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Lisa Suennen
Sailors know the concept of tacking. It’s an essential way of moving forward. Without tacking, the headwinds are too strong. The boat can go wildly off track, or stall. By steering from one direction to the other, in zigs and zags, it is possible to drive into the headwinds and make progress. Do it well, and you can gradually overtake an opposing force to reach the destination.
San Mateo, Calif.-based Evidation Health, Inc. has a long history of tacking, and it’s now maneuvered itself into position to perfectly match what the market wants. This is the well-known state of “product-market fit.” And when a company reaches this stage, the tailwinds begin to take over, helping push it even faster to the planned destination of market success.
Founded originally in 2012, the predecessor company to Evidation was called The Activity Exchange (TAE). TAE was founded early in the days of the digital health revolution, long before paths to health data monetization were clear. The company originally took data from consumer wearables and applied sophisticated predictive analytics to encourage wellness and drive patient behavior, particularly for employers and insurance companies.
In many ways, that was the right product, but it entered the market at the wrong time. It was simply much too early for customers that were just beginning to think about the role that digital data might play in encouraging better health outcomes. As such, Evidation put its boat in the water at the precise moment that the oncoming wind was strongest.
When TAE merged with the newly formed Evidation in 2014, the company made its first tack. It shifted to help the emerging digital health companies demonstrate the value and validity of their products and interventions for pharma companies, payers, and other clients.
By helping digital upstarts develop an evidence base, they posited, all boats would rise. As it turned out, the digital health startups of that period didn’t have the funds to undertake the kind of sophisticated demonstrations of efficacy that Evidation sought to manage on their behalf for that demanding set of customers – pharmaceutical companies and health insurers.
Many digital health companies of the time hit the rocks. But Evidation noticed something that led it to tack again — that the pharmaceutical companies were coming up the learning curve in digital health. They had both money and interest to invest in understanding patients’ experience when taking medications.
In response, Evidation redirected its efforts toward becoming a digital products Clinical Research Organization (CRO) of sorts. Evidation found a new angle, helping pharmaceutical companies sort through the burgeoning array of digital products to evaluate their validity and usefulness. With Evidation’s help, pharma companies, through a series of short post-market studies, began to see a more vivid and detailed picture of patient’s everyday lives as they interacted with newly marketed biopharmaceuticals.
Suddenly, Evidation was in position to provide pharmaceutical companies with new information that could help them with their sales and marketing campaigns.
Each of these tacks was complex. That’s not just because of the business shifts required, but because there was uncertainty among leadership and, at times, a lack of unanimity on the Board as to whether the pharma market was really the right course to pursue.
At the time Evidation made this move, the idea of real-world evidence (RWE) was gaining currency in the pharma/biotech realm, especially as it related to Phase IV post-marketing surveillance studies of new drugs.But the market sent out some mixed signals that would, on occasion, tug the company back toward its wellness roots.
But Evidation fundamentally stayed on course. As it picked up steam, it began to recognize that its pharma insights business, as designed, wasn’t going to get them all the way to their target destination.
Instead, the Evidation team was encountering more wind than waves, and that was keeping the business from growing to its full potential. Most of the pharma contracts were for short studies (3 month “catch and release studies” as Evidation internally referred to them) that did not produce a recurring revenue model or an ongoing relationship with customers and patients. Notably, pharma and biotech companies were also becoming far more curious and sophisticated about how data and data science could inform their business at a much more profound level.
It was time to tack again.
Ultimately, the business set its course toward gathering and analyzing patient insights over extended periods of time (not just for short bursts), developing large condition-specific cohorts drawn from its proprietary patient network (the company has built a patient network of over 4.5 million individuals willing to participate in studies for minimal compensation). This has enabled pharmaceutical companies to engage in continual and continuous learning about patient experience through longitudinal engagement with large target populations.
Evidation’s many large and mid-sized pharmaceutical and biotech clients can now continue to develop new queries and hypotheses to test and identify emerging trends over the course of a year or more to get a more holistic picture of what it’s like for people to live with various medical conditions and to take medications over the long term. At the same time, companies can satisfy patients’ hunger for education about how to best care for themselves by sharing information and personalized content, as well as relevant and individualized data with cohort participants.
Christine Lemke, co-founder and co-CEO, Evidation
It’s early going on this course, but the coordinates appear to be correct. As Co-Founder and Co-CEO Christine Lemke noted, “It’s fascinating to see how many use cases come out of the woodwork as you watch the population for longer periods. Trends over time are profound and many could not have been anticipated.”
Evidation and its biopharma clients have been experimenting, for example, with large cohorts of patients who opted in to allow programs to track possible signs of emerging illness. By monitoring certain vital signs, it has been possible to see subtle fluctuations that could portend signs of flu or COVID-19. When identified, the patients are engaged to take tests for both conditions, an action they deeply appreciate. Interestingly, this may send Evidation heading full circle to its original customer roots as the company identifies ways of predicting and preventing illness.
For now, Evidation is running with the pharma sector.
With its many zigs and zags, the big learning for Evidation has been importance of staying nimble, noting it’s much harder to tack with 300 team members than 30.
“Being ahead of the market is hard and being first is not always best,” Lemke says. “Sharks survive because they keep moving. We realized along the way that we were never going to have perfect info or judgment, so we must always watch how the wind is blowing and just keep going.”
Today’s guest on the Long Run is Ray Stevens.
Ray is the CEO of ShouTi. It’s a company that uses advanced structural biology technologies like cryo-EM images, and computational techniques, to discover small molecule drugs. The idea is to come up with orally available medicines that can build off the biological insights gained from protein or peptide drugs, but replace them with a less expensive and more convenient oral small molecule.
Ray Stevens, CEO, ShouTi
ShouTi has operations in San Francisco and Shanghai, making it a hybrid Chinese-and-American company. The company raised a $100 million Series B financing in October.
Ray comes to this position with a long and distinguished track record in structural biology. Ray was a professor at USC, Scripps Research, and UC Berkeley. He played a role in Syrrx, which was acquired by Takeda, and later co-founded Receptos – a company acquired by Celgene for $7.2 billion. The main asset there was ozanimod. It’s an oral small molecule agonist aimed at a G-protein coupled receptor target. It’s now marketed by Bristol Myers Squibb as Zeposia for the treatment of multiple sclerosis and ulcerative colitis.
In this conversation, we talk about Ray’s journey through academia and industry, the technologies that are enabling important advances in small molecule drug discovery, and a bit on what it’s like to run a company that tries to bridge the gap between the US and China.
Now please join me and Ray Stevens on The Long Run.
Luke Timmerman, founder & editor, Timmerman Report
Climbing Mt. Everest changed my life. The world’s highest mountain required digging deep — physically, mentally, emotionally.
That was four years ago.
That original climb was a success, raising $340,000 for cancer research at the Fred Hutchinson Cancer Research Center. But what came next meant more. The climb opened my mind to new ways of making a contribution, in addition to biotech journalism.
The expeditions that followed have become bigger. More impactful and more enduring.
I’m returning to the Himalayas this month. This time, it will be with a team of 18 people I recruited to trek to Everest Base Camp, elevation 17,600 feet. Before hitting the trails of Nepal, we have worked together to raise more than $1 million for cancer research at the Fred Hutch. We could exceed $1.2 million before it’s all done.
I’m proud of this team and what it has accomplished for science.
It’s been a long and hard road the past two years for everyone. I can hardly imagine what it has been like for my Sherpa friends.
I will cry tears of joy and gratitude when we meet in Kathmandu. Hugs are on the first team meeting agenda.
Luke Timmerman with Everest guide Jangbu Sherpa at Everest Base Camp. 2018
The people of Nepal are poor in material terms, yet so generous and grateful in spirit. Going back, and giving back, is one way to make a positive contribution.
We will be meeting with researchers from the Kathmandu Cancer Center. We will be learning from people in the villages. We will enjoy the mountain scenery, savor warm cups of tea, and form meaningful relationships on the trail. More good things are bound to emerge.
Expect things to be quiet at Timmerman Report the next couple weeks. I plan to be mostly off the grid, with a few brief team updates from Nepal. By mid-April, I’ll be back.
Thanks to all the TR readers. Your outpouring of comments about the 7th anniversary of TR were heartwarming. Many of you have contributed to my campaigns for Fred Hutch and Life Science Cares. A few of you have participated. Some of you may want to participate someday. There will be time to discuss all of that later.
Tumultuous things are happening in the world. But one thing I learned four years ago is that in difficult moments, people are capable of more than they realize. Sometimes a kind word, or a sincere expression of confidence, is all it takes to provide people with the spark.
When we commit to a cause larger than ourselves, and when we show faith in others, amazing things can result.
Let’s keep lifting up the people around us.
Data That Mattered
Gilead Sciences released underwhelming top-line Phase III clinical results for sacituzumab govitecan-hziy (Trodelvy), in metastatic HER2-negative breast cancer patients. The company issued a mealy-mouthed and detail-light press release which said it hit the primary endpoint of Progression-Free Survival, and that the study was powered to show a 30 percent reduction on PFS, but that only a trend toward benefit on Overall Survival was seen. These were sick patients previously treated with CDK4/6 inhibitors, but still. That’s not great news, especially for a key asset obtained in a $21 billion acquisition of Immunomedics. Baird analyst Brian Skorney summed it up well: “Although not a failure, we think this top line release indicates that the opportunity in HR+/HER2- breast cancer is likely to be constrained, as the benefit seen may not be enough to drive utilization vs. the cheap generic chemos Trodelvy was compared to in this study.” Gilead followed up its tepid clinical results by cutting 114 jobs in the former Immunomedics unit it acquired, and reallocating some resources for manufacturing in Southern California. The series of missteps at Gilead has been jarring of late, and has prompted some analysts to wonder about the state of the company under CEO Daniel O’Day. See Matt Herper’s take in STAT.
France-based Valneva, a vaccine developer, reported positive Phase III results with a single-shot, live-attenuated vaccine candidate against chikungunya virus. The data from a study of more than 4,000 subjects showed protective levels of neutralizing antibodies were observed in 98.9 percent of subjects on the vaccine after one month, and 96.3 percent of vaccine recipients after six months. The company said it plans to seek FDA approval before the end of June. If approved, this would be the first vaccine against this mosquito-borne illness that sickens millions of people around the world.
Deals
San Diego-based Illumina, the market leader in DNA sequencing, continues to struggle with antitrust regulators. This week, Reuters, citing people familiar with the matter, reported that European Union regulators are still unsatisfied and yet to approve of the company’s plan to acquire Grail for $8 billion. The acquisition would allow Illumina to expand globally into the emerging market of early cancer detection powered by DNA sequencing technology.
Cambridge, Mass.-based Voyager Therapeutics pocketed $54 million upfront from Novartis in an option agreement. The deal gives Novartis the option to license novel AAV capsids to use in gene therapies against three targets of the Central Nervous System, and potentially two more targets in the future.
San Francisco-based Cellevolve struck a partnership with Seattle Children’s Therapeutics, a venture from Seattle Children’s Hospital.
Derrell Porter, founder and CEO, Cellevolve
Cellevolve will bring its expertise in development and commercial strategy for cell therapies to the table, while Seattle Children’s Therapeutics brings its GMP CAR-T cell therapy manufacturing capability and lentiviral vector manufacturing capability for cell therapies. The organizations will collaborate on three pediatric cell therapy programs for malignancies of the Central Nervous System. Michael Jensen, a Seattle Children’s researcher and co-founder of Juno Therapeutics and Umoja Biopharma, has agreed to serve as chair of Cellevolve’s Scientific Advisory Board. (Listen to Cellevolve founder and CEO Derrell Porter on The Long Run podcast, Feb. 2022)
Our Shared Humanity
Science Features
Science
Science of SARS-CoV-2
Science Policy
Vaccines
Moderna announced its near-term global health strategy. It includes a commitment to advance vaccine candidates against 15 pathogens considered to be risks to global health, as determined by the World Health Organization (WHO) and Coalition for Epidemic Preparedness Innovations (CEPI). The company reached an agreement with the US government to build its first mRNA vaccine factory on the African continent in Kenya. It agreed to an open platform for researchers to gain access to its technology against emerging or neglected diseases. And the company agreed not to enforce its IP in 92 low to middle income countries.
Personnel File
Morphosys closed the Cambridge, Mass.-based R&D center it obtained through the acquisition of Constellation Pharmaceuticals. It’s consolidating work in Germany. (Endpoints News)
Cambridge, Mass.-based Alnylam Pharmaceuticals promoted Kevin Fitzgerald from senior vice president and chief scientific officer to executive vice president and chief scientific officer of research. He’s been with the RNA interference drug developer for 18 years.
Seattle-based Adaptive Biotechnologies hired Tycho Peterson as chief financial officer. He’s a former JP Morgan analyst. The company said it’s also cutting 12 percent of its workforce.
Waltham, Mass.-based Affinia Therapeutics, a developer of AAV gene therapies, said it’s added Diana Brainard to its board of directors. She’s the CEO of AlloVir.
Cambridge, Mass.-based Bluebird Bio said in a regulatory filing that Gina Consylman, the chief financial officer, is resigning on Apr. 3. Jason Cole, the chief business officer, will serve as the company’s primary financial officer. A few days earlier, in its 10-K, the company issued a warning to investors that it has doubt about its ability to continue as a “going concern” as it runs low on cash.
Financings
San Diego and Research Triangle Park, NC-based Creyon Bio came out of stealth with a $40 million Series A financing. It’s working on using AI to develop custom oligonucleotide therapies. DCVC Bio and Lux Capital co-led.
Concord, Mass.-based Adiso Therapeutics, backed by Morningside Ventures, announced its debut. The 25-person company is working on small molecules and single-strain live biotherapeutics for the treatment of ulcerative colitis and C. difficile infections.
Venrock led a $20 million Series B financing in San Francisco-based SmithRx, an aspiring new pharmacy benefits manager (PBM). The idea, according to Axios, is to use algorithms to help employers find “lower-priced medications based on pharmacy distribution, clinical management, rebates and special programs.”
Vancouver, BC-based Solve FSHD was founded with $100 million from Lululemon founder Chip Wilson, who suffers from facioscapulohumeral muscular dystrophy type 2.
Mountain View, Calif.-based DNAnexus raised $200 million in a deal led by Blackstone Growth to support its platform for using multi-omics data to advance precision medicine. Terms of the deal weren’t disclosed, even whether it’s equity, debt, or some combination of the two. Northpond Ventures, GV, Perceptive Advisors, Innovatus Capital Partners, and Foresite Capital joined the round.
Regulatory Action
Seattle-based Alpine Immune Sciences said the FDA placed a partial clinical hold after a patient died in the NEON-2 clinical trial that is evaluating its drug candidate davoceticept in combination with Merck’s pembrolizumab (Keytruda) for advanced cancers. The company said the death was attributed to cardiogenic shock. The treating physicians thought it was “likely related to immune-mediated myocarditis, or possibly infection,” Alpine said. The partial hold doesn’t affect Alpine’s NEON-1 trial, which evaluates its drug candidate as a monotherapy.
Tweetworthy
Good news.
Vikas Goyal, former SVP, business development, Pandion Therapeutics (now part of Merck)
[Editor’s Note: this is part of series of interviews with business development executives about some of the surprises, subtleties, and human aspects of biotech dealmaking.]
Praveen Tipirneni is a physician by training, but more than anything it was his work in business development that put him in position to become the CEO of a publicly-traded biotech company – Waltham, Mass.-based Morphic Therapeutic.
Before Morphic, Tipirneni spent 13 years at Cubist Pharmaceuticals. He was senior vice president of corporate development and global strategy in 2015 when Cubist was acquired by Merck for $9.5 billion. At the time, Cubist was best known for marketing the antibiotic daptomycin (Cubicin).
But there were other assets in the pipeline. In this interview, Tipirneni recalls another deal – Cubist’s 2009 acquisition of Calixa Therapeutics — that helped set the table for the ultimate big deal with Merck.
Let’s start with the punchline. What is your advice for your biotech BD peers out there?
My advice is to not underestimate what is possible, to not underestimate the future importance of a deal. Sometimes it’s those sleeper deals that turn out to become important. The important deals are not always the one you expect or predict.
Praveen Tipirneni, CEO, Morphic Therapeutic
So what deal are we going to talk about today?
Cubist’s acquisition of Calixa Therapeutics in 2009. Calixa were in Phase 2 at the time with a cool new anti-pseudomonal cephalosporin. Calixa was backed by Domain Associates and had a very credible antibiotics team.
That drug ultimately became Zerbaxa (ceftolozane). With Cubicin later in its lifecycle, ceftolozane had the potential to be the critical driver of Cubist’s future growth. And, ultimately, this drug became one of the assets that Merck really wanted when they acquired Cubist in 2014.
What was your role in Cubist’s acquisition of Calixa?
Do you know the baseball term Wins Above Replacement? Honestly, anybody on the technical side at Cubist could have done the Calixa deal. It was an antibiotic right up our alley. My value add was getting the deal closed.
We were almost at the end of the process. All the major terms had been negotiated; the diligence was mostly done. But then this accounting issue came up. It was December and I was literally on a ladder putting up the Christmas tree talking to Rick Orr, COO at Calixa.
There had been some very recent changes in the 409A accounting rules. Back then, there were no third-party advisors for 409A equity valuations and start-ups basically did it internally. Cubist’s diligence suggested that Calixa may have underestimated the 409A tax liability. With the risk of penalties and fines, Cubist’s accounting firms were using terms like “unlimited” liability and this very technical accounting issue got elevated all the way to our Board.
What was the deal risk? What did you do?
Cubist ended up requesting a very large escrow as part of the M&A agreement to address the 409A tax risk. And Calixa was having a very hard time accepting this escrow term.
This totally could have tanked the deal.
First the 409A analysis was a highly technical issue and both sides thought our analyses were right. Second, the acquisition had milestone-based earn outs which was still novel at the time and there were uncertainties about how to handle the accounting for those future payments. And third, the emotions and egos were so high there was no way senior management was going to meet halfway and compromise on the issue.
The deal had been going nowhere for days until the negotiation got delegated down to me on the Cubist side and Rick at Calixa. Rick was concerned that if Calixa accepted the escrow and closed the acquisition, post the deal there would be no one left to represent Calixa’s interests and Cubist could interpret the escrow however we wanted.
So there I was on the Christmas tree. I was only VP of Business Development back then and I ended up being really honest with Rick. I told him, “I’m not a decision maker for this issue, Rick. What I can do is personally commit to you that I will represent Calixa’s side after the acquisition.”
Was there a lot of pressure at Cubist to close this deal? What about on Calixa’s side?
Yes, I think both sides really did want to do the deal.
To set the stage for the Calixa acquisition, you have to look back at their predecessor company Cerexa. Calixa spun out of Cerexa in 2007. Cubist had really wanted to acquire Cerexa and we ended up bidding to our full financial capacity. The Cubist team all thought we had won the auction, but literally in the last week Forest Laboratories came out of nowhere and bid way above us. I felt totally burned.
So with that backdrop, we’re now looking at Calixa wondering if we were about to lose to Forest again. And I also think the Calixa team remembered us from the Cerexa interactions and wanted to do the deal with us.
It sounds like you really needed to advocate for Calixa’s side to get this deal closed. You were negotiating with Calixa, but also with our own colleagues and tax advisors at Cubist. Would you do it all over again?
Obviously this product was very important for Cubist. After the deal closed, we started working through the formal tax analysis. And, of course, the escrow issues all worked out in the end. And to this day, I really believe Rick and the Calixa team were right and that our advisors were overestimating the tax risks.
But I don’t know if I would do this all again.
There was no need for a BD person to be involved in this tax escrow analysis. And there was zero upside to me acting so smart on this issue. We literally had multiple major accounting firms including Price Waterhouse, Ernst & Young, and Coopers & Lybrand advising us – this was one of those nightmare scenarios where we had conference calls with 50+ people. But there I was reading the tax laws myself and questioning the work of our accounting firms. These guys were all so mad at me.
Before this deal, there had been a chance I might have gotten a shot at the CFO job at Cubist. I’m pretty sure all of this 409A stuff cost me that job (though in retrospect, that turned out to be a good thing).
You mentioned ceftolozane became a driver for Cubist’s ultimate acquisition by Merck. How so?
So first, Zerbaxa (ceftolozane) was going to be a big next product for Cubist. Merck was very interested in the drug.
Second, it also tied into a subsequent deal we did in 2013. Calixa had originally licensed ceftolozane from Eisai (which then became Astellas). The license terms were good for Calixa, but they had to leave Japan and several other Asia geographies with Astellas. It remained an ongoing annoyance that we didn’t have full global rights. And I could tell our CEO, Mike Bonney, really wanted the Japan rights back.
We were just 6 months away from Ph3 trial results, and our BD team wanted to wait until the clinical data readout before approaching Astellas. I kind of agreed with the BD team but I figured I’d give it a shot. I was able to get the full global rights from Astellas for $25 million.
Maybe it was a coincidence, but right after we got the global rights from Astellas was when we started getting really serious engagement with Merck. Hence my advice to my BD colleagues is to never underestimate what may be possible.
Alex Harding, MD. Entrepreneur in Residence, Atlas Venture; internal medicine physician, MGH
“What else can you do? The entire isolation of Russia. Nowadays we see real solidarity of the whole world to cancel or stop any economic, cultural, technological, financial connections with Russia and we urge the same from the Drug Discovery community.”
This was the message on Mar. 5 from Andrey Tolmachov, founder and CEO of Enamine Ltd., a Ukrainian chemistry services provider, to his clients in the biopharma industry.
Tolmachov’s words reflect the dire situation in Ukraine, a country under attack from the Russian army, and fighting to preserve its existence as an independent nation. His words also reflect powerful economic ties between Enamine and the drug discovery industry.
Andrey Tomalchev, CEO, Enamine
As reported by Jason Mast at Endpoints, Enamine has become a dominant supplier of chemical building blocks and gigantic chemical libraries that can be used by biopharma companies to conduct high-throughput drug screens. In its facilities in Kyiv, Enamine has enormous banks of freezers containing millions of compounds that cannot readily be obtained anywhere else in the world.
Tolmachov’s appeal, then, is not solely an emotional appeal. Numerous companies, including powerful large pharma companies, have a strong economic incentive to see Ukraine, and Enamine, pull through this war intact. Perhaps those incentives will make those companies more likely to heed Tolmachov’s words and exert economic pressure on Russia to back down.
Such dependence upon a single company based in a mid-sized emerging country is a case study on the opportunities and pitfalls of the globalized business model that has emerged in the biopharma industry over the past 10-15 years.
The vision behind this model was that companies headquartered in one location could tap into resources from diverse geographic regions, exploiting cost of living differences and strong regional expertise to obtain quick and cheap services, all while maintaining flexibility to expand and contract services rapidly depending on scientific and business needs.
That vision has taken a beating over the past two years. The war in Ukraine is only the latest example of a major geopolitical crisis to strain the globalized biopharma business model.
The biggest stressor, of course, has been the COVID-19 pandemic. Early in the pandemic, when most of China went into lockdown, biopharma companies’ work at key Chinese service providers, including WuXi AppTec, Pharmaron, and ChemPartner, and others, ground to a halt.
Just as companies scrambled to shift those services to service providers in the US and Western Europe, the virus spread globally, leading to rolling lockdowns throughout much of the world. For the past two years, managing a global network of vendors has turned into a global game of whack-a-mole as different cities and countries have gone through unpredictable pandemic restrictions that have contributed to various business interruptions and delays.
Next came the supply chain crisis. Globalized companies rely upon fast shipments between facilities. A biopharma may hire one company in Asia to produce an experimental molecule, another company in Europe to perform in vitro characterizations of that molecule, and a third company in the US to study the molecule in an animal model of a certain disease.
The drug discovery process is iterative; anywhere from a few dozen to a few thousand molecules may be made and tested in a variety of in vitro and in vivo studies before a specific molecule is chosen to enter clinical trials. Even a one-week delay in shipping between two sites that gets multiplied many times over during a drug discovery campaign can dramatically delay a company’s timeline to begin clinical trials.
Now, the Ukraine crisis has brought another stressor to the globalized biopharma business model. Enamine is no longer able to fulfill any orders from its Ukrainian facilities. While Enamine has a few facilities outside of Ukraine, including one site in New Jersey, those sites are small compared to the Kyiv headquarters and cannot perform the full range of services that were performed in Kyiv.
Beyond the preclinical services that Enamine focuses on, clinical trials are also under threat. Hundreds of clinical trials were active in Ukraine at the start of the war. Some trials are dependent on Ukrainian sites to enroll a large percentage of their overall patient quotas. Most of those sites have surely stopped enrolling new patients, and many patients who were already participating in a trial have probably been forced to discontinue prematurely because of the war.
With all the stresses to the globalized model over the past two years, it is natural to consider reverting to an entirely local and in-sourced approach to drug development. Rather than working with companies across the globe to manufacture compounds, test them preclinically, and study them in clinical trials, one could imagine building internal facilities and hiring scientists to conduct all the work of drug discovery and development within one biopharma company based here in the US. Clinical trials could all be run in-country as well.
In light of all the challenges that have arisen over the past two years, wouldn’t an “in-sourced and localized” model be safer and more efficient than the globalized model?
Absolutely not.
For one thing, it isn’t possible to internalize all the capabilities that outsourced providers offer. Enamine, for example, offers millions of compounds that can be ordered off the shelf and billions of compounds that can be synthesized on demand. No small or mid-sized biotech could dream of developing such a capability internally. Enamine has spent 30 years building up this capability.
What’s more, even if a biopharma company could build those capabilities internally in a city like Cambridge, MA or San Francisco, CA, they would likely sacrifice quality in doing so. While those cities harbor an exceptional concentration of biotech companies, they do not hold a monopoly on scientific talent. There are excellent scientists in China, India, Ukraine, and elsewhere that companies can work with, who would be unavailable to a company that insisted on working exclusively with scientists based in Cambridge or the Bay Area.
Last, we should not assume that the US and Western European countries are not themselves vulnerable to crisis. If anything, the past two years have demonstrated that we are all vulnerable, whether it be to a pandemic or even a war. A flexible, globalized model will be more resilient in the long run than one dependent on any single location.
Rather than abandoning globalization, the biopharma industry should seek a more robust network of global service providers. Companies should partner with multiple service providers in diverse geographic regions so that if one company or one country shuts down, another service provider in another region will be able to pick up the slack. Companies should get contracts in place before they need them, and those contracts should allow services to flexibly expand and contract.
Biopharma companies should also assess their supply networks for weaknesses. Wherever possible, companies should avoid relying on a single supplier for a crucial service or material. In some cases, it may be necessary to maintain a stockpile of a material that is subject to shortages or that only one vendor can provide.
Taking these measures will preserve the advantages of the globalized biopharma business model—flexibility, affordability, and quality—while making the model more resilient to unforeseeable macroeconomic and geopolitical events like those that have occurred in the past two years.
For Enamine, all we can do now is follow Andrey Tolmachov’s advice and push for a Russian withdrawal. For our industry, for the future, we can build an improved globalized model that benefits from the capabilities of excellent companies like Enamine, and does so in a more resilient, sustainable manner.
Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University
We are once again in a period of pandemic optimism — June 2021 redux. I hope this is justified, but I am reminded of the “fool me once, fool me twice” saying.
Over the past few weeks there have been four papers that examine viral infection dynamics between animals and humans — animal to human and back again (Zoonosis) that should provide a dose of caution in this otherwise optimistic moment.
The origin of SARS-CoV-2 has been hotly debated and politicized for the past two years. Origins matter – they define epidemic dynamics, and possible future variant directions. When we know where an epidemic comes from, we can better prepare for the next one.
Two papers from Michael Worobey’s team at University of Arizona (and collaborators) have been released that are compelling (although based on limited early pandemic sequence data). This latest research provides the most compelling evidence yet that the virus originated from the Wuhan Wet Market (not the Wuhan Virology Institute). One examines the genetics (phylogenetics) of the earliest cases, the other, their geographic spread.
The bottom line: the first cases clearly occurred in the wet market, presumptively via intermediate hosts known to be traded there, from a long-term animal reservoir in wild Horseshoe bats.
We have known for some time that human to animal outbreaks of SARS-CoV-2 have occurred: e.g. Danish farmed mink in 2020, and in 2022, domestic hamsters in Hong Kong. A paper from Canada documents the first (and so far, only) completed loop (human to deer and back to human). A very intriguing paper from the Journal of Genetics and Genomics in December 2021 makes the case that Omicron’s enormous number of mutations was caused by a long period evolving in mice before jumping back to humans.
Very big and surprising variant jumps can occur when a virus completes a human to animal and back to human roundtrip. All four of these papers underline the importance of animal susceptibility and surveillance if we are to understand which novel variants may evolve in humans after the Omicron wave.
Of course, all the hypotheses presented, however compelling, are probabilistic based on currently available data – as new evidence emerges these can change. Nevertheless, we are at a point of knowing a lot more than we did just one year ago.
But before digging in and summarizing conclusions and implications, there are five virus principles worth remembering (see Viral Phylodynamics for details and examples):
Geography is compelling that animal to human cross-over happened initially in the Wuhan Wet Market. Early cases were strongly concentrated in and around it, and primarily within the section dedicated to live animals.
The Viral Institute lab leak conspiracy theory was initially supported by a now-debunked false claim that the furin cleavage site of the virus genome showed signs of human engineering. Beyond that, there were two popular scenarios: a lab accident infected one or a few workers; or a more extreme version in which the release was intentional.
The latter scenario is simply ludicrous. No sound malevolent plan would involve release of a virus in the same city or country where it had been developed. The former, though is certainly possible — accidents do occur. If that had happened, the geographic infection pattern would be very different — highly centered around the few exposed individuals and those who care for them. That was the case in an Ebola-like MVD virus lab contamination event in Frankfurt and Marburg in 1967. The reluctance of the Institute to release detailed records is an unforced error that has hampered disposing of this scenario conclusively, but there is simply no positive evidence for it.
Genomic (phylogenetic) evidence is a more complex, but equally compelling, argument for wet market origins. The paper concludes that at least five separate animal-to-human viral introductions likely occurred, of which two became established (lineage A and B) while 3 (or more) failed.
A consistent challenge to the wet market theory is that no specific intermediate host animal has yet been found to be the bridge from wild bats to the wet market to humans.
At first, the leading suspect was the Pangolin, but a China CDC investigation found no Pangolins had been present in the market in late 2019.
China CDC launched an extensive testing program in January and February 2020, the full details of which have only recently been published: 457 samples from 188 animals of 18 species underwent RTqPCR testing; followed by a further 80,000 animal samples from across China. No SARS-CoV-2 was found in any of them. Surfaces in and around the market were swabbed for virus, and 73 of 923 environmental samples reported positive. 7 of these were subsequently sequenced, revealing that all were from the human contamination (earliest clinical cases of Wuhan-Hu-1), therefore shedding no light on the “missing intermediate host” mystery.
Testing techniques in 2020 were primitive by 2022 standards (and methods still not disclosed) and this likely led to this critical lack of evidence. Knowledge of the virus was very limited at the time, and testing was performed too late to have a chance to detect crossover events that must have happened months earlier, back in November and December 2019.
The most “likely to transmit” market animals were long gone by the time testing was done. The chain of transmission was broken by the market closing Jan. 1, 2020, no live animals were available to test; no serology that would have detected past infection was performed.
In a wider nationwide program (80,000 tests), the animals tested were from what we now know to be from uninfected regions; animals not then susceptible to the SARS-CoV-2 variant circulating at the time (e.g. chicken, cattle); and/or of animals butchered before the emergence of SARS-CoV-2.
Every species (including humans) that any virus inhabits presents unique mutational and immune pressures (a species-specific mutational fingerprint). All virus, e.g. SARS-CoV-2, then develop variants consistent with these unique pressures. When the virus then reappears back in humans, large mutational jumps appear to have occurred, but only because all the intermediate small steps were hidden out of sight in an animal host.
This pattern of repeated jumps between animals and humans is very similar to what happened in prior outbreaks of SARS-CoV-1 and MERS-CoV. More stable established virus types (e.g. influenza) show an incremental year-to-year evolutionary pattern, interspersed by less frequent big mutational jumps caused by cross-over from non-human avian or swine sources.
We can expect more and more of these cross-over events (animal to human) in the future since humans, not bats, are now the largest animal reservoir of SARS-CoV-2 and are frequently in contact with susceptible wild and domesticated animals. As of January 2022, 29 different species have been found to be infected with a human form of SARS-CoV-2. For example, 40 percent of free range deer tested in Michigan in 2021 were found infected with human SARS-CoV-2.
Of course, this works both ways: mouse was immune to the initial Wuhan strain, but as SARS-CoV-2 evolved in humans, a strain that could infect mouse (Beta) emerged in early 2021. Beta made only limited headway in humans, but in wild mouse a hidden epidemic occurred, during which Omicron was likely incubated: the types of mutations seen in initial Omicron (B.1.1.529) bear a mouse fingerprint on their evolution.
This is one hypothesis that could account for the enormous difference between Omicron and the prior human variant, Delta. Only the initial (B.1.1.529) Omicron has a mouse fingerprint, subsequent mutations to Omicron (BA.1, BA.2, BA.3) are consistent with typical in-human evolution, as expected.
There are other hypotheses for the novel and extensive mutational profile of Omicron, but all require a sustained period (3-6 months) of hidden mutational evolution. Three primary possibilities: a different non-human host; a single human host with long term chronic SARS-CoV-2 infection (e.g. an immunocompromised individual); or an isolated community of humans where the virus could mutate unobserved.
To conclude, we have only a limited and hence inadequate history of the earliest SARS-CoV-2/human relationship to rely upon to predict the future. The one thing we know for sure is that SARS-CoV-2 is not yet finished with us.
We must remember that this is the third time at bat for the virus. But unlike baseball, there is no “three strikes and you’re out” rule.
The Achilles heel of SARS-CoV-1 in 2002-2003 was early detection of fever concurrent with transmissibility. A decade later; MERS-CoV had a high fatality rate but only limited transmissibility in humans and animals (mostly camels).
SARS-CoV-2 hit a winning formula: hidden early transmissibility, now universal human exposure, and widespread non-human susceptibility.
The 4,000 year history of human airborne disease transmission is one of repeated “surprises” encountering ignorance and confusion. After the past two years we have developed extraordinary (although of course incomplete) knowledge of disease processes, genomic surveillance, physical protections, diagnostics, vaccination, and therapeutics. We need to concentrate our resources on preparedness plans that reflect our growing knowledge of this wily virus.
Ignorance is no longer a valid excuse. We must not allow this foundation to erode through wishful thinking and neglect.
David Shaywitz
As biotech execs cope with challenging market conditions (the XBI biotech index is off about 50% from its high of February 2021), I found myself revising a now-classic 2011 essay by venture capitalist Ben Horowitz of Andreessen-Horowitz, arguing that extremely challenging times require very different management skills, and a different leadership style.
He describes and contrasts the approaches of what he calls “peacetime” CEOs and “wartime” CEOs (an admittedly uncomfortable analogy during these harrowing days of actual war in Ukraine).
Peacetime, Horowitz says, “means those times when a company has a large advantage vs. the competition in its core market, and its market is growing. In times of peace, the company can focus on expanding the market and reinforcing the company’s strengths.”
Ben Horowitz
Under these circumstances, he continues, company leaders “must maximize and broaden the current opportunity,” and “employ techniques to encourage broad-based creativity and contribution across a diverse set of possible objectives.” According to Horowitz, Google’s Eric Schmidt and Cisco’s John Chambers were both examples of good peacetime CEOs.
When a company is facing an “imminent existential threat,” Horowitz writes, a very different, more directive, style of leadership is required, an approach historically embodied by CEOs such as Intel’s Andy Grove, Apple’s Steve Jobs, and Google’s Larry Page.
Horowitz presents some of the ways he says peacetime and wartime CEOs are different, including:
Learning how to manage through wartime is especially difficult, Horowitz contends, since “management books tend to be written by management consultants who study successful companies during their times of peace,” and thus are largely irrelevant during times of existential stress.
Finally, Horowitz notes that it’s possible “but hard” for a single individual to be both a brilliant peacetime and wartime CEO, since the demands are so different. “Mastering both wartime and peacetime skill sets,” he says, “means understanding the many rules of management and knowing when to follow them and when to violate them.”
* * *
This lens of wartime vs peacetime leadership may also provide a way of thinking about the challenge of “brilliant jerks,” a topic I’ve discussed at TR, in context of the pursuit of ethical hypergrowth as suggested by Reid Hoffman in Masters of Scale, and elsewhere, in the context of visionary geneticist Eric Lander’s recent resignation from his cabinet-level role at the White House. See also this important meditation by New York Times technology writer Shira Ovide.
Eric Lander
In some ways, what Horowitz is arguing is that when you’re facing corporate extinction, leaders don’t have time for what some might consider “social niceties.” Worse: attending to such “niceties” can actually distract leaders and organizations, and interfere with focused execution.
This argument raises at least two important questions:
First, is Horowitz right?
Does wartime require leaders to become, for lack of a better phrase, deliberate a**holes – a necessary, temporary sacrifice so that the company can survive?
Or are there other models of leadership – even under wartime conditions – that would enable a company to productively mobilize, yet continue to respect peacetime values like inclusion and civility, which of course many would argue represent foundational “table stakes” rather than social niceties.
Examples of leaders who managed through existential threats without adopting the approaches Horowitz advocates would contribute significantly to this discussion – far more than pious, feel-good advice voluminously offered by those far removed from the wartime arena, like the management book authors Horowitz derides.
The second question raised by the wartime/peacetime CEO model is whether this construct offers either an excuse for, or at least an explanation of, many of the examples of bad leadership behavior we’ve seen?
In other words, wouldn’t many CEOs who’ve been called out for bad behavior, such as Travis Kalanick, the former CEO of Uber, and Elon Musk, argue that they view every day as a life-or-death struggle for their business, and that this mindset is what drives them to advance their vision relentlessly forward? After all, if you’re trying to grow and establish a radically new business in an unforgiving world, might not you plausibly view this as requiring, inherently, a “wartime” mindset?
A number of particularly visionary, highly successful academics I know also seem to view their work in a similar fashion – they see themselves as struggling to gain traction for their ideas, and to shift paradigms, in a world that’s reflexively skeptical if not outright antagonistic. Battling against these steep odds every day often leads to adoption of many “wartime” characteristics.
Beyond what might be called the “self-deception” of visionary leaders who see themselves as perpetually at war, we must also acknowledge the possibility – perhaps even ubiquity — of deliberate malevolent deception. After all, invoking exigent circumstances and life-or-death stakes to justify self-serving, typically autocratic behavior is a tried-and-true political approach that we’ve seen more than our share of in recent years.
Bottom Line:
Managing a business through an existential crisis represents a formidable challenge for executives. One approach is to revert to what feels like our most primitive, reptilian instincts in order to persevere.
A critical question we now struggle with is whether this represents an adaptive if distasteful response, or whether it reflects our least imaginative instincts, our failure to lean into some of the values we earnestly champion and appropriately extol during peace.
Also unclear: can we prevent mindset creep, and the tendency for many business leaders — particularly visionary startup entrepreneurs — to view themselves as continuously at war, justifying the confrontational attitude Horowitz describes?
Finally, channeling Ovide: is it possible that the ready adoption of a wartime business mindset is an essential quality that defines and enables the most transformative entrepreneurs — as well those who are the most reviled? Should we embrace this trait as vital, or seek to temper it because of the dangers it can pose when unconstrained? How can we best live with these contradictions?
Now it’s your turn! TR welcomes reader contributions: is the wartime vs peacetime lens a useful construct for biotech leaders and visionaries? Are there particular biotech leaders that you would characterize as a striking example of either a “peacetime” or “wartime” CEO? Are there leaders who have successfully managed an organization through an existential crisis without resorting to “wartime” behavior? Let us know. luke@timmermanreport.com.
Luke Timmerman, founder & editor, Timmerman Report
Not long ago, biotech leaders steered clear of commenting on the issues of the day. Politics was limited to certain vested interests like drug pricing, science funding, and FDA regulation.
Then came COVID-19 and the racial justice reckoning.
Staring these terrible things in the face, people began to think more about their roles in the workplace, and in the community. The aperture widened. We are redefining what it means to be a scientific citizen.
Now we have a Russian dictator starting a war against a sovereign and democratic Ukraine. The Russian leader is issuing threats reminiscent of the old Soviet empire. He has some of the world’s most powerful weapons – nuclear, cyber, and psychological infowar tools to destabilize Western democracies from within. He’s ruthless. Political opponents or journalists who dare to report uncomfortable truths get poisoned, jailed, or killed.
Staying neutral isn’t an option. This is a serious threat to the world order.
Citizens need to pay attention, and think carefully about what’s happening, how it affects us, and what we can do.
In a globalized, hyper-networked world, it’s not just all about Putin and Zelensky and Biden and Macron. Millions of people making millions of decisions each day can each play a part. Even if it’s as small and simple as choosing what to tweet or not tweet, what we spend money on and what we don’t, we are each contributing.
It’s heartening to see biotech leadership that understands. They don’t want to be part of a generation that said nothing and did nothing when it counts. They don’t want to appease, or worse, help support the rise of a monstrous regime.
Jeremy Levin, CEO, Ovid Therapeutics
Meg Alexander and Jeremy Levin of Ovid Therapeutics, Paul Hastings of Nkarta Therapeutics, Peter Kolchinsky of RA Capital Management, Ted Love of Global Blood Therapeutics, and John Maraganore, the former CEO of Alnylam Pharmaceuticals, co-authored a forceful piece about the Russian invasion on Feb. 26 on Medium.
The open letter called for business leaders to disengage from Russian interests in a few clear ways:
All of these actions should remain in effect, the authors wrote, until “the restoration of peace and democracy in a sovereign Ukraine.”
Peter Kolchinsky, managing partner, RA Capital
One week later, more than 680 people have signed on. Many more are spreading the word through social media. More people are feeling the pressure to use their voices, use their power, to stand up for people halfway around the world who are facing terrible attacks.
By now, many in biotech have heard of Enamine, the contract research organization in Ukraine that is a trusted partner to many companies. It’s already close to home.
If Mr. Putin is able to extend his sphere of influence further into Eastern Europe, we’ll hear about many more trusted partners who suddenly find themselves no longer so free and secure.
Government leaders have their role to play. But so do we.
We aren’t helpless and voiceless. One person alone may not make much of a difference, but when we activate our networks, when we make business decisions on moral grounds and shut off the flow of money and goods, those actions send ripple effects.
John Maraganore, former CEO, Alnylam Pharmaceuticals
The US is the beating heart of biotech, but we don’t do this work alone. Great science bubbles up from all around the world. Contract development and manufacturing firms have something to contribute from all corners of the globe. Clinical research sites are almost everywhere. Patients are everywhere.
If we’ve learned one thing the past couple years, it should be that the biopharma industry is a strategic asset to the US and is a beacon of hope to the world. This industry doesn’t thrive here by accident — it’s here in large part because of our historic systems of free enterprise and democracy. Because of our laws and spirit and traditions.
The world counts on the US to hold it together, to be a serious country, to maintain our resilience. We need all that to deliver groundbreaking science and lifesaving products.
Ted Love, CEO, Global Blood Therapeutics
America hasn’t always lived up to its founding ideals. But we continually strive to form a more perfect union. We can course correct, regain our balance. We still have the rule of law, the Bill of Rights, free elections and freedom of speech.
We should remember that it’s our job to use these gifts wisely, and to pass them on to the next generation. When we operate within the laws and norms of our system, we can be at our optimistic best. We can see far out, think big, and make long-term investments. It’s what has always drawn tremendous immigrants here, and continues to draw them here.
An authoritarian state like Russia can’t say these things.
I’m thankful that the US biotech industry has a generation of leaders who are willing to stand up for our ideals. I hope to see this good fight continue. It may require some sacrifice, whether in the form of clinical trial delays, lost deals, or higher prices for oil or gas. Or maybe worse. It might be the start of a long, hard confrontation.
Paul Hastings, CEO, Nkarta Therapeutics
Some things are more important than next quarter’s earnings, or the fleeting price of a gallon of gas.
We need to rediscover a certain steeliness in our national character. We need to rediscover an ability to focus on what’s important, and not allow ourselves to be distracted.
It will be difficult. But we have to defend a way of life that’s worth defending.
Cambridge, Mass.-based Intellia Therapeutics and its partner, Regeneron Pharmaceuticals, reported follow-up data that show deep and sustained efficacy with in vivo gene editing for patients with transthyretin amyloidosis. The companies showed that this CRISPR gene editing technique could bring down serum TTR levels by 52 percent at the tiniest dose tested, and 93 percent among the 6 patients on the high dose – still a very small 1 mg/kg. The drug is getting to the liver, and it’s doing its edit safely — there were no clinically significant liver findings observed. It’s big news for the field, and sets the stage for single-infusion in vivo gene editing in many indications, because it has some practical advantages over ex vivo gene editing. Whether TTR amyloidosis will be the ideal first indication for CRISPR therapies is still an open question – I’m not sure it makes sense (TR coverage, July 2021).
San Diego and Suzhou, China-based Adagene struck partnership with Sanofi on masked monoclonal and bispecific antibody drug candidates for cancer. Sanofi is paying $17.5 million upfront, and will get the ability to advance two development candidates, with an option for two more. This partnership comes a few months after Sanofi agreed to acquire Amunix Pharmaceuticals for $1 billion upfront. Amunix was also developing masking technology to assist bispecifics against cancer.
Cambridge, Mass.-based Blueprint Medicines, the developer of precision cancer drugs, agreed to pay $20 million upfront to New York-based Proteovant Therapeutics to gain access to its targeted protein degrader drug discovery platform. The companies will work together on targets, and plan to advance two protein degrader development candidates.
AbbVie agreed to acquire Syndesi Therapeutics, a neuroscience drug developer. AbbVie is paying $130 million upfront, and getting ahold of a lead small molecule drug candidate in Phase I development to enhance synaptic efficiency. Synaptic dysfunction is believed to underlie the cognitive impairment seen in multiple neuropsychiatric and neurodegenerative disorders. If the drug pans out, Syndesi shareholders could collect another $870 million in milestone payments.
AstraZeneca’s rare disease unit, Alexion, agreed to pay $30 million upfront to Neurimmune. It’s for the right to develop a monoclonal antibody program to treat transthyretin amyloidosis cardiomyopathy.
San Francisco-based Rondo Therapeutics raised $67 million in a Series A financing co-led by Red Tree Venture Capital and Canaan Partners. The company is working on bispecific antibody T-cell engagers for solid tumors. It’s led by an entrepreneurial pair responsible for TeneoBio, a bispecifics-for-liquid-tumors company that was acquired last year by Amgen for $900 million upfront. (TR coverage).
Cambridge, Mass.-based Atlas Venture said it raised $450 million for Fund XIII. The firm didn’t announce any strategic or partner changes – just more investment in platforms and asset-centric biotech companies. Since 2015, when the biotech and tech investing sides of Atlas went their separate ways, the new biotech-only Atlas has raised over $2 billion and has created and/or invested in over 50 biotech companies.
San Francisco-based Foresite Capital said it raised $173 million to invest in companies it forms through Foresite Labs. This cash is in addition to the firm’s $969 million Fund V.
A team of eight Howard Hughes Medical Institute investigators at the University of Washington and Fred Hutchinson Cancer Research Center secured a three-year $15 million HHMI grant to work on ways to track, prevent, and treat COVID-19 as it moves into an endemic state. The team includes Jesse Bloom, Trevor Bedford, Harmit Malik and Erick Matsen at Fred Hutch and David Baker, Joseph Mougous, Jay Shendure and David Veesler at UW.
Cambridge, Mass.-based NextRNA Therapeutics secured $46.8 million in a Series A financing led by Cobro Ventures and Lightchain Capital. It’s working on medicines directed at non-coding RNA targets.
Cambridge, Mass.-based Flagship Pioneering announced the debut of Vesalius Therapeutics, with a $75 million commitment. The company is focusing on common illnesses, and using machine learning to assist with drug discovery. Vesalius says its platform uses “proprietary patient-derived experimental systems that it uses to screen and characterize drug candidates to restore circuits to healthy functioning.”
Boston-based Selux Diagnostics raised $50 million in a Series C financing. It’s working on diagnostics for infectious diseases, to help doctors better select precision antibiotics quickly.
Cambridge, Mass.-based hC Bioscience raised $24 million in a Series A financing to develop engineered tRNA therapies to address protein dysfunction. Arch Venture Partners, Takeda Ventures, and 8VC participated.
Princeton, NJ-based ArrePath said it raised $20 million in seed funding to advance its work on anti-infective drugs that will work against microbes that resist current therapies. Boehringer Ingelheim Venture Fund, Insight Partners, and Innospark Ventures co-led. Lloyd Payne, formerly EVP of anti-infectives at Evotec, joined as CEO.
London-based Epsilogen raised $41 million in a Series B financing to develop IgE antibodies for cancer. Novartis Venture Fund led.
Julie Gerberding will be the new CEO of the Foundation for the National Institutes of Health, starting May 16. She is currently Chief Patient Officer and Executive Vice President, Population Health & Sustainability at Merck.
South San Francisco-based Graphite Bio, a gene editing company, hired Alethia Young as chief financial officer. She was previously a biotech analyst with Cantor Fitzgerald. (TR coverage of Graphite, Sept. 2020)
Canada-based Amplitude Ventures hired Ali Tehrani, the co-founder and former CEO of Vancouver, BC-based Zymeworks, as a venture partner.
Merck hired Aileen Pangan, as vice president and therapeutic area head for immunology, global dlinical development, effective March 1. She previously worked at AbbVie.
Cambridge, Mass.-based Synlogic hired Michael Jensen as chief financial officer.
Needham, Mass.-based Candel Therapeutics, the developer of oncolytic virus therapies for cancer, hired Seshu Tyagarajan as chief technical and development officer.
UC Berkeley lost the high-profile patent case over CRISPR technology, which meant it was also a loss for Intellia Therapeutics and CRISPR Therapeutics – the companies that took a license from UC Berkeley. That decision by the US Patent and Trademark Office was a victory to the Broad Institute and its licensee, Editas Medicine. What fewer may have noticed is that UC Berkeley’s patent was upheld by the European Patent Office. (San Jose Mercury News)
Janssen Pharmaceutical and its partner, Legend Biotech, won FDA clearance for cilta-cel (Carvykti), a new cell therapy for cancer directed at the BCMA antigen overexpressed in multiple myeloma patients. The treatment was approved on the basis of a Phase III trial which showed a remarkable 98 percent overall response rate among heavily pre-treated patients, including a 78 percent Complete Response rate. The new treatment will now compete with a BCMA-directed cell therapy from Bristol Myers Squibb (Abecma).
Seattle-based CTI Biopharma secured FDA approval for pacritinib (Vonjo), a JAK inhibitor, as a new treatment for high-risk primary or secondary myelofibrosis.
Newton, Mass.-based Karyopharm Therapeutics said that it plans to start a new Phase III clinical trial of its experimental drug selinexor for advanced or recurrent endometrial cancer. The decision comes after the FDA told the company that its existing Phase III study results are unlikely to be enough to support a supplemental New Drug Application, which the company had been planning to submit.
Belgium-based Celyad Oncology voluntarily placed a clinical trial on hold for its experimental CAR-T cell therapy being tested in combo with Merck’s pembrolizumab (Keytruda) after learning of two deaths with similar pulmonary findings. The company said it’s investigating the nature of the deaths and in discussions with regulators.
Somerville, Mass.-based Finch Therapeutics said the FDA placed its Phase III clinical trial for a C.difficile treatment on hold, over concerns that donor-derived microbiome therapies could potentially spread the SARS-CoV-2 virus.
The FDA issued a Clinical Hold to Gilead Sciences until it can resolve the issue with glass fragments showing up in vials of lenacapavir, a long-acting treatment being evaluated against HIV-1.
The FDA rejected an application from Plano, Tex.-based Reata Pharmaceuticals to market bardoxolone for kidney disease caused by Alport Syndrome.
Our healthcare system is way too costly, but it’s also way too complex. We need not only to make things more affordable, but more simple, if we want to improve access. The President spoke about making tests and antiviral treatments available at pharmacies. It’s showing an instinct for simple problem solving. Of course, it takes work behind the scenes to make things appear simple on the surface, as Eric Topol notes.
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Today’s guest on The Long Run is Michele Andrasik.
I’m excited to have Michele on the show to talk about an undercovered aspect of the scientific enterprise.
Michele Andrasik, PhD. Director, Social & Behavioral Sciences and Community Engagement
HIV Vaccine Trials Network; Affiliate Assistant Professor, Global Health, University of Washington
Michele is the director of social and behavioral science and community engagement for the HIV Vaccine Trials Network, and COVID-19 Prevention Network.
She’s based in Seattle at the Fred Hutchinson Cancer Research Center, and is an affiliate professor at the University of Washington.
Michele’s work at the HIV Vaccine Trials Network has made her think long and hard about bridging the gap between science and the society it hopes to serve. She’s worked for years on outreach to disadvantaged and marginalized groups that scientists were hoping to enroll in HIV studies for vaccines and treatments.
When COVID-19 hit, this group was uniquely positioned for the moment.
Tony Fauci called on this NIH-funded national network to spring into action, bringing all the learned from HIV to the COVID vaccine trials. One of the underreported successes of Operation Warp Speed was that the pivotal vaccine studies were able to enroll black people, indigenous peoples, and people of color at levels roughly in line with their representation in the overall population.
If you listen to Michele, I think you’ll hear some basic principles that can be applied broadly across the biopharma industry. Everyone can agree it’s desirable to make clinical trials faster and more predictive of outcomes in the real world. Part of getting there means getting better at including traditionally hesitant groups to participate.
When more people get personally involved with science, if it’s done right, it can help with downstream issues like equitable access and distribution of therapies.
It’s a crucial first step in building trust.
For those want to dig in to the diversity of the Operation Warp Speed clinical trials, I suggest you read a paper by Michele published in October 2021 in PLoS One. Michele also co-authored a paper last July in the New England Journal of Medicine titled “Addressing Vaccine Hesitancy in BIPOC Communities — Toward Trustworthiness, Partnership, and Reciprocity.”
Please join me and Michele Andrasik on The Long Run.
Larry Corey, MD
When can we declare the SARS-CoV-2 pandemic over?
For some people, a battle is over when it is clearly won or lost. Our fight with COVID-19 doesn’t fit into such tidy categories.
The term endemic, at least in epidemiology, means chronic. It’s a constant presence, usually of an infectious organism, at some steady level. If a virus is endemic, that means it hasn’t been eradicated. There is no vanquished opponent and no real victor.
This is closer to what we’re seeing with SARS-CoV-2.
This virus will be with us for decades, if not forever.
Delta and Omicron show that this coronavirus has endurance. SARS-CoV-2 has demonstrated it has incredible talent and “natural” ability to antigenically change/mutate over time to enhance its transmissibility and ability to escape human immunity. One would expect, certainly we in the virology community all hoped, that SARS-CoV-2 would behave like other endemic human coronaviruses.
In other words, it would circulate, bother us every few years, but because of preexisting immunity, it wouldn’t pose a serious threat over the long run.
The non-SARS human coronaviruses are included within the common cold complex of infections rarely causing significant medical problems or mortality. We largely ignore them for this reason. SARS-CoV-2, including Omicron, is not in this category. SARS-CoV-2 will likely have claimed the lives of 1 million people in our country alone by June.
The least virulent variants, Omicron BA.1 and BA.2, still cause pneumonia and death—not as frequently as Delta, but a lot more than other human coronaviruses. It is still a COVID-19 virus. Clinically, Omicron is not a trivial disease in many people, even those previously vaccinated. Recently released data from California showed that among the COVID-related deaths between Dec 12 and Jan 25, 71% were in unvaccinated people, 24% in “fully vaccinated” and 5% among those boosted.
Again, this illustrates that all SARS-COV-2 strains are “variants of concern.”
The other aspect of SARS-CoV-2 that ensures its extended presence on this planet is its ability to enter into the animal reservoir. Today, humans are clearly the predominant reservoir for the SARS-CoV-2 virus, but it is present in an ever-growing number of species including deer, mink, rodent, antelope, and the occasional cat or dog.
When an infectious organism moves into an endemic phase, it means coming to terms about living with the virus in our midst. This is just not a biomedical definition. Biomedically, you could assign a quantitative measure—a milestone to be reached at which point we could breathe a collective sigh of relief. But what is that signpost? Is it 100,000 cases a day, 100,000 deaths per year? Or 10,000 cases a day? And 1000 deaths a year? Do we get different answers by race or political party? So, who decides? Does it matter what is decided?
During the COVID-19 pandemic, we have seen excess mortality, a term used to describe the number of deaths from all causes above and beyond what we might expect to see under otherwise “normal” conditions. Twenty to thirty percent of the deaths from COVID-19 are not written down as COVID-19–related but they occur at a much higher rate than the pattern seen for decades when COVID-19 was not around.
For the last year, this has been seen most prominently in the 30- to 50-year-old age group. How does this “excess death rate” happen? In many people, the SARS-CoV-2 virus travels beyond the nose and lungs and invades the heart, kidneys, and vascular beds of many organs. This tissue damage results in heart damage and blood clots that lead to organ damage. Those that suffer these problems often do not have COVID-19 directly attributed in their death certificate. But the death is still recorded and shows up in excess mortality data. As a physician, I would like to see this excess mortality metric seen during COVID-19 go back to normal (pre-COVID-19) as the medical definition of attaining endemicity. But in the end, I don’t think this issue of defining when COVID-19 is endemic is really that important except to the people who monitor this disease for medical and economic impact.
I don’t really think that “When does the pandemic end?” is the important question to ask, but rather when does normalcy return?
The meaningful metric of when does the pandemic end lies more in the sociological/behavioral arena than in case counts. Endemic really means that we as a society cope with the virus by using widely available countermeasures which will let us return to “normative” behavior.
Does that mean attending school without a mask? Or walking around indoors at the stadium without a mask? Or does that mean just feeling like, hey, I can go to a basketball game or a football game and if I do get COVID-19, it’s no big deal? It’s really knowing—on an individual and collective basis—that the effectiveness of available countermeasures no longer pales in comparison to the risk of infection and its consequences, and we can resume our lives.
We assess normalcy through individual risk assessments. It’s something we have done for all other respiratory illnesses. During influenza season, we get flu shots that are usually 50% to 60% effective. We all know we could get flu for a few days. But we also know the vaccine and oral antiviral treatments keep us out of the hospital. Our lives aren’t upended. We walk around, do our normal things each day, and don’t worry so much about flu.
We tolerate influenza A with a large number of cases and 30,000 deaths a year. When we get flu, we don’t strictly quarantine from everyone around us, worry about becoming hospitalized, or be told by society that we have to do X, Y, or Z, that will alter our lives.
Is that how we will eventually perceive SARS-CoV-2? It’s still too early to say. The problem is that COVID-19 is a considerably more complicated disease than seasonal influenza and the levels of excess mortality that we have seen from the SARS-CoV-2 virus exceeds that of seasonal flu, especially in the 30-to-55-year-old age group.
So endemicity, to me, is when we make widely available all the effective countermeasures we can, so we collectively feel that opening up our society fully is not only possible but a reachable goal.
How close are we?
Our vaccines, at the moment, don’t give us the level of confidence that we had a year ago, prior to the emergence of the variants. Many people are worried about getting infected.
But if we had oral antivirals widely available and implemented programs to properly administer these, or the more expensive monoclonal antibodies for older, higher-risk populations, and immune-suppressed individuals, I think we could get to behavioral endemicity.
The manufacturers are working quickly to increase available supplies. But even after supplies are made widely available, it will take work to implement and socialize—people need time to absorb the possibilities of what endemic means to them personally. Some people are more risk averse than others. But what will occur is that we’ll have more options and can make decisions based on a personal risk assessment.
Can I go to a movie theater and sit shoulder to shoulder with a stranger? Am I safe enough to eat indoors at my neighborhood family-style restaurant with 50 people eating, talking, and laughing? What about an indoor basketball game or a concert hall, even with its vast ceilings, and yet 2,000 people present?
These are the kinds of questions each of us will have to assess and answer in our own lives.
A second strategy I think we must pursue is improving our vaccines so they prevent acquisition altogether. No breakthroughs, no sickness, no hospitalizations, no complications, no anything.
The monoclonal antibody work in COVID-19 treatment suggests that at really high antibody neutralization titers we appear to prevent people from acquiring the virus in the first place. We have some evidence that when the vaccine matched the ancestral strain, in the first couple of months, perhaps 40% of the time it prevented people from becoming infected altogether.
My own bias is that if we could make vaccines that achieve the same level of neutralization that we see in the monoclonals — currently 10 times higher — we might be able to prevent acquisition of the virus and truly reduce the widespread dissemination of disease.
The COVID-19 pandemic and its ubiquitous impact has startled—if not frightened—everyone. Every economy in the world has suffered, every community has been touched, every person in some behavioral way has altered their life. We all long for our own personal normal, which today seems just beyond reach because of the setbacks the variants have dealt us.
So, while our scientific triumphs against COVID-19 are incredibly impactful and praiseworthy, I’m raising the bar to say we need to improve them and make them better. Importantly, I’m confident we can do better. Science can—and should—up its game to match its cunning opponent. Pursuing better with our best gives us a fighting chance to emerge victorious with a new normal that feels possible for us all.
Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.
E. Blair Clark-Schoeb, SVP of communications, Aruvant Sciences
I can’t believe my daughter is about to turn 16, and I have been living with COVID for two years.
Having contracted the virus on her birthday, it will seemingly always be my Covidversary.
She has blossomed over the past two years, while I feel like I have wilted. I still lean hard toward the sun, but it’s not easy. Some of my symptoms have persisted.
Almost two years out, I am feeling better, but different.
COVID-19 changed my life.
No one would have suspected this. Two years ago, I was a working mother of four in my mid-40s. I exercised almost every day, alternating between cardio and yoga days. The data are still there in my Peloton app. I was a college athlete, so staying fit and healthy has always been an important part of who I am.
For two weeks after getting COVID, it was a struggle to even get out of bed. Many people can relate to that feeling. But something was clearly off for me. For months, I felt like an old lady. My hips hurt. I couldn’t sleep through the night because of leg pain. Even the slightest exertion brought on shortness of breath.
Thankfully, most of those symptoms went away. But I’m still not done.
The headaches are the most annoying residual symptom. Most days I can function, but sometimes my head hurts so bad, sleep is the only remedy. I have tried NSAIDs, Tylenol, other prescription medications, vitamins and acupuncture. Nothing seemed to help, so I don’t even bother anymore.
I also have intermittent muscle and joint pain. This used to happen every night, but now it only happens some nights. My sleep has greatly improved.
Other times, chest pain reappears. I have worn a heart monitor twice, had a couple of EKGs and an echocardiogram. The tests show changes to my heart, but nothing that needs to be addressed or requires medication.
Some of this is surely because we still know so little about what causes Long COVID, and the effects it has on tissues and cells. But what scientists are learning every day is confirming what many of us long haulers have felt – the virus is harmful to the heart, lungs, and neurons. We now know from multiple studies that 10 to 30 percent of people who get COVID will suffer some long-term symptoms. This Feb. 7 article in Nature provides a helpful overview of recent biology.
Part of the struggle is physical, and another part is psychological. It’s a loss of a certain part of myself, and some of the things my former self enjoyed. These things are hard to quantify, but it can be done. The best measure that I have is my Peloton activity. Prior to Covid, I regularly did the bike and would do 45-minute-to-one-hour classes.
There have been periods over the past two years where I couldn’t bike at all. Now I am back to doing the Peloton regularly, but a 30-minute class is a hard day. While I’ve regained a consistent exercise routine, my output is substantially less. I am finally back to breaking 200 output. Before Covid, I could take some pride in going above 300 or even higher.
I also used to love to eat sushi and fish, and a good spicy margarita. Something has now happened to my taste buds. Fish always tastes bad these days. After one too many times of complaining about how there was something wrong with the sushi we ordered, I realized that I was the issue. Now, I am fully vegan. I miss the old days of a good sushi dinner. Those spicy margaritas are also a thing of the past. Because of my headaches, I have cut out alcohol. I have to say I don’t miss alcohol as much as I miss good sushi.
I have met other people who suffer from Long COVID. People often reach out and ask me if I will speak to their friend who is struggling. So often the conversations are the same. We share lists of symptoms. While many symptoms are similar, the combinations and what bothers each of us the most are not the same. While I always want to help the people I speak with, the only thing I can do is empathize. Exercise is one remedy I suggest, because I do feel like that has helped me. It has helped, but it’s not a cure.
One lingering frustration is with the healthcare community. Ignorance and disbelief about Long COVID remain widespread.
Not too long ago, I ended up in the Emergency Room because of a stomach bug. It left me dehydrated and unable to stop vomiting. That wasn’t the worst of it.
The ER doc demonstrated an almost total lack of understanding of Long Covid. When asked if I had any other issues, I mentioned that I have post-COVID symptoms that have persisted for almost two years.
“Two years?” the doctor said, with a tone that indicated disbelief.
Two years, yes, I repeated.
It is remarkable that two years into this pandemic, we still have healthcare providers who don’t understand the potential lasting effects, and don’t seem all that interested in learning more about the signs and symptoms and potential treatments. It will take a lot more research, a lot more medical education, and a lot more willingness to learn before we can get to a better place.
My experience with Long COVID has brought me a better understanding of what those living with rare diseases experience on a daily basis. We need to do better in the healthcare world to better educate our providers.
While we seek to learn more about the biology, and we figure out how to better treat Long COVID, a little sympathy goes a long way.
Luke Timmerman, founder & editor, Timmerman Report
Every thriving biotech hub can trace its origins to one or two outstanding scientific institutions. But every thriving region can also trace some of its success back to community leaders.
These are people who attend boring night meetings. They aren’t household names. They’re fine with that.
These people were especially common in America after World War II. They laid down the physical infrastructure and social norms for those of us who came next.
One of these people in Seattle, where I live, was named Jim Ellis.
Ellis died three years ago at 98. He was a named partner at one of Seattle’s top law firms, Preston Gates & Ellis. He worked with William Gates Sr., Bill’s dad. The firm today is known as K&L Gates.
But that’s not why we remember Jim Ellis.
When he was a up-and-coming lawyer, Lake Washington, a freshwater jewel linked to Puget Sound and the Pacific, was full of sewage. People at the time said the water was like “split pea soup.” Various government fiefdoms and unrestrained private land developers contributed to it. It was a mess. Fingers were pointed.
Jim Ellis
Ellis got involved. Behind the scenes, he brought his energy and creativity to the task of herding the necessary cats to clean it up.
But there was more. The Seattle region was growing beyond its natural resource-based economy – logging, fishing, the seaport. Boeing was emerging. Newcomers were coming. The region needed to think about how to manage the growth intelligently.
Highways needed to be expanded. Parks, trails, public swimming pools and youth centers needed to be built and upgraded. It was going to cost money. Ellis mobilized community support for a series of bond initiatives in the 1950s and 1960s that were collectively known as “Forward Thrust.”
All of this was happening in tension with the natural splendor of the Cascades. Millions of acres of forest needed to be preserved for wildlife habitat, for outdoor recreation, for clean air and water, and to preserve natural beauty. The competing interests between economic growth and environmental preservation needed to be held in balance.
Ellis thought about common interests, the common good. By the early 1990s, he put it all together with his greatest achievement — the Mountains to Sound Greenway. It’s 1.5 million acres of preserved land between Ellensburg, on the east side of the Cascades, stretching to Seattle in the west.
I first saw it as a 21-year-old kid from Wisconsin. It was Memorial Day weekend of 1997. I was excited to start a summer reporting internship at one of the nation’s great regional newspapers – The Seattle Times. I had driven my rusty Pontiac 2,000 miles across the Great Plains, long stretches of Montana, and the arid Columbia River basin.
Then came the mountains. They were covered in Evergreen trees. Alpine lakes shimmered.
From Snoqualmie Pass to Seattle, for 50 miles, it kept going. No strip malls or tacky billboards. People lived in the suburbs east of Seattle, the foothills of the Cascades. But the trees were everywhere, swallowing you up. Nature felt big. Individual people felt small.
This seemed like a great place to live, to explore, to build a career.
For years, I knew nothing about the history of the Mountains to Sound Greenway. Maybe a decade ago, I learned for the first time about Jim Ellis. There was no statue to the man. When he died, I looked for more information, but there wasn’t much. Recently, I found this touching tribute published in 2021 by the Trust for Public Lands.
It’s hard to imagine what Ellis was up against in his day. Think of the vision and tenacity it must have taken with all the federal, state, and private landowning interests. A lot of people with different viewpoints needed to rally around a shared vision.
Ellis wasn’t in it for money or ego. He never ran for public office.
One secret to his success was his philosophy on how to spend his time. He spoke of a one-third/one-third/one-third way of life. One-third was for professional work, one-third for family, and one-third for community.
Where did this philosophy and drive come from? It’s hard to say for sure. But Ellis’ brother died in World War II in 1945. That, according to the Trust for Public Lands, lit a fire in him to honor his brother’s memory. I also have a hunch that the community work, and the family time, helped energize him and make him even more effective professionally. It could have been a virtuous cycle.
Ellis was on my mind last weekend, when I took a small group of biotech people on a hike up Mailbox Peak. It’s a 4,800-foot peak near North Bend, smack in the middle of the Mountains to Sound Greenway.
Around Noon, there were about 20 people on the summit when my small group arrived. Most were in their 20s and 30s. The skies were sunny and clear. You could see snow-capped peaks more than 100 miles away.
Biotech people enjoying the mountains, Feb. 13, 2022. Aleena Arakaki, postdoctoral research fellow, Fred Hutch; and Sam Blackman, co-founder and chief medical officer, Day One Biopharmaceuticals
Two young people we met on the hike happened to be from the biotech community. A postdoc on my team, Aleena Arakaki, wasn’t surprised. It’s part of what draws young scientists to the Fred Hutchinson Cancer Research Center – the chance to occasionally get away, to clear the head, get a little exercise, maybe get a beer afterwards with lab friends and colleagues.
Seattle’s biotech community exists because of decades of public investment in science at the University of Washington and Fred Hutch. But it also thrives today because we have such amazing quality of life in the Northwest that continually attracts people from around the world.
For that, we can thank unsung heroes like Jim Ellis.
This also makes me wonder: Who are the people doing similar things in Boston, San Francisco, San Diego, Philadelphia, Los Angeles, Chicago, Raleigh-Durham, New York, New Jersey and elsewhere?
Who laid down the critical scaffolding that made it possible for those regions to thrive?
Who’s continuing this work today?
There are people out there doing this hard and thankless work to strengthen our communities. Let’s show a little respect. Maybe get involved personally. It’s meaningful work, and it can be lasting work.
New York-based Kallyope, the developer of treatments based on the science of the gut-brain axis, raised $236 million in a Series D financing. Mubadala Investment Company and The Column Group co-led.
Natalie Holles, CEO, Third Harmonic Bio
Cambridge, Mass.-based Third Harmonic Bio came out of stealth mode, announcing it has closed a $105 million Series B financing and raised a total of $155 million since inception. General Atlantic and BVF Partners co-led the B round, and Atlas Venture and OrbiMed led the A round. The company is in clinical development with an oral KIT inhibitor for treatment of severe allergy and inflammation. Natalie Holles, formerly of Audentes Therapeutics, is the CEO.
Pasadena, Calif.-based Terray Therapeutics raised $60 million in a Series A financing to advance its work on AI drug discovery. Madrona Venture Group led.
Redwood City, Calif.-based Synthego, the genome engineering company, raised $200 million in a Series E financing. Perceptive Advisors led.
The Mark Foundation for Cancer Research announced a new $500 million funding commitment from founder Alex Knaster. The foundation also announced Ray DuBois has joined as executive chairman of the board.
Lewis “Rusty” Williams, CEO, Walking Fish Therapeutics
South San Francisco-based Walking Fish Therapeutics, a developer of B cell therapies, closed an expanded $73 million Series A financing co-led by Northpond Ventures and First Spark Ventures.
South San Francisco-based Electra Therapeutics raised $84 million in a Series B financing co-led by Westlake Village Biopartners and OrbiMed. It’s developing antibodies against signal regulatory proteins.
South San Francisco-based Twist Bioscience, the DNA synthesis company, raised $269 million in a stock offering at $55 a share.
Cambridge, Mass.-based Remix Therapeutics secured $45 million upfront through a partnership with Janssen Pharmaceuticals. The companies will work together on small molecules designed to work by reprogramming RNA processing. (TR coverage, Dec. 2020)
Watertown, Mass.-based Neumora Therapeutics obtained an exclusive worldwide license to an M4 muscarinic receptor allosteric modulating drug from Vanderbilt University’s Warren Center for Neuroscience Drug Discovery. The company is getting two novel series of compounds in late preclinical development, which it says has the potential for a better safety profile and once-daily dosing. Terms weren’t disclosed. (TR coverage of Neumora, Oct. 2021).
Waltham, Mass.-based ImmunoGen pocketed $13 million upfront through a deal with Eli Lilly to develop antibody-drug conjugates for cancer.
Health Affairs came out with a series of articles on Racism & Health. There is a lot here to read and think about carefully. This issue deserves some quiet reading time over the weekend. (Health Affairs)
The Millions of People Stuck in Pandemic Limbo. What Does Society Owe Immunocompromised People? The Atlantic. Feb. 16. (Ed Yong)
The Internet is fundamental to life in the 21st century. It’s hard to communicate with the healthcare system, find out where vaccines are available, make an appointment, etc. without it. And yet in America, a lot of people don’t have easy access to the Internet, and that fact makes it harder for them to access healthcare. Read more about it in “Advancing Diversity, Equity, and Inclusion Through Web Accessibility” by Mona McCarthy, Senior Director of Data and Technology, and Warner Santiago, Senior Director of DEI and Workforce Development at MassBio.
Cambridge, Mass.-based Sage Therapeutics and Biogen reported that a Phase III trial of zuranolone hit its primary and secondary endpoints in a study of patents with major depressive disorder. The effect kicked in quickly, after three days, and lasted through the two-week treatment period.
Eli Lilly won FDA Emergency Use Authorization for bebtelovimab, as a new therapeutic neutralizing antibody against SARS-CoV-2, including the Omicron variant. It’s for patients ages 12 and up, for the treatment of mild to moderate COVID, for patients who are at high risk.
Cambridge, Mass.-based Agios Pharmaceuticals won FDA approval for mitapivat (Pyrukynd) as a treatment for hemolytic anemia in adults with pyruvate kinase deficiency.
Somerset, NJ-based Legend Biotech said the FDA placed its Phase I trial of an autologous CAR-T cell therapy for T-cell lymphoma on clinical hold. The first patient dosed in the trial experienced low CD4+ T cells, and the company notified the FDA before the hold. The patient hasn’t suffered a serious adverse event, the company said.
The State of Innovation in Antibacterial Therapeutics. BIO Industry Analysis. Feb. 2022. (David Thomas and Chad Wessel)
The Calorie Counter. Evolutionary anthropologist Herman Pontzer busts myths about how humans burn calories—and why. Science. Feb. 17. (Ann Gibbons)
We’re Entering the Control Phase of the Pandemic. The Atlantic. Feb. 17. (Katherine Wu)
The US Senate voted 50-46 to confirm Robert Califf as FDA commissioner. The acting commissioner, Janet Woodcock, will stay on as principal deputy commissioner. There’s not a lot here worth analyzing. It’s simple. An experienced, visionary and utterly non-controversial nominee to run this critical public health agency was delayed three months for no good reason.
The White House, days after Eric Lander resigned as science advisor, said former NIH director Francis Collins will step in as science advisor to the President. Alondra Nelson will perform the job of director of the Office of Science & Technology Policy, stepping up from her current role as deputy director for science and society at OSTP. These two have important work to do in continuing to shepherd along the reboot of the Cancer Moonshot, and the creation of the Advanced Research Projects Agency for Health (ARPA-H).
San Francisco-based Vertex Ventures HC hired Christine Brennan as a managing director. She is based in Cambridge, Mass. and was previously a partner with MRL Ventures Fund.
New York-based Stablix hired Tony Kingsley as CEO. He previously did a brief stint at Scholar Rock.
Brett Giroir, former assistant secretary of Health and Human Services, was hired as CEO of Atlanta-based Altesa Biosciences. The company is working on antiviral drugs against common respiratory viruses such as rhinovirus and parainfluenza, and global viral threats like Dengue fever and Yellow Fever.
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Today’s guest on The Long Run is Derrell Porter.
Derrell is the founder and CEO of San Francisco-based Cellevolve. This is a different kind of biotech startup.
Derrell Porter, founder and CEO, Cellevolve
Most startups are all about the R&D. Traditionally, many haven’t built up commercial capabilities in the early days for one big reason — they don’t have anything to sell. They have tended to think that commercial strategy was something they could always figure out later.
Cellevolve was born out of the idea that isn’t necessarily the best way to do things anymore.
Derrell has had a long career in the business side of biotech, including stops at Amgen, AbbVie and Gilead Sciences. He was well-positioned for the new commercial challenge when cell therapy came along a few years ago. Derrell’s insight was that many of the new generation of biotech startups were going to need some help with commercial strategy, even in the early days.
This is a thought-provoking conversation on a couple different levels. Anyone who enjoys learning about the business of science ought to enjoy this one.
Now please join me and Derrell Porter on The Long Run.
Luke Timmerman, founder & editor, Timmerman Report
The future of biotech isn’t limited to a few square miles in Cambridge, Mass. and South San Francisco.
Biotech is starting to spread its wings in minor league towns. That’s good news. It’s also necessary for the industry to grow and continue to better integrate into the wider world.
Let’s look at an example close to my home in Seattle.
Everett, Wash. is a small city of about 110,000 people about 45 minutes north of Seattle. It’s best-known as the home of the world’s largest building in the world by volume – the Boeing factory that makes jumbo jets like the 747.
It’s a blue-collar town that has seen better days. Boeing’s troubles over the past two decades have taken a toll. A lot of post-World War II housing stock is worn and mossy, in need of a good scrub. The Seattle Mariners have a Single-A minor league baseball affiliate there, the Everett Aquasox. A family of four can have some affordable fun watching the Aquasox, but the high-tech cool kids from Seattle don’t go there to hang out.
Except Seagen. The maker of antibody-drug conjugates for cancer and the region’s anchor biotech company looked North and didn’t see a place that’s run-down and tragically unhip.
It saw opportunity.
Seagen grew up in suburban Bothell, Wash. It has 11 buildings there in a hilltop office park with labs, offices, and its own biologics manufacturing space. That’s not enough anymore. Nearing its 25th anniversary, Seagen saw its revenues grow 38 percent last year to $1.6 billion. It now has three marketed cancer drugs, a big partnership with Merck, and a growing appetite for space with 2,675 employees on the payroll.
In June, Seagen made a big investment in the future. It signed a lease to build a 258,000 square foot building on about 20.5 acres of land in Everett. The property is in a business park with an Amazon distribution center, as well as Funko LLC and US Foods distribution centers. Seagen has said in regulatory filings that it plans for this new building to house additional manufacturing, laboratory, and office space.
The company, in its 10-K filing on Feb. 9, said it plans to spend $350 million to $400 million over the next three years in capital expenditures on this facility.
Company officials have declined to comment publicly. Surely there will come a time when they invite the local media and elected officials in for a ribbon-cutting.
Why Everett?
First, infrastructure. The Seattle region, now one of the world’s top tech hubs, has been growing fast for two decades. There’s a need for a second airport, in addition to Sea-Tac. Local officials in Snohomish County have cleverly positioned Everett’s Paine Field to fulfill that need. Paine Field was built in 1936 as part of a New Deal infrastructure project. It has a long history of military aviation and general aviation, and as the home for many maiden flights of new planes built by Boeing. It attracts aviation buffs from around the world. It has a remarkable collection of restored World War II-era fighter planes acquired by the late billionaire Paul Allen.
Over the last couple years, Alaska Airlines, working with local officials, made a long-term investment in commercial passenger flights from Everett’s Paine Field. It surely didn’t live up to expectations in the early days, because the pandemic depressed flight traffic of all kinds. But if you’re a company like Seagen, this easy access to a low-traffic airport has to be extremely attractive for your executives who need to fly, and for your manufacturing operations that need steady and easy flow of supplies.
Second, ground transportation. The local transit authority, Sound Transit, has funding to build passenger light rail that extends all the way from Seattle to Everett. It’s in the planning phase, and isn’t supposed to open until 2037-2041. That might sound impossibly far off, but if you think in long run terms, like a company with lifesaving cancer drugs to manufacture consistently and reliably, you need to think in 30-40-50 year terms. By the time the light rail is complete, making it easy to get around Everett and nearby suburbs, the Seagen facility should be operating full tilt.
Third, housing. The cost of living in Everett is 18 percent higher than the national average, while Seattle is 36 percent higher than the national average, according to Salary.com. The median home in Everett costs $572,000, according to Redfin. That’s not cheap, but it’s a bargain compared with the $765,000 median home price in Seattle (and I can tell you from shopping around, that’s a conservative number in Seattle, where pretty crummy homes sell for $800,000 and up.)
The point here is that if you’re a thriving mid-to-large biotech company like Seagen, you need room to grow. We’ve learned from the pandemic that it makes sense to invest for the long-term on domestic soil for national security reasons, for shipping and logistics reasons, and for domestic economic development reasons. Moving to a location away from the hottest scientific ZIP codes can save a company money. It can also be an attractive lure for employees – especially young employees trying to get established – to be in a place where they can imagine making a decent enough salary to afford a home and put their kids in a decent school.
This scenario can easily be applied in other biotech hubs. Moderna has its key R&D facilities in Cambridge, Mass., and a strategically vital manufacturing facility in Norwood, Mass. (pop. 31,000). South San Francisco-based companies can look for second facilities all over the East Bay, and points north toward Sacramento. Recently, I wrote about a bispecific CAR-T therapy startup founded on technology from UCLA. It decided to start up in Camarillo, Calif. (I needed to look it up on the map). That’s about an hour away from UCLA in Ventura County, a bit past Amgen in Thousand Oaks.
That startup, ImmPACT Bio, wants to stay in touch with the scientific wizards at UCLA. It also needs to invest in an in-house cell therapy manufacturing facility to make these complicated cells. That facility will be close by in the West Hills area of Los Angeles.
Some of the next-generation cell and gene therapy manufacturing facilities will be making custom products. They’ll need to be small and nimble. It helps to be close to the scientists who can have a healthy exchange over various process refinements, and go over subtle differences in products that can happen during scale up. These facilities definitely don’t need to be as big and costly as a Boeing factory.
But these biotech manufacturing jobs are important jobs, and important investments, for the future of the biotech industry. Some of the work being done in these facilities will save lives around the world. The work done in these places will provide upward mobility for a certain number of operators who may or may not have college degrees. These jobs will provide stability, and good pay and good benefits. They’ll provide people with dignity – pride in a job well done.
Boeing showed us what that formula could look like after World War II. It is part of what made the aerospace company so integral to the emergence of Seattle as a dynamo of the Northwest. But Boeing lost its way. It got swept up in the shareholders-above-all-else movement of the past 40 years. It cut costs. It neglected its employees. It allowed its fastidious engineering quality culture to wither. Its community bonds faded.
By putting shareholders above all else, Boeing ultimately has paid a high price.
Biotech would be wise to learn some lessons. The industry has never been stronger, despite what the XBI might say. Many companies are capable of doing things that were hard to imagine a decade ago. The time to invest boldly in the future is now, and to simultaneously do all kinds of things to better integrate into the communities where we live and work, and where patients live and work.
Let’s think 50 years down the road, and break some ground now.
Eric Lander resigned as President Biden’s chief science advisor – the first science advisor with Cabinet-level status – after Politico reported he had bullied people repeatedly, especially women. I don’t know Lander, but did attend his famous Introductory Biology course at MIT when I was a Knight Science Journalism Fellow at MIT in 2005-2006. His brilliance is obvious to anyone who meets him within minutes. This brilliance and tenacity served him well during the Human Genome Project, and in building the Broad Institute into one of the world’s great scientific institutions for the 21st century.
I’ve also heard from trusted sources that he can be a real jerk — abrasive and condescending and sharp-elbowed. Especially toward women.
This kind of behavior couldn’t stand because President Biden promised to run the White House with not only a higher degree of competence, but with more kindness and decency. The key questions now center on who will take over the important scientific leadership jobs, and what they will do with the opportunity. The new scientific leaders need to find the right balance of being forceful and demanding enough to push the bureaucracy to get things done with urgency, but without being abusive.
Robert Califf should get the FDA commissioner job ASAP. Senate Democrats should extract a few concessions, like limiting his post-FDA job prospects, to gradually rebuild public trust in the agency. They should also quit the dilly-dallying and let him get to work. Biden would be wise to call on Frances Arnold or Jennifer Doudna or Cori Bargmann or Sue Desmond-Hellmann or Paula Hammond or Amy Abernethy or Carolyn Bertozzi or another outstanding female scientific leader for the top jobs at the White House Office of Science & Technology Policy, NIH, and the future ARPA-H.
The class of PD-1 inhibiting drugs for cancer have been hugely important for cancer patients. They’ve also generated tens of billions in sales, with price tags well into the six-figures. Despite multiple market entrants, no one has yet come in to disrupt the category by competing on price. Eli Lilly sought to change that in partnership with China-based Innovent. Lilly pledged to offer its PD-1 inhibitor at a 40 percent lower wholesale acquisition cost than the incumbents. Most people concerned about drug pricing generally want to see market-based price competition. But getting there through China might be tricky. The China-only development strategy was called into question last week when FDA cancer drug boss Rick Pazdur and Harpreet Singh wrote Feb. 4 in The Lancet Oncology that they have increasing concerns about approving drugs based on data gathered entirely in China, as it might not be enough data to generalize the drug’s safety and efficacy profile for the US population. It cast something of a cloud over drugs studied entirely in China, under the headline “Importing oncology trials from China: a bridge over troubled waters?”
The FDA’s Pazdur and Singh, buttressed their points further in a Feb. 10 advisory committee public hearing, saying the key study in the Lilly / Innovent application suffered from data integrity issues. The FDA’s Oncologic Drugs Advisory Committee reviewed the data and voted against the application/ We certainly haven’t heard the last word in this story, as other companies seek to adjust to the FDA’s data requirements, while keeping a lean-and-mean development strategy to bring forward lower-priced PD-1 inhibitors. Cambridge, Mass.-based EQRx has also licensed in a PD-L1 and PD-1 inhibitor program from Cstone in China. (TR coverage, Jan. 2021)
Bayer hired Christine Roth as the new head of the oncology strategic business unit. She comes from GSK.
San Diego-based Halozyme promoted Nicole LaBrosse to chief financial officer. She replaces Elaine Sun, who is stepping down to pursue another opportunity.
Somerville, Mass.-based Finch Therapeutics, the developer of orally administered biologics that act on the microbiome, brought in a new management team. Bryan Gillis is the new chief technology officer, Alka Batycky is the new chief development officer, and Howard Franklin is the new senior vice president of late-stage development and GI therapeutic area lead.
San Diego-based Biosplice, formerly known as Sanumed, cut 41 workers, or 22 percent of its workforce. (STAT).
Boulder, Colo.-based OnKure Therapeutics, a precision oncology drug developer, hired Jason Leverone as chief financial officer.
San Francisco-based Verge Genomics said Al Sandrock, the former EVP of R&D at Biogen, joined its board of directors. (TR coverage of Verge, December 2021)
San Francisco-based VIR Biotechnology hired Johanna Friedl-Naderer as EVP and chief business officer. She comes from Biogen.
Cambridge, Mass.-based Strand Therapeutics, the developer of programmable mRNA therapies for cancer, hired Prashant Nambiar as SVP of research and translational development. He previously worked at bluebird bio.
South San Francisco-based CytomX Therapeutics, a cancer drug developer, promoted Amy Peterson to president and chief operating officer.
San Francisco-based Sixth Street, a global investment firm, said Jennifer Doudna will be its chief science advisor.
Cambridge, Mass.-based Generation Bio promoted Antoinette Paone to chief operating officer. (TR coverage).
Boston-based GentiBio, a company developing engineered T-reg cells as therapies for immune diseases, hired Chuck Silberstein as chief financial officer.
France-based Transgene, the developer of viral based immunotherapies for cancer, hired Steven Bloom as chief business officer.
The FDA approved sutimlimab-jome (Enjaymo) to reduce the need for red blood cells transfusions for adults with cold agglutinin disease. The drug was first developed by True North Therapeutics, and is now part of Sanofi.
Waltham, Mass.-based Ardelyx failed in its appeal to the FDA. The company received a Complete Response Letter in July 2021 for its application to market a treatment for control of serum phosphorus in chronic kidney dialysis patients.
The FDA said it’s investigating the possible increased risk of death in cancer patients on umbralisib (Ukoniq) from TG Therapeutics.
Watertown, Mass.-based Seismic Therapeutic raised a $101 million Series A round. Lightspeed Venture Partners led, and was joined by founding investors Tim Springer and Polaris Partners. The company is combining structural biology expertise and protein engineering, aided by machine learning in each area, to enable discovery of new drugs for autoimmunity. Jo Viney is the CEO, and is being reunited with several colleagues from Pandion Therapeutics. (TR coverage).
Jo Viney, co-founder, president and CEO, Seismic Therapeutic
Seattle-based Curevo Vaccine raised a $60 million Series A financing led by RA Capital Management. The company’s lead asset is a shingles vaccine candidate in Phase II development. If successful, the sub-unit vaccine would be the first non-live varicella (chickenpox) vaccine for shingles.
New York-based Koneksa raised $45 million in a Series C financing to advance its work on digital biomarkers. AyurMaya, an affiliate of Matrix Capital, led.
Boston-based Day Zero Diagnostics raised $21 million in a venture financing led by Sands Capital, with new investors, including BD, Panacea Venture and Hongkou Capital. It’s developing infectious disease diagnostics with whole genome sequencing and AI.
Montreal-based Congruence Therapeutics raised $50 million in a Series A financing led by Amplitude Ventures. It’s using computational and medicinal chemistry to discover small molecules for rare diseases of protein misfolding.
Waltham, Mass. and Montreal-based Ventus Therapeutics secured $140 million in a Series C financing co-led by SoftBank Vision Fund 2 and RA Capital Management. It’s using structural biology and computation assist small molecule drug discovery.
Watertown, Mass.-based Arkuda Therapeutics raised $64 million in a Series B financing co-led by Cormorant Asset Management and Pivotal bioVenture Partners. The company is working on lysosomal and microglial biology to treat neurodegenerative diseases.
San Diego-based Endeavor BioMedicines raised $101 million in a Series B financing to advance precision medicines for oncology and fibrosis. Ally Bridge Group and Avidity Partners led. Endeavor said it plans to have three drug candidates in the clinic by the end of 2022. Serial entrepreneur John Hood is the co-founder and CEO. He sold his previous company, Impact Biomedicines, to Celgene.
Emily Leproust, co-founder and CEO, Twist Bioscience
South San Francisco-based Twist Bioscience, the DNA synthesis company, said it plans to raise $200 million in an underwritten public offering.
San Diego-based 1859, Inc., a company seeking to discover small molecule drug candidates with AI, raised $40 million in a Series A financing led by Northpond Ventures and OMX Ventures.
San Francisco-based Indapta Therapeutics raised $50 million in a Series A financing to develop engineered NK cell therapies. The deal was co-led by co-led by RA Capital Management, Vertex Ventures, and Leaps by Bayer. Mark Frohlich, formerly of Juno Therapeutics, is the CEO.
Cambridge, Mass.-based Public Health Vaccines LLC said it started its first clinical trial with a live, attenuated vaccine candidate for the deadly Nipah virus. The program is supported with $43 million from the Coalition for Epidemic Preparedness and Innovations (CEPI).
Palo Alto, Calif.-based Medable announced a partnership with CVS Health to expand access to more patients who might enroll in clinical trials. CVS MinuteClinic locations will use Medable software. Medable, in a press release, specifically pointed to the opportunity to improve enrollment in diverse populations.
San Diego-based Resilience said it secured a contract from the US military worth up to $250 million to make a monoclonal antibody treatment to defend against a botulinum toxin nerve agent attack. The military considers botulinum toxin to be a top priority biowarfare threat. Resilience will manufacture the antibodies in Florida for US government stockpiling.
Cambridge, Mass.-based Foundation Medicine formed a partnership with Eli Lilly to develop tissue and blood-based assays as companion diagnostics for Lilly’s RET inhibitor and other therapies from its Loxo Oncology unit.
Janice Chen of Mammoth Biosciences got to celebrate her 22-year-old brother Nathan Chen winning the Gold medal in figure skating for the US at the Winter Olympics.
Larry Corey, MD
The Omicron wave has been shocking. We in the virology community knew the SARS-CoV-2 virus had an exceptional ability to mutate, but the pace of its evolution was surprising.
We were just as surprised by the even-faster speed by which this variant spread.
Omicron became the dominant variant almost two years into the pandemic because it’s more transmissible and able to escape immunity that people had developed from prior infection and vaccination.
The virus has made a lot of people sick. We’ve seen confirmed cases rise a breathtaking 10-fold over the Delta peak. Hospitals were overwhelmed. Tests, N95 masks, and vaccine boosters couldn’t arrive fast enough for many people.
It has brought us all a winter of discontent.
The Omicron variant was first recognized in mid-November in sub-Saharan Africa. It arrived in the United States, including my own city of Seattle, three weeks later. Omicron dampened the feelings of scientific accomplishment that had buoyed us all. Just 12 months prior, in December 2020, we celebrated the success, and the Emergency Use Authorizations, of the mRNA vaccines from Pfizer/BioNTech and Moderna.
The national vaccination program that ramped up in the first half of 2021 significantly curtailed the Alpha wave. The success of that campaign fueled hope that we were winning the war. Yes, the Delta variant arrived in late summer, creating a tsunami of infections, hospitalizations and deaths. But that tsunami came because we were unable to implement mandatory vaccination policy, and we had a large reservoir of unvaccinated people here, and around the world.
The Omicron variant’s ability to spread more rapidly than the Delta strain is disconcerting.
It leads me, today, to step back and ask: How did this occur?
I can look at my own thinking and writing. But if you don’t take action from thinking and writing, it doesn’t do much good, does it?
Some knowledgeable colleagues in the virology community say an animal reservoir likely played a role in Omicron’s genesis and the animal passed the virus to a human. That’s the zoonotic spread theory.
I have long suspected that it’s more likely that an immunocompromised person served as the critical host. I raised that possibility in Timmerman Report last July, and again with colleagues in the New England Journal of Medicine in August.
Researchers from South Africa published a preprint case report in June 2021 about an individual with HIV who was co-infected with COVID-19 and accumulated mutations of interest over a period of 200 days. More data have now arrived from South Africa, published this week in Cell Host Microbe, to strongly support this view that humans are the reservoir and genesis of Omicron.
My colleagues and I discussed saltational evolution and the rapid, multimutational steps that SARS-CoV-2 can take in immunosuppressed persons. (In biology, saltation, which comes from Latin saltus, “leap” or “jump,” is a sudden and large mutational change from one generation to the next.)
We showed that this happened with the Alpha variant in early 2021. While most of the variants that are generated in immune suppressed persons don’t jump to the community, some do. What defines the ones that do and those that don’t is unclear—much depends on the virus finding a way to persist, as well as to enhance its ability to spread to others.
With Omicron, it seems like it may have found an efficient and alternate way into the cells of our throats and noses and onward from there. Yes, it’s not as likely to cause pneumonia deep in the lower lungs as other strains—that’s good. But it’s adept at immune evasion.
There is no reason to believe the SARS-CoV-2 virus’s tricks are over.
The story of Omicron shows 50 mutations between its ancestral origin, nearly 20 of them in the immunodominant region of the receptor binding site. The genetic tree of Omicron points its origin way back to early 2020 in the time of B.1.1.7—or around the Alpha variant time frame.
The phylogenetic tree also shows that the Omicron sub-variant 1 and variant 3 have recombination events—when two molecules of DNA exchange pieces of their genetic material with each other—essentially showing that they existed from the same person or from a small group of coinfected people. Variant 1 and variant 2 also have some recombination events that look like they also came from the same individual or small group of people. Were they the exact same individual? Or someone who transmitted to another immune-suppressed person and it took a few weeks to emerge as BA.2? Hence there are two immune compromised persons but they are essentially epidemiologically related?
No one really knows the answers, and for Omicron it’s uncertain we will ever be able to decipher this. But the likelihood of two immune compromised people being in close contact is pretty high in townships and communities with high HIV prevalence.
But it’s clear Omicron variant 1, or BA.1, got into the population first because it spread throughout the world first. Now, some six weeks later, we’re seeing variant 2, or BA.2, start to emerge and take over. We initially thought BA.2 to be the weaker sibling, but as it turns out, it might be the stronger one because it’s more rapid. The best explanation we in the field can come up with is that BA.2 emanated from the same person or some small initial group of people that were infected with BA.1, and the virus evolved into BA.2 in another person, transmitting slightly later into the community—six or eight weeks later—and it’s taken off by itself, after it learned how to become even more transmissible than its older sibling.
I’ll use a sports analogy. It’s like the Williams sisters, Venus and Serena. Venus was the initial breakout tennis star. Serena is younger, but eventually surpassed her sister, in time and space. And that looks to be the case with the Omicron siblings.
The analogy falls short though because you can get beaten by both Venus and Serena and I’m not sure you can get beaten by the Omicron variant BA.2 if you’ve had BA.1. I think our immune systems know how to play against BA.2 if we played against BA.1 since our cells are left with the memory of playing the immune match with the virus—and that memory arms us against the other sibling. We’ll see how the cross-protection plays out. At present, very few BA.1-infected people have gotten BA.2.
The good news is that our vaccine booster dose saves the day, taking efficacy against hospitalization from 70% to close to 90% and from infection from 40% to 70%. But Omicron is a tougher adversary for the vaccines. There are still breakthrough cases of Omicron infection in people who received three vaccine doses. We saw very few breakthrough cases when the ancestral strain was circulating, and many people had two doses.
That’s what’s hard to like or accept. Why can’t we get back to December 2020 in our level of protection?
Scientists have created a few new tools — primarily the monoclonal antibodies sotrovimab and Evusheld and the antiviral pill Paxlovid — but supply shortages are making it difficult to implement these treatments at scale.
Controlling an epidemic takes combination strategies, which my colleague Myron Cohen and I wrote about at the beginning of our battle with SARS-CoV-2 in May 2020 in Science, before we had medical countermeasures.
Behavioral measures such as social distancing reduce the risk of exposure. High-quality masks work. But people can’t be asked to maintain vigilance on non-pharmaceutical interventions forever.
The three primary biomedical interventions are vaccines, monoclonal antibodies, and antivirals. Vaccines and monoclonals came earliest and were hugely effective. Monoclonals have been shown to be effective for early outpatient therapy and as prevention for persons with high exposure or at greater risk (e.g., household exposure or immune compromised).
When available, monoclonals provide the backup treatment for the breakthrough infections. They are more expensive than vaccines but also highly effective in preventing hospitalization, death, and more recently for unvaccinated persons — reducing the risk of getting COVID-19. Their disadvantages are the requirement for more frequent administration and higher cost than vaccines.
The new tool that has emerged more recently are antiviral medicines. Few people were working on antiviral research against coronaviruses before SARS-CoV-2. The SARS-CoV-2 virus is complicated enough that figuring out what to target and what compounds would selectively inhibit the viral genes and not inhibit important proteins in our cells took time.
Remdesivir was one potential solution. An off-the-shelf drug initially tested for Ebola that had efficacy against other coronaviruses such as MERS, remdesivir has been useful in hospitalized persons and has been available since early in the epidemic. But we couldn’t build on this knowledge and needed a better drug against the viral protein. So, different targets of the viral life cycle needed to be evaluated.
This is where Paxlovid, an inhibitor of the viral protease enzyme comes in. Unfortunately, little has been published on the drug yet, but in one study, when taken early after infection, the pill prevented hospitalization in nearly 90% of persons. This is a great outcome.
Importantly, it appears additional drugs against the viral protease enzyme are also emerging. Antiviral therapies will I think be a major part of the medical response tool kit. I believe it’s important for people to know there is an oral pill that can prevent severe disease progression if you get sick with SARS-CoV-2. Another antiviral drug called molnupiravir has also been discovered and authorized for Emergency Use by the FDA. It has its advocates and detractors; the main issue for my discussion of antivirals for COVID-19 is that recent data indicate it’s not nearly as good as Paxlovid.
Why is conceptual reassurance from therapies needed? Obviously, it helps the unvaccinated, but it is important for vaccinated people as well. We have seen that for Omicron, even the vaccinated can get ill and some get pretty sick, especially the elderly and those who have several risk conditions for severe illness. Waning immunity increases this chance. Knowing there is a backup medicine has enormous implications medically and psychologically.
I think if we knew we had a therapy we could get at a pharmacy, whether a monoclonal injection or an oral antiviral pill that would keep us from getting really ill, our ability to cope with COVID-19 would markedly change.
Healthy people could start going to restaurants and feel closer to a sense of normalcy. For the less well, perhaps with rapid testing and the availability of these therapies, people would feel more comfortable in restaurants or at family gatherings. Flying on an airplane wouldn’t feel risky, nor would one feel like they might get trapped in another city or country in quarantine or worse, hospitalized.
Our options would expand, our economy open up fully, and our social well-being would improve.
When will this happen? These additional tools to ward off Omicron are to become widely available in April or May. They are, in some cases, more available than currently known. More education for physicians, pharmacists, and the public is needed.
What happens next is speculative but recognize that the virus has learned to select itself against many of the immune responses that we currently have. I think it’s hubris to feel confident that we know all of the virus’s immune-evasion strategies or all of its ways to increase its transmission efficiency. The host immune response that we avidly test is evasion of antibodies, but not the other factors that slow virus control especially escape from host non-antibody responses. These are less predictable.
One strategy I think must be pursued is to improve our vaccines so they prevent one from acquiring infection in the first place. No sickness, no breakthroughs, no hospitalizations, no complications. By not acquiring it, or just getting transient infection in the nose at a level not associated with high likelihood of transmission, we really get what people called “herd immunity” — immunity that stops the carriage to others. This is what I call population-based control of the epidemic.
The monoclonal antibody work suggests that at really high neutralization titers, we appear to prevent people from acquiring the virus in the first place. We have some evidence that when the vaccine matched the ancestral strain, in the first couple of months, maybe 40% of the time it decreased acquisition.
My own bias is that if we could make vaccines that achieve the level of neutralization we see in the monoclonals — currently 10 times higher than we presently achieve — we might be able to prevent acquisition and truly reduce the widespread dissemination of disease.
There are a lot of people who will say to me, Larry, that’s just naïve—but I’ve always been an optimist. Conceptually, I think it helps in research to say, well, can our current technologies push our antibody titers to the circulating strain up a full order of magnitude? That’s ten-fold, so let’s say from 800 to 8,000 neutralizing titers in blood. Such titers appear to protect monkeys from experimental challenge in the nose…no virus is detected even with high-grade challenge.
I can’t guarantee this will happen in humans, but I can feel pretty comfortable that if I can maintain a level of 8,000 for a long period of time, I’d take that over 800. And it would be harder for a viral escape to occur, since as we’ve seen, the escapees generally originate in the immunocompromised population, which have low antibody and cellular immune responses. So, I do think it would help. It may require augmenting current vaccines with a mucosal vaccine delivered by drops or spray—these technologies exist. They need to be developed and administered.
Personally, I rank developing vaccines or vaccine regimens that achieve population control a higher priority than what people call universal coronavirus vaccines — a vaccine that might provide baseline immunity to all types of coronaviruses. Of course, accomplishing both goals is best.
Now, back to my own personal admonition of writing without action. I wrote about immunosuppressed people being an important source of new variants and needing better medical monitoring. I wrote the article mainly directed to cancer patients and what was going on in our country at that time. But having worked with HIV, I know that the very largest number of people who are immunosuppressed who walk our planet are the number of people with chronic, inadequately treated HIV. And in sub-Saharan Africa, that’s up to 20% of the population. This is twice as great as the number of immunosuppressed people in Europe or the United States.
Is it surprising then that the Beta and Omicron variants came from sub-Saharan Africa where population coverage of highly effective vaccines is less than 20% of the adult population?
We in the western world; governmental, pharmaceutical and, yes, our global health implementation bodies such as the WHO did not do enough to provide early enough access to effective vaccines. We have learned that the implementation of vaccine science is far behind the research discovery process. Moreover, African governments have also been, to this observer, passive in their insistence of protecting their citizens from this pandemic. Solving this inertia is perhaps our greatest current challenge.
This failure means we still have millions of immunocompromised, unvaccinated people walking around with a high likelihood of becoming the next host for a new variant.
We haven’t proven that vaccinating people will help reduce the emergence of Variants of Concern, but it’s pretty logical. It certainly couldn’t hurt and probably would help. And if that’s not true, then we should at least try and prove it one way or the other. Health services have gone down in low- and middle-income countries because of the COVID-19 epidemic. Most would argue that there’s an 80% likelihood vaccination would decrease the percent of people with persistent COVID-19 and hence, the milieu for generating multi-mutational variants of concern.
Nor is there proof yet that developing vaccine strategies for HIV-infected people would alter the emergence of variants. But, again, it’s logical and I could have raised our collective awareness about these issues sooner.
True, suggesting an idea in the summer of 2021 wouldn’t have changed what happened in November 2021. But there is a momentum for everything that leads to a call to action. I hope to build some more momentum for the idea of vaccinating immunocompromised people in need around the world, in the hope that it will compel us to determined action on global distribution of vaccines.
It is this reflection that leads to my personal “winter of discontent.”
Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.
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