2
Apr
2020

A Baffling Coronavirus Response, Arch & Flagship Reload, & Merck Passes 2 Phase IIIs

Luke Timmerman, founder & editor, Timmerman Report

The world now has more than 1 million confirmed cases of infection with an insidious virus that spreads from person to person with exponential speed, is spread by people who don’t display symptoms, and kills an estimated 1 percent of people who get infected.

As the US death toll now exceeds more than 1,000 a day from COVID-19, we are heading our way up that horrifying curve we’ve been staring at, and dreading, for weeks. Federal officials looking at the best disease models now publicly say they expect between 100,000 and 250,000 deaths in the US.

We have a good idea of what to expect. Data has been mounting for a couple months, from China, Italy, and other countries. We know COVID-19, the respiratory illness caused by the SARS-CoV-2 virus, sends about 15-20 percent of those infected to the hospital. Patients struggle to breathe, and they often need to stay in the hospital for a couple weeks. We in the US are scrambling. Odds are high that we don’t have enough hospital beds, ventilators, ICU rooms, and skilled staff to grapple with a contagion that moves this fast and has this kind of devastating effect on human health.

Our healthcare workers are now being forced into battlefield triage situations. They themselves are being put at great risk. They’re like soldiers being asked to storm the beaches of Normandy, and we’re asking them to do it without boots.

The great tragedy is that we failed to use our one big advantage over the virus: our superior intelligence as a species.

We in the US wasted precious time in denial, hurling daggers of misinformation and misdirection. Certain leaders displayed incompetence, and then got busy hiding it. Experts knew what we needed to do to #FlattenTheCurve, and yet politicians still haven’t mustered the necessary, unified response as a country to actually make it happen. Early-to-mid-March was the time to get serious to prevent the worst. We didn’t.

We have the money, and technological expertise, to do so much better. Polymerase chain reaction tests are not hard to perform. We have God-like power to collect and analyze the data spitting off those diagnostic instruments. The information could have been used to identify the early cases, so we could isolate them and their contacts in a classic containment strategy. We could have begun widespread testing, quarantining anyone with the virus, not just people who already felt sick. If done right, it’s conceivable we could have avoided the worst of this population-wide mitigation strategy which is forcing so many to stay at home for weeks, maybe months. We could have nipped this pandemic in the bud here in the US.

Yet on Apr. 2, the Governor of Georgia admitted at a press conference that he was unaware until the previous day that the SARS-CoV-2 virus could be spread by people who display no symptoms. Once he realized that, he said he issued a stay-at-home order to Georgia residents.

It’s baffling. And infuriating.

I’m cycling through the same emotions you all are – positive and negative. I admire the heroic frontline workers. I get frustrated and angry with the delays and incompetence. I’m personally grateful to still have a job, to have a healthy family, and to be able to work from home. I feel guilty that I’m not a doctor, that I can’t do more to help the sick or the unemployed.

As the editor of this publication, the main thing I can do is provide useful information. Books will be written for decades about what went wrong. Historians will sift through this story 100 years from now, trying to figure out how it could have happened. For now, I’m seeking to uplift and amplify voices that have something constructive to say about what we can learn from other countries, how we can respond, and how we can get through this difficult time as humans.

To help you absorb the many dimensions of this fast-moving story, I’ve compiled some resources. For starters, I’ve created a landing page for ongoing TR coverage of the pandemic. Everything there is free. So you are all welcome to share this link with friends, family and colleagues who don’t subscribe but who could benefit from this in-depth coverage.

See all TR coverage of COVID-19 here.

I’m proud of this body of work, but also see truly exemplary journalism being done on an hour-to-hour basis by many outlets. Over this past week, I’ve sought to compile some of the most useful articles from a variety of angles – science, policy, human and more – so you can hopefully slow down at some point and absorb the story to achieve some greater understanding.

You can see all of that below, in the usual weekly Frontpoints format. Afterward, you’ll find other biotech news of the week.

Stay well. – Luke

Science of the Pandemic

  • Virological Assessment of Hospitalized Patients with COVID-19. Nature. Apr. 1. (Roman Wolfel et al)
  • Susceptibility of Ferrets, Cats, Dogs to SARS-CoV-2 Infection. (Jianzhong Shi et al.)
  • Dutch Scientists Find Early Warning Signal in Sewage Surveillance. Bloomberg News. Mar. 30. (Jason Gale)
  • Olfactory Dysfunction Outbreak Coincident with COVID19. MedRxiv. Mar. 27. (Seyed Hamid Reza Bagheri et al)
  • What Explains COVID19’s Lethality in Elderly? Scientists Look to Twilight of Immune System. STAT. Mar. 30. (Sharon Begley)
  • Case Series on 24 Critically Ill Patients, Followed 14 Days, in Seattle Area. NEJM. Mar. 30. (Pavan Bhatraju et al)
  • Asymptomatic and Pre-symptomatic SARS-CoV-2 Infections in the Kirkland Nursing Home. Mar. 27. (Centers for Disease Control and Prevention)
  • Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at University of Nebraska. MedRxiv. Mar. 26. (Joshua Santarpia et al)
  • Turbulent Gas Clouds and Respiratory Pathogen Emissions. JAMA Insights. Mar. 26. (Lydia Bourouiba)
  • Why We Should All Wear Masks. New Scientific Rationale. Medium. Mar. 26. (Sui Huang)

Policy / Response

Testing

Vaccines & Therapies

  • Developing Vaccines at Pandemic Speed. NEJM. Mar. 30. (Nicole Lurie et al)
  • Treatment of 5 Critically Ill Patients with Convalescent Plasma. JAMA. Mar. 27. (Chenguang Shen et al).
  • Blood Plasma from Survivors Will be Given to COVID19 Patients. NYT. Mar. 26. (Denise Grady)
  • Renin-Angiotensin-Aldosterone System Inhibitors for COVID19 Patients. NEJM. Mar. 30. ( Muthiah Vaduganathan et al)
  • Novartis and Incyte plan Phase III test of Jakafi for Cytokine Storms in COVID19 Patients. (Incyte statement)
  • Chloroquine/Azithromicin and the Doctor Behind It. In the Pipeline. Mar. 29. (Derek Lowe)
  • Johnson & Johnson announces lead COVID19 vaccine candidate, pledges $1 billion effort with BARDA on manufacturing scale-up, plans to enter clinic in September. (Company statement)
  • What Can Initial Remdesivir Data Tell Us About Covid-19? C&EN. (Lisa Jarvis)

Other Countries

  • India’s Lockdown Leaves Vast Numbers Stranded and Hungry. NYT. Mar. 29. (Maria Abi-Habib and Sameer Yasir)
  • Germany Will Issue Antibody Certificates to Allow Quarantined to Re-Enter Society. Mar. 29. The Telegraph. (Daniel Wighton)
  • Lessons From Italy’s Response. Harvard Business Review. Mar. 27. (Gary Pisano et al)
  • View from the UK. The Lancet. Apr. 4. (Richard Horton)
  • Switzerland: What Went Right, and How to Better Prepare for a Second Wave. Timmerman Report. Mar. 31. (Alex Mayweg)

Health Advice

  • Everyone Thinks They’re Right About Wearing Masks. The Atlantic. Apr. 1. (Ed Yong)
  • What We Need to Know About Asymptomatic Spread. ProPublica. Apr. 2. (Caroline Chen)
  • Wearing Masks Must Be National Policy. NYT. Apr. 2. (Aaron Schildkrout et al)
  • Doctors Recommend Isolation for Those Losing Smell & Taste. NYT. Mar. 22. (Roni Caryn Rabin)

Communication

  • Anthony Fauci Shows Us the Right Way to Be an Expert. Scientific American. Mar. 26. (Gregory Kaebnick)
  • This is Real. Science. Apr. 3. (Holden Thorp)

Regulatory Response

  • Updated FDA guidance on Clinical Trials During the Pandemic. FDA. Mar. 18.

Humanity, at Its Best and Worst

  • How Washington’s Health Care Workers Have Risen to the Pandemic Challenge. New England Journal of Medicine. Apr. 1. ( Lisa Rosenbaum)
  • Deluged System Leaves Some Elderly to Die, Rocking Spain’s Self-Image. NYT. Mar. 25. (Raphael Minder & Elian Peltier)
  • Doctor Who Blew the Whistle on PPE Shortages in Bellingham, WA is Fired. Seattle Times. Mar. 28. (Ron Judd)
  • US Navy Removes Commander Who Wrote Scathing Letter About Coronavirus-Stricken Aircraft Carrier. Reuters. Apr. 2. (Idrees Ali and Phil Stewart)
  • A Million N95 Masks Are Coming From China on the New England Patriots’ Team Jet. Wall Street Journal. Apr. 2. (Andrew Beaton)
  • Taxpayers Paid Millions for a Low-Cost Ventilator for Pandemic. Instead, the Company is Selling Versions of it Overseas. ProPublica. Mar. 30. (Patricia Callahan et al)
  • In March, 60 Choir Members in Washington State Went Ahead With Choir Practice. None Had Symptoms. They Were Careful. Now, 45 Have COVID19. Two Are Dead. Los Angeles Times. Mar. 29. (Richard Read)
  • Ban Alcohol Sales in Pandemic, as Domestic Violence is Rising. Boston Globe. Apr. 2. (Peter Bach)

Epidemiological Modeling

  • The Institute for Health Metrics and Evaluation, University of Washington. The “Chris Murray Model
  • Forecasting Needs for Hospital Beds, ICU Days, Ventilator Days, and Deaths, by State. Institute for Health Metrics and Evaluation / University of Washington. (Chris Murray).

Video

 

In Other Biotech News…

 

Data That Mattered

Merck said its PD-1 inhibitor pembrolizumab (Keytruda) hit its primary endpoint, progression-free survival, in a head-to-head Phase III trial against standard treatment for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. This builds on the company’s strategy to push further into “tumor agnostic” indications based on a cancer’s molecular signature, not its organ of origin. (Subscribers: See related TR coverage by Stacy Lawrence, Mar. 30, 2020)

Merck said it passed a Phase III clinical trial with a heart failure drug candidate. The drug, vericiguat, is an orally administered soluble guanylate cyclase (sGC) stimulator. This was from an outcomes study that looked at heart failure hospitalization and death as a composite endpoint. Bayer is a partner on the program. The data would have been presented at the American College of Cardiology meeting in person, but instead were presented virtually.

San Francisco-based Akero Therapeutics said it met its 12-week primary endpoint for efficacy in a Phase 2b study of patients with NASH. Absolute reductions in liver fat were between 12-14  percent from baseline, and quite consistent across three dose cohorts.

AstraZeneca said it halted a Phase III study because of overwhelming efficacy. It was a study of patients with chronic kidney disease who were getting the SGLT2 inhibitor dapagliflozin (Farxiga). Full results will be released at a future medical meeting.

New Haven, Conn.-based Biohaven Pharmaceuticals said it passed a Phase III clinical trial with its experimental medicine for chronic migraine headaches. The company said its drug candidate reduced migraine days by 3.7 to 4.5 days per month. The Biohaven drug, rimegepant, is a CGRP receptor antagonist.

Personnel File

CureVac, the Germany-based mRNA therapeutic and vaccine developer, named Jean Stephenne as chairman of the board. The company has gone through leadership changes of late after it was reported that the US government tried to seek exclusive access to a program against SARS-CoV-2.

Pfizer named Dr. Susan Desmond-Hellmann to its board. She most recently served as CEO of the Bill & Melinda Gates Foundation. Before that, she was the chancellor of UCSF, and president of product development at Genentech.

Deals

Amgen struck a partnership with Seattle-based Adaptive Biotechnologies on the SARS-CoV-2 pandemic response. Adaptive is the leader in deep sequencing of the immune system’s repertoire of T and B-cells – a unique and valuable set of capabilities in this pandemic. The companies will work together to find neutralizing antibodies against the virus. (See Adaptive CEO blog).

San Francisco-based VIR Biotechnology and Cambridge, Mass.-based Alnylam Pharmaceuticals expanded their partnership to evaluate RNA interference drug candidates against SARS-CoV-2 viral infections. In this case, based on the latest understanding of the biology, they are going after host factors – specifically ACE2 and TMPRSS2. In a joint statement, the companies said ACE2 “is known to be the viral entry receptor for SARS-CoV-2 and other coronaviruses, while TMPRSS2 is believed to cleave the SARS-CoV-2 spike protein to facilitate cellular attachment.”

San Diego-based Fate Therapeutics agreed to work with Janssen Biotech, a J&J company, on CAR-T cell and CAR-NK cell therapies that use Fate’s induced pluripotent stem cell technology. Fate is getting $50 million in cash, and another $50 million via a stock purchase by its new partner at $31 a share.

Financings

Arch Venture Partners raised $1.46 billion for a pair of funds to keep doing what it does – invest large sums in ambitious biotech startups. The news coincided with an announcement from Flagship Pioneering, a stylistically simpatico venture firm. Flagship raised $1.1 billion in new capital for startups. The two firms know each other well, and sometimes syndicate together when their scientific interests and priorities align. 

Cambridge, Mass.-based iTeos Therapeutics, a cancer immunotherapy developer, raised $125 million in a Series B2 financing co-led by RA Capital Management and Boxer Capital.

Legend Biotech, the China and US-based CAR-T cancer immunotherapy company, raised $150.5 million. New investors included Hudson Bay CapitalManagement LP, Johnson & Johnson Innovation, Lilly Asia Ventures, Vivo Capital and RA Capital Management.

France-based Dynacure raised $55 million in a Series C deal to advance its programs for rare diseases, including myotubular myopathies. Perceptive Advisors led.

Cambridge, Mass.-based Pandion Therapeutics raised $80 million in a Series B financing to advance its work against autoimmune disease. Access Biotechnology and Boxer Capital co-led.

San Diego-based Aspen Neuroscience raised $70 million in a Series A financing to develop autologous neuron cell replacement therapy for Parkinson’s disease. OrbiMed led the deal, which included ARCH Venture Partners, Frazier Healthcare Partners, Domain Associates, Section 32, and Sam Altman.

Toronto-based Zucara Therapeutics raised $21 million in a Series A financing to advance work on a treatment for a once-daily treatment for insulin-induced hypoglycemia. Perceptive Xontogeny Venture Fund led.

Waltham, Mass.-based Affinia Therapeutics raised $60 million in a Series A financing to develop gene therapies. F-Prime Capital and New Enterprise Associates (NEA) co-led.

 

1
Apr
2020

What’s the Real Risk of Death from COVID19? It Can Be Deceiving

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

“There are three kinds of lies: lies, damned lies, and statistics,” quote popularized in the US by Mark Twain

This is an almost direct follow-up to my latest article for Timmerman Report (“Let it Rip or Shelter at Home?)

Usual caveats apply: I am not an epidemiologist, and not a virologist. This is still a new virus for us as a species so there is no natural immunity. There is still a ton we do not know about the virus and its biology, blah blah blah…

How bad is this virus, really? As we are spending endless days locked up in our apartments (yes, I am running low on pasta), what is the real risk for the individual? This is especially an issue in countries, like the US and some other Western democracies, where individual rights are prized above all, and where there is a natural tendency to be skeptical of government intervention.

Erring on the side of caution (precautionary principle) might sound good in theory, but how can we go on as a society for more months when entire swaths of the economy are basically veering towards bankruptcy as I write?

What is, then, the “real” fatality rate (number of people dying after being infected)? Should we expect a 0.04% fatality rate, or a horrific Northern Italian / spaghetti western-style situation with a crude case fatality rate (CFR) of almost 12%?? (More on these numbers below).

Obviously, there is potentially a very wide range of policy actions depending on this “real” fatality rate. For a great discussion of this (and of everything coronavirus), please follow Kai Kupferschmidt (@kakape, a German journalist who writes for Science and has been following this outbreak from the beginning).

Starting from the premise that every death (according to my Roman Catholic upbringing, at least) should be avoided, especially if in excess to what a “normal” fatality rate is, I would like to offer, first of all, some important clarifications.

The fatality rate for any given infectious pathogen is, as for everything, context-dependent: population demographics (age structure) and overall health conditions (rate of pre-existing conditions, including obesity, diabetes, smoking rates, etc), as well as status of healthcare infrastructure (ICU beds, ventilators, number of nurses, availability of drugs, etc) are all huge factors. This is not a good time to be infected with SARS-CoV-2 if you are an elderly obese male smoker with heart conditions, to be honest.

So, it is to be expected that different countries’ populations, especially since they might well be at different stages in their own outbreak, might see different fatality rates.

I think it might be useful to describe some basic terminology used in the field below.

IFR: Infection Fatality Rate, also referred to above as “real” fatality rate: this is a “simple” calculation (expressed as a percentage): It’s expressed as the number of fatalities divided by the number of infected individuals. NOTE that infected individuals = detected + undetected (asymptomatic / other infected but not tested) infections. The obvious problem in calculating this “real” fatality rate is the denominator: knowing how many people have been infected. When you don’t adequately test across the population, you don’t really know the denominator.

CFR: Case (or “Crude”) Fatality Rate: also a percentage. It is often calculated by simply dividing the number of deaths by the number of confirmed cases. This is obviously a much rougher (hence “Crude”) measure since not every infection leads to disease and not every infected individual is identified and counted (see above about the number of asymptomatic carriers).

Because a limited number of tests have been performed, it is presumable, and even very likely, that a large number of people have been infected with the virus but have not been tested. In this case, the denominator should be MUCH larger, and therefore this virus that you are all worried about is really. Not. That. Bad!!! The latest data published in The Lancet Infectious Diseases on March 30 pegs the death rate from confirmed COVID19 cases at 1.38 percent, and the overall death rate, including unconfirmed cases, at 0.66 percent.

Indeed, if we are overestimating the eventual IFR, (by relying on CFR, and correspondingly underestimating the number of infected patients, the denominator, due to the lack of testing) then CFR will appear much higher than the real one. There has indeed been a recent “surge” in pundits discussing various epidemiology models which suggest the overall infection rate is far in excess of the official numbers (everybody is an epidemiologist lately). If there were so many more people infected than have been detected, fatalities across the entire population would then appear less dramatic and might lead one to reconsider some of the current strict stay-at-home policies.

To be fair to this argument, there are a number of studies, including in the town of Vo’ in Italy as well as from many other studies, that establish that ~50-55% of people infected are asymptomatic (see Timmerman Report “8 Days Later”). It is also true that most countries, with the possible exception of Korea and Germany, have not yet implemented a broad testing program across their population (Germany just announced a study testing 100,000 individuals at random from the community to assess more concretely these very same prevalence statistics).

That said, current very crude CFR rates in Germany are close to 1.2% (and starting to really go up, as the virus starts reaching more of the elderly population). For South Korea the numbers are higher, ~1.7%. Assuming (big assumption here) ~50% of infected are asymptomatic, we might end up with an IFR here of between 0.7-0.9% or close to 1%.

There are a few sources of additional information: the Princess Diamond cruise ship had ~1% fatality rate (7 deaths / 619 infections: I have been REALLY trying to find out if they had tested everybody in the ship, but I could not ascertain that). These are very small numbers, obviously.  

Let’s now look at the numerator, the number of deaths. Yes, that should be not much of a discussion, really. After all, “in this world nothing can be said to be certain, except death and taxes” (Benjamin Franklin, in a letter to Jean-Baptiste Le Roy, 1789).

Well, I beg to differ on the former (and yes, I do pay my taxes in the US, thank you very much).

I will not comment on the recent multiple media reports on China having possibly concealed the extent of the coronavirus outbreak, under-reporting both total cases and deaths suffered from the disease. However, there are other statistics that are worth quoting and discussing.

Starting in the UK: the government (finally…) announced today, April 1, the criteria for counting a fatality as related to COVID (2,352 as of 5pm GMT on March 31): only people who tested positive and died subsequently to hospitalization were counted.

Obviously, this undercounts (possibly substantially) the real number of fatalities attributable to the virus (even more so as testing is still not provided at scale in the UK). (source: www.gov.uk). As of 9am GMT on April 1, 152,979 people have been tested, of which 29,474 have tested positive (~19.2%). Using the government criteria, this is a CFR of ~8%. I would really like to know what the number of fatalities in assisted living facilities, as well as homes, has been during the same period versus, say, last year. I think it is very fair to say that the denominator should be higher, but then, perhaps, the numerator as well should be.

If only there were a way to compare overall fatality rates in a defined place affected by the virus now versus, say, a year ago when we were presumably dealing with seasonal flu and other pathogens we have tools to deal with. Interestingly enough, there is: Italy might provide once again some perspective and interesting statistics.

Bergamo (source: ecodibergamo.it) is one of the most severely hit municipalities in Northern Italy (Lombardia). In March 2020, more than 5,400 people have died in the province (6x more than in March 2019), 4,500 apparently due to the novel coronavirus, SARS-CoV-2. Of those, only 2,060 deaths have been officially certificated as caused by the respiratory illness we now call COVID-19 (the entire number of fatalities in Italy officially attributed to the virus is 13,155 as of right now, ~7 pm ET, Apr. 1).

Many of the additional fatalities are in the demographics most susceptible to the infection (elderly), who died at home, or in assisted living facilities. They were never tested for the virus, despite exhibiting the telltale symptoms. The official death cause is reported as interstitial pneumonia (the virus causes pneumonia by invading the lungs: the immune system response to the invasion then causes a severe inflammatory reaction leading to death).

Another source of information, from ISTAT (the Italian statistics agency), highlighted by Matteo Cavallaro (@matheusagaso), reports comparative fatalities data from 1,084 Italian municipalities in March 2020 vs 2019: March 2019: 8,054 deaths; March 2020: 16,216 (~2x).

Those excess fatalities were highly concentrated (4,079 of 8,162 excess deaths) in 4 provinces: Bergamo with 2,043, which roughly tallies with the Eco di Bergamo stats above; Brescia (+879), Milano (+639) and Cremona (+518), all of them in Lombardy, the epicenter of the Italian outbreak.

The increase in fatalities is also more frequent in men (+144% vs March 2019) than women (+79%), and in the elderly (in Bergamo, 1,949 of the 2,043 excess deaths are in the population >65 years old). These excess deaths are largely, and clearly, attributable to the new coronavirus.

Keep in mind: People in Italy, and especially in the provinces hardest hit, were in lockdown since March 9 to flatten the curve as much as possible. So, the overall number of car accidents, heart attacks, etc, which are other causes of mortality, are actually DOWN substantially in March 2020 vs 2019. I could not find the numbers for those municipalities, but I did find out that in Los Angeles (yes, they drive almost as badly as Italians) March car accidents were down more than 26% versus March 2019. For the week ending March 27, when people really started taking the stay-at-home instructions seriously, accidents were down 60%! Simple explanation: when people stay at home, they drive less, and get into fewer traffic accidents. However, at the same time, hospitals in the region were unable to withstand the onslaught of new patients: people were counseled to stay home, until the most severe symptoms emerged. As a result, most people dying in houses or nursing homes will not be tested for the virus.

Finally, there are factors to consider: the concept of “excess deaths” versus a period pre-pandemic. Excess deaths are caused not just by the virus itself, but also by the lack of normal standards of care which are suddenly not available any more to any patients suffering from other illnesses. If the hospital is completely full, and you have a stroke, you could be in a tough spot. There are indeed signs that excess overall deaths are climbing in Italy, especially (again) for demographics over 65.

In conclusion, many people want to know — exactly how bad is this outbreak? Is it worse or better than we thought a few weeks ago? (Note, the word “we” is doing a lot of work here, as there is a lot of variability in outbreak severity and response between  countries and even different states / regions within countries).

The simple, terrible math is driven by the number of deaths. They are mounting and increasing the numerator. We are getting a clearer sense now that we know some deaths haven’t been officially attributed to COVID19, but would have been if proper testing had been in place. Now that we can begin to get at the true death toll, and we’re beginning to roll out large-scale testing, a clearer picture is emerging of the infection fatality rate and case fatality rate.

For the time being, I’m basing my answer on the following: 1 case of death not officially associated with COVID-19 “offsets” 50-100 non-tested / asymptomatic individuals (if we believe the real IFR is between 1-2%, which is probably not too far from the truth). So, the numerator and denominator effects described above are not equivalent. Each increase in the numerator offsets A LOT of increases in the denominator.

The realization that a large number of virus-associated deaths went un-reported in several countries like UK, Italy, now France and possibly China should strengthen even more our resolve. We need to stick to the physical distancing orders in place to limit the virus spreading as much as possible, at the same time we work at breakneck speed to increase capacity for testing and manufacturing of protective equipment for healthcare workers struggling with the surge of COVID-19 patients.

I would like to leave you with a quote (translated by GoodQuotes from the French):

“But again and again there comes a time in history when the man who dares to say that two and two make four is punished with death. The schoolteacher is well aware of this. And the question is not one of knowing what punishment or reward attends the making of this calculation. The question is one of knowing whether two and two do make four.” –Albert Camus, La Peste

Hope all of you are safe and sound.

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.

31
Mar
2020

Diagnostic Test Developer Points to Academic Blind Spot That Hampers Translation

David Shaywitz

The COVID-19 pandemic has highlighted the need for reliable diagnostic tests for the new  SARS-CoV-2 virus, and treatments that can cure or mitigate its devastating effects. 

To have an impact, these diagnostic tests can’t just work brilliantly in a single academic lab. They ultimately need to be rapidly deployable across this large country with 330 million people. Developing an approach that can function at this scale is an aspect of innovation that can easily be overlooked — and often is.  After all, some argue, the role of academic science is to discover new things, and publish the findings; what happens next is often viewed as an intellectual derivative, tedious-but-necessary crank turning task that can and should be relegated to commercial organizations.

This mindset seems both surprisingly common and dangerously short-sighted. It adversely impacts not only the translation of academic science, but also the quality of the science itself, depriving researchers the opportunity to pressure-test assumptions in real-world situations, and gain fresh insights from these observations.

I’ve written about the value of a commercial perspective in driving translation (here). The key point: there is value in an intellectual approach that actively contemplates real-world usability. This examination can often sharpen the question and better guide the science. 

Bringing real-world considerations into the innovation process early and often has been championed by many experts. Leading proponents include MIT’s Eric von Hippel, who’s highlighted the critical value of lead users. Lean Startup guru Steve Blank advocates entrepreneurs get real-world feedback from potential users as early as possible. He has said this is especially challenging to do in healthcare, as academic biomedical innovators often regarded themselves as the market experts. Since they see themselves as the authority already, they often see little need to spend time truly testing their assumptions in the marketplace. 

The importance of getting the translation piece right, and more generally, ensuring university research (where appropriate) finds expression in the real world and helps patients (not just academic CVs) has been a focus of several courageous academic leaders who prioritize diverse engagement over perceived intellectual purity. Some of the leaders include Sue Desmond-Hellmann, former CEO of the Bill & Melinda Gates Foundation and chancellor of UCSF, Atul Butte, a distinguished biomedical data scientist at UCSF, and Bob Langer, the prolific bioengineering professor at MIT.

The gap between sexy science and implementable technology was brought to the fore this week, on the podcast Marketplace Tech, produced and distributed by the non-profit American Public Media. On Monday, host Molly Wood interviewed Purdue University bioengineering professor Jacqueline Linnes, who’s working on developing and implementing a useful diagnostic test for the virus. 

The entire discussion is fascinating; I was especially struck – as was Wood – by the translational challenges. As Wood put it, “the science is complicated, but getting from lab to market is even harder.”

As Linnes tells Wood:

“There’s a difference between getting a test to work in the lab 5, 10 or even 100 times, and then getting it to a point that’s manufacturable at the scale that we need. A lot of times when these are in development, the exciting part is getting the actual sensing to work. There’s lots of really cool sensing techniques that are out there that actually are not deployable at all, so there’s a big disconnect between what is manufacturable at scale and what is actually getting made in the lab. For us, if we are developing a device and we’re able to publish a paper on it, we’re super-excited. It’s only after that, that we come back and look at it and realize, ‘This has way too many layers and alignment issues.’ Getting that discussion with manufacturers in the process is really critical.”

Linnes goes on to explain how in general, manufacturing considerations should enter the conversations earlier than they often do.  This mindset, including engagement with manufacturers, “has certainly sped things up in my lab as far as developing technologies with manufacturing in mind,” Linnes said, adding, “It’s been beneficial, I think, so that we can reframe how we’re developing these devices and focus on how we’re not just going to make a cool device, but how it’s actually going to go from the lab into usability.”

Part of the challenge in academia, Linnes says, is the way projects are funded.

She explained:

“[W]hen we’re submitting proposals, and they undergo peer review, people get really excited about the innovative new biosensor and they’re not very excited about the mundane development processes to get things out into the world. The way that we’re even reviewing each other is contributing to that.”

Finally, Linnes points out that part of the challenges is that the lab to real world transition represents the “valley of death,” and is “something that nobody’s quite figured out whose job it is. Companies are out there scouting for potential technologies, but the further along the universities can get them, the better, because it’s a risk from them [i.e. companies] to translate something out of the lab into the company.”

Bottom line:

A model of innovation that enables greater continuity and mutual feedback between discovery scientists, including – especially – at universities, and industrial scientists focused on implementation and scaling, could sharpen science and catalyze translation. 

Conversely, efforts seeking to construct walls between academia and industry, ostensibly to protect the putative purity and sanctity of the research within academia, are likely to adversely impact translation; make it harder for academic researchers to learn from the real world experiences of industry colleagues; and ultimately harm the patients who most of the academic research was funded to serve.  

29
Mar
2020

COVID-19 Teaches Us the Real Definition of a ‘Novel’ Drug

Peter Kolchinsky, managing partner, RA Capital

Will the world care how we beat COVID-19 – whether with a drug we make from scratch or an older one that turns out to get the job done? As people concerned for our families, we all know the answer. Just get it done!

But as drug developers, let’s be honest that it doesn’t feel quite as heroic unless it’s really novel.

I think we may have developed an unhealthy, facile relationship with the word “novel,” looking to it for security against the attacks on our industry that, while deserved by some companies, seem indiscriminate at this point. As if experiencing Stockholm Syndrome, we are on the brink of accepting the public’s notion of novelty at the expense of the novelty that really matters.

After years of being ridiculed by Congress, the media, and the public as highly profitable, greedy, and not innovative — merely retweaking old drugs — it’s no surprise that the drug industry would want to emphasize all of the incontrovertibly novel breakthroughs of late. Gene therapy is hardly a modest tweak. Neither are RNAi, antibody-drug conjugates, and protein folding correctors. Those who are working with technologies like these can rightfully claim the term “novel” in the most straightforward way most people mean it, which is to say “never before seen” or “had to be developed from scratch.”

Many of our industry leaders believe that pursuing such novelty should be the industry’s sole purpose. Recall the letter signed by over 200 biotech CEOs in January that promised:

We will invest only in novel therapies that address unmet patient needs.”

If indeed we did that, presumably the public would have a harder time claiming that high drug prices are unjustified because the drugs weren’t innovative-looking enough, so I can understand the merits of this imperative.

The reality is that the public doesn’t actually care about novelty. The public only claims to care, or maybe only thinks that it cares. Consider the urgency with which the public has looked to innovators to come up with treatments for COVID-19. Companies are running new discovery programs and screening for novel inhibitors of various viral components. I have no doubt some of these programs could eventually succeed, but they are far from the market and each faces long odds.

Meanwhile there are already dozens of older drugs, including many generics, being tested individually or in combination for the treatment of COVID-19. Dozens more older but unapproved compounds, like Gilead’s remdesivir, that failed in their original indications, are being reheated. If we’re lucky enough that any of those programs really can reduce the severity of the disease, keep patients out of hospital, and/or save lives, then the world will have been saved by… drug repurposing.

Yes, we could end up saving lives with an old drug that most people wouldn’t consider “novel.”

Does that mean developing those drugs for COVID-19 will have been easy? No. Without risk? No. Inexpensive? No.

Will it matter to the people whose lives are saved and to everyone who will be able to come back to work once the pandemic is resolved that their salvation wasn’t “novel”? It absolutely shouldn’t, though some of the harshest critics will never be satisfied, but the vast majority of people would be grateful. And certainly all of us in the drug industry should know better than to denigrate a COVID-19 treatment simply because it didn’t require inventing a new drug from scratch. We should be so lucky.

COVID-19 might just leave us with a novel definition of the word “novel” that we’ve long needed. Specifically, all anyone should care about is whether we’ve addressed an unmet need. That’s what society should reward, and that’s what our industry should commit to doing.

Whatever therapy or intervention solves a previously unmet need is inherently novel. Any treatments for COVID-19, that turn out to work will be “novel” in every way that matters.

For many in our industry, swearing by novelty is a means of, let’s say, #socialdistancing themselves from notorious drug companies that the public reviled for charging high prices without engaging in almost any actual drug development. Here I’m thinking of the Marathons and Belchers of the world, which, seeing no competition from altruists, stepped up to earn high rewards for doing low-risk paperwork the FDA needed someone to do.

Though they make for bad press, we mustn’t overreact to these fringe cases. If we feel that the few outliers like this are a stain on our names, we should push for reforms that empower the FDA to contract with a nonprofit to, for example, get a foreign generic drug licensed, labeled, and marketed in the US at a low price so patients don’t have to illegally import it. Turning our noses up at Marathon and Belcher just because their work didn’t seem novel enough to merit a high price is not only unproductive, the unintended consequences could be counter-productive.

Here’s the harm of committing to “novelty” at all costs. Imagine if a company suspected it could repurpose a low dose of an old generic HIV drug combined with an old generic epilepsy drug to treat a different neurological disorder. They know the combination would likely be safe because the drugs, as single agents, have already been in millions of patients. Yet studies would still need to demonstrate efficacy in the new indication and determine proper dosing limits. But the company would worry that payers, enjoying the support of a jeering public conditioned to denigrate anything that isn’t clearly novel, will refuse to pay for this combination drug. The company might fear that insurers would tacitly nudge physicians to prescribe the old generic drug components together, failing to reward the company that invested significant time and money in teaching the world about the medical value of this new drug combination. Would it risk the ridicule and financial uncertainty of repurposing these generics?

Or would it instead develop an entirely new molecule that does the same thing? That would take longer and be riskier. The final product would have a high price, and payers might resent having to pay, but at least no one could say that the product wasn’t “novel” in the conventional sense.

What would patients want? A safe and effective treatment they can afford. In other words, for insurance to pay for whatever works. So what should society want? The same.

To the extent that the public, the media, and Congress are concerned about novelty, it’s because it’s a litmus test for whether they think an innovation deserves to be rewarded with a high drug price. The corollary is if it’s not novel, then calls for price controls are fair.

The public, the media, and Congress are outraged over drug prices because many patients can’t afford the treatments they need. Unfortunately, society has collectively misdiagnosed the reasons drugs are unaffordable. It isn’t systematic price gouging by drug companies (the industry’s profit margins are too modest to tolerate even a 20% cut in US drug prices); it is, has always been, and continues to be America’s terrible insurance coverage. While many Americans do have good insurance and can afford their copays, some are crushed by their out-of-pocket costs, and ~15% of Americans have no insurance at all. Nothing about healthcare is affordable without insurance.

If there were ever an illustration of how stupidly counter-productive America’s health insurance designs are, recall the people who dutifully reported for COVID-19 testing and were sent home with massive bills, deterring others from seeking testing at all. They went home, or back to work, and unwittingly started spreading the new coronavirus. And even when ordered to cover COVID-19 testing, some payers interpreted that narrowly, sticking patients with bills for necessary but ancillary tests, such as those for flu, that doctors would order to help them interpret COVID-19 testing results. We all see the absurdity of that because we know that testing is essential for our collective public health. We’re outraged that payers, as our chosen agents for making appropriately-prescribed care affordable, are deterring healthcare that is essential for the public health.

But what’s true for COVID-19 and for testing is also true for all diseases and all treatments. And while it’s not as obvious as with COVID-19 coverage, affordable healthcare for all diseases for any individual is also a public health issue for all.  When payers don’t cover insulin well enough for patients to afford it, then some will ration it and suffer. Later, when they go blind because they couldn’t afford to manage their diabetes, the added cost of that care is unavoidable. Yet so much individual suffering and societal cost could have been avoided had the insulin been covered properly by the insurer in the first place. It’s an example of being penny wise, pound foolish.

So let’s recognize that the pressure that we as drug developers feel to only develop and charge for what society agrees is “novel” is really an outcry over two things.

First, we need proper insurance to make all appropriately-prescribed drugs affordable for everyone. Second, the pharmaceutical industry should only develop and charge America high prices for products that solve problems that are still unmet by all the known uses of our existing armamentarium of generic drugs (which, with few exceptions, it already does – just consider how impossible it would be to even run a trial for a new drug that aspired to be no better than a statin).

Society doesn’t want anyone playing games with REMS programs to price-jack an old, off-patent drug for the same old use, as Turing notoriously did with Daraprim. But the public does want biosimilars. By design, those aren’t novel, but they will bring down drug prices. The public doesn’t want companies exploiting ASP+ loopholes in Medicare Part B reimbursement to enjoy high revenues from branded drugs that are undifferentiated from generics. But it does want fast-followers (aka me-too drugs) in new classes that offer a greater variety of treatment options and drive price competition, as has happened with PCSK9s, SGLT2s, GLP-1s, CGRPs, and and many of the other acronyms we’ve ever drugged. Consider that America would have enjoyed greater negotiating power and discounts from Humira had there been a comparable me-too; developing competitors to branded drugs should be encouraged, not shunned by a commitment to “only invest in novel therapies.”

So what should we as an industry commit to so that it shows that we are aligned with what society really wants and deserves from us?

I propose this:

We will invest in drug development to address healthcare needs that are not yet met by the known uses of generic drugs.

Some might not find this satisfying because it doesn’t include the word “novel,” which the public likes to hear. Yet this statement captures everything we are doing to solve COVID-19 as quickly as possible, including new drug discovery and old drug repurposing.

And this statement applies to all of drug development for all our remaining unmet needs. Whether that means we will repurpose an old drug for a new use, reformulate an old drug to make it safer or more effective, invent an entirely new drug, or launch a similar competitor to another branded drug, it’s all in the public’s interest.

As long as all Americans are properly insured with affordable (or no) out of pocket costs, they will all be able to get the care they need. And as long as all those drugs go generic without undue delay — which means patents expire when they should, and aren’t extended through patent gamesmanship — then America and the world will be getting value for its money. I’ve written elsewhere, including a book, proposing specific reforms to shore up genericization for all drugs that would spur innovation.

So let’s either retire the word “novel” or at least resist the urge to cave to the public’s old notions of what it means. The COVID-19 crisis has primed the public to appreciate both the value of having an armamentarium of approved drugs and the benefits of searching for new uses for them. Let’s therefore learn together to see all solutions of important unsolved problems as “novel, in every way that matters.”

Peter Kolchinsky, a biotechnology investor and virologist, is Managing Partner of RA Capital Management, L.P., and author of The Great American Drug Deal.

27
Mar
2020

The Seattle Scientific Community, Mobilized

Kristin Anderson, postdoctoral fellow, Fred Hutch

“When I was a boy and I would see scary things in the news, my mother would say to me, ‘Look for the helpers. You will always find people who are helping.’” – Fred Rogers

The Seattle scientific community has always been tight-knit and collaborative, but we have mobilized like never before to respond to the threat of COVID-19. My friend and fellow Climb to Fight teammate, Bob More (@Bobmorevc), recently wrote an excellent piece recognizing a number of Unsung Heroes in this battle.

My hope is to share just a few stories of people working behind the scenes which you may not have heard yet. From the scientists who led the charge to make testing widely available, to the community members who have stepped up to support all of their efforts – we see you. And we are grateful.

Here are just a few stories to highlight how our Seattle community has come together to support each other.

Dr. Helen Chu (@HelenChuMD) is an infectious disease expert and the lead scientist for the Seattle Flu Study (@seattleflustudy). In short, the project asks volunteers in the community with flu-like symptoms to send in nasal swabs. Her team of scientists studies those samples to learn more about the flu.

Dr. Helen Chu, assistant professor, allergy and infectious diseases, University of Washington

In January, when the outbreak in Wuhan, China was in the news, Dr. Chu hypothesized that the coronavirus was already in the United States and being transmitted through the community, not just by people who had recently traveled to the US from China. She asked Washington state, the Centers for Disease Control and Prevention, and the Food and Drug Administration for permission to test the Flu Study samples for the novel coronavirus. The samples and all the infrastructure to study them were already in place. The study was up and running, collecting samples. It wouldn’t take much to shift gears to look at those same samples for the new virus. But Dr. Chu was firmly denied. That wasn’t part of what participants had signed up for. A new consent form, potentially taking weeks or months, would normally be required to move ahead on such a major amendment to study protocol.

Dr. Chu considered the ethics of the situation. This was a fast-moving and deadly pathogen. She discussed it with colleagues. Ultimately, she decided to test for the novel coronavirus anyway. They couldn’t wait any longer. Her results, from samples tested Feb. 25, are the reason we know the virus was spreading undetected through the community in Washington state. Her results are the reason that public health experts began sounding the alarm about the virus in the United States. Her results are also the reason we now have the Seattle Coronavirus Assessment Network (SCAN) program, the first coronavirus surveillance program in the country, which can begin to assess the basics of how many asymptomatic spreaders we have in the community, and where they are, so they can be isolated. Like the Seattle Flu Study, SCAN utilizes simple nasal swabs that community members can perform at home. Dr. Chu’s decision to persevere has been instrumental in our fight against this virus.

Keith Jerome, head of UW Virology division

Equally important in the early stages was the work of Dr. Keith Jerome and Dr. Alex Greninger, experts in virology at the University of Washington (@UWVirology) and Fred Hutchinson Cancer Research Center (@FredHutch). Shortly after the new coronavirus was being discussed in the news, they realized the country needed a diagnostic test for the virus and decided to divert some of their lab resources to develop one. When the Centers for Disease Control and Prevention’s tests did not work, these UW / Fred Hutch scientists applied to have their lab, and the test they developed there, certified by the Food and Drug Administration. That way, they could perform diagnostic tests for healthcare providers across the country. Their decision to develop a test using their own resources, even if it had not ever been needed, is saving lives every day.

This is not the norm for a research lab to turn itself, virtually overnight, into an industrial-scale high-volume diagnostic testing facility. Normally, they’d focus entirely on research questions, such as incubation times for a new virus, viral shedding rates, or various modes of transmissibility. They put their horsepower into doing an industrial task for patients in need in our community because somebody had to do it.

Once their clinical lab was approved to run patient samples, their small team started running diagnostic tests as fast as humanly possible. But even at peak speed they could only run about 200 samples per day. Knowing they needed to ramp up their throughput, they purchased machines to automate some of the process, but there were some steps that still needed to be done by hand. UW Virology put out a call for help. The Seattle science community answered. Volunteers from a variety of scientific disciplines, many of whom are young graduate students and post-doctoral fellows, set aside their own research to learn molecular virology techniques so they could process patient samples and open up the bottleneck. These volunteers are currently working in shifts around the clock and have helped increased the lab’s throughput to a maximum of more than 3,000 patient samples per day.

Processing thousands of samples is a massive undertaking. Administrators from multiple departments at the University of Washington quickly began volunteering their time providing logistical support. Almost immediately, the lab realized they were short on a critical lab supply: pipette tips. They again sent out a blast for help, this time on social media. Within 24 hours, local research labs and Roche (@Roche) delivered thousands of tips.

In response to the request, members of the community also reached out asking what they could contribute. One generous volunteer made hundreds of bags of healthy snacks for the researchers to “grab and go” between processing samples. Portage Bay Café (@portagebaycafe) donated breakfast, Starbucks (@Starbucks) donated coffee, and Pagliacci Pizza and Taste of India donated dinner for all the volunteers. Ellen Kuwana (@EllenKuwana) organized a Facebook Fundraiser and to date has raised over $15,000 to provide meals for the lab volunteers and healthcare workers while simultaneously supporting local restaurants.


Pavitra Roychoudhury

Once the clinical lab received the first sample containing coronavirus, bioinformatician Dr. Pavitra Roychoudhury (@pavitrarc) led UW Virology’s effort to analyze the complete viral genome in each of the local samples. Their goal is to develop a better understanding of transmission dynamics and viral genetic diversity. To do that, they plan to sequence every positive sample run in the clinical UW Virology lab. So far, they have deposited over 230 sequences to the Global Initiative on Sharing All Influenza Data (@GISAID) database. With sequences from this database, Dr. Trevor Bedford (@trvrb) and the team at Nextstrain (@nextstrain) construct a map of global transmission dynamics and viral evolution. These sequences are now open to the international scientific community to study, and to help other locations get a jump on the virus that’s likely headed their way.

Importantly, sequencing, assembling, annotating, and depositing sequences in these databases is no small feat. To speed up this data sharing, UW Virology again put out a call for support. Within 24 hours, they had dozens of offers from people with computational expertise volunteering their time. This collaborative effort to make data available as quickly as possible is a sea change in how scientific findings and data are often shared. Science and knowledge are being made freely available, and in real-time. There’s no waiting around for six months to get your manuscript published. It is inspiring.

The timing of this massive open science movement seems particularly appropriate. In an age when misinformation is so widely available on the internet, many people have been turning to scientists for answers. Community members are offering appreciation and virtual support through social media to scientists who they might otherwise not meet, or might not understand well in normal times. Parents are sharing that their kids want to be scientists. People are raiding their homes for supplies to donate, like masks, hand sanitizer and disinfectant wipes, which are desperately needed by caregivers in local clinics and hospitals. For people in the lab or the clinic, working long days and putting their own health at risk, gestures like this provide an immeasurable morale boost.

We are all contributing to something monumental that will likely be the defining events of our lifetimes. I could not be prouder of my friends, colleagues, and community. #WeGotThisSeattle #WeGotThisWA

27
Mar
2020

Singapore: Braving the Second Wave of COVID19

Carolyn Ng, managing director, Vertex Ventures HC

A week ago, I wrote an article for Timmerman Report on Singapore’s COVID19 response, and how the country has kept its cases low with no COVID19-related deaths.

In that article on Mar. 19, I elaborated on how Singapore had not ordered any businesses to shut down. Instead, the country had kept the number of cases low over the last few months through early and aggressive targeted containment policies, which were reinforced and implemented with high efficiency before cases surged.

That’s all changed in one week.

Literally a day after my article was published, it was announced that two patients (a 75-year-old female, and a 64-year-old male) died in Singapore from COVID19-related complications. Not unexpectedly, the country is now facing a second and larger wave of case spikes. The main reason for the surge in cases is coming from Singaporeans and long-term residents returning home from the UK and US, where uncontained outbreaks have clearly been raging for weeks, largely undetected. At this point in writing, Singapore has reported a total of 732 confirmed cases in the country – more than double from 313 a week ago.

Something Else You Need to Know About Singapore — Not Shown in “Crazy Rich Asians”

A little blurb on Singapore, this small, densely populated city state: we gained independence from our British colonial masters in 1946 after WWII and Singapore joined the Federation of Malaysia in 1963. In 1965, Singapore was expelled from the Federation of Malaysia as a standalone country with absolutely no natural resources, not even a clean water supply of its own. Every Singaporean grows up being intimately familiar with the famous historic scene of our former Prime Minister Lee Kuan Yew shedding tears into a piece of tissue when he announced the separation of Singapore from Malaysia as he had grave concerns for the survival of the island state.

I often hear my tourist friends complain that Singapore is “boring,” that there is nothing else to do in the country other than walking down Orchard Road, the shopping mecca of the country lined with gigantic shopping malls, one after another.

To them I calmly say: as you look around these ridiculously clean surroundings, which some criticize as “overly sterile,” please bear in mind that you are in fact standing on the ground of a miracle of an economy. Within a few mere decades, Singapore transformed itself from third world to first world. It is now one of the highest-ranking countries in the world in terms of GDP per capita. All that with zero natural resources.

That also means one thing: the country’s service and trade-dependent economy is all it has to ensure its survival and prosperity. The economy is its bloodline. Officials there think very carefully about how to best balance public health and the country’s economy.

Singapore’s Hybrid Model: Not (Yet) a Full Lockdown, But “Don’t Play Play”

In view of the second wave of case spikes in late March, Singapore took tough new steps to curb coronavirus spread. There are two specific objectives. One is to isolate and reduce imported cases. The second is to slow down community transmission.

1. Stemming Imported Cases: Borders Closed and Stringent Isolation of All Returnees

Singapore is an important transportation hub, with a significant fraction of its GDP generated from its airport and shipping ports. Last week, the government took the painful step of shutting its borders to all short-term visitors. Only long-term work pass holders working in essential sectors such as healthcare and transportation are allowed re-entry into the country.

As for Singaporeans and Singaporean Permanent Residents returning home from abroad, every single returnee is made to serve a 14-day isolation notice – with no exception. In particular, Singapore residents returning from the UK and the US are taken from the airport to designated hotels directly with special transportation arranged by the authorities to minimize their human contact during the commute. Accommodation and all meals are to be provided for by the government.

There is a common Singlish lingo used by us Singaporeans, known as “don’t play play,” which literally means “don’t mess around with me.” Consistent with that spirit, the Singaporean government means it when they serve you a 14-day stay home (or hotel) notice. Spot checks are done via text messages, video calls and surprise visits. People can choose to wait for two weeks before heading out to their favorite chicken rice stall, or face jail time of up to six months and/or up to a $10,000 fine in Singapore dollars. In just a few days, 89 work passes have already been revoked by the government for flouting stay-at-home notices.

2. Curbing Community Transmission: Stepwise Approach in Social Distancing

Singapore’s multi-ministry COVID19 task force has announced mandatory closures of bars, cinemas and all other entertainment outlets from Mar. 26 to Apr. 30. These are the island state’s most draconian measures yet. The order also include suspension of tuition centers, religious services, and gatherings of more than 10 people.

Is the country now considered to be in “lockdown” or even a partial lockdown? No. Schools have thus far remained open. Restaurants have been required to create more space between patrons, but they do remain open. Working-from-home is not mandatory, but has become the norm. Except for those served stay-at-home notices, other residents are not required by law to stay at home.

In a typical Singaporean fashion, even in the absence of a lockdown, the government is unmistakably serious about its social distancing measures. One just need to look at the headline splashed across Singapore’s Straits Times (the country’s most dominant media channel) yesterday:

 

Lockdown or Not?

Not surprisingly, given the various forms of lockdown/shelter-in-place in various cities around the world, people are questioning if Singapore should be more strict, and start enforcing a full lockdown immediately.

When asked that question at a press conference on Mar. 24, co-chair of Singapore’s COVID task force Lawrence Wong explained that Singapore’s measures have been designed, right from the beginning of the COVID19 crisis, to be meted out in tiers and in response to close monitoring of fast evolving risks.

The intent of the Singaporean government has always been, from the beginning, to introduce targeted containment measures early, swiftly and decisively so that the country will be able to nip the spread in its bud without triggering an emergency lockdown that will bring the country’s economy to a halt.

BUT, before I go any further, let me emphasize that this decision was taken by Singapore in January when the world first heard of COVID19. Most parts of the world ignored it at that time.

To put things in perspective, Singapore currently has, since the first reported case in January, a total of only 732 confirmed COVID19 cases, and two COVID19 related deaths. The magnitude of the COVID19 crisis in Singapore, even with the second surge (and adjusting for population), does not come close to the crisis that’s unfortunately occurring in the United States. Since the world first heard about COVID19 in January, the US has largely responded with delays and inaction. As of this writing, the US now has the most confirmed cases in the world — more than 87,000 — exceeding both Italy and China. More than 1,300 Americans have died, and the numbers are increasingly rapidly every day.

So, please, my dear American friends, please do not point to my beloved country Singapore as an exemplar of how to best balance public health and economic prosperity.

Yes, Singapore has managed to keep its schools and businesses open, economy running AND cases low. Some people argue that the US can do the same. But that’s impossible. The reason is that, simply, for many parts in the US, such as New York, it is too late: we have lost the window of opportunity for less drastic measures. A virus that spreads with exponential speed, and which has been spreading nationwide without containment for weeks can no longer be contained. It can only be mitigated with the kinds of extraordinary physical distancing and shutdown measures that are currently being employed in a number of states and localities. However, some of the other strategies deployed in Singapore may still be applicable and useful in the US, which the following sections will describe.

Saving Lives with the 3Ts: Test, Track and Treat

While the world awaits a prophylactic vaccine, the “3Ts” approach of test, track and treat remains the gold standard. Singapore is throwing its weight aggressively behind these efforts.

  1. Test: Singapore has one of the highest COVID19 test rates in the world. So far, at least 39,000 tests have been conducted to date, which translates to 6,800 tests per million people in Singapore. This compares favorably to around 6,500 in South Korea, another country lauded for high test rates. To that end, it is also very encouraging to see the United States ramping up its effort on that front, with New York leading with the most tests per million people (about 5,300).
  2. Contact Tracing and Tracking: Singapore has done a particularly impressive job of contact tracing to identify target hot spots for isolation. In fact, Singapore is making its contact tracing technology freely available to developers globally. The app, called TraceTogether, allows Singapore’s health ministry to access users mobile app data to identify people who had close contact with the infected individual. (Readers may cringe at the thought of alleged state surveillance with such a technology, this is a topic for another day — perhaps after we overcome this COVID19 crisis. For now, infected patients in Singapore are required by law to assist the health ministry in mapping out their location timelines for contact tracing.)
  3. Treat: The nation city has started its preparation to substantially expand its healthcare infrastructure and capacity. Unlike China and Italy, where healthcare workers may be deployed from other states or provinces, Singapore has no hinterland to draw resources from. Instead, the country has devised creative solutions for the private and public hospitals to work together. For example, stable COVID19 patients will be transferred to selected private hospitals to free up bed spaces for the public sector.

Last But Not Least, Saving Livelihoods

Returning to my earlier introduction of Singapore, with no hinterland and no natural resources, Singapore’s trade-dependent economy is the country’s lifeline. Deputy Prime Minister Heng Swee Keat announced an unprecedented COVID19 Resilience Budget of $48B Singapore Dollars package to carry the country through this difficult time. Another $17B Singapore dollars in stimulus will also be drawn from Singapore’s past reserves, increasing this budget to 11% of the country’s GDP.

I am not an economist, so most of the finer technical details were lost on me as I watched the parliament session in which this budget was worked out. What did catch my attention was:

  1. A Training Support scheme was included for self-employed individuals to improve their skills during the downtime. How thoughtful!
  2. On the next parliamentary session’s agenda, the Ministry of Law is set to address the issue of upfront deposits paid for large gatherings such as weddings, which are now cancelled/postponed. (As an anxious bride-to-be who has literally just paid an arm and a leg to our wedding venue and vendors in California, we are now struggling to find the right — legal and non-legal — recourse to our situation, which admittedly is very minor relative to everything else that the world is going through. To see Singapore’s government going to this level of extreme detail to address their citizens’ day-to-day issues is nothing short of impressive and reassuring.)
  3. Lastly, all political office holders in Singapore are taking a three-month pay cut in salary. To demonstrate solidarity with our home country and with our portfolio companies, the senior management at Vertex HC, Vertex Southeast Asia, Vertex Growth and Vertex Holdings, have also taken a voluntary salary cut, with proceeds being donated to not-for-profit organizations which aid families in need in Singapore.

The Worst is Not Over

I said it last week, and unfortunately I will have to say it again: the worst is not over – not for Singapore, and certainly not for the US or the rest of the world.

May the strong carry the weak, may the wise lead the way for the masses, and may the masses stay on their couches, for now.

Disclaimer:

This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Vertex Ventures HC, or any officer, director, partner, member, manager or employee of Vertex Ventures HC, or any of its affiliated entities. 

26
Mar
2020

Adjusting to Telemedicine: A First-Hand Account

David Shaywitz

One consequence of the present crisis is the urgent embrace of telemedicine, as I recently discussed. Whether the adoption is sustained beyond the crisis period remains to be determined, although use seemed to be increasing overall even before the pandemic hit. 

As more physicians and patients find themselves pressed to adopt telemedicine, I thought it might be helpful to better understand what this transition and experience is like, first-hand. So I asked my brother Jonathan, a psychiatrist in Los Angeles and a relatively early adopter of telemedicine, about his experience.   

Jonathan is an adult psychiatrist, with a focus on anxiety and affective disorders (depression, bipolar, mood disorders), and a particular expertise in psychopharmacology.

Here is what he had to say.

Jonathan Shaywitz, psychiatrist, Los Angeles

Timmerman Report (TR): For starters, help us understand what you typically cover with patients in a (pre-COVID) in-person visit?

Jonathan Shaywitz (JS): Most visits are follow-ups, tend to be extremely targeted, about 15-20 minutes long, and focus on medication management, following up on side-effects, for example.  There’s no physical exam; the questions are generally subjective.

TR: How did you first get involved in telemedicine?

JS: About six years ago, I was medical director at a Southern California hospital system with two large hospitals, half an hour from each other. At the time I joined, the hospital had already installed a telemedicine capability to enable staff at one location to see emergency room (ER) patients and floor [in-patient] consults from the other hospital – you could provide care from one site while physically being in the other. Most importantly, this allowed the ER staff to get in touch with a psychiatrist right away, so it wouldn’t delay the care of patients, and interrupt the flow of ER patients waiting to be seen. In many ER settings, a common hold-up can be waiting for a psychiatrist to come and evaluate a patient.

TR: When you first heard about this set up, were you skeptical? Interested?

JS: I was both interested and skeptical. I was especially skeptical about the technology, because you are really relying on it. I am at my desk at one site, and on the other end, they are wheeling a robot with a video screen with you projected on it. You are counting on the fact that the robot is available and functioning – plus you need someone to appropriately set up the machine. In my experience, this tended to work very well in the ER – basically because there was a single person responsible, and they were very familiar with the technology. Floor consults tended to be more challenging – depending on the floor, you might not have someone around who really knew how to set up the technology.

TR: Do you feel you were able to do as good an exam remotely as if you had seen the patient in person?

JS: I do. There were no procedures involved. Emergency room patients tended to be especially accepting because they were so happy to see a psychiatrist and not have to wait – there was a real sense of time being an issue. The typical evaluation would be for acute depression, often focused on the question of whether the patient was at risk for self-injury.

TR:  Seems like a high stakes evaluation to do remotely – did you feel comfortable, and was it a difficult adjustment?

JS: I did feel comfortable, and it didn’t seem like a difficult adjustment, at least not in this setting, because the exam is so targeted and focused, and the patient is in a well-controlled environment. Floor consults were a little more challenging, both because of the technology issues I mentioned earlier, and also because the consults could be more vague, and less focused.

TR: Did you feel that on these floor consults, you were able to be as effective when you used the robot?

JS: It can be a little more difficult; when you consult in person, you often are dependent on collateral information, such at what you might learn from a family member who’s nearby or waiting outside. It’s harder to get some of that information when you’re using the robot.

TR: You went on to use telemedicine extensively in out-patient psychiatry; what was that experience like?

JS: In the outpatient setting, you can’t control the environment, in contrast to the hospital ER and floor consults. You’re at the whim of the patients, and often they take it a little less seriously. When patients come to the doctor’s office, they tend to be more focused, and in the moment. The big advantage of telemedicine, of course, is the convenience, but this can also mean a patient is multitasking, or not speaking from a conducive location. Many telemedicine doctors talk about this challenge. I’ve had patients who would be talking with their friends, watching television, or just in a crowded place. This is a problem not only in terms of security and privacy, of course, but also, at least as importantly, because the patients tend to be distracted by the environment. Telemedicine doctors try to manage this by setting limits and having boundaries.

TR: So given all this, what’s your view of telemedicine? 

JS: I encourage it. Even with all the challenges, it is still better than people not being able to make it to appointments. The overall quality of care you can deliver because of the continuity more than makes up for the occasional challenges of a session.

The overall quality of care you can deliver because of the continuity more than makes up for the occasional challenges of a session

TR: How do you have to adjust your style for telemedicine?

JS:  You need to be more structured with patients. You also have to set limits.

TR: For your outpatient interactions, was technology an issue? 

JS: No, not at all – we used a HIPAA-compliant app, which worked extremely well.

TR: What about reimbursement – it sounds like that can be a problem for many?

JS: When I first started, some insurance companies would only reimburse for face to face encounters – but that’s really improved now. 

TR: And is there a requirement for an initial meeting face to face? 

JS: Initially that was true, but it seems to have gotten relaxed over time for many payors.  Often, it’s the physician that wants the initial meeting in person.

TR: Finally, what do you see as the future of telemedicine?

JS: Even before COVID-19, telemedicine was skyrocketing. It is the future, especially in areas like psychiatry. Because it’s not procedural, the major factor is convenience – time and geography – and telemedicine allows patients to fit in appointments much more easily. The key needs are checking in and continuity, and telemedicine affords this.

26
Mar
2020

The Coronavirus Tsunami, Lyell’s $492M Megaround & Some Deals You Missed

Luke Timmerman, founder & editor, Timmerman Report

When a story moves with exponential speed and deadly force, it’s hard for a human being to keep up.

Hard for you, and hard for me.

My approach these past few weeks has been to work with purpose and passion on this story that touches all of humanity. The plan has been to seek out diverse voices with fresh perspectives on the pandemic, recruit them to write for TR, and aggressively edit and publish their work in addition to mine. All of the pandemic coverage is being made completely free (no ads, no subscription required), so you can share this quality coverage with family, friends, and colleagues. I am grateful to see so many of you appreciate it.

Human life is on the line. People need quality information to make the best decisions in their daily lives. Journalism always has a public service duty, but it’s never more important than times like now. That’s why everything on Timmerman Report related to the pandemic is being made free, so you can share it with your loved ones, friends, and colleagues who need quality news and information, as opposed to the propaganda and entertainment that tends to drive too much public discourse.

My hope is that in the weeks ahead, you can count on TR to keep things in perspective, while you do what you have to do to keep your families safe and your companies operating under stress. Expect a mix of informative, data-rich voices, and fresh perspectives that can help guide us all through the crisis. Knowing the emotional strain the pandemic puts on people, expect these pages to also shine a light on writers who tap into the human dimension which is too often overlooked in the business world. You may even get a dose of humor once in a while, like yesterday’s piece by Lisa Suennen.

As a Timmerman Report subscriber, I want you know my inbox is open to you. I’m listening.

If you have suggestions of people and ideas that I should consider, let me know. luke@timmermanreport.com.

Now on to your regularly weekly Frontpoints.

The Table That Has Me Most Worried

The US healthcare system apparently relies on threadbare-thin just-in-time inventory stocking for essentials, like personal protective equipment, to a far greater extent than most of us imagined. The shortages of PPE this early in the pandemic response, along with woefully inadequate diagnostic testing in too many parts of the country, are deeply troubling at this late date of Mar. 26. Why in the world didn’t we scale up manufacturing starting Feb. 1, when the alarm bells were clear from China. Or how about Mar. 1, when it was abundantly clear we had uncontained community transmission in the Seattle area for the preceding six weeks? The federal government’s denial, incompetence, short-term thinking, and outright dangerous lies  — it’s a nightmare beyond even my darkest fears from the past few years.

I’ve spoken with doctors and nurses. The fear in their voices is palpable. They know this virus is highly contagious. They know it sends about 15-20 percent of people who get it to the hospital. Many patients need ventilators which we don’t have. Where in the world are all these patients going to go to get the adequate first-world care they need to survive?

How far do we have to go to catch up? Forgive the crude table below, which includes data compiled by OECD on hospital beds per 1000 people, through 2017. You have to scroll a long way down to find the United States.

The United States ranks No. 32 in the world, with fewer than 3 hospital beds per 1,000 people (below countries like Italy and Spain, which have been overwhelmed).

 

Beds are something of a proxy for hospital capacity. Now, you might say, beds can be obtained and rolled out in surge hospitals like the Javits Center in New York. Sure. But even if beds are installed, who will tend to the patients? Anyone familiar with unionization drives for nurses over the past 10 years knows that they are being run ragged and overscheduled,  even in normal times. We don’t have a deep bench of reserves to call up. If these frontline workers start getting sick, we simply won’t have enough skilled people to provide care. (See table below from Kaiser Family Foundation, based on OECD data).

 

Dashboards to Help You Keep Up (Which You Probably Already Have)

The New York Times has a nice visualization of the US map, along with new cases, and deaths, reported on a daily basis. (NYT Latest Map and Case Count). The NYT, given its resources, should lead the US media. It has been simply superb in its overall team coverage.  

Johns Hopkins University is a go-to source for worldwide case counts, and deaths, updated in real-time. Sadly, you can see the US moving up to the top of the list, surpassing China as of Mar. 26, in terms of total number of confirmed cases. (Johns Hopkins dashboard).

Covidactnow.org is an excellent resource that provides colorful state-by-state projections of what various scenarios look like, with aggressive community mitigation and without. (H/t to TR subscriber Steve Dickman of CBT Advisors for sharing).

Covidly.com. A simple display. US is now No. 1 in the world in terms of confirmed cases.

Sad, but Predictable Fallout

Eli Lilly announced something that should have been pretty easy to anticipate a couple weeks ago. Clinical trial activity is being curtailed during the COVID19 pandemic. New trials in the queue aren’t being started. Enrollment of new patients in existing trials, are being paused. Existing patients in trials who need to stay on protocol as part of their care plan, will maintain continuity on study. I’d watch for more shoes like this to drop in coming weeks.

Silver-lining Department

Scientists, doctors and nurses will be the new heroes in our society in the 2020s and beyond.

A few highlights from the world of science:

Seattle is a few weeks ahead of the rest of country in the coronavirus outbreak. The Seattle Flu Study, which was set up as a $20 million project to gather samples from people suffering flu-like symptoms in the community to better understand that virus, has been nimbly, and heroically, repurposed to evaluate the community spread of SARS-CoV-2. These scientists from the University of Washington and Fred Hutch have not only provided a crucial set of data-driven warnings to scientists around the US, they’ve turned virology labs into a high-volume testing center when the federal government failed to keep up with a virus that spreads with exponential speed. Read about the Seattle team’s new research plan here.

A brute force team of scientists led by the famous drug hunter Kevan Shokat at UCSF published what you’d have to call a tour de force of a preprint on BioRxiv. They described their work probing for an Achilles heel in SARS-CoV-2. They found “332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays.” Talk about working with purpose and passion. Who knows where this will lead, but holy mackerel. Read the preprint yourself here.

Scientists in China, alongside US peers, are looking at lightning speed for broadly neutralizing antibodies against SARS-CoV-2. Chinese scientists reported Mar. 25 on an almost incredible 206 broadly neutralizing antibodies against the receptor-binding domain on the virus. Antibodies can provide exquisite specificity to a target. The Chinese team reported surprisingly little cross-reactivity with SARS and MERS. But one challenge with antibodies is they are difficult to scale up for all-out mass production quickly. If these go anywhere, antibodies in beginning small batches could be an especially important tool for treatment of patients in severe distress, and potentially for prophylaxis of healthcare workers on the front line. That would be an interim step before we get a cheap, effective vaccine that can be given worldwide.

Disease modelers at Imperial College London rocked the world with their original report on Mar. 16 that as many as 2.2 million people in the US could die from COVID19 in a worst-case scenario. Some skeptics wondered if this was alarmism, given the thin gruel of actual hard testing data that the modelers had to work with in order to make their projections, including the crucially-important Case Fatality Rate. Data on hospitalization rates, similarly, is hard to pin down with sweeping, and accurate, testing data. Even so, a lot more data has come in worldwide in the last 10 days. Now the Imperial College London team is out with a new report on Mar. 26. The updated report expects 7 billion infections and 40 million deaths worldwide this year with no interventions. Mitigation strategies could cut the death toll in half, but would still result in overwhelmed healthcare systems. (Full Mar. 26 report here).

COVID-19 Reading from Around the Web

 

TR Coverage of the Pandemic (Free & shareable with friends, family & colleagues)

Tweetworthy

Craig Spencer is a physician in New York City. Healthcare workers there are in serious trouble. The wave of COVID19 patients is coming to parts of the US, too.

Read this tweet, which sums up this disastrous state of affairs, and boils with frustration.

In Other News…

Deals

Redwood City, Calif.-based Codexis formed a partnership with Takeda to make novel enzyme sequences for use in gene therapy preclinical development. Terms not disclosed.

South San Francisco-based CytomX Therapeutics pocketed an $80 million upfront payment from Astellas to co-develop bispecific antibody treatments for cancer. 

Pfizer partnered with Germany-based BioNTech to work on an mRNA-based Covid-19 vaccine. Plans to work out financing terms will get worked out later, given the urgent need. Cambridge, Mass.-based Moderna staked out a lead in the category, dosing the first patient in a healthy volunteers trial in Seattle, the epicenter of outbreak in the US.

Data That Mattered

Genentech and AbbVie reported that venetoclax (Venclexta) improved overall survival time, in combo with azacitadine, compared with the standard chemo, in a Phase III trial of patients with acute myeloid leukemia. Details coming at a future medical meeting (whenever they might be held again).

Financings

South San Francisco-based Lyell Immunopharma raised $492 million in a Series C equity financing that included 10 investors, according to a regulatory filing with the SEC. The company didn’t issue a press release on the financing, but Bob Nelsen of Arch Venture Partners confirmed to me that Arch participated, and has plans to continue with three large financings in coming weeks, despite the pandemic. Lyell is led by CEO Rick Klausner, a former director of the National Cancer Institute and a co-founder of Juno Therapeutics.

South San Francisco-based CERo Therapeutics raised $40 million in a Series A financing. The company is working on engineered T cells for solid tumors. Arch Venture Partners participated. (See TR coverage on T cells for solid tumors, March 2020). CERo also said it struck a partnership with Lyell Immunopharma.

San Diego-based Design Therapeutics raised $45 million in a Series A financing led by SR One. The plan is to work on nucleotide repeat disorders, starting with Friedreich’s ataxia.

Menlo Park, Calif.-based ReCode Therapeutics secured an $80 million Series A financing, co-led by OrbiMed Advisors and Colt Ventures. The company pools some assets for mRNA and tRNA therapeutic development for lung diseases, starting with primary ciliary dyskinesia and cystic fibrosis.

Emeryville, Calif.-based Eureka Therapeutics raised a $45 million Series E financing to advance its cancer treatment programs. Lyell Immunopharma led.