Your Edge In Biotech.
7
May
2020

Randomized Controlled Trials For Healthcare Delivery Work; Now Let’s Do More At Scale

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07 May 2020

David Shaywitz

The value of randomized controlled trials (RCTs) in healthcare delivery was highlighted earlier this year with the publication in the New England Journal of Medicine (NEJM) of a paper that rigorously evaluated a deeply appealing hypothesis: that you can improve care and reduce costs by focusing on “superutilizers” – the patients who consume the most healthcare resources. 

I discussed this paper, and some associated issues, at a recent Harvard Department of Biomedical Informatics (DBMI) faculty journal club, and thought a few highlights might be of particular interest to TR readers.

The story of the trial is captured magnificently by the Tradeoffs podcast – you can listen here, and read a helpful summary here. 

The protagonist is a New Jersey physician named Jeffrey Brenner, who became interested in better serving patients in Camden, New Jersey. It’s a city with 74,000 people across from Philadelphia. About 42 percent of the population is African-American, and about 37 percent of the population lives in poverty, according to the US Census Bureau. After reviewing hospital data, Brenner realized that hospital use, and more generally, healthcare costs, weren’t evenly distributed. 

In this population, like others, a small percentage of patients (about 5%) accounted for the vast majority of healthcare costs (~ 50%). This group of people has been dubbed the “5/50’s.” Many of these “superutilizers” are patients facing a remarkably complex group of social and economic challenges that can make life, and health, disproportionately difficult for them. 

Brenner’s hypothesis was that a key challenge these patients face is engaging effectively with the healthcare system, and by providing them with a team of guides (sort of like sherpas), to help coordinate their care, the patients’ health would improve, and hospital utilization would decline. Initial work seemed to bear this out – healthcare costs and utilization seemed to go down for the first several dozen patients treated in this program.

It all seemed to make a lot of logical sense.

Brenner’s star really began to rise after his efforts were profiled by Atul Gawande in an inspirational New Yorker article, “The Hot Spotters,” in 2011; Brenner received a MacArthur genius award in 2013, and his program was widely hailed as a success, which many sought to emulate.

Yet Brenner, it turns out, encountered skeptics at health conferences. To his exceptional credit, he recognized the need to further test his hypothesis, and really pressure-test his program, through a randomized control study.

This trial was led by an independent, trusted group from MIT, led by noted economist Amy Finkelstein. Brenner himself left to join United Healthcare Group in 2017, attracted, he said, by the opportunity to apply some of his learnings from an even larger platform – that of the world’s largest insurer.

The MIT results, published in the NEJM in January 2020, were disappointing. There was no difference between control and treatment arms in the number of hospital readmissions within 180 days – the primary endpoint.  Moreover, both groups showed a decline in utilization, suggesting that the previously-observed decrease seen in the first group of patients may well have represented simply an example of the well-described phenomenon of “regression to the mean.”

There are several relevant lessons we might learn here.

First, the study highlights that even – perhaps especially – when there’s a compelling narrative, it’s critically important to perform the rigorous study to be sure that what you might so desperately want to believe is actually true. There are so many ways we can fool ourselves, and so many potential confounders; RCTs – while not without their own issues, in particular, generalizability – help minimize the effect of bias, which is why they’re appropriately considered the gold standard.

The value of randomized controlled trials (RCTs) is perhaps most acutely felt in situations where the truth feels self-evident, to the point where actually doing a study can strike some as unethical. 

Prominent examples from the history of medicine are the use of an anti-arrhythmia drug to reduce sudden cardiac death after heart attacks (the intervention seemed intuitive, yet the CAST study revealed the drug actually made things worse); the routine use of pulmonary artery catheterization in critically ill patients (collecting more data intuitively seemed better, yet RCTs revealed no evidence for improvement; a wag even penned an obituary for the device); and perhaps most famously, the use of hematopoietic stem cell transplant for the treatment of breast cancer (the trial was derided by some as unethical given the assumed benefit, yet the approach was found not to improve survival significantly).

The need for careful study is particularly important, and particularly challenging, in areas characterized by what tech entrepreneur Jim Manzi (Tech Tonics interview here; TR discussion in context of AI here) has called high “causal density.”

This is a term referring to “the number and complexity of potential causes to the outcome of interest.” It’s a factor in biological experiments, of course, and an even greater factor, Manzi argues, in areas of social science. If a vaccine works in one population, he says, he’s reasonably confident it will work in another. But if an educational intervention works in one setting, he’s far less confident it will be generalizable, because of all the factors that could be involved.

Perhaps not surprisingly, when many policy measures are actually evaluated by RCTs, most fail.  A study from Arnold Ventures revealed that of “13 instances in which the federal government commissioned large randomized controlled trials to evaluate the effectiveness of entire, Congressionally-authorized federal programs,” 11 essentially failed, one yielded modest/marginal benefit, and only one clearly and repeatedly seemed to work: the Department of Defense’s Guard Youth ChalleNGe, intensive, residential youth development program for high school dropouts.

A frustratingly common observation is that initially promising data often fail to stand up to the test of time.  As I discussed in a recent Wall Street Journal review of their book, The Power of Experiments, Harvard Business School professors Michael Luca and Max Bazerman share the story of a thoughtful behavioral intervention developed by University of Pennsylvania faculty Katherine Milkman and Angela Duckworth.  While initial results looked promising, the effects soon receded – prompting Duckworth (of Grit fame) to observe, “Behavior changes are really *#$@ing hard!”

Yet all may not be lost.

In 2014, a White House Social and Behavioral Sciences Team (SBST) tried to reduce the over-prescription of addictive medicines (Schedule II controlled substances) by sending out a letter informing these doctors they prescribed far more of these medicines than their peers; this type of approach (as I discussed in the Journal) was demonstrably successful in another context — increasing delinquent tax payments, for example. 

Yet here, a RCT evaluating this approach failed to demonstrate an impact on prescriptions.

Instead of giving up, however, the team refined their approach, modifying both the targeting of their letter (now focusing on primary care doctors who were unusually heavy prescribers of quetiapine [Seroquel], specifically) and the language used (in addition to peer comparison, the letter noted the doctor was under review by the Centers for Medicare & Medicaid Services [CMS]), and performed another RCT.  This time, it seems, the approach worked well; prescribing was reduced by over 11%, a statistically significant effect that persisted for at least two years.

According to experts like Manzi, success in environments of high causal density require just this sort of iterative approach. 

“Run enough tests,” he advises, “and you can find predictive rules that are sufficiently nuanced to be of practical use in the very complex environment of real-world human decision making.” 

Testing at this scale, Manzi says, requires “integration with operational data systems and standardization of test design,” approaches that are already adopted by a number of organizations within the business world. 

Examples, as I discussed in the Journal, include not just tech giants like Google, Microsoft, and Amazon, but also companies like Nike and State Farm, the insurance company. I’ve also discussed the value of “high velocity incrementalism” to use Harvard Business School Professor Stefan Thomke’s term, in TR, here, and in the context of COVID, here.

Strikingly, “run enough tests” turns out to be the advice of Amy Finkelstein, the MIT economist leading the Camden RCT, as well. In an April 2020 Perspective piece in the NEJM, Finkelstein argued that the key to improving healthcare delivery was conducting more RCTs, noting “the increased availability and use of administrative data have made implementing RCTs easier and less expensive than it once was.”

She noted that improved data systems (versus what were available two decades prior) capturing hospital discharge data enabled the Camden RCT study to be done “at substantially lower cost and effort and with less risk of nonresponsive bias” that would have been possible in an era that relied upon survey data collection.

Finkelstein added that “administrative data also enable use of RCTs for low-cost, rapid testing of repeatedly fine-tuned interventions,” citing a 2019 NEJM study from NYU Langone Health, led by my med school colleague Leora Horwitz, reporting the completion of “ten randomized, rapid-cycle quality-improvement projects in one year.”

We’ve seen the ability of deliberate experimentation at scale to impact website traffic and hone the appeal of political messages to voters. 

How exciting to contemplate the integrated — and, I hope, routine — use of this process to improve the delivery of care to patients.

5
May
2020

Giving Models and Modelers a Bad Name

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05 May 2020

Ruth Etzioni, Full Member, Division of Public Health Sciences, Fred Hutch Cancer Center

As someone who has spent a career building and studying disease models, primarily for cancer, the latest update from Chris Murray and the IHME model makes me cringe.

The IHME model, readers will recall, has been frequently cited by the White House coronavirus task force. On May 4, the IHME called a press conference to release the results of their COVID-19 model update which showed a staggering departure from their prior predictions of about 60,000 deaths through the end of August.

Obviously, this earlier model had to be updated – and  fast: the official US death toll was already at more than 68,000 at the time of the May 4 press conference.

The new prediction from IHME through August estimates 134,000 deaths – more than double the previous model’s estimate. Murray, the institute’s director, told reporters that the death toll was significantly increased because the latest update had taken changes in mobility into account. Indeed, travel patterns now show an uptick in movement in states that are beginning the re-opening process, and increased mobility means increased opportunity for infection.

Murray, in a May 4 interview on CNN with Anderson Cooper, said the earlier model was built on an assumption of statewide social distancing measures remaining in effect through May in order to suppress transmission. Now that states are lifting the orders, the model had to be revised to incorporate the fact that “more people are getting out and about.” 

While I am in total agreement that premature relaxation of social distancing will lead to an explosion of new cases and deaths, you don’t need a model to know that. That’s how epidemics work when a population is as far away as the US is from herd immunity. And models everywhere are showing the same thing.

Where I live in Washington State, Gov. Jay Inslee and his advisors looked at models that predicted dramatic growth of infections if the state were to relax the Stay Home, Stay Healthy order prematurely. Those models were part of the rationale for extending the stay-home order until the end of May.

It makes a nice story, to tell the world that the reason your model’s predictions have changed is because the population’s behavior has changed. The implication is that it’s not the model’s fault, it’s the politicians and the people’s shifting behavior. Indeed, that was the same explanation given by IHME for their model revising its early death toll of about 90,000 dramatically downward to about 60,000 in early April. At that time, Murray explained that the change in predictions showed that social distancing had been a wild success – better than we could ever have imagined.

The lowering of the death estimate, in turn, led to howls of protest that we had over-reacted by shutting down and staying home. Those howls put pressure on elected officials to relax social distancing. Clearly, models do matter.

On Apr. 14, I wrote in these pages that that the interpretation regarding social distancing success was wrong and misleading and placed far too much credibility in the early predictions. The early model results were based on an oversimplified empirical model. It extrapolated death curves from the earlier experience in China, Italy, and eventually Spain. It assumed that social distancing would work as well as in those settings, and that the pattern of deaths after the peak would be a mirror image of the pattern before it. Revisions of the model tried to soften these assumptions, making many other assumptions along the way. It is likely that these revisions, rather than social distancing success, drove the dive in the deaths predicted in that April revision.  

The same thing is happening now. A quick skim of the IHME’s model updated site leads one to an eye-glazing list of changes, including some that have nothing to do with mobility and everything to do with improving how well the model matches the data on cases and deaths recorded up until this point.

When Murray spoke about mobility patterns causing an update to the model, he neglected to say in the same breath that the team had made fundamental changes to its model-building approach in order to arrive at its current set of predictions. IHME is now more like a hybrid of empirical and mechanistic approaches. What we aren’t seeing from IHME is a clear and transparent statement on the truly humbling “back to the drawing board” nature of what it has just done by rebuilding its model.

Here is one change that truly raised my eyebrows: 

“Since our initial release, we have increased the number of multi-Gaussian distribution weights that inform our death model’s predictions for epidemic peaks and downward trends. As of today’s release, we are including 29 elements… this expansion now allows for longer epidemic peaks and tails, such that daily COVID-19 deaths are not predicted to fall as steeply as in previous releases.”

This change alters the shape of the assumed mortality curve so it does not go down as fast; it alone could explain a substantial portion of the inflation in the revised mortality predictions. 

The proof is in the Washington State pudding. The IHME is no longer predicting that we will have less than one case per million on May 28 and can therefore safely reopen, as it did in its previous incarnation. But little has changed here on the policy front and in residents’ mobility patterns, according to Google Mobility reports, through April.  

I am not aiming my comments at the IHME modeling team, which I imagine is sincerely doing its best to deliver results that match the data and produce ever-more-complex predictions of the future. They are working overtime to fit the rapidly evolving and imperfect data, marching to a drumbeat of deadlines from everyone that wants the impossible – crystal clear and precisely accurate forecasts. To their credit, the last part of the May 4 update does note that both model changes and increased mobility projections could account for the change in predictions. But that never made it into the headlines. And that is a problem of transparency.

Transparency begins in the sincere effort by those who communicate models to make sure that they are properly interpreted by the policymakers and public that are using them. The IHME pays lip service to transparency by documenting their model’s updates on their website. But their pages-long description is chock full of technical fine print and is hard to understand, even for a seasoned modeler like myself.

A key part of transparency is acknowledging your model’s limitations and uncertainties. This is never front and center in the IHME’s updates. It needs to be.

It is ironic to me that I am being this critical when I agree so strongly with the message that is being broadcast as a result of this update. Make no mistake – if some states that are opening prematurely, or some that are considering doing so, change their minds as a result of this update, it will a very good thing. 

We have to remember that this epidemic took root and grew massively in every state from miniscule beginnings. We should all be sobered by our real-time experience of exponential growth. If there is an ambient prevalence of more than a handful of cases in any state, then anything that increases the potential for transmission will lead to a re-growth. We do not need a model to be able to predict that. But, as we plan for how to reopen in each state of our union, we need to know what extent of growth in new infections we can manage. And models can help us with that. 

When and how much we can reopen will depend on the surveillance and containment infrastructure that we put in place to control upticks and outbreaks. I am convinced that models can help us think clearly about complex policy questions – such as finding the balance between changes that increase transmission and measures to contain it. Models, along with other data and evidence, can guide us towards making sensible policy decisions. I have seen this happen time and time again in my work advising national cancer screening policy panels.

But as modelers, we have a responsibility. We have to be humble. We must make sure that the key caveats and uncertainties that are the nature of our work find their way into the headlines and are not relegated to the fine print.

If we don’t, we will give modeling, and modelers everywhere, a bad name.

1
May
2020

A Time for Empathy

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01 May 2020

Luke Timmerman, founder & editor, Timmerman Report

This is a fragile moment.

It’s May 1. Some of us have been in social isolation for two solid months. Everyone’s at some point on the continuum of stir crazy. More than 30 million people are out of work. Tempers are flaring. Protestors are carrying guns. It’s obvious we can’t sustain a maximalist social-distancing policy much longer.

Today, we have half of the 50 states doing some kind of partial lifting of stay-home orders, some variations on gradual re-opening of their economies – even though only 14 states are reporting declines in new cases. Masks, regular deep cleaning, shift work, and physical spacing in normally crowded spaces are all being tried out to mitigate the spread.

This virus is so befuddling, it’s hard to say much of anything about it with certainty. But it seems safe to say that some places will be more successful than others at keeping infection rates down with a careful turning of the dial.

The curves are deeply disappointing. We’re in what looks like a long plateau of steady infection and death. We now have more than 1 million confirmed cases of COVID19, and more than 63,000 confirmed deaths. More than 2,000 people are dying per day.

Our failure to run adequate diagnostic testing leaves us flying blind, unable to execute on the classic test/trace/isolate strategy that everyone agrees is essential, and which South Korea and others have shown works.

We had the tiniest glimmer of encouraging news this week about an antiviral medicine, remdesivir. It was shown in a rigorous NIH-sponsored study to reduce hospitalization time by four days. It’s not much in the grand scheme of things. An improvement in survival rates would be a bigger deal. Still, the result counts for something, because it can relieve some pressure on hospitals.

Really good news, in the near-term, would be the US getting its act together on testing, tracing and isolation. If we do that, then it should be possible for as little as 7 percent or so of the population to be isolated at any one time, allowing the rest of us to go about our business. Betz Halloran, an outbreak modeler at Fred Hutch working with collaborators at Northeastern University, made that remark in a panel discussion I moderated for Life Science Washington a week ago.

How much work needs to be done to get to adequate testing? As of May 1, we have done 6.5 million tests in the US. Grand total since late January. A Harvard group says we need to do 5 million tests A DAY by early June, and 20 million A DAY by midsummer.

We have our work cut out in more ways than one. We can’t duck the testing issue, because vaccines or seriously good treatments in the form of neutralizing antibodies will almost certainly not magically appear before the second wave.

Which brings me to my final point.

Our society needs to take a look in the mirror about how we treat each other, because we’re going to be in this betwixt-and-between mode, with partial re-opening and partial re-tightening, for a while. It’s a psychological tension we will all have to manage for longer than any of us would like.

Pathological selfishness, cruelty, and callousness has been coursing through our information ecosystem for years. Bad faith has been ascendant. A 24/7 information war has been raging, driving millions of people to extreme views that were unthinkable not that long ago.

The virus has struck us at a dark time.

The infowar has depleted our society’s empathy reservoir. You see it in popular Internet memes, like “Boomer Remover.” You see a guy in the Michigan state capitol, taunting National Guardsmen by breathing in their face, as if to blow smoke from a cigarette. You do see acts of kindness and empathy and courage on the news, but they are offset by this ugly behavior. It’s like a stain on our soul.

This is a test for our society.

This moment reminds me of something passed down from my Dad. He was idealistic at first, and then disillusioned, like many Vietnam veterans. He didn’t want his son to enlist in the Army. And yet, he was deeply patriotic. He instilled that spirit in me. It’s still there with me every day. I believe in our institutions like NIH, CDC, FDA. In our universities. In our entrepreneurial spirit. In our form of democratic self-governance – of the people, by the people, for the people. In our Bill of Rights. In our checks and balances that protect us from monarchy and tyranny.

It’s painful to see people traffic in abject cynicism, thumbing their noses at CDC guidance, clamoring for hydroxychloroquine without evidence, and injecting bleach. The erosion of support for and belief in science — as the best rational means for understanding the world — is a devastating indictment of life in the 21st century.

Now we can see how this cynicism about our institutions and our fellow citizens compounds.

We see it in sharp relief in a pandemic that disproportionately harms the most vulnerable. The elderly. Veterans. Prisoners. Black and brown people who can’t flip the switch and work from home. Low-wage workers in meat-packing plants. Native Americans on reservations.

I remember another thing my Dad taught me.

“A society is judged by how it treats the most vulnerable,” he said.

This quote, or variations of it, have been attributed commonly to Fyodor Dostoevsky, to Mahatma Ghandi, and Harry Truman.

We should remember those wise words, and act on them as best we can.

If we can foster some more humanity toward our fellow citizens, we might just come out the other side of this in a more perfect union. If we can resist the urge to call people names, even when they do things like stick hair dryers up their noses or go to the grocery store without masks, we can begin the process of turning down the cruelty and viciousness and ignorance and extremism. There are plenty of other things to do. Donate to your local food bank. Send a kind letter to an old friend from the other side of the aisle.

We can’t swing a sledgehammer to eliminate the cruelty. We have to radiate kindness.

What are you doing every day to uplift people?

Now, on to the rest of the week in biotech.

The Big Data Readout

The NIH reported results from a randomized study of 1,063 hospitalized patients with COVID19 who got Gilead Sciences’ antiviral drug remdesivir or a placebo. The median time to recovery from illness was 11 days for patients on the drug, and 15 days on the placebo – a 31 percent improvement, which was statistically significant. The drug didn’t show a statistically significant benefit on survival rates, although there was a slight trend in the right direction. Tony Fauci, director of the National Institute of Allergy and Infectious Diseases, called it “quite good news” and the kind of data that will create a new standard of care.

Gilead Sciences separately reported that another study showed that a 5-day course of treatment was about as good as a 10-day course of treatment. That’s meaningful because it means Gilead will be able to treat more patients with whatever supplies it can manufacture.  

Worthwhile Reading From Around the Web

Testing

Vaccines

  • An Oxford Group Takes the Lead in Vaccine Race. NYT. Apr. 27. (David Kirkpatrick)
  • What You Need to Know About a Vaccine. Gates Notes. Apr. 30. (Bill Gates)

Science Features/Commentary

Science

  • A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing. Nature. Apr. 30. (David E. Gordon et al)
  • Deaths from COVID19. Who Are the Forgotten Victims? MedRxiv. Apr. 28. (Kieran Docherty et al)

Epidemiology

  • A Grim Milestone at 100 Days. From 1 case to 1 million. Medium. Apr. 30. (WA Dept of Health)
  • Almost half of US – 45 percent of the Population – Is At Increased Risk from COVID19 Because of Co-Morbidities. Centers for Disease Control and Prevention. Apr. 27. (Mary Adams et al)

Investigations

Policy

Communication

  • Journalism Is Under Attack from Coronavirus and the White House. But We’re Winning. NBC News. Apr. 27. (Andy Lack)

Worth a Listen

Non-Covid Science

Feasibility of Blood Testing, Combined with PET-CT, to Screen for Cancer and Guide Early Intervention. Science. Apr. 28. (Bert Vogelstein et al)

Data That Mattered

Regeneron and Sanofi reported a not-so-encouraging update on the IL-6 inhibitor, sarilumab (Kevzara). A Data Safety Monitoring Committee recommended a halt to enrollment in an ongoing Phase III of COVID-19 patients with “severe” disease, but recommended continuing enrollment of the cohort with “critical” disease. The companies will also quit giving the low dose, and give everyone the higher dose.

Regeneron and Sanofi had better news from a trial of their PD-1 inhibitor cemiplimab (Libtayo). The drug reduced the risk of death by 32.4 percent in a study, compared with chemotherapy, when evaluated in patients getting their first round of therapy for locally advanced or metastatic non-small cell lung cancer, and with greater than 50 percent of their tumor cells positive for the PD-L1 protein. The finding was so strikingly positive that a Data Safety Monitoring Committee recommended the study be halted early so all patients could get the drug. The companies said they will take the data to US and EU regulators in 2020.

Roche reported that orally administered liquid risdiplam, a survival motor neuron-2 (SMN2) splicing modifier, passed a Phase II clinical trial for infants ages 1 to 7 months with Type 1 spinal muscular atrophy. Researchers reported a significant increase in motor function after 12 months of therapy. If approved by regulators, it would be an alternative to Novartis’ Zolgensma gene therapy, and Biogen’s Spinraza. For this product, Roche leads clinical development, in collaboration with the SMA Foundation and PTC Therapeutics.

Financings

Cambridge, Mass.-based Rome Therapeutics raised $50 million in a Series A financing from GV, Arch Venture Partners and Partners Innovation Fund. The plan is to make drugs for cancer and autoimmunity based on knowledge of repeat sequences of DNA, aka “the repeatome.”

San Diego-based Erasca Therapeutics, a targeted cancer drug developer, raised $200 million in a Series B financing. Arch Venture Partners and Cormorant Asset Management co-led. Jonathan Lim, former CEO of Halozyme and Ignyta, is the co-founder and CEO.

Shanghai-based Mabwell Biotech raised $280 million in a Series A financing. It’s reportedly a rollup of nine R&D and production companies in China.

Oakland, Calif.-based Dascena, a machine learning for diagnostics company, said it raised $50 million in a Series B led by Frazier Healthcare Partners. The company also announced a publication in the BMJ of an algorithm it made to help doctors treat severe sepsis.

Seattle-based Avalyn Pharma raised $35.5 million in a Series B to continue work on pulmonary fibrosis and chronic lung allograft dysfunction. Norwest Venture Partners led. Bruce Montgomery is CEO.

Dallas-based Taysha Gene Therapies raised $30 million in a seed financing co-led by PBM Capital and a fund led by former AveXis CEO Sean Nolan. The company said it’s working on 15 AAV gene therapy programs.

Personnel File

Nathanael Gray and Priscilla Yang, star chemical biologists, are moving from the Harvard/Longwood Medical universe to Stanford University. See the fist pump below from Stanford’s Carolyn Bertozzi. (See was a guest on The Long Run in 2019).

Sue Desmond-Hellmann joined GV as an advisor. She’s the former CEO of the Bill & Melinda Gates Foundation, chancellor at UCSF, and president of product development at Genentech. See the fist pump below from GV partner David Schenkein, who worked with Sue at Genentech.  

New York-based Health Reveal, a clinical AI company, hired Julie Stern as chief technology officer.

Waltham, Mass.-based Xilio Therapeutics, a cancer immunotherapy company, hired Martin Huber as chief medical officer.

Rosana Kapeller was named CEO of Cambridge, Mass.-based Rome Therapeutics (see above). She’s the former chief scientific officer of Nimbus Therapeutics.

Deals

Vertex Pharmaceuticals struck a research collaboration with Waltham, Mass.-based Affinia Therapeutics to work on novel adeno-associated virus (AAV) capsids for gene therapy. Initial focus will be on Duchenne muscular dystrophy, myotonic dystrophy type 1 and cystic fibrosis. Affinia will get up to $80 million in upfront and milestone payments during the research term.

Just Evotec, a leading biologics manufacturer, agreed to work with Ology Bioservices on antibodies for coronavirus. Ology is supported by a defense contract, and is tapping Just as a subcontractor. Terms weren’t disclosed. (See Just Evotec EVP Jim Thomas, on scaling antibodies and vaccines for COVID-19, in this Apr. 16 editorial on TR).

UK-based AstraZeneca and the University of Oxford, also in the UK, announced plans to collaborate on a recombinant vaccine candidate for SARS-CoV-2. Academics bring the discovery work, while industry brings development, manufacturing and distribution capabilities to the table. The first Phase I trial started last week. Terms weren’t disclosed.

Catalent, a contract drug and biologics manufacturer, agreed to work with Johnson & Johnson on manufacturing scale up for the company’s lead COVID19 vaccine candidate. Catalent said it will hire 300 workers to do the job.

Regulatory Action

San Diego-based Neurocrine Biosciences won FDA clearance to market opicapone (Ongentys) as a once-daily oral pill in addition to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes.

GSK secured the FDA green light to start marketing its PARP inhibitor niraparib (Zejula) as monotherapy maintenance treatment for women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status. This is one of those anticipated label expansions that GSK anticipated would make its acquisition of Tesaro pay off.

30
Apr
2020

Real-Time Tracking of Viral Outbreaks: Emma Hodcroft on The Long Run

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30 Apr 2020

Today’s guest on The Long Run is Emma Hodcroft.

Emma Hodcroft, molecular epidemiologist, University of Basel; co-developer, NextStrain.
Photo: Oliver Hochstrasser / www.oliverhochstrasser.ch

Emma is a molecular epidemiologist at the University of Basel, and the co-developer of Nextstrain.

NextStrain is the open-source toolkit built for real-time tracking of viral outbreaks. In the early days, teams led by Trevor Bedford at Fred Hutch and Richard Neher in Basel used it to track viral evolution of Ebola and Zika. Over time, the resource has been adapted to study flu, and now – of course — SARS-CoV-2.

Lots of questions remain about this virus. It’s brand new to science. But a fair bit of what we do know from the early days can be attributed to Nextstrain.

This resource provides real-time information on where community transmission of the virus is occurring, where certain variations are coming from, the estimated size and scope of the outbreak, and more.

It’s a treasure trove. The whole world is watching.

In this episode, Emma provides clear, simple explanations of the basics of viral family trees, what we can learn from them, and what kinds of things we hope to learn later this year.

The Long Run is sponsored by RareCyte.

RareCyte delivers Precision Biology products and services for circulating tumor cell and multiplex tissue analysis designed to accelerate your cancer research. RareCyte leverages a world-class assay design team and end-to-end platform with biomarker-enabling technology to provide CTC assays that are rigorously validated for accuracy and reproducibility.  

RareCyte is the only full-service provider delivering custom assay development services, long-term biobanking of patient samples, CLIA-validated CTC enumeration, multi-biomarker analysis, and single cell retrieval for DNA sequencing.

RareCyte products for comprehensive CTC analysis include the AccuCyte Sample Preparation System, RarePlex Staining Kits, and CyteFinder Instruments, all of which are easily deployed in research labs worldwide.

RareCyte currently supports a wide range of global clinical trials with deep expertise, personalized service, and short turn-around times. Keep your research on track by engaging the RareCyte services team at info@rarecyte.com or at rarecyte.com.

27
Apr
2020

How a Simple Gesture Morphed Into a Full-Time Effort to Feed the Frontline

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27 Apr 2020

Ellen Kuwana, founder, WeGotThisSeattle, a volunteer effort to feed the frontline

As a night owl, I relish the “me time” hours from midnight to 2 a.m. Snuggled in bed, the rest of my family asleep, I scroll through the news and laugh at friends’ video posts.

Like many other science writers, I spent many of those quiet hours in February following the relentless spread of the new SARS-CoV-2 virus, especially as my hometown of Seattle emerged as the first US epicenter.

On Mar. 5, I started working from home. The next week, I arranged for my college-age daughter to come home from UCLA. I was relieved when Seattle Public Schools closed and my younger daughter didn’t have to walk down any crowded halls. I wanted everyone home and safe.

My husband, however, is a physician–scientist who does essential work at the University of Washington and a nearby hospital. So we could not all keep entirely safe.

Just one meal for UW Virology

As the UW Virology department scaled up its breakneck efforts to process as many COVID-19 tests as possible, I started hearing from my friends at the university that some of their grad students and postdocs were pitching in at the testing center.

I remembered how tedious it is to pipette all day—right out of college I had worked as a lab tech at the Human Genome Mapping Center at UC San Francisco. As I scrolled through Twitter one night, a tweet from UW Virology landed atop one from a pizza place offering free pizza for healthcare workers.

Something clicked. “Who’s feeding the scientists?” I said to my dog.

She looked back at me as if to say: “Good question.”

On Mar. 13, past midnight again on Twitter, I typed a hurried “Who wants to help me feed UW Virology?” with a #COVID-19 hashtag.

Pagliacci, one of the biggest pizza franchises in the region, responded within minutes. They donated enough pizzas and salads to feed 70 people who were helping out, working long hours and taking extra shifts.

As I drove to deliver the food, I marveled at the lack of traffic, but it also felt sort of weird in Seattle. I greeted the person who came out to load the food onto the cart. She was all smiles. I remember her commenting on how the food would boost morale.

I offered to get the door for her.

“Best not to touch it, or we’ll have to wipe it down,” she said somewhat apologetically.

At first, I thought I would pay for all the food as a one-time gesture of appreciation to UW Virology. But as the adrenaline of that first donation wore off, I started to think more broadly about how to support local medical researchers and hospital workers. It was a bit overwhelming to think of all the medical and research staff in Seattle who were working so hard, day and night, from processing specimens and COVID-19 tests, to caring for patients.

Getting them food was one thing that I could do, and would help to keep their energy and spirits up for a prolonged siege. An army, some famous general once said, marches on its stomach.

Pretty soon, I found myself thinking about this a lot more than just during the wee hours of the morning. With money I was prepared to spend on my own for donated meals, on Mar. 20, I called a friend, placed an order for Rubinstein Bagels and went to buy cream cheese, plates and knives.

People were not social distancing at the grocery store, which made me nervous. I needed to keep myself safe and healthy in order to be able to deliver the food to hospitals safely. Now, to figure out where the bagels could go…

I started working my contacts at UW Medicine, which had closed its hospital to visitors. Through a surgeon friend, after many emails, I reached a point person who could accept the bagels. We did the social-distance dance to unload them onto a cart.

I made a mental note: next time, let the institutional contact unload the food right from my car.

Third meal for UW Virology and WeGotThisSeattle was born

Next time came quickly. I had put up a personal fundraiser on Facebook, inviting friends in Seattle to donate money for meals to UW Virology and other sites. By this time, news was everywhere about the lack of testing nationwide, and our UW Virology lab’s heroic efforts to meet our region’s need for more tests. Within a few days, I had enough donations for a third meal delivery.

Because so many restaurants had shut down, what had started out as a token of appreciation was now more like a lifeline to those who had nowhere else to get a quick bite during their work shift. My original question, “How can I be useful?” was clearly answered. People in the labs posted pictures and thank-you notes on social media. My inbox received a few heartwarming notes. It all confirmed that this was something I should run with.

Pizza, bagels…what next? I remembered Taste of India, one of my favorite local restaurants. On the phone, the explanation of what I was doing had hardly left my lips when the owner interrupted me.

“Ellen, what do you need? We will donate it all.”

His calm, swift response made me choke up.

It was a powerful moment, and not just personally. A tweet I posted describing that act of kindness was viewed by more than 2.5 million people, with more than 31,000 likes.

I can’t explain why this tweet went viral, but I think it has to do with so many of us wanting to help, but not knowing how.

Helping local restaurants

Things took off from there. Donations poured in — donations of funds, but also of food from many restaurants. When restaurants I contacted asked me to pay full price, I happily did. Those that had to ask almost certainly need the funds. And that, too, is part of supporting our community.

From what I’ve heard, many restaurants in Seattle are down at least 80% in revenue. As I’ve picked up food, I’ve seen many places where only the chef and owner (sometimes one and same) are working. They tell me how they hope to hire back their staff, how they don’t know how to make their rent payments. I’ve learned that some of the restaurants that donated food were not in a position to do that, when they were falling behind in their rent.

It all felt quite heavy. But their hope and their eagerness to help feed healthcare professionals and others risking infection to do vital work was also uplifting.

Now when I contact restaurants, I emphasize that I want to help them as well, and it’s OK to charge something for the food. The donated funds enable us to support local business while we feed the frontline.

A recipe for success

With encouragement from friends old and new (and I am forging strong connections with restaurant owners and the point people at the hospitals and UW Virology who have promised me hugs when this crisis subsides) and support from former strangers who have contacted me to help (and I finally got smart and said Yes to offers of help), we are moving ahead with getting systems in place to scale up.

We’re now collecting tax-deductible donations at WeGotThisSeattle. Since starting this project in early March, we’ve raised about $36,000 in donations from individuals. We’ve coordinated food to 30 sites in and around Seattle from 35 local restaurants and businesses, feeding more than 6,300 people. The meals have fueled workers at nursing homes, fire and police stations, and homeless shelters. They have fed bus drivers, EMTs, hospital janitors, and switchboard operators.

I quit my job to focus full time on this volunteer effort. It seemed like time for a change anyway, and I’ll find a new job when this is over. This is the best way I can contribute, right now.

Our meal-delivery effort is one of many: since mid-March, the University of Washington has received more than $300,000 in donated meals from a wide range of groups. The Swedish Hospital system in Seattle estimates that its workers have received 190,000 meals from 280 donors.

I attribute the growth and success of WeGotThisSeattle to four crucial factors:

  1. Contacts to gain access and find the right point of contact at the recipient institution;
  2. Processes that demonstrate your reliability and generate confidence in those partners;
  3. Protocols that food-delivery drivers and recipients follow to keep all involved as safe as possible by preventing any contact with the food during transport and hand-off; and
  4. Social media presence to reach a wide audience.

Thanks to everyone who has contributed to our effort thus far, and to those who are finding their own ways to help.

To Learn More:

  • WeGotThisSeattle.co for media coverage, list of restaurants, sites, and a tax-deductible donation portal (all fees waived until June 30)
  • NASEM Forum on Postsecondary Response to COVID-19

Photo Gallery:

 

25
Apr
2020

A San Francisco Doctor Answers the Call to New York

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25 Apr 2020

Ethan Weiss, MD, Associate Professor of Medicine at UCSF; Principal Investigator in the Cardiovascular Research Institute

The week things got really interesting was the week of March 16.

That’s when Sara Cody, the Santa Clara County public health officer, and her legion of public health heroes made the gutsy call – the first of its kind in the nation — to shut things down in the entire 6-county San Francisco Bay Area, home to more than 6 million people. Only two deaths from COVID-19 had been reported at the time. She stuck her neck out there, saying we had to get in front of this pandemic, or else.

That same week, I had agreed to cover the inpatient service for a colleague at UCSF who was advised to avoid the hospital by their physician.

I’m a cardiologist, not an ER doctor. I remember feeling intense uncertainty and fear – mostly fear of the unknown. Everything was eerie and everyone was anxious. We all expected the hospital to be overrun by the weekend. That was how it had happened elsewhere.

When I actually got into the hospital, my fears faded. I got busy and distracted, which created a weird sort of calm. We were just waiting for the surge. I was comforted by how prepared everyone and everything was. Sure, there was concern over lack of PPE, but mostly people were feeling good and seemed focused. There were tons of empty beds. It seemed like we were ready even despite the strange act of waiting for disaster. I don’t remember ever feeling that way before.

And then nothing happened. By the end of the first weekend, the residents were asking for teaching – from me. They were bored. I’ll admit that I started to wonder how long we’d have to wait to know if the surge might not be coming. I was counting days from the lockdown on Mar. 16. I didn’t talk about it at first but I definitely started thinking. No one wants to be overconfident, in that “famous last words” sense.

By the next weekend, I was comfortable to talk about how we were doing well at UCSF. I got this text from a friend on Mar. 26:

“how bad is SF rn? seems quieter compared to nyc”

“It is quieter,” I responded. “I believe that is meaningful. They are still expecting a big surge and are opening closed hospitals, but with each passing day, I get more optimistic. We are now 11 days into the quasi-lockdown, and there has been very little sign of badness at least at our hospital”.

We all played this game for a few more weeks while we were told the surge was coming but it was clear it was not. At the same time, it was clear that other parts of the country were being devastated.

On Mar. 20, I sent this tweet: “I don’t mean this in any other way except genuine concern but I am very worried about what is happening in NY”.

At that point, there were 2,468 cases in NYC.

As of Apr. 24, there are more than 150,000 confirmed cases and over 11,800 deaths. (Source: NYC Health). 

My colleagues and I watched the heartbreaking news from New York like everyone else.

Toward the beginning of April, I started to ask when we would consider sending people from UCSF to help in New York hospitals or to other hard-hit areas. I was told it was too soon. Then on Apr. 10, I tweeted: “Wow @UCSF is sending a team of clinicians to NY tomorrow for a month!”

I was happy. I was happy for New York. They so desperately needed the help. I had talked to friends and colleagues there. They were depleted and tired in every sense of the word. I was also happy for my colleagues – but honestly, I was also jealous.

I was busy. Not busy helping out in the ER at UCSF Medical Center, fortunately. But I was as busy as I have ever been, balancing seeing patients on Zoom with writing papers and grants while also trying to help guide this nascent startup I had helped found just a year and half ago. And then I got very caught up in the story about thrombosis and COVID-19 and have been working on helping to spin up at least two clinical trials to see if anticoagulant therapy could be helpful.

And of course at home, while my two daughters are mostly self-sufficient, there was plenty of work to be done. My wife’s business has been decimated. We are all crowded into a small house and we are doing things we don’t usually do (like clean). There were some amazing upsides and the most notable was spending so much time with the three people that mean the most to me on this planet. One of the most surprising daily joys was making and eating lunch as a family. It feels very European.

But despite all that, I still felt drawn to New York. I mentioned it at a faculty meeting a few weeks ago and was told there was no need for us. Then I heard UCSF was actually going to send a second team and they were asking for volunteers from Cardiology.

I spent at least 24 hours thinking about it. I tried hard to think about all the many reasons I wanted to go and tried as best I could to think about how much was motivated by a genuine sense of mission or perhaps a desire to be in the middle of the action or maybe even from a little envy of my colleagues or maybe even just curiosity or attention-seeking.

I wrestled with it. I finally asked my wife. I reassured her that I was not worried from a health perspective and that I’d be careful. I also acknowledged that it would be a tremendous burden on her to have to parent alone for two weeks in this absurd time, when she’s naturally stressed about her business and the kids are at home all the time. But I also said that everything else could wait. I reminded her that we had planned to take a two-week vacation to Japan in June and that I had numerous meetings and they had all been cancelled and that it was actually a very good time to go in many ways. My lab is basically closed. Most other activities are slow or non-existent. The startup is making it. And the thrombosis trials would/could go on without me.

We also talked about my motives. She grilled me about why I wanted to go, and I told her that I was not entirely sure, but I also told her that I was hearing a dog whistle and it was driving me mad. However, I also said I could not go without her support – her genuine support. After a short time, she looked me in the eye and said, “Ethan, you have to go.”

This “dog whistle” is a mysterious thing to explain. It’s some kind of call of duty, like a ghost of a first-year med school professor whispering in my ear to go. No one is explicitly calling on me, as if I have to go do this. But maybe there’s a little guilt implication in some conversations, as if to say “hmm, wonder why you aren’t getting on a plane to come to New York?”

So I told Jeff Olgin, my division chief, that I wanted to go. He connected me with Michelle Mourad who was managing the process here. By Wednesday, I was credentialed and licensed with maybe 10 minutes of work on my part. Do I have a medical license? Check. It was spectacular.

By Friday, we had a flight scheduled and had an orientation call with the hospital in New York where we are headed.

This morning, Apr. 25, three amazing women joined me in a desolate SFO airport and we boarded a plane. There was a very nice little ceremony. Mark Laret, the CEO of UCSF Health, came and gave a short talk. Sam Hawgood, our chancellor was there, as was Josh Adler and also Kim Murphy, the Director, Special Events & Community Relations at UCSF Health and the person who organized all this.

As our team of four medical personnel gathered in the jetway, we all muttered to each other about how uncomfortable we were with the pomp and circumstance. We just wanted to get there. We wanted to get to work. When we finally got on the plane, we found many other health care practitioners of many stripes from around the Bay Area – ALL of whom were volunteering to go work in NYC. Nobody gave them a ceremony.

So this brings me to the tension I have over the attention doing something like this might bring. I don’t want it to be about me. None of us does. But I also think there is value in telling the story. I think there is value in telling people about how I decided to come, how I feel and some of what I see. I don’t know too much about what I am going to do. I found out yesterday that I will be an attending physician in what used to be a cardiac ICU but that has been transformed (like all ICUs in NY) into a COVID ICU.

I’m not scared of getting sick. I am uneasy about how brutal it will be, tending to wave after seemingly endless wave of critically ill patients. But I will try to stay focused on the task.

What really bothers me is that “first day of school” fear. It’s a lot like how I felt 20 years ago when I came back from the lab to do my clinical fellowship. Will I know what to do? How do I manage a ventilator or volume status? Can I still put in a central line, and will I need to? My wife reminded me this morning on the way to the airport that it’s like riding a bike. But I also have not worked at a new hospital since 2001, so I am feeling uneasy and unsure of myself. There could be slightly different equipment, procedures, colleagues who have already been through the ringer and are moving at warp speed, while I’m trying to get up to speed.

However, all of that is balanced by a strong desire to get in there and get to work. I am excited to learn, to see, to make myself useful.

I’m slightly surprised by the emotions. I did not expect tears at the airport this morning. Ultimately, I am going to miss my family desperately. There is nothing I will ever be able to do to repay them for letting me go and answer this dog whistle.

Over the next two weeks, I will try to write occasionally about my experiences. If I do this right, it will foster a little more understanding of what it’s like on the frontlines. Those of you who know me know that I will be honest and raw and maybe even sometimes crass. But I have such tremendous respect for how people have pulled together to contribute whatever way they can in this wicked moment. This challenge is vastly bigger than any individual effort. I have been trying to remember to thank everyone who has a role to play — from the TSA agents to the custodial staff to the flight attendants (even if they are not serving coffee on this flight!).

It is precisely at times like this that I remember the lesson my Dad taught me when I started my first clinical rotation in medical school now 27 years ago: always appreciate and thank everyone – everyone and most importantly the people who never get thanked.

Now more than ever, there should be no thankless jobs. Everyone has their purpose, everyone is answering a different kind of dog whistle.

24
Apr
2020

A Sad Week of Reckless Leadership

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24 Apr 2020

Luke Timmerman, founder & editor, Timmerman Report

The first US death from COVID-19 was reported on Feb. 29.

Today, Apr. 24, the US death toll exceeds 50,000.

That’s more than Italy and Spain combined. Even though we had early warning. It’s tragic.

There’s also a reason why the death toll hasn’t been higher. It’s because of large-scale physical distancing in this expansive country of 330 million people.

After a few weeks, people are understandably getting restless. Tens of millions are unemployed and fearful for their livelihoods. The federal government has thrown up its hands in many respects, passing the buck of leadership to state and local governments. Now we’re seeing a mishmash of local decisions.

The state of Georgia – a place with 10.6 million people, more than 20,000 confirmed infections, and the busiest airport in the country – is led by a Governor that is opening up large swaths of the economy today, relaxing the physical distancing restrictions there. He’s doing that even though his state hasn’t complied with the federal guidelines that say reopening can begin in phases after new infections go through a 14-day decline.

Local decisions like these will determine just how ferocious the second wave of infections will be across the entire country this summer and fall.

Jeff Duchin, MD. Health officer. Public Health – Seattle & King County

“It’s like peeing in one end of the pool. It doesn’t just stay there,” said Jeff Duchin, the leader of Seattle and King County’s public health agency, on a webinar I moderated yesterday for Life Science Washington, the local trade association.

Duchin called the decision of Georgia Gov. Brian Kemp “reckless.” Given the latest models he’s been reviewing, Duchin said he believes the second wave of infection this fall could be two to three times larger in magnitude than what we’re seeing now in Seattle and King County.

Meanwhile, the CDC – once the gold-standard agency in public health — is still AWOL when it comes to coordinating a national testing program. We are nowhere near the number of tests (20 million a day at peak according to one Harvard estimate) we need to be doing to gain the knowledge necessary to suppress the virus with targeted quarantines. Without knowledge from tests, it’s hard to imagine a safe and responsible reopening of the economy.

Still, without any clear idea of where the virus is, we have protestors agitating in state capitols to lift the physical distancing orders. Some people who are sick are even being urged to show up, to exercise their rights as Americans to travel freely. They revel in thumbing their noses at the experts. They’re good at provoking all of us to gape in amazement and horror, good at distracting us from what’s important.

Yesterday, the President suggested that people might want to try ingesting bleach to fend off the coronavirus. Or maybe ultraviolet light.

Talented journalists who could otherwise be investigating breakdowns in our national testing system and kicking the bureaucracy in the rear end are now writing about why it’s a bad idea to drink bleach.

How did we get ourselves into this tragedy? This farce?

How do we get out?

I don’t know all the answers. But I do know that people with education, drive, and good faith – that’s you – need to do constructive things to be part of the solution. That extends beyond this pandemic, and goes into repairing the social fabric, investing in science and education, and helping vulnerable populations. It’s a heavy topic, rethinking citizenship, rethinking what our responsibilities are to our fellow human beings. This will take time to sort out. I believe we can come out the other side better.

Be safe. Be strong.

To borrow a quote from my late father-in-law:

“Be Good to Each Other.”

Science

Testing

  • Contamination at CDC Lab Delayed National Rollout. Washington Post. Apr. 18. (David Willman)
  • Testing Needs to Triple Before Reopening. NYT. Apr. 17. (Keith Collins)
  • Unapproved Tests From China Being Used in 2 States. NBC News. Apr. 16. (Gretchen Morgenson)
  • Antibody Test, Seen as Key to Reopening the Country, Does Not Deliver. NYT. Apr. 19. (Steve Eder et al)
  • Will Antibody Tests Really Change Everything? Nature. Apr. 18. (Smrity Mallapati)

Treatments & Vaccines

  • Novartis is Running a Randomized Study of Hydroxychloroquine. STAT. Apr. 20. (Matthew Herper)
  • A Guide to Disrupted Clinical Trials. BioPharma Dive. Apr. 22. (Ben Fidler)
  • Data on Gilead’s Remdesivir, Released by Accident, Shows No Benefit. Company Still Sees Reason for Hope. STAT. Apr. 23. (Ed Silverman et al)
  • Gilead Statement on Remdesivir Leaked Abstract. Apr. 23. (Gilead Sciences)

Policy

Models

Worth Watching

Policy

  • CDC Director Warns Second Wave Could be Worse. Washington Post. Apr. 21. (Lena Sun)
  • Advice from Abroad for US Governors. ProPublica. Apr. 18. (Stephen Engelberg et al)
  • The Inside Story of how the SF Bay Area Got Ahead of the Curve. Kaiser Health News. Apr. 21. (Angela Hart & Anna Maria Barry-Jester)
  • What Makes SARS-CoV-2 the Perfect Pathogen. The Bulwark. Apr. 21. (David Shaywitz)
  • US Should Allow Volunteers to Get Infected with Coronavirus to Test Vaccines, Lawmakers Argue. Apr. 21. Science. (Jon Cohen)
  • Barr Threatens DOJ Legal Action Against States Over Lockdowns. Bloomberg News. Apr. 21. (Chris Strom)
  • FDA Cautions Against Use of Hydroxychloroquine or Chloroquine Outside Clinical Trials. Apr. 24. (FDA Statement, Repeated on Twitter by Dr. Janet Woodcock).

Humanity at Its Best and Worst

  • Seattle ER Doctor Saved from Cytokine Storm by IL-6 Inhibitor Actemra. LATimes. Apr. 13. (Richard Read)
  • In Pursuit of PPE. New England Journal of Medicine. Apr. 17. (Andrew Artenstein)
  • Healthcare Workers Stand Against Lockdown Protestors in Colorado. NBC News. Apr. 20. (Ben Kesslen)
  • Pandemic Victims. Sick & Dying, but Not from The Virus. NYT. Apr. 20. (Denise Grady)
  • It’s My Job to Call People To Tell Them They Are COVID-19 Positive. STAT. Apr. 24. (Caroline Schulman)

TR Coverage

  • Build Back Better. Apr. 22. (David Shaywitz)
  • Massachusetts Biotechs Consider How to Return Safely. Apr. 22. (Adam Thomas)
  • Singapore’s Crisis: How It Forgot to Check Its Blind Spot. Apr. 21. (Carolyn Ng)
  • How to Navigate a Blizzard of Antibody Studies. Apr. 21. (Ruth Etzioni)
  • Cultivating a Tolerance for Adversity. Apr. 20. (Eric Murphy)

Personnel File

Rick Bright, the head of the US government’s Biomedical Advanced Research and Development Authority (BARDA), a key unit for vaccine development, abruptly left his post. He later filed a whistleblower complaint, saying he was being sidelined by the administration because of his unwillingness to promote unproven therapies. See his statement.

Greg Guyer was hired as chief technical officer and EVP of global manufacturing and technical operations at BioMarin Pharmaceutical. He was formerly SVP of operations at Bristol-Myers Squibb. He takes over from company veteran Robert Baffi.

Investing

  • Value Creation and Destruction. Biotech IPO Performance. LifeSciVC. Apr. 17. (Bruce Booth)
  • It’s Time to Build. A16Z Blog. Apr. 18. (Marc Andreesen)
  • Big Pharma Calls for Billions in Upfront Coronavirus Funding. Apr. 20. Financial Times. (Andrew Jack)

Financings

Cambridge, Mass.-based Affinivax, a vaccine developer with a lead program for pneumococcal infections, raised $120 million in a Series B, led by Viking Global.

South San Francisco-based ORIC Therapeutics, a company working on cancer resistance, raised $120 million in an IPO of 7.5 million shares at $16 apiece.

Lexington, Mass.-based Accent Therapeutics, a cancer drug developer focused on RNA-modifying proteins, raised $63 million in a Series B financing. EcoR1 led.

San Diego-based Arcturus Therapeutics, an RNA-based medicine developer, raised $80 million in a stock offering of 4.7 million shares at $17 apiece.

San Francisco-based Nitrome Biosciences raised $38 million in a Series A financing co-led by Sofinnova Partners (the European-based venture group) and AbbVie Ventures. The company is working on Parkinson’s disease.

Bethesda, Maryland-based Aledade raised $64 million in a Series C financing to continue expanding its network of physician-led Accountable Care Organizations. OMERS Growth Equity led.

San Francisco-based Unlearn.AI, a company that creates ‘digital twins’ to serve in clinical trial control arms, raised $12 million in a Series A. 8VC led.

Deals

Ann Arbor, Mich.-based Esperion Therapeutics pocketed $60 million upfront from Otsuka Pharmaceuticals as part of a deal to commercialize its two new cholesterol-lowering products in Japan.

Gilead Sciences struck a three-year collaboration with oNKo-innate to work on engineered Natural Killer cell therapies for cancer.

Veracyte announced an exclusive license from Yale University to develop the first genomic test for idiopathic pulmonary fibrosis, based on a 52-gene signature.

Regulatory Action

The FDA gave the green light to Incyte to start marketing pemigatinib (Pemazyre) for patients with locally advanced or metastatic cholangiocarcinoma. The drug is made to target fibroblast growth factor receptor 2 (FGFR2) fusions, which are detected by the FoundationOne CDx test.

Sanofi got FDA clearance for a new quadrivalent meningococcal vaccine.

Data That Mattered

Exelixis and Bristol-Myers Squibb reported that they hit the primary endpoint in a clinical trial of patients getting their first round of treatment for renal cell carcinoma. Patients got the combo of nivolumab (Opdivo) and cabozantinib (Cabometyx), and were evaluated for progression-free survival, overall survival, and overall response rate. Details to come at a medical meeting.

AstraZeneca and Merck’s PARP inhibitor, olaparib (Lynparza), passed a Phase III trial for men with advanced metastatic, chemical castration-resistant prostate cancer. The study looked at men with homologous recombination repair gene mutation (HRRm). Data to come at a medical meeting.

Tweetworthy

Someone we all need a little gallows humor.

Sometime you laugh, sometimes you cry. Sometimes you just have to slap your forehead.

“Some experts say” it’s bad to drink bleach. Golly, you don’t say?

And sometimes members of the evidence-based, reality-based community decide they have to get involved in the debate, however messy and ugly it can sometimes be.

22
Apr
2020

Build Back Better

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22 Apr 2020

David Shaywitz

As the nation has struggled to cope with the devastation of the COVID-19 pandemic, New York Governor Andrew Cuomo has become the voice so many have looked to for support and leadership.

What Cuomo seems both to offer and effectively communicate is not just a mastery of the facts, but also a grounded yet hopeful narrative. The story he projects serves as a resonant, unifying, activating force that helps us to see our collective trauma as a valuable opportunity to grow.

He’s challenging us “to learn the lessons and to build back better.”

The ability to reimagine your life story in a more constructive way allows some to endure unimaginable suffering and emerge intact, even stronger, in the aftermath. Such “super-survivors,” David Brooks wrote in 2015, leaning on extensive psychology research on post-traumatic growth by Richard Tedeschi among others, have traits “that enable them to come back stronger than ever. These people are often deluded in good ways about their own abilities, but completely realistic about their situations.”

Post-traumatic growth “is not blind optimism, denial, or deception of self or others,” Tedeschi told me. “It does not dismiss distress and loss.” Rather, he argues in his latest book, Transformed by Trauma, which focuses on military veterans, the experience of growth “is a process – a difficult one, and an outcome that is life-changing and worth the struggle.”

The key, Brooks continues, is the ability “to write a new story that imagines a life better than before.” He adds, “Researchers have found that people who thrive after a shock are able to tell clear, forward-looking stories about themselves, while those who don’t thrive get stuck ruminating darkly about the past.”

Holocaust super-survivors are in this group. These are people who went on to live fulfilling lives, raise families, and in some cases even win Nobel Prizes, start great companies, and write books that moved the human spirit. One thing these people had in common, Alana Newhouse explained on a recent podcast, was that they were “people who understood a story, understood that the holocaust was the prologue, and the rest of their lives was actually the book.”

I’ve seen the value of this reframing up close as well, in the context of my parents’ dyslexia research, and their “Sea of Strengths” model, which enables dyslexics to understand that while they have specific challenges matching sounds to letters, this is occurring in the context of many other strengths, including often high intelligence and exceptional creativity. 

Dyslexics, as my mother and brother Jonathan describe in the new edition of Overcoming Dyslexia, are not “stupid,” despite what misinformed teachers or other adults might have said about them in their youth, when the children struggled to read. By helping dyslexics reframe their life story — and to receive the accommodations they require (realism, again) — this research has enabled so many previously despondent, struggling people to pursue ambitious careers that many had never thought possible.

California Gov. Gavin Newsom, another state leader standing out like Cuomo in crisis management, happens to be dyslexic.  So is Johns Hopkins biologist Carol Greider, who received the 2009 Nobel Prize in Medicine; Nancy Brinker, founder of Susan G. Komen for the Cure; and surgeon and former CEO of the Cleveland Clinic Toby Cosgrove, who candidly discusses his struggles with dyslexia with Lisa Suennen and me on our latest episode on Tech Tonics.

The power of a reframed narrative also comes through in recent interview of legendary quarterback Tom Brady by radio personality Howard Stern (each GOATs in their own right). Brady was asked how he handled seemingly hopeless situations. His response:

“We were down 28-3 against Atlanta in Super Bowl 51. You can look at that situation and basically quit and say, you know, ‘F— it. We have no shot of winning,’ or you can say ‘This is going to be an amazing comeback. When we come back from this, this is going to be the defining moment in life,’ or a defining moment in a professional career. 

“I think when you shift your mind and think that way, it becomes very empowering as opposed to very discouraging. So anytime we’re down in a game, I think, ‘Man, if we come back and win this game, we’re the hero,’ rather than ‘Oh, s—, we’re screwed. We have no shot.’”

As usual, Brady’s right. Mindset matters. 

The nation now confronts the overwhelming challenge of pulling ourselves out of a devastating crisis that has left 47,430 Americans dead as of this writing on Apr. 22. Our economy is in ruins, and the nation is distraught.

To emerge as super-survivors, we need not just to persist, as Cuomo emphasizes, but to advance with energy and hope. We need to embrace a new story, one that acknowledges the brutal reality, while allowing us to envision a more promising future. We need a restorative narrative, one that recognizes our loss, supports us through our painful struggle, and enables us to move forward.

The narrative emerging from the White House — our response has been perfect and flawless, plenty of tests are available, all problems are someone else’s fault — lacks both face validity and emotional resonance. 

This is not the narrative most of America is looking for. Nor is it the redemptive vision we need.

The country recognizes the global pandemic is a humbling experience for us all. No one anticipated this “perfect pathogen” with perfect clarity. We still struggle to understand even the basic scientific facts of its spread, how the virus interacts with the immune system, and ultimately how to best contain it with testing, treatments, and ultimately a vaccine. The path forward is uncertain. We get this.

We’re neither expecting nor awaiting a flawless, omniscient protagonist to lead us forward. Instead, we’re poised to be inspired by someone one who, like the rest of us, has been roughed up by this experience, yet has emerged, bruised but not defeated, wiser, and determined to coax a traumatized country through this difficult time. 

Growth through adversity isn’t a partisan message — it’s as conservative as it is progressive. As Cuomo points out, it’s deeply ingrained in the American experience. And, as he suggested, in the human experience.  

“We’re going to be the better for this,” Cuomo promised this week. “It’s the hard times in life that actually make you better, make you who you are, if you’re intelligent enough to learn from them.”

He added, “We have to do this individually and collectively.”

Preach.

21
Apr
2020

How to Navigate the Blizzard of COVID-19 Antibody Studies

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21 Apr 2020

Ruth Etzioni, Full Member, Division of Public Health Sciences, Fred Hutch Cancer Center

What is the single thing you wish you knew about COVID-19?

Here is what I wonder about most.  

How many of us have had it already without knowing it – either because we did not have symptoms, or because we thought it was something else, or because we thought it might be COVID-19 but we could not get tested?

My interest in this matter is both personal and societal.

Personal, because three days after I came back to Seattle from London Jan. 27 on a packed Delta flight, I came down with a major chest cold.

During the day, I was OK. Things went downhill as evening came on, and I suffered with coughing fits and fevers through each night. This went on for 12 miserable days.

Was it COVID-19? If, like me, you have searched for “did I have the coronavirus,” it’s clear that plenty of people are wondering the same thing.

Having recovered from that nasty cold, and having gotten a negative test earlier this month, my interest is now more societal in nature. Societal because we need to know how many people have had COVID-19 to understand the real reach of the virus, its true contagiousness. We must be able to identify who is immune in order to carefully plan our exit from lockdown.

So I have been drawn to three new studies that report the results of serology tests conducted on persons without a prior COVID-19 diagnosis – in the City of Chelsea, Massachusetts; in Gangelt, a municipality in the Heinsberg district of northwestern Germany; and in California’s Santa Clara County.

All three of these places are known virus hotspots. Chelsea has the highest rate of infections in Massachusetts, Gangelt had an outbreak following a superspreading carnival event in mid-February, and Santa Clara County (the home of Silicon Valley) became an epicenter in early March.

Their results are strikingly different. In Chelsea, 33% of individuals tested were positive, in Gangelt 15%, and in Santa Clara 1.5%.

Like all diagnostic tests, antibody tests can be wrong in two ways. First, they may produce a false negative – you have had the virus but the test doesn’t detect it. Or they may produce a false positive – you haven’t had the virus, but the test says you have. The false negative and false positive error rates define the test accuracy. There are concerns that the majority of the tests currently being marketed (more than 95 to date) do not make the grade.

Because antibody tests are not perfect, we can’t simply use the reported fraction testing positive to estimate how many people have really had the virus. If the false negative rate is high, that means we have likely undercounted; if the false positive rate is high, we have overcounted. We can use these error rates to fix the fraction found to have antibodies so that we get the right result. Let’s see how this worked in Chelsea, Gangelt and Santa Clara.

The Chelsea study used a rapid test to look for antibodies in the blood from BioMedomics. The company says its false positive and false negative error rates are around 10%. When the researchers accounted for these error rates, they found that although 33% of cases tested positive, the actual number with antibodies was lower – around 30%. That’s still a startlingly high prevalence, much higher than the 2 percent officially diagnosed via the standard RT-PCR diagnostic test. It tells us that in Chelsea, there are 15 cases that we don’t know about for each case already reported.

The Gangelt study did not specify which antibody test they used. Researchers there reported a low false positive error rate (less than 1%) but did not provide a false negative rate. More clarity on the product being used, and its error rate, is needed to evaluate the results. But as things stand, the number of people estimated to have been infected in Gangelt is between 15-17 percent. (That assumes false negative rates in the range of 5-15%.)  In the Heinsberg region, in which Gangelt is located, almost 4% of the population was officially diagnosed via the RT-PCR-based diagnostic test. This implies that in Gangelt, there are roughly 4 cases we don’t know about for each diagnosed case.

And in Santa Clara? This study used a test from Minnesota’s Premier Biotech. Based on the reported performance of their test (and some independent validation at Stanford University), the authors did the math. They concluded that 2.5% had previously been infected. Based on an even tinier fraction of the population with a confirmed diagnosis, the researchers concluded that there are at least 50 cases that we don’t know about per diagnosed case in Santa Clara County.

So. 4 to 1, 15 to 1, and 50 to 1.

That’s a lot of variation in the balance between cases we know about and cases we don’t. What gives?

One answer is that the estimates may be incorrect; for example, a chorus of criticism has surfaced about the Santa Clara study. Critics argue that the method of sampling (via Facebook ads) preferentially enrolled subjects who had had symptoms, and the study likely understated the false positive rate, both of which could have inflated the estimated prevalence of antibody-positive individuals.

But a study done in Los Angeles just reported very similar results, suggesting as many as 55 undiagnosed cases per known case of COVID-19 there. This study was better designed because it used a more random sampling method, but it used the same serology test as the Santa Clara study. Therefore, it doesn’t address the false positive rate issue. This is important, because if you don’t get the error rates right, you can’t properly fix the reported fraction testing positive to figure out the real prevalence of antibody positivity.

Another answer, one that bears serious consideration, is that we’re oversimplifying. The notion that there is a single number – of silent, undiagnosed COVID-19 cases for each reported diagnosis – is just too basic. Clearly, it depends on where you live.

Going deeper, we can look to three key factors that drive the balance between cases that we know about and those that we don’t: testing, timing, and demographics.

Germany is famous for its massive testing response to COVID-19, particularly in the region of Heinsberg, the location of one of the country’s largest outbreaks. The opposite was true in Santa Clara, where testing got off to a slow start. By Apr. 1, half the number of cases per capita had been diagnosed in Santa Clara County compared with Washington State, despite both being among the locations with the earliest recorded US cases of the virus, in late January.  

More testing leads to more people being diagnosed. This means more cases that we know about, and fewer that we don’t, and ultimately, less of an imbalance between undiagnosed and diagnosed cases. With much less testing, the number of known cases drops, and this could explain the Santa Clara findings.

Timing is critical too: when infections took off, when testing ramped up, when social distancing and other restrictions began, when the antibody test was actually done.

Timing impacts not only the balance between diagnosed and undiagnosed cases, but the overall size of the infected population. It’s a little hard to know how much this played a role in the dramatic difference between Chelsea (30%) and Santa Clara (2.5%) but, for the record, the Bay Area’s shelter-in-place order came on Mar. 16 when there had been just two reported deaths in Santa Clara County. Massachusetts came later, ordering the shutdown of non-essential businesses on Mar. 24 after 9 COVID-19 deaths in the state.

The size of the infected population and the balance of known infections don’t just depend on testing and timing. Demographics also matter.

According to an article in the Boston Globe, about 65% of the residents of Chelsea are Latino, and only 21% are white. Many live in crowded conditions, where it is hard to isolate. And many work in service industries and health-related fields, so they can’t shelter at home.

In contrast, only about 25% of the residents of Santa Clara County are Latino and 51% are white. Many work in the tech industry and are able to work from home. Population density in Santa Clara County is an order of magnitude lower: around 1,500 versus 18,000 per square mile in Chelsea. So, contact rates that drive infectious transmission are likely far higher in Chelsea than in Santa Clara County.

These factors are some you might want to think about when interpreting the impending blizzard of antibody studies, which I am guessing will continue to show highly variable results.

The take-home message though is this. The balance of undiagnosed to diagnosed COVID-19 cases is not just about biology. It depends on many other things. Ultimately, while 50 to 1 seems high to me, these studies make me think that the size of the undiagnosed population in the US is a lot bigger and the virus a lot more contagious than we imagined. State and national policy makers can and must use this knowledge to shape our strategy for carefully exiting from COVID-19 lockdown.

21
Apr
2020

Singapore’s COVID19 Crisis: Forgetting to Check the Blind Spot

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21 Apr 2020

Carolyn Ng, managing director, Vertex Ventures HC

It is with a heavy heart that I pen this follow-up piece on Singapore’s COVID19 situation.

In the past few months, the city state has been hailed as an exemplar of early, preemptive and targeted response to combat the pandemic. Other countries have studied its response.

As I wrote here on Mar. 19, despite being a densely populated high-risk state, Singapore managed to keep its cases extremely low. No deaths were reported between late January and mid-March. But even then, there were warning signs. In that same piece, I expressed concern for a potential second wave of cases that could be triggered by the massive influx of Malaysian foreign workers who rushed to enter Singapore before Malaysia closed its borders on Mar. 18. Interestingly, while Singapore did experience a second wave in late March, the new cases were not attributed to foreign workers. Most of the new cases were from Singaporeans returning home from travels to global hotspots such as the UK and US (covered here).

As it turned out, that source of new cases was only the beginning. It will be a long time before Singapore can pop the champagne, (or throw back a Tiger beer in celebration, in Singapore’s case).

At time of writing today (Apr. 21), there is a total of 9,125 confirmed COVID19 cases in Singapore – and we are now seeing more than 1,000 new cases a day. So far, the death toll remains low at just 11. Source: https://www.moh.gov.sg/covid-19. While my earlier concern for the Malaysian foreign workers who rushed into Singapore overnight has fortunately not (yet) been borne out, the primary cause for this third wave of COVID19 cases did, however, turn out to be similar.

Migrant workers who come to Singapore from Bangladesh, India and China, and who have been residing in crowded dormitories, are now suffering. Of the 1,426 new confirmed infected cases announced today — the highest single-day total reported so far — the vast majority are foreign workers living in dormitories. Only 16 cases of the new cases were Singaporeans or long-term residents.

After all that deliberate, thoughtful, and swift COVID19 response, how did Singapore see its curve move in the wrong direction?

Behind our beautiful Garden City (and the glorious food)

Anthony Bourdain, before his tragic suicide in 2018, filmed a CNN series called Parts Unknown. One of the episodes featured his visit to Singapore. While I was reminded fondly of home by the tantalizing street food of Singapore featured in the show (I went searching for chicken rice in San Francisco the next day), there was one particular conversation he had with the locals which struck me somewhat uncomfortably:

On that episode, a few local Singaporean ladies shared with Bourdain that in this country, most Singaporean women are in the corporate workforce. They further elaborated, rather matter-of-factly, that the career progression of Singaporean women isn’t hampered by childbearing.That’s because low-cost domestic helpers are widely available. These domestic workers live under the same roof as the local families, and are responsible for daily chores and childcare.

Bourdain, in his signature candid style, retorted, “that’s like bourgeois, man. You are living off the labor of an oppressed underclass.”

That conversation made me, a Malaysian-born Singaporean, and a proud one at that, rather unsettled. Deep down I knew that Bourdain was most probably right.

No system, or country, is perfect. Behind the ultra-modern high-rise buildings that dominate our stunning skyline are the faceless migrant construction workers from other developing countries who have toiled under the hot tropical sun to build them. Behind the ultra-clean streets of Singapore lined with gorgeous flowers and trees, that have earned us the moniker of “Garden City,” are the invisible cleaners. Many of them earn a low wage at jobs which few local Singaporeans would take.

When my significant other visited Singapore with me for the first time, he was quick to point out workers’ vehicles passing us by on the roads. They sit shoulder-to-shoulder at the back of open trucks. No seats. No seat belts.

These trucks are hard to miss. They are on the same roads as the luxury sedans driven by the locals who work in those office towers.

It was not a proud moment for me, nor should it be for any Singaporean.

While this situation is not unique to Singapore, we cannot deny the fact that we have more than 200,000 foreign workers living in cramped and relatively unsanitary conditions. On Mar 23, before the current turn of events, the Transient Workers Count Too (TWC2) organization, a local non-profit workers’ rights group, submitted an open letter to warn the government officials of a potential outbreak within the foreign worker dormitories.

As detailed in that public letter, these migrant workers are often housed in crowded dormitories of 12-20 men per room. In addition, some employers levy heavy fines, which can amount to a few times a worker’s daily salary, if they fail to show up at work; some even refuse to recognize medical leave of more than one or two days. These conditions render it almost impossible for these foreign workers to exercise social distancing or to stay at “home” even when unwell.

Knowing how this virus transmits so easily between people in close proximity, and how much pressure the workers are under to work even when feeling ill, this is an almost ideal situation for the virus to spread.

Unfortunately, the public warning from the workers’ rights group fell on deaf ears. It is always easy to realize on hindsight, but these migrant workers represent the exact demographic that was left out of Singapore’s early, effective COVID19 response. For example, the country’s nationwide mask distribution early in February to every household did not include these foreign laborers. In another instance, the government’s bid to reduce virus spread by restricting physicians to single hospitals has also severely impacted volunteer health services required by this vulnerable community.

These workers operate in a kind of blind spot to many Singaporeans. It showed in the country’s response.

As Bilahari Kausikan, the former Permanent Secretary at Singapore’s Ministry of Foreign Affairs remarked, the country “did drop the ball on foreign workers who are invisible to most Singaporeans.”

Not All Hope is Lost: Correcting the Course

While it is disheartening to see Singapore’s current setback, it is however encouraging to see the city state tackling the crisis head on with new and concrete measures. Josephine Teo, the Minister of Manpower, has outlined a three-pronged strategy:

  1. Testing and Isolation: affected dormitories have been locked down to contain the spread. Testing has been massively expanded among workers to identify and isolate those who have been infected.
  2. Social distancing: even for dormitories that have not been infected, aggressive social distancing measures have now been implemented. In total, 200,000 foreign workers are now in quarantine. Local reports have only mentioned rehousing of workers involved in essential services to separate facilities. It appears that the rest of the workforce under quarantine still have to remain in their dormitories although the government has now expanded isolation facilities on-site for the infected clusters, and is enforcing staggering shower times and communal toilet use, as well as providing them with all meals so as to reduce the use of communal kitchens.
  3. Medical screening and medical support: for the 7000 workers who have been identified to be required for essential services, strict measures are taken to ensure their safety as they continue to work. Masks are provided and are to be worn at all times at work; medical screening including temperature checks are performed routinely at workplaces. Teams of healthcare workers have been deployed to attend to the workers so that they can get timely medical attention.

In these special times of need, tens of thousands of Singaporeans have rallied and donated funds to help support these migrant workers. Prime Minister of Singapore, Lee Hsien Loong, publicly pledged his commitment to take care of the welfare of the affected migrant workers. The government is also working closely with employers to ensure that these workers continue to receive their salaries and to facilitate their overseas remittance to send money home.

It is also particularly heartwarming to see the volunteers at Healthserve, a Singaporean non-profit organization, step up during this time of crisis to roll out counseling via virtual means for migrant workers hit by this pandemic, with a strong focus of ensuring their mental and emotional wellness.

Apart from efforts to combat further virus spread within the foreign workers clusters, Singapore continues to combat local transmission. After resisting a nationwide lockdown for months, it eventually became apparent to Singapore that even the most aggressive and effective contact tracing and isolation measures are not sufficient to contain the virus spread. Partly, this is because of the difficulty of stemming all imported cases.The traditional method of public health can be effective, but struggles to keep up with a virus that spreads this fast. The country has since Apr. 7 been in a one-month lockdown, which the government termed, quite curiously, the “circuit breaker” (maybe someone with an electrical engineering background conjured this term?).

New Learnings

  1. The chain is only as strong as its weakest link

It is not only in Singapore where we witness an exceptionally severe impact of COVID19 on the lower socioeconomic classes. In the US, data showing racially disproportionate mortality rates have emerged in some of the poorest regions of the country. For an instance, 70% of fatal COVID019 cases in Louisiana are African Americans, even though they only make up one-third of the state population. Poverty, higher rates of co-morbidities, less access to healthcare and unfeasibility of practicing social distancing because of crowded housing conditions and jobs that can’t be done from home render certain populations particularly vulnerable. As countries all over the world get embroiled in the chaos of this pandemic, it is of utmost importance that we do not neglect the most vulnerable communities in our midst. Their lives are at risk more so than ever, and especially if we do not take the prudent steps in our policies.

As my esteemed friend Dr Jeremy Lim at Healthserve said in an interview, “If we don’t proactively look after the weakest link, then collectively, we will all pay the price.”

  1. A flattened curve may not stay flattened

Singapore’s case study is a reminder that even when the curve appears to be flattened, as was the case initially, COVID19 can rapidly rear its head again when stringent social distancing measures are not in place. Short of an effective vaccine and/or herd immunity, subsequent waves of infection are highly possible if we were to loosen social distancing measures too liberally or prematurely.

In my new home in the United States, I’m watching nervously as Georgia — a state with 10.6 million people and more than 19,000 reported cases of COVID19 — announced plans to reopen its economy this Friday, Apr. 24. In the meantime, states like New York and California have recently extended their stay-at-home order to later dates in May than originally planned.

These highly varied individual state responses do not make it easier for what should have been a more coordinated nationwide effort to combat COVID19. We all know by now that a hotspot can quickly seed new clusters elsewhere, especially from a place like Georgia with one of the busiest airports in the US. But many US states did act quickly, and citizens quickly adapted to the stay-at-home orders, so hopefully we can respond quickly again if necessary. The coming months will be critical to watch as we thread the needle to save as many lives as possible, while also saving people’s economic livelihoods.

It is now Virus versus All Men. May those who have lost their lives in this pandemic live in our everlasting memory. In order for them to not have died in vain, let’s learn the right lessons to prevent more unnecessary death. For all of mankind, I pray.

Disclaimers:

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.

17
Apr
2020

The Real Question is How to Restart

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17 Apr 2020

Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)

When??

When can we finally go back to something resembling a “normal” life, go back to work and restart our economies, embrace again long-lost family, friends, co-workers? And, in too many cases, when can we get together to properly mourn those we have lost?

I cannot tell you “when.” Everyone wants the answer to that question. I do, too. But that is not the first question to ask.

The first question is “how”?

So, let’s discuss “how”.

First, just as much as “when” depends on “how,” “how” depends on “where”.

We are still in the “first wave” of the pandemic. There are substantial differences in rates of localized spreading as well as containment measures: differences between countries and also within different regions/states of the same country.

For example, Lombardia (Milan region in Italy), London (UK), and New York City are all at a very different stage in their pandemic than the vast majority of the rest of the countries they are in. There are all sorts of very messy complications in assuming what a “second wave” could look like and when it could hit. A LOT of these complications arise from having different regions not maintaining contemporaneous strict lockdowns (because the virus spreads there later, or because of much lower population density, or because of different local health policies). I will not go into that as my head hurts just by thinking about it (I am maintaining a strict regimen of responsible alcohol consumption during the lockdown, so that is NOT the reason for the headache, thanks very much for asking).

I will add, however, one comment from Rhode Island Governor Gina Raimondo (another fellow Italian, and a former medtech VC) on Mon. Apr 13. Her remarks came during the launch of a regional coordination initiative between governors of NY, NJ, CT, RI, DE, PA, MA: “The reality is this virus doesn’t care about state borders, and our response shouldn’t either.”

I will focus below mostly on the US, since this is where I now live. I will also try to translate some lessons hopefully learned by other countries who entered the peak of their regional clusters before the US. For some background, please refer to the previous articles in the Timmerman Report.

Before I start, a (not so quick, it turns out) reminder. Lesson No. 1 with exponential infection spreading: you might think you are running ahead of the viral spread, but it is probably the virus that is way ahead of you.

There is now substantial evidence, as if things were not bad enough, that this virus has an R-naught (R0) probably well in excess of 2, which makes it very infectious indeed. If you want a primer on this, and do not want to read my older Timmerman Report posts, you should watch a movie. 

“Contagion”, the eerily prescient film from 2011 on a fictitious pandemic originating from Hong Kong, in my opinion, should be shown in every house all around the world for the next 6 months. It should become practically required school viewing, and get a “posthumous” Oscar. Watch, in particular, the TV interview Jude Law’s character gives roughly mid-film. Though a great actor (one of my wife’s very favorites), he is not a good guy in the movie (and I am still confused by how he manages an Australian accent at times). BUT he is spot-on about exponential spreading. The scientific consultant to the movie, Larry Brilliant, helped eradicate smallpox. Apart from having the most apt last name in the universe (can you tell I am jealous? No? Did you forget my first name? Go check your Shakespeare), Larry is a GREAT epidemiologist: read more about him here.

Apart from a few, required dramatic Hollywood flourishes (a vaccine created, manufactured and distributed in only 133 days against a totally new virus is practically science fiction; viruses do not “mutate” dramatically that quickly, etc.), the movie covers incredibly well virus provenance (also from bats originally), infectivity from touch (do not touch your face, wash hands), and contact tracing, as well as many other important aspects (who gets vaccine first etc.). I watch it almost once a week now. It does also have a happy ending, I think. This tragedy we are living through will, too.

Now, back to “when”.

I am assuming by now that you are all more or less familiar with the three gating “phases” to re-open US states’ economies in the coming months: after all, the audience of this report is quite knowledgeable about Phase I, II and III trials. And this is very much a trial we are all going through.

For those who are not as avid a consumer of news (or not US-based), the US administration has given state governors guidance and criteria on how to reopen state economies. Note that states (from the very little I know of the US Constitution) very much have discretion on how to execute these guidelines. The full outline from the administration is here.

There are a number of gating criteria which need to be satisfied before entering Phase I:

  • Downward trajectory of influenza-like illnesses (ILI) AND COVID-like syndromic cases reported within a 14-day period;
  • Downward trajectory of documented positive cases within a 14-day period AND downward trajectory of positive tests as a % of total tests within a 14-day period (with flat or increasing volume of tests)
  • Hospitals need to be able to treat all patients without resort to crisis care (i.e., I guess, without having to ration critical care like ICU beds or ventilators); AND they need to have a robust / at scale testing program in place for healthcare workers (including serological testing, not yet available).

Subsequently to satisfying these criteria, each of the phases should last, at a minimum, 14 days. Phase I includes many of the current lockdown measures (avoid non-essential travel; do not gather in groups). BUT it says venues such as restaurants, churches and sport arenas “can operate under strict physical distancing protocols”. In Phase II, non-essential travel can resume, schools can reopen and bars can operate “with diminished standing-room occupancy”. Phase III is almost back to our old definition of “normal”, in which states that are seeing a continued downward trend of symptoms and confirmed cases could allow “public interactions” with physical distancing and unrestricted staffing at worksites. Visits to care homes and hospitals can resume and bars can increase their standing room capacity. The at-risk demographic should still avoid public, crowded areas.

So, back to “how”. What do we need to achieve to get even to Phase I?

  • Testing: the guidelines rightly focus on tests as a key gating criterium for starting to think about re-opening. We need two types, and probably many different formats of test, since there is a tradeoff between speed vs volume to think about: a) RNA tests, to check if you have virus genetic material in you (which, presumably, means you are / have been infected); b) serological tests, unfortunately not yet really available at scale in the US, to check if you have developed antibodies against the virus (which, presumably, means you have been infected and have developed some sort / level of immunity, at least for some time). What we need is BOTH types of testing, in massive scale, deployed as soon as possible BEFORE we can think of re-opening. Ideally you should be able to test ~1% of the US population per week with RNA tests, and very, very roughly half of that in serological tests. We are, unfortunately, very far from achieving that level of scale in the US. Just to give some statistics, as I write this morning Eastern Time April 17, the US (population ~330M) has performed ~a total of 3.4M RNA tests (~1% of the US population, or ~10k tests/1M people), of which ~678k came back positive (~20%). In comparison, Germany and Italy (population ~80M & 60M respectively), have performed ~1.7M and ~1.2M tests, or roughly 2x as many as the US per 1M population. So, it is absolutely essential to increase the volume of RNA tests by a factor of at least 5-10x in the US in the next 4-5 weeks. The speed of obtaining a test result also needs to dramatically increase: developing rapid testing formats that can provide a response within 15-30 minutes is essential to allow contact tracing and to isolate infected people immediately (more on contact tracing below). Serological testing is also absolutely necessary. There have been, and continue to be, a series of issues on these tests but a number of diagnostics companies (from Abbott to Roche) are announcing rapid plans to scale up their platforms to address these. That said, there is unlikely to be any serious availability of serological testing until June at the earliest. Without serological testing, it is very hard to identify immune people and therefore to “release” them back into the community, with the obvious positive implications for the economy, healthcare infrastructure, etc. Also, and very important: as I write, NY State + NJ represent ~44% of all confirmed cases in the US, and have performed ~21% of ALL tests in the country (worldometers.info/coronavirus). So, we have a long way to go. If you want to really geek out on what does it mean to “scale testing”, I have written a few words in a little appendix at the bottom of this post. (See “Addendum”)
  • Contact Tracing: this piece of the puzzle is extremely important, as ramping up testing capacity is necessary but not sufficient to contain the pandemic. What should you do once somebody has tested positive to the RNA test? They should be isolated immediately, ideally away from their family, and everybody they have been in contact with should also receive the test: all their “contacts” need to be “traced” and tested. This is all the more important as there is now substantial evidence that: a) there is a substantial (probably ~50%) number of people who are infected and contagious but asymptomatic, BUT ALSO b) that people who will go on to develop symptoms start spreading the virus starting ~2 days AHEAD of showing symptoms. Contact tracing is equivalent to old shoe-leather detective work, and involves extensive interviews with the people who tested positive, their families, their co-workers. Therefore, it requires a large number of trained individuals to be performed correctly. It is very labor intensive. There are initiatives for automating some of that hard task by using phone apps to supplement human operators (S. Korea and Singapore have used similar apps with great success): Google and Apple are joining forces to use their combined dominance of mobile phone operating systems to develop such an app. Salesforce is also joining the fray. There are obvious privacy concerns associated with such an app and its use of location and contact data: those are not for me to address, here or elsewhere, and they are important concerns. That said, I do not personally believe, seeing the level of spread of the contagion in the US, that there will be a sufficient number of qualified trained human operators that could perform this task without some technology support.
  • PPE / Masks: we need to continue (start??) ramping up manufacturing of protective equipment and masks for healthcare workers (and eventually for the general population). Data reported from Italy are staggering and scary: roughly 10-20% of all healthcare workers in Lombardia tested positive to the virus. These selfless warriors are literally sacrificing their lives to care for patients. No effort should be spared to provide them and the hospitals they work in with equipment and relief. We are talking multiple hundreds of millions of masks needed per month: healthcare workers need to be able to use multiple (3-5) N95 masks / day to take a break, drink and eat, and not have to recycle the same mask, which is sadly the case right now. It is also important, since there is evidence of aerosol transmission with this virus, that people use masks in general if/when leaving their homes. Since we do not know if a person is spreading the virus or not, masks help “contain” the radius of infectious particle spread, as well as provide some protection for at-risk demographics (especially if masks are N95 or N99 type).

Until we see ALL these fundamental steps in place, NATION WIDE, it is very hard to start thinking about “when.” If only New York were to follow these steps, then it’s only too easy for people to spread the virus elsewhere as people travel around the country by planes, trains, buses and cars. What we are doing right now with social distancing measures, and at incredible, horrific economic costs, is lowering R-naught (R0), the rate of infection of the virus, below 1. This is essential if we are going to catch up.

There is evidence it’s working. Every day there is a lower number of new people who become infected. This is a prerequisite step to be able to reduce the number of infected people to manageable numbers.  The painful work of social distancing to bring down the rate of transmission has to be done first. Without that step, testing and contact tracing are impossible: there are just too many people infected to trace all their connections.

Think of New York City, with roughly ~50% tests coming back positive: how do you trace contacts in a densely populated urban area, which necessarily requires the use of public transportation to function, when there are so many cases? Also do not forget, New York was very much part of the first wave: the same will apply to any other large metro area as soon as we relax restrictions, without having a commensurable capacity of performing tests/contact tracing (and provided we have rapid assay formats).

So, it is sensible, in the government’s guidelines above, to stress a “reduction” in the number of positive tests over 14 days (roughly the period required for a person to not infect others any more). This should allow the current pool of people infected to shrink, perhaps even very substantially, to numbers low enough to be traced if tested positive. I also encourage you (if you have not gotten to watch the movie yet) to do a mental exercise of how many people we interacted with in close proximity, and how many surfaces we used to touch during the “old normal” days we used to live in. It is literally hundreds, at least in my case (Italians are eminently social and we are also quite tactile in our social interactions). Again, watch “Contagion” (Disclosure: I do not receive royalties on the movie streams…). 

So, now to the (blind) guessing part: “when” do we think we might have figured out the “how” well enough to hazard some projections for when Phase I will start?

Spoilers: I do not think it is going to be before June, at the earliest. This is not a pessimistic projection, I believe. PLEASE take that with a “couple of mines” worth of salt. I would really like to see some random RNA and serological testing in a couple of places (outside of NY or NJ or Michigan) to understand more how diffused the virus is in the country. As of this writing on Apr. 17, we are still flying blind. I cannot wait to see the results of the serological random survey of 100,000 people that Germany is performing.

Some other random data points to support the very rickety framework I used to come to that “June” guess:

On Apr. 14, Anthony Fauci (in the impossibility that anybody who reads this does not know who he is, “Tony” is director of the National Institute of Allergy and Infectious Diseases (NIAID) and member of the White House Coronavirus Task Force), told the Associated Press that the May 1 reopening projection was “a bit overly optimistic” for many areas of the country. That’s because a strong testing and tracing system would be needed before social distancing measures were lifted. I guess we all agree with the good doctor here, especially since Fauci is an Italian name (which, hilariously enough, means “Jaws” in Italian: the comic implications / associations with the movie of the same title and the various decisions made by elected officials in said movie are too funny to mention). “Overly optimistic” feels a bit “overly kind” to that prediction statement, but, you know, some people have to be mindful of their audience.

Yesterday, Apr. 16, New York Gov. Andrew Cuomo said that his state would remain under stay-at-home orders until May 15. New York is likely beginning to descend the slope of the infectious spread. Note that a number of other countries (from Italy to the UK) have repeatedly pushed off the timing of a potential “re-opening” due to the scale of the infection spread being detected as more testing has gone online. I am guessing the same thing will happen here, especially since New York is detecting a positive testing rate of ~50% of tests – an incredibly high rate. The statistic can be biased since they are only testing people at high probability of being infected, but still.

Germany will reopen schools on May 3, with Austria even earlier than Germany. Both countries did a great job of containing the infection early on, have first-class and abundant hospital critical care units (Germany has the highest ICU bed concentration probably in the world) and both scaled up testing very early. So, even states and cities which were very much hit in the first wave might need to wait longer to get there. Not every city / state hit in the first wave is in the same spot: The San Francisco Bay Area and all of California are way ahead of the curve. So is Washington state: both acted early and ramped up social distancing / testing early, and have also much lower population density than New York City.

The issue is then, again, the “where” to decide the “how” that gets us to “when”: you can see here when different states issued stay-at-home orders. The differences are very wide, and frankly, puzzling. How do we solve for interstate travel/traffic to avoid a large second wave, at the same time as summer kicks in and people want to escape their home confinements and rejoin families/ friends as soon as restrictions are lifted?

This is a huge problem, and has massive implications for how we behave. I do not think we can simply rely on individual self-policing of behavior. I know this does not jibe with the ruggedly individualistic, “frontier” culture of the country. But, guess what: the virus does not care. We should.

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.

Addendum: More on Testing

“Testing capacity”, as well as “contact tracing” are very vague terms. As I am not sure everybody is familiar with what they actually mean, here are some thoughts: to test and contact trace effectively, at the scale we are talking about here (literally hundreds of millions of test), you need to think and coordinate a huge number of factors (each of which is very likely a rate-limiting factor). Some of these factors are: type of testing (batch testing in a central laboratory, which can process at high throughput a large number tests but has slow turnaround, vs localized testing in city hospitals?); number of locations where tests are available (dense cities vs rural areas: you do not want people piling up in a queue to get tested); number of total test kits; reagents needed to produce the tests (which are in very scarce supply right now); personnel trained to extract the material needed to perform the test; personnel trained to perform the test (they are not necessarily the same); protective equipment needed for all this personnel. Same thing for contact tracing: it is a process that needs to be taught, requires a certain amount of psychological expertise and understanding of what is going through the head of the person in front of us, who might well be under a certain amount of distress. So it’s hard to train thousands of people to perform this without some technical tools to aid in contact tracing. So this is not simple. And every US state should not have to go through a steep learning curve to develop all this infrastructure, in all its complexity and inevitable mistakes, on their own. This is where it pays to adopt best practices in a coordinated fashion across the country.

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