&D.
- Phase I – Usually assessing safety and dosing. This takes about 1 year or more.
- Phase II – More safety and initial efficacy data (e.g. does the therapeutic work?). This is usually 1-3 years.
- Phase III – Larger studies to assess safety and efficacy. This is usually a 3-5 year process.
- Regulatory approval – The regulatory agencies review the data collected and will either grant regulatory approval or ask more questions. This usually takes 10 to 18 months. Once they gain approval, a company can then market and sell its therapeutics.
It’s certainly an eye-opener to see that Phase III of the clinical development stage alone usually takes 3-5 years. Could this timeline be accelerated given the global crisis?
All of the above steps are being shortened and expedited during this pandemic, but the steps are required in some capacity, nonetheless. For example, I would expect Phase III for a coronavirus vaccine to be less than 1 year. However, you have to know that the therapeutic is safe and that it works before you can make it broadly available.
There’s been a number of sobering features on what it’s like to be a healthcare professional in this environment, and the pressure is on for the biopharma industry to develop treatments that will help. What is the outlook for the 400+ COVID-19 treatments that are in development now, is it hopeful?
As we’ve discussed, treatments fall into one of two types – antivirals that target the virus itself, or treatments that target the body’s response to the viral infection. Of the 400+ therapeutics being pursued, 40% (167) are antivirals and 60% (239) are treatments. Given the wide range of responses to the viral infection, such as inflammation, pulmonary dysfunction, and antibody development, there are more varied approaches being deployed in this area, as well as attempts to repurpose previously approved drugs.
Nearly 70% of these potential treatments are in pre-clinical development, so there is a lot that has to happen. However, some companies are moving extremely aggressively with novel approaches. One exciting example is Regeneron. They announced on June 11 the initiation of the first clinical trials (four in total) of an antibody “cocktail” for both treatment AND prevention. There are attempting to development a mixture of antibodies that neutralizes the virus and therefore could either accelerate a person’s recovery if already infected and/or prevent infection – almost a vaccine “shortcut.”
Since you mentioned vaccines, let’s discuss the outlook there?
Vaccines are designed to be protective and enable the body to generate an immune response to a virus, with the goal of generating neutralizing antibodies against some component of the virus itself. The genetic sequence of SARS-CoV-2 was published on January 11, 2020, triggering a frenzy of scientific research to develop a vaccine. Given that this is a new virus, the overwhelming amount of effort is in the pre-clinical phase and many labs across the world are racing to get the first one approved.
The global effort to get a vaccine to market is unprecedented in terms of scale and speed. Given that, there are discussions that a vaccine could be available under emergency use or similar protocols by early 2021. This would represent a fundamental step change from the traditional vaccine development pathway, which takes on average over 10 years, even compared with the accelerated 5-year timeline for the first Ebola vaccine. A recent NY Times article chronicled a discussion moderated by Siddhartha Mukherjee that is a wonderful encapsulation of the scale and scope of this challenge. The article opens with this telling statement: “In the history of medicine, rarely has a vaccine been developed in less than five years.”
Industry benchmarks for vaccine development paradigms cite attrition rates of more than 90%v, meaning that more than 90% will not produce a usable vaccine. The approaches being applied for COVID-19 — which involve a new virus and often novel technology platforms — are likely to increase the risks associated with delivering a licensed vaccine and will require careful evaluation of effectiveness and safety at each step. So overall, I am hopeful, and there is an unprecedented amount of resources being deployed to achieve the previously unachievable – developing a novel vaccine in 12-18 months.
It’s no wonder so many vaccines are in development given an astonishing 90% attrition rate. Can you tell us more about some of the specific vaccines that are currently in development?
There are over 160 in various stages of development. Of those, one is in Phase III and seven are in Phase II, with the overwhelming majority in Phase I or pre-clinical.
The most promising are those under development by Moderna, Pfizer-BioNTech, AstraZeneca-University of Oxford, and CanSino. All of these (with the exception of CanSino) are part of Operation Warp Speed, and therefore are receiving billions of dollars in federal funding and support. These are viewed as the most promising based on where they are in development as well as some of the early promising data that they have generated. Other larger players such as J&J, Sanofi and Merck are developing vaccines as well, however they are at earlier stages of development.
Moderna’s mRNA-based vaccine is viewed generally as the most promising and aggressive program. On June 11, they announced the design of their Phase III, which will start in July. It will include 30,000 subjects. They also stated that they are working with Lonza to scale up manufacturing to 500M to 1B doses per year. If successful, this could be available as early as the first half of 2021.
I think we’re all relieved to hear that a vaccine could be available by 2021 – but are there nuances to that availability? Once a vaccine is approved, how quickly will it be accessible to the general public?
Given the urgent need, once a vaccine is approved it will be available immediately and likely even “before approval” via emergency use authorization for healthcare workers and other at-risk populations.
Meanwhile, the headlines have been full of references to testing – testing for COVID, testing for the antibodies…what’s the difference?
A test for the coronavirus generally is assessing whether there is some fragment (genetic or protein fragment) of the virus in your respiratory tract. This is evidence of an active infection. Meanwhile, an antibody test is designed to assess whether your body has mounted an immune response to a coronavirus infection. In other words, the virus test looks for an infection and the antibody test looks to see whether you have ever been infected, but not whether you are currently infected.
What purpose does antibody testing serve? Are there limitations? We’ve seen some pretty dismal numbers in the headlines about the accuracy of the tests.
Serologic testing, or antibody testing, detects immunoglobulins (IgM and IgG) specific for coronavirus. Ultimately, these tests will tell us who has been exposed to coronavirus (regardless of whether they are asymptomatic) and therefore provide a sense of the total population exposed. Right now, we do not know how many people have been exposed. Additionally, and critically, we assume prior exposure provides some level of protection and prevents re-infection and therefore infecting others.
There are limitations, however. The main concern about antibody testing has been the number of false positives, where a test shows that a person has antibodies (and presumably some protection) but it is INCORRECT; thereby giving the individual a false sense of security and possibility placing them in harm’s way (e.g. they do not wear a mask, or they go into high-risk environments).
What are your recommended sources for additional information on COVID-19/coronavirus?
BIO (the Biotechnology Industry Organization), the New England Journal of Medicine and JAMA (The Journal of the American Medical Association) are great sources for data on coronavirus, including the state of drug development. Eric Topol of Scripps is a great follow on Twitter @EricTopol. He is prolific, and one of the smartest and clearest voices regarding COVID-19.
Thank you for the enlightening technical deep-dive there, and the recommended resources. With all that’s going on with the protests and the outcry for racial justice in America and the world, we would be remiss not to also ask you, as both a biopharma expert and as a Black man in the U.S., about the intersection of race and healthcare during this pandemic.
Thank you for the question. Given the long history of systemic racism and police brutality, and in the aftermath of George Floyd’s murder, there has been a global cry for change. One of the results of our long-standing refusal to address our original sin has been health disparities. During this pandemic, there has been a disproportionate loss of black and brown life. The current protests and demand for change seem to show a growing and diverse choir of voices saying “No more.” It gives me hope, and let’s ensure that action follows.
Now, someone looking at your background – a Neuroscience major & Marshall scholar at UCLA, a joint MD and MBA from an Ivy League institution, working at the most prestigious consulting firm in the world, holding executive positions at major companies – might argue you’ve had it great your whole life. You’ve got nothing to complain about, right? Well, what’s become clear to the U.S. population over the past month is that that’s just not the truth. Would you be willing to share how you have experienced racism and discrimination in your life?
Unfortunately, I have experienced many of the oft quoted experiences that Black people endure on a regular basis. From being called the “N” word, to being pulled over by the police regularly, to being followed in shopping outlets, to the incredulous and occasionally angry reactions when I share my educational background or professional accomplishments. What is critical to understand in that answer is that it is pervasive and systemic. In order to thrive and to continue to grow, I have learned to ignore these insults, barriers and slights, and to hold my head high and to keep moving forward. As the saying goes, “it takes what it takes” to succeed in this life.
It’s enlightening to hear about that, again in the context of someone with your academic and professional background – it underscores the pervasiveness of the problem. So as a final question – what can each of us individually as non-BIPOC (Black, Indigenous, and People of Color) do, in your opinion?
I am humbled and grateful that so many of my friends and colleagues have been asking this heartfelt question. Given that many of you have the power to hire and create jobs, hire and support a person(s) of color at your organization or as part of your team, in roles of importance. The talent exists, although it may take some searching. It is one very high leverage action that you can take. It affects the individuals, their family and their community at large in one move. Thank you for asking the question and for the platform.
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Footnotes:
i Matt Ridley, “So Where Did the Virus Come From?” The Wall Street Journal, May 29, 2020. https://www.wsj.com/articles/so-where-did-the-virus-come-from-11590756909
ii Amy McKeever, “Here’s what coronavirus does to the body” National Geographic, February 18, 2020. https://www.nationalgeographic.com/science/2020/02/here-is-what-coronavirus-does-to-the-body/
iii Elizabeth Whittaker, MD; Alasdair Bamford, MD; Julia Kenny, MD “Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2” JAMA, June 8, 2020 https://jamanetwork.com/journals/jama/fullarticle/2767209
iv Bio COVID-19 Therapeutic Development Tracker https://www.bio.org/policy/human-health/vaccines-biodefense/coronavirus/pipeline-tracker
v Tung Thanh Le, Zacharias Andreadakis, Arun Kumar, Raúl Gómez Román, Stig Tollefsen, Melanie Saville, Stephen Mayhew “The COVID-19 vaccine development landscape” Nature.com, April 9, 2020 https://www.nature.com/articles/d41573-020-00073-5
