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David Shaywitz
Crises can serve as catalysts. History has shown they increase the recognition that change is needed, and lower the activation energy required for it to occur.
The COVID-19 crisis has already been widely recognized as potential catalyst for telemedicine, and more generally for the accelerated adoption of digital tools in both clinical medicine and clinical trials. In just the last week, the FDA released urgent new guidance (here, here) seeking to smooth the way for both.
The surprise is: some of the most ardent champions of digital health are thinking critically about the current moment, warning that if we abandon vitally important safeguards in our rush to embrace technologies, the adverse impact on patient trust will poison the field for decades to come. Moreover, they argue, even in a crisis, you don’t need to choose between rapid execution and good data privacy rights – indeed, they suggest, especially in a crisis, we can, should, and must push for both.
***
Telemedicine has long seemed like an application of technology particularly well suited to pragmatic incorporation into care, enabling patients and providers to engage remotely, without the time and aggravation of traveling to a medical office.
In concept, it embodies at least some aspects of the house call, albeit without the laying on of the hands.
Yet, telemedicine long struggled for real traction. Some, like Eric Topol, a thought leader in this area, believe that “[the] past decade saw telemedicine finally cross [the] chasm,” described by Geoffrey Moore, where the adoption of emerging technology moves from a few visionaries to the “early majority of pragmatists,” as Topol and E. Ray Dorsey recently wrote in The Lancet.
Others would surely argue that even if telemedicine hasn’t quite crossed the chasm in most areas, it is at least getting close. But almost everyone agrees that the adoption over the past two decades has been much slower than many had expected.
Why has telemedicine been such a hard sell, especially in an age where consumers routinely use their phones for everything else?
To oversimplify only a bit, a big part of the answer is: incentives. Providers have struggled to get paid for telemedicine, at least at levels comparable with in-person visits. As venture capitalist and health systems expert Bob Kocher says, Medicare requires an in-person visit before a patient can access care virtually, and even then, the reimbursement for a telemedicine visit tends to be relatively low.
My Tech Tonics co-host and digital health guru and investor Lisa Suennen agrees reimbursement is an important issue –“telehealth-provided services needed to be reimbursed the same as the equivalent service provided in person,” she says. As Peter Antall, chief medical officer of telehealth company American Well recently told STAT’s Erin Brodwin, “The reimbursement challenge still exists for telehealth,” a lament echoing the complaints of genetic testing companies a few years back.
Suennen also highlights another challenge: the need for in-state medical licensure adds another wrinkle: a licensed California physician can’t provide telecare in New York — or Nevada, or any other state — unless she is also licensed in each of those states. The burden is therefore on the practitioner – who’s already loaded with responsibilities — to jump through a series of hoops to get licensed in multiple states if they want to create a thriving telemedicine practice. By design, this makes it more difficult for less busy physicians in one state to ease the burden of overwhelmed doctors somewhere else.
An additional hurdle, physician-entrepreneur and telemedicine guru Dr. Seth Feuerstein points out, is “general inertia in a system filled with risk averse folks who have little or no incentive to do things in a better way.”
Add to this the problem of what Kocher calls “clunky technology.” As Suennen points out “some technologies are really good and some aren’t – you need to choose wisely.” (Providers generally need to use technology that is compliant with HIPAA regulations, meaning you can’t just use whatever consumer videochat app you have available.)
Yet another often appreciated challenge is cultural: as one expert pointed out, “some doctors don’t like the loss of control” that might be associated with telemedicine. Suennen says there’s a lot of “provider discomfort” with the idea, and many don’t like being on screen.
Many patients are equally reluctant to change; Kocher cites as another barrier “the lack of demand by patients who are happy with the status quo.” Or as Suennen bluntly puts it, “people still want healthcare mostly from people” rather than videoscreens.
* * *
Enter the COVID-19 crisis, which has changed, at least for the moment a few key factors. Today, both patients and physicians are highly motivated to minimize clinical visits, which intrinsically introduce an increased risk of infection for both physicians and patients – hospitals and clinics are good places to avoid these days, if at all possible.
In addition, some reimbursement and HIPAA barriers have been waived to make it easier for seniors to access telecare, and for physicians to get reimbursed for this – changes that actually unleashed a tidal wave of demand that overwhelmed telehealth providers, according a recent STAT article. (STAT’s coverage of the pandemic in general, and this aspect in particular, has been superb.)
Of course, many of these COVID-19-motivated changes may revert after the pandemic subsides.
On the face of it, the crisis would seem like a transformative opportunity for telehealth (at least once the initial crush of interest is managed). Yet, as I spoke with a number of savvy stakeholders who have been champions of digital health, I was struck by their caution, which seems almost more prominent than their enthusiasm.
The key issue for many, including Andy Coravos, CEO of Elektra Labs, and Eric Perakslis, a Rubenstein fellow at Duke, is precisely the potential of a crisis to drive – and justify – significant change. Both Coravos and Perakslis advocate for the importance of privacy (Coravos prefers the term data governance). They both emphasize that even in a crisis, we must not be lulled into a perceived false choice between speed and privacy (or speed and good governance).
Coravos and Perakslis contend that there are plenty of opportunities to have speed and privacy, and argue we should push citizens and governments to renegotiate for those opportunities. Privacy policies, terms of services, and end-user-license agreements can be re-written during public health emergencies, they suggest, to protect those who are vulnerable. Hospital systems, governments and others purchasing on behalf of those who cannot make these decisions, Coravos and Perakslis emphasize, can and should factor these considerations into their procurement negotiations. (For more on the risks of data governance in telehealth, see this recent opinion piece in STAT by Kirsten Ostherr).
The core issue, Coravos suggests, is trust; for telemedicine and other digital tools to truly gain traction, users need to be able to engage these tools with trust – trust in the fidelity of the measurement, and trust that the data won’t wind up being used, without their permission, to sell them ads (best case), or deny them insurance, a worrisome concern.
For Coravos, the key opportunity of a crisis isn’t to accept the necessity of a false, bad choice — such as supporting public health at the cost of personal privacy — but rather, to use this moment to push for strong governance, so that the tools and approaches developed at this moment of need will earn the trust needed to support their use once the emergency has passed.
A particular concern raised by Perakslis is that, in the context of the crisis, many “people are running in with dubious products and solutions,” adding “lots of dodgy stuff is going on.” Echoing the flavor of concern raised by Coravos, Perakslis adds he’s very worried that “Silicon Valley and the VC world are pushing for relaxation of every basis of regulation and ethics. The harms will be significant, and this could set things back.” In other words, if people don’t trust the system, they won’t willingly participate in the system, especially after the pandemic is over, and perhaps even during the current crisis.
Adds Coravos: “Good regulation is a necessary precondition for innovation because it creates trust in a system.”
Bottom line: The COVID-19 crisis has created a potential breakthrough moment for telemedicine and other digital technologies. But if these aren’t implemented with care, security and good data rights, any short-term benefit is likely to be offset by the corrosion of trust critically required for enthusiastic patient engagement and long-term success.
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Praveen Tipirneni, CEO, Morphic Therapeutic
For some US biotech companies today, the ability to maintain business and societal continuity during the COVID–19 pandemic comes with assistance from a surprising source.
Contract research organizations (CROs) based in China were the first – and most severely — impacted by the new coronavirus outbreak in January. But they are now rebounding to provide their traditional services to biopharma clients worldwide, and they’re doing it with an extraordinary level of dedication during COVID-19 disruption.
It has been reported that China is mounting a “diplomatic offensive” through generous donations to Europe. On Wednesday, Mar. 18, China said it would provide 2 million surgical masks, 200,000 advanced masks and 50,000 COVID–19 testing kits to Europe.
“We’re grateful for China’s support,” Ursula von der Leyen, the president of the European Commission, said in a tweet. “We need each other’s support in times of need.”
Social media is ablaze that China is seeking to build stronger relationships with America’s traditional allies, and that this is what happens when American diplomacy looks inward. That may be so on a macroeconomic and geopolitical scale. But on a microeconomic and social scale, it’s quite a different story, at least for some US biotech companies working in collaboration with Chinese CROs.
A significant percentage of all US biopharma companies rely on contract research conducted in China. There’s a reason: many of these companies perform first-rate work, meet their deadlines, and do it all at a lower cost than in the US or Europe.
So, when the SARS-CoV-2 virus began spreading in Wuhan and its surrounding Hubei Province, and the ensuing COVID–19 respiratory illness prompted a lockdown in China, it was immediately a cause of concern for the majority of US biotech companies who depend on work being done to develop their drugs in China.
The drastic containment measures and work disruptions in China rippled through US biotech almost immediately, throwing wrenches into product development timelines.
Two months later, the story is quite different. The US is now rapidly beginning to implement severe containment and mitigation measures. The FDA, the regulatory agency that all companies must work through to keep new drug applications moving along with proper designs, is operating at reduced capacity. Social isolation is the new norm.
Meanwhile, many CROs in China are returning to, or are already at, full capacity. Their current efforts extend far beyond making up lost productivity though – more on that to follow – but include acts of kindness and assistance that symbolize a gesture of global solidarity during an unprecedented interruption in society and business.
Morphic Therapeutic is a Waltham, MA-based company developing small molecule inhibitors of integrin receptors (See previous Timmerman Report coverage of our company in June 2016 and October 2018).
We work with several CROs in China. Cheng Zhong, a chemist at Morphic, has experienced unexpected support from a CRO in China that he feels is an effort to work side-by-side with customers who have become friends during times of need.
For example, Zhong recently received an email from a counterpart in China offering surgical and N95 masks because the partner was unsure if masks were freely available in the US. Dr. Zhong accepted the offer and immediately received the shipment of masks via express delivery.
The following is an excerpt from the email sent by his counterpart expressing their hopes for a return to normalcy in business – and the personal wish that the leader of Cheng’s team, Blaise Lippa, would be able to have the simple experiences that are so often taken for granted:
“Just as Cheng said, we fight together and we win together!!! I hope Blaise and his son could watch the NBA games together very soon.”
The stories move further than goodwill and friendly support. In late February, Morphic inquired about the potential impact on our research timelines and when operations might return to normal.
The reply from the Chinese CRO was surprising and heartening:
“In order to make up for the lost week of work, we plan to create a work schedule for everyone that can come and make up during weekends. Starting this weekend, each chemist will first make up 5 days, by working on the following Saturdays until early April.”
Others in the biotech community have experienced similar collaborative efforts by companies in China to deliver on shared projects despite the challenges with the new coronavirus restrictions.
Mark Tebbe, co-founder and chief technology officer, Quench Bio
Mark Tebbe is co-founder and chief technology officer of Cambridge, MA-based Quench Bio, another company that relies on contract research work in China to support operations. Quench discovered behavior that embodies alignment beyond the traditional vendor-client relationship.
“We worked through plans with them as they were returning to work – ensuring they stay safe but also get paid. They were acting as true collaborators not as fee for service vendors,” Tebbe said.
Shakti Narayan, CEO of Lexington, MA-based Accent Therapeutics, shared a similar experience that may provide assurance to US companies as they face escalating impact from the pandemic in the US – and as they increasingly rely on their Chinese counterparts to keep research moving.
“As virus went West, the Chinese CROs came back online much quicker than anticipated. And it was not just a gradual return, they came back to 100%. I was very impressed with the level of productivity and speed which they were able to come back online,” Narayan said.
Shakti Narayan, CEO, Accent Therapeutics
As the CEO of Morphic however, like leaders of many companies, I remain cautious and concerned about the global impact of COVID-19. But our company is also energized by the solidarity we feel with collaborators around the world. It’s inspiring to see their efforts, which exceed the already-impressive standards they operate under in normal times.
In a turn of events that illustrates how rapidly the conditions are escalating, scientists at Morphic became aware of more acute shortages of personal protective equipment at Boston-area hospitals after they received the masks from our China-based CRO. The Morphic scientists, in turn, arranged to donate most of the PPE to healthcare workers on the front lines of COVID19 diagnosis and treatment in our community, the Greater Boston area.
In these tumultuous times of pandemic, these collaborative efforts may be summarized with a final excerpt from the email to Dr. Zhong:
“Seneca said: We are waves of the same sea, leaves of the same tree, flowers of the same garden!”
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Carolyn Ng, managing director, Vertex Ventures HC
I was born in Malaysia, but left my family for the promised land of Singapore at the age of 12 under a scholarship program known as the ASEAN program. I lived more than half my life in that country, and have long since become a Singaporean. I currently manage a major Singaporean life sciences VC fund from a San Francisco Bay Area office.
Since the first confirmed case was identified in Singapore 55 days ago, the country has done a remarkable job of containment and mitigation. As of this writing, there have only been 313 confirmed COVID19 cases in Singapore with no COVID-related deaths. Those are remarkably low numbers compared with South Korea, Italy, Iran and other countries.
While Singapore is bracing itself for a spike of cases (more on that later on), what has worked well thus far?
The Beginning
Having lived away from home since I was a child, I make it a point to return to Malaysia and Singapore every year for the Chinese New Year festivities in late January / early February. It makes my parents and family happy. It brings me joy, too.
This year was no different. My fiancé and I flew back to Singapore, and took a rental car across the border to Malaysia. We landed January 23. That was the day Wuhan city was locked down to curb the spread of what was then just called the “novel coronavirus.” That same day, Singapore reported its first confirmed case of the illness we now call COVID—19. The coronavirus was all over the news in the ensuing days. Fear and confusion about the virus loomed over our lunar new year festivities.
Three days later, when my family crossed the border from Johor Bahru, Malaysia to Singapore, things had changed. On January 26, after the first FOUR confirmed cases of COVID19, we were told that every single traveler entering Singapore by plane, by foot or by car will have his or her temperature taken.
Something You Should Know About us Singaporeans
Before I go any further, there is an interesting Singaporean concept I need to introduce to our readers: it is called “Kiasi.”
“Kiasi,” in Hokkien (a common dialect in multi-lingual Singapore), literally means “afraid of death.” Those familiar with the history of the country would understand why. Singapore was kicked out of Malaysia in the 1960s in the post-colonial times, and was left to fend for itself with no clean water supply and zero natural resources. It is no wonder that this mentality of “the need to survive,” or the “fear of death,” has been core to the survival and later on, the flourishing of this nation city.
And this national mentality has, despite its derogatory connotation with cowardice, served us particularly well in times of crisis. I remember vividly living through the dark days of SARS in 2003. We lost 33 precious lives out of the 238 confirmed cases. Many in the US and elsewhere might scoff: “33? Did you say 33? Does this small number matter?”
Yes, to a small nation with a “Kiasi” mentality, IT MATTERS. Ever since SARS, Singapore has become much more crisis-ready.
Learning from our SARS experience: There Is No Time to Lose
The SARS experience, and, more importantly, the willingness to learn from the experience, is now paying off. The country is bracing itself now for the worst of COVID19 spread. Singapore is particularly vulnerable, given that it is one of the most densely populated city states in the world. with 5.6 million inhabitants in 278.6 square miles — about 25% more densely populated than San Francisco. It’s also one of the top destinations visited by tourists from Wuhan, the epicenter of the outbreak. Given what we know about where the infection started, and how it spreads in densely populated spaces, Singapore is in a particularly vulnerable position.
In recent days, I had the opportunity to chat with a long-time friend, Dr. Jeremy Lim, co-director of Global Health at the Saw Swee Hock School of Public Health at National University of Singapore (NUS). He and his colleagues are doing incredible work treating migrant workers pro bono at a non-profit clinic. Dr. Lim has been at the frontline of Singapore public health policies for most of his career.
He shared that Singapore’s multi-ministry COVID19 task force was formed BEFORE the country even had the first confirmed case. This decisiveness and strong political will in taking forceful actions have been key. Public health and top political leaders have been aligned since the start on a fast, systemwide effort to prevent a pandemic.
It is also noteworthy that the country, despite its dense population, has been able to control the COVID19 situation without a city/countrywide lockdown. While it remains to be seen if the city state can hold out much longer before taking that type of draconian action, it does warrant some attention to review what have worked well to date.
It is not that interesting nor helpful to list out every single measure in boring technical detail, so I would like to discuss them thematically instead:
1. Concerted Political Effort and High Level of Transparency
Instead of wasting precious time politicizing the issue, ignoring the issue, or pointing fingers at our neighbors who might or might not have started or worsened the COVID19 crisis, the Singaporean government focused since the early days on mounting a concerted effort with strong political will in ensuring its success.
For example, a 14-day quarantine in Singapore for those who have been suspected to have been exposed to the virus, is not a “we are advising you to stay at home and we think you most likely will” type of exercise. There are at least THREE daily spot checks done by video conferences at random hours every single day to ensure that households under quarantine are indeed staying at home. Punitive measures are taken against those who violate these quarantine rules. The government is not fooling around with this and the administration executes its plans with exceptional efficiency.
2. Transparency, Data availability, and Clear Communication
The government has been extremely transparent in the number of cases confirmed, with full details of the background of the patient, along with the source of the infection. The authorities took painstaking effort in contact tracing. Every single case is laid out clearly on this official website.
The country’s leadership consistently and clearly communicates directly with its citizens, and control local media outlets to carry public messaging of washing hands and social distancing. Singapore has always been under fire for the lack of freedom of speech, but in this crisis, it has helped to curtail the spread of misinformation in Singapore. It has also avoided the entire “this is serious” versus “this is just a flu” kind of public debate. The message is unmistakable to everyone — common folks must do what is socially right to curb the spread of the virus.
3. Strong Fiscal Support for Those Affected
The government was quick to decide that all patients, whether confirmed to be positive or negative, will not have to bear the cost of COVID19 testing. Hospital bills for all confirmed and suspected cases are to be footed by the Ministry of Health. Self-employed individuals who have to be quarantined at home even receive $100 per day from the government. Lastly, it was made a rule that employers are not allowed to deduct paid-time off from employees for their days spent in quarantine.
In times like this, these measures matter tremendously to the affected pool of population and also help contribute to compliance with the quarantine measures.
Even for those households who have not been infected, the government has distributed four face masks to every household. Hand sanitizers were also distributed to support those in need.
4. Strong Collaboration Between the Government and the Scientific Community
China shared the sequences of SARS-nCoV-2 – the virus that causes COVID-19 — with the international scientific community on Jan. 11. Immediately, scientists at all the institutions of Singapore, private and public, were urged to work collaboratively on developing diagnostic tests, which were in dire need. By late January, Singapore-based Veredus Lab announced the development of its VereCoV detection kit. On March 3, Singapore’s Health Science Authority approved the provisional use of the test kit as an in-vitro diagnostic product. This effort was not done solely by the biotech company though, but as a collaborative effort between Veredus and a statutory board under Singapore’s Ministry of Home Affairs.
A research team in DUKE-NUS Medical School developed serological testing that was used for establishing links between COVID19 clusters. This test, based on virus-specific antibodies, has been used by Singapore for effective contact tracing.
There Have Been Mistakes
Not every system is perfect, and neither is Singapore’s. On Feb. 7 (with still only four confirmed cases), officials announced a national alert at the “Orange” level. Orange was the same level of alert triggered by the SARS pandemic, which so many citizens vividly remember.
The Feb. 7 announcement induced a panic, as citizens cleaned out the shelves of grocery markets overnight. This was neither the most gracious nor rational reaction. Singapore’s Prime Minister Lee Hsien Loong had to go on television to urge calm and to tell people that there is “no need to stock up with items such as instant noodles or toilet paper.”
As Jeremy Lim remarked, in hindsight, the upgrade to DORSCON Orange could probably have been better communicated to avoid public panic.
Moreover, it is unknown whether Singapore is able to scale its healthcare infrastructure and workforce to cater for a “real” spike in COVID19 cases. Unfortunately, unlike China and other countries, Singapore has no hinterland or other provinces/states to draw resources from.
The Crisis Is Not “Over,” Not Even for Singapore
The Singapore government has just mentally prepared its people that numbers could remain high in the coming days, as more Singaporean students and workers return home because of lock downs in cities around the world.
In addition, in a dramatic turn of events, my birth country Malaysia just ordered a countrywide lock down on Mar. 18. This ruling has a severe impact on the 300,000 people living in Malaysia who commute across the border every day to work in Singapore. As a result, there was an insane rush of at least 100,000 people trying to cross the border into Singapore before midnight on Mar. 18. The Singaporean government is now working round the clock to find housing solutions for these 100,000 Malaysians who made it through the borders, with subsidies of $50 a day provided to them.
With this episode of mass border-crossing, it is only to be expected the country will experience a spike in COVID19 cases in days to come. Singapore has not had to impose national lock down so far, and although its containment measures have been reasonably successful, time will tell if this still holds.
I pray for my ENT doctor brother working at the front line in a hospital in East Malaysia, for those being affected back home in Singapore, and to my new beloved home the United States. We have lost precious time. We have to put all our political and ideological differences aside to get over this crisis together with swift and decisive actions.
Disclaimer:
This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Vertex Ventures HC, or any officer, director, partner, member, manager or employee of Vertex Ventures HC, or any of its affiliated entities.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)
The following is an update to my article on March 10, also published on Timmerman Report. The initial article is available (free to read here).
Before I begin, I would like to sincerely thank everybody who has reached out with comments / feedback after my first article. Thank you also for the outpouring of well wishes for my family in Italy. So far, they are all safe and sound (though increasingly going stir crazy from being locked up in their homes: you should really see the videos going around our family’s social media. They are hilarious).
So: it’s been a bit more than a week since that note of warning. Where are we now?
Unfortunately, the daily situation in Italy has continued to worsen: as I write, Italy has had more than 31,000 confirmed cases and over 2,500 fatalities. This is a Case Fatality Rate (CFR) of ~8%. If any more proof was needed, this is not the flu. China, where the outbreak began, has had a total of ~81,000 cases and ~3,100 deaths. Italy is quite likely to surpass China’s fatalities shortly (it has almost as many fatalities after 21 days as China did after 35). Note Italy has a population of ~60 million, compared with a Chinese population of ~1.5 billion.
Of course, China led the crisis response by initiating drastic social distancing measures and testing, followed by quarantines among those infected, very early on. These draconian actions probably did save a lot of lives.
As shown in the chart below (from the FT), other European countries (UK, France, Spain) are more or less tracking a similar path to Italy. The Spanish situation is even more dire than Italy at a comparable stage. It is to be hoped than the severe quarantine measures which have been put in place will contribute to “bending the curve” back to reduce the death toll. There is no time to lose if we want to preserve hospital and healthcare system infrastructure to adequately care for the 15-20 percent of those infected who require hospitalization.
Also from the chart above, the US seemed (at least at the beginning) to be following a very different curve from European countries, at least so far: it appears almost as benign as South Korea (which has had an exemplary response to the virus and has managed so far to contain the outbreak and limit the number of fatalities). As I write, the US has had ~6,500 confirmed cases, with ~116 fatalities, for a CFR of ~1.8%. Considering the US has had very limited testing capacity online to date, this is remarkable. Note, however, the curve seems to be steepening, not bending down.
I can almost hear your thoughts: this is not THAT bad! We are winning this! We are almost as good as South Korea! (I knew I did not have to study math in high school…). Why are we worrying about this virus so much AND shutting down the entire economy?? I do not want to be stuck at home with my children all day!
I will argue below that this is not necessarily the case. We are NOT “winning.” Again, I do hope I am wrong. Please bear with me as this becomes a bit wonky below (and yes, you should have studied math in high school).
We Are All Living in the Future
This is an important point.
I think I know most of the people who read this newsletter: you are living in the now, avidly watching today’s news. And I assume, as readers of the Timmerman Report, that you are well informed and are up to date with the zeitgeist. Good for you. Sorry to disappoint your own self-esteem, but that is not necessarily accurate for this situation.
To clarify: it takes ~17 days from initial infection to death on average. Fatalities we see TODAY are people who were infected more than two weeks ago.
Today’s news (and the increasing level of panic in financial markets, our own social networks, etc.) is based on the equivalent of the information coming from the light from a star (17 light-days away, ~3.6*1011 km, roughly 100x farther away than Pluto, you can make your own conversion in miles if it is important to you). It was sent out 17 days or so ago. That star might as well have exploded since and you will only find out in 17 days (and what a great sunburn that will be).
Therefore, to recap, the fatalities reported TODAY are a snapshot of infections that happened THEN, not NOW.
Since then, remember the virus spreads exponentially, with an R0 (a measure of infection spreading, no need to get into that now) that is very high without social distancing measures. The R0 can be moved in a lower, more manageable direction with aggressive social distancing. But the US did not put those type of strong interventions in place until recently. And as of this writing, they don’t extend to every geography in the country.
One consequence of us living in the future is that, even if you start immediate, radical social distancing measures right NOW, the number of infections and fatalities reported will continue to climb for those ~17 days. Italy’s fatalities have grown almost 10-fold since northern Italy begun its quarantine.
Testing is (VERY) Important: Asymptomatic Carriers Contribute Massively to Spread
Let me introduce you to the small town of Vo’, in Veneto, West of Venice (Italy, not California). The town was in one of the initial cluster of cases in Northern Italy, and is close to the University of Padova, where there happens to be a great virology department, led by Prof. Andrea Crisanti.
The town’s mayor, may the fates be always in his favor, decided to test EVERYBODY in the town (~3,300 people). He tested them TWICE, at a distance of 10 days. In the first round of tests, ~3% of the town (~88 people) was infected. Asymptomatic carriers were the majority of infections detected (50-75%, I cannot seem to nail that number down from my Italian sources). Everybody infected, including asymptomatic carriers, were isolated (including from their own families). In the second test, 10 days later, the number of people infected had gone down to 7 from 88 (these were new cases who somehow had gotten infected in the intervening period). Now the town is virus free.
An article recently published in Science (Li et al., Science March 16, 2020, DOI: 10.1126/science/abb3221), using Chinese data, also broadly corroborates this finding. According to that article, ~86% of infections are estimated to be undocumented prior to the Jan 23 travel restrictions put in place. Undocumented infections (which for all intents and purposes we can understand to be asymptomatic, though that is not a 100% accurate assumption) seem to have a transmission rate of as much as ~55% of documented infections. However, because of their much greater number, undocumented infections were the source of almost 80% of documented cases!
What this means is that huge numbers of people – for practical purposes, let’s assume almost everyone you could potentially come into contact with over the course of a day – could be spreading the disease without even displaying symptoms.
This again validates the Chinese and South Korean approach of population-wide, massive rapid testing. Once cases are confirmed (and note that individuals are held in isolation away from hospitals and families, while tests are underway), the infected individuals are isolated (even if they aren’t displaying symptoms). Note that the information from Vo’, though on a small sample size, seems also to indicate that isolating infected individuals seems to prevent the disease from evolving into a severe state.
These experiences and data point to a very important lesson: there is a very direct trade-off between capability to perform lots of (rapid) tests and the need to impose radical social distancing to prevent healthcare system collapse. The more you frequently test AND isolate individuals infected (including asymptomatic spreaders), the lesser there is a need for radical social distancing.
Unfortunately, the U.S. did not heed this lesson from Korea (Japan did not perform extensive testing, but they did isolate their entire demographic of >70 year olds, thereby reducing the fatality rate so far). The lack of testing in the U.S. has contributed to possibly quite widespread community-based spreading.
The implications of this are very broad, particularly for the young demographic in the U.S. population (the U.S. skews young, see below): your partying and drinking in bars and restaurants during St. Patrick’s Day is not helping here. Stay home. One case, early in the outbreak, infects ~2.5 people on average (many, many more if in close physical contact like at bars, dance parties etc. I would not know personally, I am a terrible dancer, but so I am told). ONE SINGLE CASE, under those assumptions, can lead to ~244 more cases in one month. If you halve that transmission, by reducing social contact, that single case only infects 4 people in that month.
Now is a good time to teach young people about exponentials before letting them go out in the evening.
Viral Load is Also VERY Important for Disease Severity
The latest news from Italy is that ~9% of the fatalities are healthcare workers. This is tragic. These individuals have been working selflessly for weeks now in conditions akin to a World War II conflict zone, performing triage on patients, without adequate supply of protective equipment and often in isolation from their own families.
It also seems to point out that it matters how much of the virus you are exposed to when you are infected. These heroes on the frontlines are exposed to high virus titers for long periods of time.
It makes sense: the lesser the number of copies the virus has infected you with to begin with, the more it has to replicate (and the longer that takes) before it overwhelms your immune system. Logically, if fewer copies of virus enter the body in the first place, that gives the immune system more of a chance to adapt to the invader and mount a defense.
So: wash your hands. Stay home. ESPECIALLY stay away from people at risk (immune-compromised cancer patients, people with co-morbidities, etc.). The government needs to step up manufacturing of protective equipment for healthcare workers ASAP.
Social Structure & Demographics Makes a Difference
So back to the graph above. Yes, I hear you thinking: your graph (it is not “my” graph, but whatever) says we are doing better than the Italians so far. Almost as good as the Koreans! I thought we were winning (everybody likes winning, I get it) and you have not provided me with any counterfactual. Am done reading this!
My, what an impatient bunch. Go watch some less complicated news channels (lots of choices there) and then come back when you feel like you want to discuss complex issues. This is important.
Differences in social interactions and social networks seem to play a very important role early on in the epidemic, especially when coupled with different demographic structures (huge thanks to Prof. Moritz Kuhn at University of Bonn for publishing on this, I really invite you to read his stuff, he is on Twitter at @kuhnmo).
Let’s start from the assumption that the virus was imported in Europe from mostly work-related travel. Different European countries are (very roughly) split in two categories: “A” countries, where grandparents do not live with their children and their grandchildren (France, Switzerland, Netherlands, Germany), and “B” countries (Italy, Spain) where there is a larger % of the population (close to 23% in Italy) in households with the three generations living together.
In “A” countries, the initial exposure of the elderly to the outbreak will be limited. This will lead to an increase in infections overall but with a reduced initial fatality rate (like we see now in Germany, and we saw earlier in France).
In “B” countries (sadly, Italy and Spain) the most at-risk demographics are exposed relatively early in the outbreak. This overwhelms hospitals sooner.
If I were to guess (remember, I am a recent guest to this country), the U.S. is an “A” country. So, I would assume that elderly demographics were less exposed early on at the population level.
In addition, the overall demographic skews much younger in the US. Have been trying to find graphs but I do have a day job. Trust me on this, Italy is overall a much older country (see all those monuments in Rome? Yes, current day Italians built those).
This factor probably helped reduce the initial fatality rate in the US. That is, until the epidemic has spread broadly enough that the cases reach more at-risk populations in the country.
This seems to explain the observation that infection growth rate (growth in nr of cases detected) in the US is actually higher than in Italy to date BUT fatalities are much lower to date (worryingly, starting to curve up).
When Hospitals are Overwhelmed, Fatalities Climb Rapidly
This is what worries me the most. See what is happening in Italy, Spain, look at the initial data from Indonesia, etc. etc.: all with CFRs exceeding 5-6%. As soon as hospital systems are overwhelmed, conditions resembling war zones start to apply and people who normally would have recovered in a healthy, functioning healthcare system are unfortunately not able to and perish.
We should not let that happen. Demographic and social structure have probably given us all a (short?) reprieve. Let’s use it productively.
Follow Otello Stampacchia on Twitter: @OtelloVC
This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Omega Fund Management, LLC or any officer, director, partner, member, manager or employee of Omega Fund Management, LLC or any of its affiliated entities.
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David Shaywitz
This week, I reviewed for the Wall Street Journal a pair of books about the increasing use of experimentation by businesses and other organizations: Experimentation Works, by Harvard Business School professor Stefan Thomke, and The Power of Experiments, by Michael Luca and Max Bazerman, also of Harvard Business School.
These books in some ways represent the sequel to one of my favorite books about experimentation (both its uses and limitations): Uncontrolled, by Jim Manzi (his recent TechTonics podcast here; additional useful links in show notes).
There are two related topics that I didn’t have the space to cover in the WSJ review, but which I thought would be of particular interest to the TR biopharma readership; both are connected to the necessity for, and value of tinkering.
Implementation Gap
A recurrent theme in of this column has been the challenge of implementation – the difficulty of ensuring a promising idea or technology finds meaningful real world expression. We see a particularly striking instance in the history of experimentation, in a study that’s often cited as the first clinical trial: James Lind’s scurvy experiment, an example that’s cited in both books.
The year was 1747, and James Lind, a surgeon in the British Royal Navy, was desperately seeking a treatment for scurvy, a debilitating disease that killed an estimated 2 million sailors between 1500 and 1800, and which we now know is caused by vitamin C deficiency. Lind selected 12 afflicted sailors, divided them into six pairs, and gave each pair a different dietary supplement – orange and lemons for one group, cider for another, seawater for a third. The group receiving the citrus was protected from scurvy, leading to the inclusion of lemon juice in sailors’ daily rations – 50 years later.
Why the delay? As Thomke explains, Lind assumed his results reflected the acidity of the solution, and “tried to create a less perishable remedy by heating the citrus juice into a concentrate, which destroyed the vitamin C.”
The dual lesson is Thomke’s throughline: experimentation can drive exceptional value for organizations, from the Royal Navy to Google, but it’s really hard to get right, and there are many opportunities to stumble along the way – especially when your conceptual model ostensibly explaining the results is uncertain or, as in this case, entirely incorrect.
For a more nuanced and fulfilling explanation of the experiment, and a deeper understanding of the historical context, check out two episodes of Dr. Adam Rodman’s unfailingly captivating “Bedside Rounds” podcast that tends to focus on the intersection of medicine, history, and culture: this episode, on the history of the randomized clinical trial, and this episode, focused on the four humors, especially relevant given that Lind attributed scurvy to an imbalance of humors, which influenced (for the worse) his interpretation of his data.
Incrementalism
The A/B experimentation discussed in both books isn’t meant to apply to all innovation – it “may not be the best way to evaluate a completely new product or a radically different business model,” I wrote, and can’t reliably anticipate or assess Clay Christensen-style disruptive innovation.
That’s okay. A remarkable amount of innovation and improved productivity stem not from an original innovation, but from all the work of front-line innovators seeking to make the product better – the “lead users” who von Hippel valorizes, practicing the “learning by doing” Bessen champions (see here and references therein).
A 2006 von Hippel paper, for example, revealed that 60% of novel indications for existing medications originated from practicing clinicians. (I suspect the percentage has subsequently gone down, since much of this exploration is now pursued more deliberately by the drugmakers themselves as part of a product’s so-called “life-cycle management.”) More generally, it’s been estimated 77% of economic growth is attributable to improvements in existing products.”
As I wrote in a 2011 tribute to incrementalism, it’s worthwhile to aim for revolutionary improvements – the polio vaccine is clearly much better than even the most refined iron lung — but:
“The unfortunate truth is that such revolutionary change is exceedingly rare, and I worry that in anticipating, expecting, and benchmarking our expectations against a magic bullet, we may be underestimating the value of incremental change, evolutionary advances that have nevertheless contributed in a significant and largely underappreciated way to our improved treatments of a range of ailments.”
Medicine, as a domain, is associated in the public mind with breakthrough innovations like antibiotics in World War II, yet it’s the less-heralded “incremental steps that produce sustained progress,” according to physician-author Atul Gawande, who Thomke cites.
Incremental innovation is sometimes disparaged, wrongly, as nibbling around the edges. People pursing such strategies are sometimes dismissed as excessively conservative, insufficiently bold. But this critique ignores much of the history of where innovation actually comes from.
Among the most compelling examples of incremental innovation is the remarkable progress in pediatric leukemias, discussed with characteristic eloquence by pediatric cardiologist Darshak Sanghavi (now chief medical officer of UnitedHealthcare’s Medicare & Retirement, the largest U.S. commercial Medicare program) in Slate in 2008. “Between the early 1970s and the late 1990s,” he writes, “the long-term survival rate of children with leukemia skyrocketed from less than 20 percent to around 80 percent.”
How?
“The leukemia doctors saved lives simply by refining the use of old-school drugs like doxorubicin and asparaginase. Over the course of almost a dozen clinical trials, they painstakingly varied the doses of these older drugs, evaluated the benefit of continuing chemotherapy in some kids who appeared to be in remission, and tested the benefit of injecting drugs directly into the spinal column. The doctors gradually learned what drug combinations, doses, and sites of injection worked best. And they kept at it. With each small innovation, survival rates crept forward a bit—a few percent here and there every couple of years—and over decades those persistent baby steps added up to a giant leap.”
Sanghavi notes that while “we’re far more likely to hear exaggerated tales of breakthrough new drugs… it’s the leukemia story that’s the historical norm.” He cites a 70% reduction in the mortality of tuberculosis the occurred in the pre-antibiotic era, “due largely to careful studies of nutrition and hygiene,” and a 50% reduction in deaths from heart disease between 1980 and 2000, “almost entirely from the use of existing medicines and surgical treatments.” (You can listen to our recent Tech Tonics interview with Sanghavi here.)
Bottom line
We’re entranced by the idea of achieving medical progress through magic bullets, disruptive innovations that appear on the scene and immediately change everything. The reality is that progress usually occurs far more gradually. The effective implementation of potentially transformative technologies (whether citrus fruit or high-throughput DNA sequencing) can take a while to really figure out and become widely accepted. A remarkable amount of improvement in human health can come from, and has come from, the deliberate tinkering, of inquisitive front-line providers, relentlessly focused on improving, increment by increment, the care of their patients.
Alex Harding, MD
The Massachusetts General Hospital COVID-19 Surge Clinic is a converted parking garage normally used as the ambulance bay for the Emergency Department. It is isolated from the rest of the ED by two sets of sliding glass doors and can only be accessed by badge.
The garage has blue fluorescent lights and no windows, making it impossible to tell day from night.
In a corner of the garage, I stand over a masked patient who is pale and subdued. I’m wearing a long yellow gown, a turquoise, cone-shaped N95 mask, and goggles. My hands are crossed in front of me so that I don’t touch anything by accident, and I fire questions at him.
“Have you had contact with someone who has COVID-19?”
“Have you had any contact with Biogen employees?”
“Do you have fever? Cough? Headache? Sore muscles?”
I feel sweat trickling down my back. My goggles are fogging up, indicating that there is a leak around my mask, and I open my mouth slightly, trying to form a better seal with the bridge of my nose. The mask makes it hard to breathe; I’ve felt like I’m slowly suffocating for the past 4 hours.
The patient answers “Yes” to many of my questions. I ask a nurse to swab his nose for COVID-19 and we give him IV fluids.
I learn later that he tested positive for COVID-19.
This has been my life over the past week, on the front lines of the COVID-19 pandemic.
In retrospect, I realize that, given the globalization of our economy, an event like this pandemic was inevitable. Yet it still has come as a surprise to me and most of my colleagues. The past week has created a set of strong emotional responses here on the front line: confusion and frustration are certainly among them.
But the emotion that I’ve seen the most is fear. Fear of becoming ill, of passing that illness to family, fear of an impending surge in cases that overwhelms our hospital’s capacity to care for patients, fear that if the infection becomes widespread, we may need to ration care, fear of running out of protective equipment.
My biggest fear is the loss of other hospital staff. Doctors, nurses, and other caregivers who develop cold or flu symptoms are all getting tested for COVID-19. Aside from my concern for their own health, if these health care workers test positive for COVID-19 it means that they will be unavailable to see patients for at least 14 days. As the line of patients gets longer, our list of available caregivers is starting to dwindle.
The line of patients is getting longer fast. The volume of patients in the Surge Clinic has doubled almost every day for the past few days. This rate of increase seems to mirror the exponential growth in infections seen in other places affected by the virus. So I’m afraid that the hospital will see an overwhelming number of cases of COVID-19 and there won’t be enough healthy doctors and nurses to take care of everyone.
I mentioned frustration also. The biggest point of frustration is with the botched early response to this infection at the state and federal level. For the past several weeks, in my regular walk-in clinic at MGH, we were seeing patients who had clear risk factors and symptoms of COVID-19, but we were unable to test anyone. We saw patients coming directly from high-risk countries, with healthcare exposures, and with fever and cough, whom we could not test. For a long time, only patients who were sick enough to be admitted to the hospital as inpatients could get tested. I can’t help but think that some of those patients were in fact infected with COVID-19 and continued to spread the infection in the community.
Testing has improved over the past week or two but is still way below where it needs to be. Unless someone is coming in with specific exposures or risk factors (e.g., a healthcare worker), we are not testing them for COVID-19. Yet, we also know that the infection is spreading within the community and multiple confirmed cases have no known exposures. So, I have no doubt that we are sending patients with COVID-19 home without testing.
MGH is working as quickly as possible to develop an in-house COVID-19 test, which should be ready for use this week. I’m sure other institutions are creating their own tests also, in an effort to compensate for completely inadequate preparation and responsiveness at the national level.
So we’re frustrated that this catastrophe could have been kept under much better control if governmental leaders had taken faster action.
Confusion is also a prominent feeling. Guidance on COVID-19 testing, self-quarantine, and use of protective gear changes by the minute as the infection spreads. Masks and goggles become increasingly scarce. It is common to be told two or three different policies by different administrative leaders during the course of a shift. To some extent, this is a reflection that we are adapting quickly to rapidly changing circumstances. But it still adds to anxiety, as staff don’t know whom to believe or what policy to follow.
In spite of all this fear, frustration, and confusion, I am still grateful for my colleagues who are able to find a reason to smile or laugh. I can feel the esprit de corps growing as we all adjust to the new circumstances and prepare for what is going to be a long battle. The only way we’re going to get through this crisis is by working as a team and signing up for more than is expected of us.
For people outside of healthcare who want to help, my advice is to take immediate measures to avoid spreading the infection in the community.
You can no longer continue business as usual. Companies should advise employees to work from home. People who are sick should call before coming into the doctor. If you’re wondering whether you need to be tested for COVID-19, call before coming in. And if you are sick—whether or not you have been diagnosed with COVID—isolate yourself from other people. These measures will slow the spread of the virus. The healthcare infrastructure is being stretched. We need to bend the curve of infections to make sure it doesn’t snap.
UPDATE: 8:50 am ET Mar. 15. MGH is developing an internal qPCR test. Local biotech companies can help. See this list of kits and instruments that are in need.
Luke Timmerman, founder & editor, Timmerman Report
The alarm bells have been ringing for weeks. Stunningly, millions of people in the US weren’t listening, or didn’t want to listen.
We have wasted precious time in defending ourselves against the coronavirus pandemic. The horrible news from Italy is slowly starting to sink in for us in the US, and other parts of the world.
Sports cancellations, a prime-time Presidential address, a stock market crash, and celebrity diagnoses have all come together in the last few days to grab the country by the throat. This virus has the makings of the worst pandemic our generation has seen.
What was written here two weeks ago bears repeating:
It’s all-hands-on-deck time. Collective problem-solving time. Not every man for himself time. Not finger-pointing / blame-shifting time. Not cynical attention-grabbing time. Not “I told you so” time.
Half-measures like the ones we’ve seen from federal and state officials aren’t going to cut it. Much more aggressive action needs to be taken on social distancing – perhaps a nationwide shutdown of schools, or nationwide shutdown of non-essential air travel. Drive-thru Covid-19 testing with protected healthcare workers, like in South Korea, needs to sprout up everywhere in the US next week. High school gyms around the country may need to be commandeered to become isolation units for the infected.
To do something this massive and painful and disruptive, we have to focus honestly on the task at hand. We’re talking about potentially saving hundreds of thousands of lives here in the US, and probably millions worldwide.
In moments of crisis like this, people find a way to reprioritize.
It can be done.
We have tremendous assets in the scientific enterprise. Research labs, for instance, can be temporarily transformed into Covid-19 medical testing facilities.
See this from the University of Washington:
I’m proud of the people in the Seattle scientific community who are meeting the challenge. I’m proud of the many people in the broader US biotech community who are stepping up.
It’s amazing what can be accomplished with talented people, strong leadership, and a clear and urgent mission.
Leaders of all organizations – this is your cue to re-think who you are, what you do, and how you can help.
As you think about where you can have maximum impact, refer to this list of stories and resources below.
Epidemiology
Biology
Policy
What We Can Do
Mobilization / Therapeutics
Mobilization / Diagnostic Testing
Humanity
Who to Trust
Responsible Leadership
Microsoft was quick to show leadership on the Covid-19 outbreak in its home state of Washington. In telling workers to stay home, it promptly did its part to #flattenthecurve. But it didn’t stop there. The company recognized the ripple effect that action would have on hourly wage earners who drive shuttles, staff company cafes etc – who would be losing their livelihood from the shutdown. Remember, capitalism has gotten itself into such a cold and cruel and dangerously individualistic place that we are having an election this year that in some ways amounts to almost a referendum on our economic system itself. Microsoft, recognizing a moral imperative to encourage sick workers to stay home, and to replace lost income for wage earners, was a couple steps ahead of political leaders who are re-assessing our tattered social safety net in this time of crisis. Companies would be wise to read Microsoft’s message.
Tweetworthy
If you hear someone say, “It’s Just the Flu” here’s a simple chart you can show.
Once people are snapped out of denial and complacency, then you can begin to present how individual actions can add up to make a profound difference. See #flattenthecurve
If people are still skeptical or unsure of the need for urgent action, then you can show what happens when a country doesn’t respond with speed and force.
And in other biotech news this week…
Clinical Data
BMS said it failed in a Phase III clinical trial of elotuzumab in combo with Revlimid/dexamethasone (Rev/dex) for newly diagnosed multiple myeloma patients.
Merck and AstraZeneca failed in a Phase III clinical trial of cediranib and olaparib (Lynparza) in platinum-sensitive, relapsed ovarian cancer patients.
Acceleron Pharma said it failed in a Phase II clinical trial with a drug candidate for Charcot-Marie-Tooth disease.
Personnel File
Corcept Pharmaceuticals named Gregg Alton, the longtime former Gilead executive, to its board of directors.
Flexion Therapeutics hired Melissa Layman as chief commercial officer.
TScan Therapeutics added Doug Fambrough to its board of directors. He’s the CEO of Dicerna Pharmaceuticals.
Financings
Cambridge, Mass.-based Kymera Therapeutics raised $102 million in a Series C financing. Biotechnology Value Fund led. It’s working on drug designed to work via protein degradation. (See TR coverage of the Series A and original concept, October 2017).
San Francisco-based Nurix raised $120 million to support its targeted protein modulating drugs. Foresite Capital led.
Cambridge, Mass. and Netherlands-based Harbour Biomed raised $75 million in a Series B deal. It’s working on cancer and immune disorders.
GenFleet Therapeutics raised $80 million in a Series B financing. The China-based company is working on treatments for cancer and autoimmune diseases.
Seattle-based Silverback Therapeutics raised $78.5 million in a Series B financing to advance antibody-conjugate work against cancer. US Venture Partners led.
Watertown, Mass.-based Kala Therapeutics, the developer of treatments for eye diseases, raised $126 million in a public offering.
Flagship Pioneering announced it has merged a couple of its companies into Repertoire Immune Medicines, a company working on cancer, autoimmune disease and infectious disease. It has raised $220 million combined. Former Bioverativ exec John Cox was hired as CEO.
Israel-based Compugen, a cancer immunotherapy company, raised $75 million in a public offering.
Boston-based Imara, a developer of sickle-cell disease therapies, raised $75 million in an IPO at $16 a share.
Deals
San Francisco-based Invitae agreed to acquire YouScript and Genelex and Diploid. YouScript helps clinicians decide what to do with genetic information. That deal was worth $79.3 million. Genelex offers pharmacogenetic testing. Deal value: $20.7 million. Diploid uses AI to assist with genetic diagnoses. That one was worth $95 million.
Bridge Biotherapeutics struck an AI drug discovery partnership to work on as many as 13 small molecule programs with Atomwise.
Regulatory Action
Boston-based Intarcia Therapeutics, for the second time, was unable to secure FDA clearance to start selling its drug-device combo treatment for diabetes.
Boehringer Ingelheim won FDA approval to market nintedanib (Ofev) for interstitial lung disease. The drug was first approved in 2014 for pulmonary fibrosis.
The FDA announced that two people have died, and four more are hospitalized, after getting stool transplants from OpenBiome
Personal Note: I’m working from home in Seattle — the heart of America’s uncontained Covid-19 outbreak. I’ve been social distancing since Feb. 29. Have spent a fair bit of time on the phone with family members in the Midwest, urging them to be cautious ahead of what’s to come.
Many of you – members of the biotech / biopharma community — are doing similar things for your families. If you have good ideas on things this we can do, let me know. luke@timmermanreport.com.
Stay well.
Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)
As background: I am Italian-born, and was raised in Italy. My entire family works and lives there, mostly in Milan or nearby areas. I have been communicating with family members about the noval coronavirus for the last month.
I have a PhD in Molecular Biology from Geneva, Switzerland, and I have been in biotechnology venture capital since the early 2000s. I live in Boston now.
The following is a personal account of what I think the lessons should be from the Italian situation, and their response, as well as what I think should be the immediate US response.
First, some facts (see graph below):
Cases started in Wuhan, China, probably late November / early Dec. 2019.
Reporting to the World Health Organization of cases of pneumonia, of unknown etiology, started on Dec. 31, 2019.
First death reported was on Jan 9, 2020.
First sequence of the 2019-nCOV virus was shared with the scientific community on Jan 12. The number of daily confirmed cases passed ~500 on Jan 16.
Wuhan City was shut down on Jan 23. Another 15 cities were shut down in China on Jan 24. WHO declared “a public health emergency of international concern” on Jan 30.
The first virus infection cases in Italy were confirmed on Jan 31, with two Chinese tourists (in Rome) positive for the virus.
It is unclear if the current outbreak in Italy derived from lack of containment of potential virus spread from those cases: on Feb 7, an Italian man repatriated back to Italy from Wuhan, China, was hospitalized and confirmed to be the third case in Italy.
A cluster of confirmed cases were detected later on. By Feb. 21, 16 cases were confirmed in Lombardy, in northern Italy. A day later, an additional 60 cases were reported. The first deaths in Italy were reported the same day.
As you all should know by now, the virus has an incubation time of roughly two weeks (with significant variability between individuals likely). The incubation time is defined as the time it takes between the day a person is infected, and the day that the person starts having symptoms of the disease. When people are suspected of having been in contact with the virus, it is highly recommended that they undergo quarantine for that two-week period, to limit infection spreading.
By the beginning of March, 11 cities in northern Italy (all close to Lombardy) were placed under quarantine. By March 8, Italy had performed ~50,000 tests for the virus. Also on March 8, Italian Prime Minister Giuseppe Conte extended the quarantine to all of Lombardy and 14 other northern provinces; this was extended to all of Italy just one day later — on March 9.
Some background on Italy and in particular Lombardy: this is the richest region in the country, with excellent healthcare infrastructure. Italy has ~3.2 hospital beds / 1,000 inhabitants (a higher proportion than the US). Doctors and healthcare professionals in general are well-trained and dedicated. There are no negative incentives to getting tested (and skipping work) early in the disease progression phases, like there are in the US. Italy has universal healthcare insurance and coronavirus tests were made widely available very early on.
The case fatality rate in Italy has also been extremely high: close to the Chinese numbers, of roughly 3-3.5% CFR rate. Much higher than Korea, which has implemented massive scale testing and extensive contact tracing and quarantine since very early on. Some of this high number in Italy might be an artifact of the relative lack of testing of asymptomatic carriers, some might be due to an aging population (Italy skews very old in its demographics, and the elderly are particularly susceptible to high level of morbidities and fatality with this virus). Some more might be related to social customs (Italians are an extremely social culture and congregate regularly in large groups with extensive physical contact: greetings are two kisses on the cheeks even with relative strangers).
What does “quarantine” mean? It means everybody is stuck at home. People who can, are working from home. Shopping is done online preferably: alternatively, one household member only at a time can go to shops. Shops are closed on weekends. No schools, no gyms, no cinemas, no restaurants unless they can guarantee a minimum distance of ~3 feet (damn Imperial measurement system) between customers. No concerts, no conferences, nothing. If you are leaving / driving somewhere, the police will stop you, and will ask for the reasons for your travel. If it is not justified (medical reasons, urgent work reasons), you will be indicted for violating the quarantine and reported to the courts. And these measures are being enforced (startlingly enough).
I have family members who have been stuck at home for days now and are literally going nuts. And they have a way to go (weeks, if not months).
Early on, I had the hardest time making my family understand how serious this was (I started pestering them more than four weeks ago to prepare). This is called “Social Distancing.” It feels undemocratic, excessive. We are not China! We are a vibrant democracy of individualists who like to go out every night!
Why is Italy now shutting down its entire country? With incalculable economic consequences (in a country already pretty much in recession)? For a virus with a likely case fatality rate of close to ~1% maybe? Are we insane?
No.
The country is, arguably belatedly, making a dry, cold calculation. The choice is the following: shutting down the country and preventing as much as possible fast spreading of the virus (“flatten the curve”) and in so doing limit its current, catastrophic impact on hospitals and caregivers; OR: continue life as usual and basically overwhelm the healthcare system.
What is happening to hospitals around Milan now (and it has been happening for days): ALL routine treatments / diagnostics, operating room procedures, even emergency procedures like trauma and strokes are being delayed / diverted to other centers to preserve what little capacity they have to treat virus patients. Virus patients with severe co-morbidities and/or over 65 years old are not being provided with ventilators: caregivers are triaging, like in a war zone, for people that have a possibility to recover and that they can save. ICU bed capacity has been nil for days.
Think of the implications. Caregivers are physically and emotionally exhausted. They were / are not being provided with protective gear: they are making mistakes. They are falling ill themselves. All doctors / nurses, of any specialties, are only caring for virus patients. More and more people will suffer fatal consequences of this. Not stopping as much as possible the spread of the virus is not an option. China and Korea did it. At great economic cost, for sure, but in so doing saved immeasurable number of lives.
I know what some (maybe most of you are thinking): Why should I change my way of life? This is overblown. It is like the flu. I am not in at-risk demographic.
It is not like the flu. There is no vaccine or natural immunity. The severity and fatality rate of the disease on the elderly and patients with co-morbidities is horrific (up to 18% of people over 70 years old seem to be fatally affected). Hospitals cannot possibly cope with hundreds of patients in intensive care, all at the same time. There are not enough beds, equipment, protective gear. By not contributing to reducing the spread / flattening the curve, even if you are not in an at-risk demographic, you are still contributing to spreading the virus.
So, what could / should the US do?
I personally think time for containment is over. A few hours ago, New Rochelle, New York was cordoned within a 1-mile radius by the National Guard. There were a few cases detected there days ago. Those people were infected ~2 weeks before that. There has been no extensive testing performed in the US at all for the last few weeks. Testing capacity is only coming up online now.
Here are my suggestions:
I hope to be wrong. I do. I fear I am not.
This needs to happen now. Looking at infection curves, the US is now where Italy was 11 days or so ago.
We have no time to lose. And may the fates look upon us with mercy.
Follow Otello Stampacchia on Twitter: @OtelloVC
This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Omega Fund Management, LLC or any officer, director, partner, member, manager or employee of Omega Fund Management, LLC or any of its affiliated entities.
David Shaywitz
Technology has been hailed for its ability to connect us; we’ve tended to view this is a positive development, but as rare, high-impact events like the coronavirus epidemic reminds us, a densely-networked world may also be more fragile.
The mixed blessing of interconnectivity was acknowledged back in 2005 by New York Times columnist Thomas Friedman, who observed:
“…we are now in the process of connecting all the knowledge pools in the world together. We’ve tasted some of the downsides of that in the way that Osama bin Laden has connected terrorist knowledge pools together through his Qaeda network, not to mention the work of teenage hackers spinning off more and more lethal computer viruses that affect us all. But the upside is that by connecting all these knowledge pools we are on the cusp of an incredible new era of innovation, an era that will be driven from left field and right field, from West and East and from North and South.”
For techno-optimists like Erik Brynjolfsson and Andrew McAfee, authors of The Second Machine Age, improved interconnectivity catalyzes what they call “recombinant innovation.” This is the idea that “the global digital network” enables us to “mix and remix ideas, both old and recent, in ways we never could before.”
They continue:
“Digitization makes available massive bodies of data relevant to almost any situation, and this information can be infinitely reproduced and reused because it is non-rival. As a result of these two forces, the number of potentially valuable building blocks is exploding around the world, and the possibilities are multiplying as never before.”
Brynjolfsson and McAfee add, “as the number of building blocks explode, the main difficulty is knowing which combinations of them will be valuable.”
Enabling promising ideas to be shared certainly sounds like a promising premise if the global community is collectively seeking cures for cancer or approaches to sustainability. But what about when the agenda is less benevolent? Increased connectivity enables members of hate groups to find each other and mobilize. It also helps autocrats gain and maintain power (see this New York Magazine article, “Facebook Used the Philippines to Test Free Internet. Then a Dictator Was Elected”).
While many technologists see a fundamental strength of technology as its ability to quickly reach global scale – Facebook, as I recently wrote in a Wall Street Journal book review, now connects about a third of the humans on our planet – huge scale is not an unalloyed good. While 10 distinct communities may not benefit from the efficiencies that might be possible from a single large community, they would also not be as susceptible to rare but harmful events, so-called “black swans.”
As Nassim Taleb (who popularized this term and concept in his 2007 book, The Black Swan [my Wall Street Journal review here]) writes in his 2012 treatise, Antifragile:
“Black Swan effects are necessarily increasing, as a result of complexity, interdependence between parts, globalization, and the beastly thing called ‘efficiency’ that makes people now sail too close to the wind….One problem somewhere can halt the entire project… The world is getting less and less predictable, and we rely more and more on technologies that have errors and interactions that are harder to estimate, let alone predict.
And the information economy is the culprit.”
The risks of such rare, concerning events are of course especially on our minds today in the context of Covid-19. Taleb anticipated this in a supplemental essay he wrote for the paperback edition of The Black Swan when it appeared in 2010: “As we travel more on this planet, epidemics will be more acute—we will have a germ population dominated by a few numbers, and the successful killer will spread vastly more effectively.”
Niall Ferguson (author The Square and the Tower, about the historical impact of networks) argues in a recent Wall Street Journal essay that you can’t understand epidemics without a sophisticated understanding of networks. “Standard epidemiological models,” he writes, “tend to understate the threat posed by a virus such as 2019-nCoV, because they don’t take account of the topology of the social networks that transmit it.”
In particular, says Ferguson, traditional theories tend not to incorporate “the social-network hubs known as ‘superspreaders.’”
This is exactly the concern Taleb had originally articulated in The Black Swan. A fundamental property of networks, Taleb writes, is that:
“there is a concentration among a few nodes that serve as central connections. Networks have a natural tendency to organize themselves around an extremely concentrated architecture: a few nodes are extremely connected [analogous to the superspreaders]; others barely so…. Concentration of this kind is not limited to the Internet; it appears in social life (a small number of people are connected to others), in electricity grids, in communications networks. This seems to make networks more robust: random insults to most parts of the network will not be consequential since they are likely to hit a poorly connected spot. But it also makes networks more vulnerable to Black Swans.”
It’s difficult to imagine that we are likely to return (willingly) to a less-networked world. But this also doesn’t mean we need to reflexively embrace every effort to expand and intensify our networks.
I suspect Taleb’s instincts may be right: large, taut networks promising efficiency in the short run may endanger us down the line, and we might do well to deliberately trade a measure of immediate convenience for more durable stability. Our challenge – both individually and collectively — is to figure out how best to achieve this trade-off, and learn how we can most effectively leverage the power and promise of networks without succumbing to their pronounced vulnerabilities.
Today’s guest on The Long Run is Isabella de la Houssaye.
Isabella is a former attorney on Wall Street, a mother of five kids, and a terrific endurance athlete. She’s run marathons around the country, ultramarathons, and even completed an Ironman triathlon.
Isabella de la Houssaye
She’s also a Stage 4 lung cancer patient.
She owes her life, and her vitality, to some extraordinary advances we’ve seen in cancer biology. You can listen to her describe her molecular profile, and how that fortunately matched her up with a drug from AstraZeneca that worked wonders.
She’s now making the most of every day.
Some of you may have read about Isabella in the New York Times last year. The Times wrote about Isabella climbing Aconcagua — the highest peak in South America at 22,840 feet — with her daughter AFTER being diagnosed with Stage 4 lung cancer.
If you haven’t read that story, I encourage you to go back and read it.
Seeing people like Isabella thrive is wonderful. Essentially she’s the living, breathing personification of everything I dream of through my charity work for the Climb to Fight Cancer at Fred Hutch.
Isabella’s now on a new mission. She’s bicycling across America to raise awareness for early diagnosis and better treatment for lung cancer patients. She will also be spreading the word about mindfulness and positive thinking, and how that has gotten her through some tough times.
You can follow her journey, starting in San Diego, at bikebreathebelieve.org.
As members of the biopharma industry, you get to go to work each day with people who have the capacity to extend life, and improve quality of life, for people like Isabella. It’s an amazing thing when it works.
I hope you find her story inspiring.
Now, please join me and Isabella de la Houssaye on The Long Run.
Luke Timmerman, founder & editor, Timmerman Report
Everywhere I look — to the North, South, East and West of my home office in Seattle — there are confirmed cases of Covid-19.
It’s one thing to read about a distant outbreak and intellectually understand the pandemic math, the morbidity and mortality rates, and responsible steps for containment and mitigation.
It’s another thing to live in the middle of an outbreak.
It’s stressful. I’m not worried about myself, my wife or my daughter. We’re healthy. I am worried about healthy people like us getting sick and transmitting the bug around the community, sickening and killing other people.
So, I’m practicing self-isolation and social distancing, as recommended by infectious disease experts at the WHO.
In case you’re wondering, Fred Hutch decided this week to postpone the Everest Base Camp Climb to Fight Cancer planned for Mar. 19-Apr. 4 in Nepal. This is a team expedition I’ve organized and worked hard on for eight months. We plan to do the trip in October instead. It’s the right thing to do. Fred Hutch, by the way, also imposed a mandatory work from home policy for non-essential employees, effective Mar. 5-31.
Why the drastic action, you might ask?
This bug is highly contagious. It’s transmitted in the community via asymptomatic and mildly symptomatic people – meaning people who don’t even realize they are spreading a dangerous bug to other people. It started circulating in the Seattle area, my hometown, for about six weeks before anyone knew.
We have little idea how many people are infected in the U.S., because of a slow, bungled response to diagnostic testing. Estimates are that the fatality rate is between 1 percent and 3.4 percent. The hospitalization rate is in the 15-20 percent range. We have no proven treatment or vaccine. We don’t have enough intensive-care unit beds, or respirators, to handle a massive influx of people with Covid-19.
Many people appear to be slow to appreciate the magnitude and urgency of the threat. Some are carrying on with business as usual – like holding a 100,000-person Emerald City Comic Con conference in Seattle within days. This is foolish and dangerous at a time Gov. Jay Inslee has declared a State of Emergency.
In all likelihood, Emerald City Comic Con will help speed up the spread of Covid-19 around the country. [Update: 9:09 am Mar. 7. Comic Con chose to postpone the event.]
We are just beginning to experience a tremendous stress test on our hospitals and public health system. One-fourth of the fire department in Kirkland, Wash. has gone into quarantine, and some have developed “flu like symptoms” after responding to help people at an infected nursing home.
Think about how many first-responders around the country are now at risk.
Take a look at this statement from a registered nurse at a Kaiser Permanente facility in Northern California:
Everyone needs to pull together to find a way to contribute – federal, state, local authorities, as well as academic scientists and private industry. As written in this space last week — it’s collective problem-solving time.
The biopharma industry – vaccines, therapeutics, diagnostics companies and more – has tremendous resources to bring to bear against this challenge. People in this business have the brains, the resources, and the tenacity to step up. This is a moment for the scientific enterprise to show what it’s made of.
To help you stay on top of this fast-moving situation, I’ve curated a variety of important sources on Covid-19 from the past week, broken into topic areas.
COVID-19 Reading Summary
Epidemiology
Policy
Biotech Response
Science
Communications
Human Dimension
Tweetworthy
See this chart from the Bloom Lab at Fred Hutch. Those of you with family and friends in the elderly age bracket – this chart is a good reminder of the seriousness of Covid-19. It’s more deadly than flu, at least when looking at vulnerable elderly populations.
Also Tweetworthy
There was also a Super Tuesday election this week.
Joe Biden’s epic comeback was the story. Larry Levitt of the Kaiser Family Foundation reminded folks that while the former vice president isn’t advocating for Medicare for All, he does plan to finish some of the unfinished business in the Affordable Care Act.
Deals
Gilead Sciences, the infectious disease powerhouse that has spent the last decade trying to diversify into other therapeutic areas, made another move in oncology. This week, it acquired Forty Seven, the company working to modify the “Don’t Eat Me” signal that cancer cells hijack to escape macrophages. Gilead agreed to pay $4.9 billion in cash to acquire the company, or $95.50 a share. Forty Seven is advancing drug candidates for myelodysplastic syndrome, acute myeloid leukemia, and diffuse large B-cell lymphoma. (See Oct. 2015 TR coverage on the early movers in macrophage biology for cancer).
Thermo Fisher Scientific agreed to acquire Qiagen, the diagnostics company, for $11.5 billion. Whatever merger activities have to happen must now be secondary to an all-hands on deck approach to ramping up test capacity for Covid-19.
GlaxoSmithKline is apparently shopping around its antibiotics business, according to Bloomberg News. Maybe this isn’t the best time for pharma powerhouses to throw in the towel on infectious disease defenses, even when the market failures of the antibiotics space are well-documented. Someone needs to do this work, and that someone needs serious resources of the kind that companies like GSK can provide. Maybe you guys can tell your bankers to put that deal on the back burner?
Vir Biotechnology, the infectious disease drug developer, expanded its existing collaboration with Alnylam Pharmaceuticals, the RNA interference drug developer, to use this powerful treatment modality against Covid-19. These companies have the key ingredients – the staff, the stuff, and the space, as they say in public health – to make some fast progress. They also have the cash in the bank necessary to turn their attention to this outbreak for a while without putting their companies at risk.
Financings
UK-based Immunocore, a company modifying T-cells for cancer and infectious disease, raised $130 million in a Series B financing. General Atlantic led.
Waltham, Mass.-based Akrevia Therapeutics raised $100.5 million in a Series B financing to advance its tumor-selective cancer immunotherapy programs. Takeda Ventures led. The company also changed its name to Xilio Therapeutics.
Mountain View, Calif.-based Amunix Pharmaceuticals, the developer of T-cell engaging antibodies and cytokine agents for cancer treatment, raised $73 million in a Series A financing. Omega Funds led.
Boston-based Akouos, a gene therapy for ear disorders company, raised $105 million in a Series B. Pivotal bioVenture Partners led. (See TR coverage of the $50 million Series A deal, August 2018). Vicki Sato and Heather Preston joined the board of directors.
Theravance Biopharma took on $400 million in debt financing due in 2033.
Personnel File
Cambridge, Mass.-based Unum Therapeutics laid off 60 percent of its workforce.
Unity Biotechnology, the company in Brisbane, Calif. seeking to extend healthy lifespan, named Anirvan Ghosh as CEO. He comes from Biogen, where he headed research and early development. Ghosh replaces Keith Leonard.
London-based Autolus said two top executives – Jim Faulkner and Neil Bell – are heading out the door, and being replaced by David Brochu and Vishal Mehta. The company is working on modified T cell therapies.
Regulatory Action
The FDA cleared Sanofi’s isatuximab-irfc (Sarclisa), in combination with pomalidomide and dexamethasone, for the treatment of relapsed patients with multiple myeloma. It’s a CD38 directed antibody.
The FDA said on Feb. 27 it is aware of a shortage of one human drug because its active pharmaceutical ingredient is made in China, and the Covid-19 outbreak has caused supply disruption.
European Union regulators cleared Alnylam’s givosiran (Givlaari) as a treatment for acute hepatic porphyria in adults and adolescents.
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Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
