Your Edge In Biotech.
11
Feb
2021

Long COVID’s Insidious Toll, Novo’s Victory Against Obesity, & Gilead’s Stumble in IPF

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11 Feb 2021

Luke Timmerman, founder & editor, Timmerman Report

Our culture tells us to fear death.

Every day, we hear updates on the COVID-19 death toll. Deaths are broken down by age, race, ethnicity. By state and nationality.

The US numbers – 473,000 and increasing by more than 3,000 a day – are tragic and numbing.

But while we fixate on death, we are devoting scant attention to the insidious, cumulative toll of morbidity from COVID-19. The ‘Long COVID’ story is one of those gradual ones that sneaks up on us over time.

The types of symptoms, the number of people struggling, the severity of chronic disease, how long the symptoms might last – these are all important questions are only beginning to come into focus.

The Mt. Sinai Center for Post-COVID Care in New York estimates that 10 to 30 percent of all COVID patients will suffer from long-term symptoms. As of this writing, we have had 27.3 million confirmed cases of COVID-19. That’s an undercount, but if you use that number for the sake of argument, we could be looking at 2.7 million-8.2 million people in the US alone who are struggling with some sort of chronic disease stemming from COVID-19.

Doctors who see COVID patients are telling me that Long COVID is the real thing, not just a few anecdotes here or there, and not some minor bellyaching from hypochondriacs as was sometimes implied by some stressed-out clinicians early in the pandemic.

“The Long Haul story is not one that has been fully told,” said Peter Hotez, a virologist at Baylor College of Medicine in Houston, and director of vaccine development at Texas Children’s Hospital Center, in a recent appearance on CNBC. “Literally millions of people could have some lingering symptoms.”

Deaths are “the tip of the iceberg,” Hotez said.

What are common Long COVID symptoms?

  • Lung fibrosis / shortness of breath
  • An inability to concentrate, or “brain fog”
  • Blood clotting
  • Heart arrythmias
  • Kidney damage
  • Metabolic dysregulation that looks like Type 1 diabetes
  • Long-term fatigue
  • Depression and anxiety that stems from any of the above chronic conditions

Data are just beginning to surface to tell the story. A 6-month follow-up study from Wuhan, China, published last month in The Lancet, found that 63 percent of COVID-19 survivors complained of fatigue and muscle weakness, and 26 percent reported sleep difficulties. About one out of every four people discharged from the hospital reported depression or anxiety. One-fourth of patients were unable to reach the lower limit of normal distance on the 6-minute walk test.

Tony Fauci has described some of the symptoms as similar to myalgic encephalomyelitis (aka chronic fatigue syndrome). While lingering inflammation may be a common thread in the two conditions, the set of symptoms don’t exactly overlap. To collect more data from Long COVID patients, Johns Hopkins Bloomberg School of Public Health is conducting an online survey. It hopes to recruit 25,000 participants. (Survey Here).

My hope is that in the coming weeks, as our country continues to ramp up the biggest vaccination campaign in history, that we keep these devastating long-term consequences in mind.

I’ve heard stories in my extended family. There’s a distant cousin, a 20-something college undergraduate. She dropped out of college because of brain fog from Long COVID. She can’t concentrate. She’s unsure if or when she’ll be able to go back.

What must that be like, to be 21 and get a bug that doesn’t seem too terrible at first, but that ends up altering the trajectory of your life?

Often, the Long COVID effects show up in middle-aged, healthy people. Recall the Dec. 7 TR article by Blair Clark-Schoeb. She’s in her mid-40s, a parent, an athlete, and a successful biotech professional.

E. Blair Clark-Schoeb, SVP of communications, Aruvant Sciences

Her struggle with Long COVID began in March. It continues. She described it on a recent podcast.

Entire biotech funds will probably be raised in the months ahead to deal with the whole new set of chronic diseases that our healthcare system will have to confront. There will be ideas for treating chronic inflammation, for the clotting disorders, the depression, the anxiety, the diabetes-like symptoms.

The demand for biopharma to step up and deliver will be clear.

That’s a good thing. It will give purpose and drive to many in this industry. If biotech can rise to the occasion with vaccines, therapies and diagnostics, it can find a way forward here.

The main thing to remember in the urgent here and now is the importance of hunkering down for another couple of months, with masking and distancing, until the vaccines have a chance to crush the curve.

I’m much more optimistic than I was at the start of the year, because we have not just two outstanding vaccines, but two more excellent and practical options on the way from J&J and Novavax.

Let’s do everything we can to help everyone see why getting vaccinated is so vital, and so urgent. It’s not only about saving lives. It’s about helping us all live long and healthy lives.

 

Public Health

The CDC – still the world’s premier epidemiology and public health agency – screwed up big-time with testing at the start of the biggest pandemic in a century. Things got worse when it was muzzled and marginalized. But now that CDC has a capable leader in Rochelle Walensky with support from the White House, the CDC is in a stronger position to bring down community transmission. To that end, the CDC urged the public to consider “double-masking” as a more rugged defense against the more troubling B117 and B.1.351 variants now in circulation. For more, see this Feb. 10 JAMA article on “Effectiveness of Mask Wearing to Control Community Spread” by a couple of CDC scientists.

Vaccine Hesitancy

The CDC reported on vaccine hesitancy in its Morbidity and Mortality Weekly Report (MMWR), and the numbers are moving in the right direction. If you group together respondents who said they were “absolutely certain,” or “very likely,” or “somewhat likely” to be vaccinated, the intent to get vaccinated increased overall from September (61.9%) to December (68.0%). Those household surveys, it should be noted were taken during the intense emotions of election season, news reports of astounding efficacy for Pfizer and Moderna, and FDA Emergency Use Authorizations in December.

People age 65 and older, the ones at highest risk of COVID-19, showed increasing willingness to get the shot.

And yet, the pockets of resistance are high, and stubborn. See this recent snapshot from the Kaiser Family Foundation Vaccine Tracker. The percentages below are people who say they will “Definitely Not” get a COVID-19 vaccine. That’s 13 percent of the country, including 25 percent of Republicans and 21 percent of Rural people. (Survey data: Jan. 11-18, 2021)

Some people, on the extreme left and right, are going to be unreachable in their anti-vaccine attitudes. Maybe the biggest area of concern are the people who are in the middle, suffering from the breakdown of trust, the epistemic crisis at the bottom of the barrel of cynicism. Millions of people don’t know who or what to believe. As David Shaywitz wrote here last week, this is the result of “manufactured nihilism.”

The results are plain to see. Weeks after news about 95 percent effective vaccines becoming authorized by the FDA – one of the greatest achievements in the history of science – we still see huge swaths of the US public struggling along, saying they’ll “Wait and See.” (See the demographic breakdown from the Kaiser Family Foundation survey, Jan. 11-18.)

 

Will these numbers trend in ever-more positive directions in coming weeks and months? I hope so. The NYT ran an editorial co-signed by 60 Black members of the National Academy of Medicine urging African Americans to get vaccinated. The Kaiser Family Foundation notes that openness to vaccination tends to increase when people know someone else who has been vaccinated.

Treatments for COVID-19

Repurposed Antiviral Drugs for Covid-19. NEJM. Feb. 11. (WHO Solidarity Trial Group)

Tocilizumab IL-6 inhibiting therapy in COVID-19 patients admitted to the hospital. Overall, 596 (29%) of the 2022 patients on tocilizumab and 694 (33%) of the 2094 44 patients on usual care died within 28 days. MedRxiv. Feb. 11. (RECOVERY trial group)

Good News for Obesity

Researchers reported that once-weekly subcutaneous injections of semaglutide (Ozempic), a GLP-1 peptide analog drug for diabetes from Novo Nordisk, significantly increased weight loss when boosted up to a 2.4 milligram dose (the drug is usually given in a 0.5 to 1 mg subcutaneous once weekly shot for diabetes).

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group compared with −2.4% with placebo, according to investigators from the STEP1 trial, writing in the New England Journal of Medicine. Nausea and diarrhea were the most common side effects; but were typically mild to moderate and went away over time. See comment from Sek Kathiresan, a cardiovascular genetics expert, and CEO of Verve Therapeutics.

Given the huge and rising prevalence of obesity in the US, this is maybe the most clinically relevant result I’ve seen on a population level in a long time. See the CDC state-by-state graphic below that shows rates of obesity, defined as people with Body Mass Index of 30 or higher. Obesity, by the way, is an added risk factor for COVID-19 complications.

Variants vs. Vaccines
  • mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Feb. 10. (Michel Nussenzweig et al Rockefeller University)
  • Coronavirus Variants and Mutations. An Excellent Graphic. Feb. 11. (Jonathan Corum and Carl Zimmer)
  • Variants mean the coronavirus is here to stay — but perhaps as a lesser threat. Washington Post. Feb. 9. (Carolyn Johnson)
  • Could a Single Vaccine Work Against All Coronaviruses? NYT. Feb. 9. (Carl Zimmer)
  • Herd Immunity Might be Unattainable. But Vaccines Can Still Help End the Pandemic. The Atlantic. Feb. 9. (Sarah Zhang)
  • Mapping Which Coronavirus Variants Will Resist Antibody Treatments. NIH Director’s Blog. Feb. 9. (Francis Collins)
  • S. rushes to fill void in viral sequencing as worrisome coronavirus variants spread. Science. Feb. 9. (Meredith Wadman)
Epidemiology
  • Quantifying asymptomatic infection and transmission of COVID-19 in New York City using observed cases, serology, and testing capacity. PNAS. (Rahul Subramanian et al)
  • The effects of school closures on SARS-CoV-2 among parents and teachers. PNAS. (Jonas Vlachos et al Stockholm University)
  • The role of children in the spread of COVID-19: Using household data from Bnei Brak, Israel, to estimate the relative susceptibility and infectivity of children. PLoS Computational Biology. Feb. 11. (Itai Dattner et al)
Science of SARS-CoV-2
  • Exhaled aerosol increases with COVID-19 infection, age, and obesity. PNAS. (David Edwards et al Harvard University)
  • Rapid Coronavirus Tests: A Guide for the Perplexed. Nature. Feb. 9. (Georgia Guglielmi)
  • COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses. Cell Immunity. Feb. 9. (Agnes Bonifacius et al Hannover Medical School, Germany)
  • Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection. Cell. Feb. 9. (Scott Hensley et al Penn Medicine)
Access and Distribution

The US government agreed to order 100 million more doses of the mRNA vaccine from Moderna. That means that US government has agreements to get 300 million doses out of the 631 million doses Moderna has lined up in supply agreements with governments around the world.

Merck is reportedly in negotiations with governments, public health agencies, and other companies to fire up its considerable capabilities for manufacturing COVID-19 vaccines. The Kenilworth, NJ-based company, one of the world’s major vaccine producers, scrapped its novel vaccine programs after they failed to generate an adequate immune response.

Pharmacies around the country were due to get 1 million doses of COVID-19 vaccines from the federal government as of yesterday, Feb. 11. The companies, including national chains like CVS and Walmart, have confirmed they don’t want to let any doses go to waste. That raises the question of who will get leftover doses. Their employees, or the public?

A Houston doctor had 10 doses of vaccines that were due to expire, and had to be used. He gave them to people with medical conditions. He got fired and publicly humiliated for trying to do the right thing, trying to avoid a travesty. This is one of those zeitgeist stories about a society suffering from a breakdown of trust. (NYT, Feb. 10, 2021)

Our Shared Humanity

Vaccinated People Are Going to Hug Each Other. Julia Marcus writes: “The vaccines are phenomenal. Belaboring their imperfections—and telling people who receive them never to let down their guard—carries its own risks.” The Atlantic. Jan. 27. (Julia Marcus of Harvard Medical School)

Pandemic Effect on Cancer R&D
  • Dramatic drop in new cancer drug trials during the COVID-19 pandemic. The Lancet. Feb. 4. (Emma Wilkinson)
  • Cancer groups aim to broaden clinical trial participant pool. Bloomberg Law. Feb. 9. (Jeannie Baumann)
Financings

South San Francisco-based Day One Biopharmaceuticals, the developer of pediatric cancer drugs, raised $130 million in a Series B deal led by RA Capital Management. (Timmerman Report coverage).

Boston-based Ensoma raised $70 million in a Series A financing to develop adenoviral vectors for cell therapies that can be made more accessible around the world. 5AM Ventures led. Ensoma also announced a partnership with Takeda Pharmaceuticals to work on in vivo gene therapies for up to five rare disease programs. (Timmerman Report coverage).

Menlo Park, Calif.-based PacBio, the developer of long-read DNA sequencing instruments and technology, raised $900 million in convertible debt from an affiliate of Softbank Group.

London-based Quell Therapeutics, a developer of T-regulatory cell therapies, expanded its Series A to $84 million.

New York and Stamford, Conn.-based Sema4 went public by combining with a Special Purpose Acquisition Company (SPAC) sponsored by Casdin Capital and Corvex Management. Sema4 describes itself as an “AI- and machine learning-driven patient-centered genomic and clinical data intelligence company.” The deal is expected to bring $793 million in total cash.

Seattle-based Nautilus Biotechnology, a proteomics company, merged into a SPAC sponsored by Perceptive Advisors, going public in a deal that’s fetching about $350 million. (TR coverage of Nautilus, June 2020).

New York-based Nuvation Bio went public via a merger with a SPAC sponsored by EcoR1 Capital. Nuvation, led by former Medivation CEO David Hung, is working on novel cancer drugs. It secured $646 million through the SPAC and related transactions, bringing its cash balance to $830 million.

Vancouver, BC-based Notch Therapeutics raised $85 million in a Series A financing to develop induced pluripotent stem cell-derived therapies for cancer. Allogene Therapeutics, Lumira Ventures, and CCRM Enterprises Holdings, EcoR1 Capital, Casdin Capital, Samsara BioCapital, and Amplitude Ventures participated.

Cambridge, Mass.-based KalVista Pharmaceuticals raised $193 million in a stock offering at $36 a share. It’s developing small molecules against hereditary angioedema and diabetic macular edema.

San Mateo, Calif.-based Sagimet Biosciences raised $80 million in a crossover financing. Its lead program is for NASH.

San Diego-based Pipeline Therapeutics said it raised $80 million in a Series C financing to advance its work on small molecules for neurodegeneration. New investors include Perceptive Advisors, Franklin Templeton, Casdin Capital, Samsara BioCapital, and Suvretta Capital.

Menlo Park, Calif. and Boston-based Adicet Bio raised $120 million in a stock offering. It’s working on allogeneic T cell therapies.

Lexington, Mass.-based Cyteir Therapeutics, the developer of synthetic lethal cancer drugs, raised an $80 million Series C financing. RA Capital Management led.

Baltimore, Maryland-based Personal Genome Diagnostics, a cancer genomic profiling company, raised $103 million in a Series C deal led by Cowen Healthcare Investments.

San Francisco-based Adagene, the developer of antibody drugs for cancer, raised $140 million in an IPO at $19 a share for American Depositary Shares.

San Carlos, Calif.-based BigHat Biosciences raised $19 million in a Series A financing to advance its AI-guided antibody design platform. A16Z led.

London-based Autolus, a T-cell therapy developer, raised $100 million in a stock offering.

Charlottesville, Virginia-based Hemoshear Therapeutics, the developer of treatments for rare metabolic disorders, raised $40 million in a Series A financing led by Suvretta Capital.

Indianapolis-based Apria Health, a home healthcare equipment and sleep apnea equipment provider, raised $150 million in an IPO at $20 a share.

Durham, NC-based Bioventus, the developer of orthobiologics for musculoskeletal conditions, to avoid elective surgeries, raised $104 million in an IPO at $13 a share.

New York-based Kadmon Holdings took on $200 million in debt.

Regulatory Action

Eli Lilly won FDA Emergency Use Authorization for the neutralizing antibody combination of bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) for COVID-19. It’s for mild-to-moderate COVID-19 patients at high risk of progression to severe disease. The FDA is also allowing a shorter infusion time of 16 or 21 minutes, compared with the previous 60 minutes, which ought to make the infusion more practical in a pressure-packed hospital environment where minutes count.

Regeneron said it won FDA clearance to market evinacumab-dgnb (Evkeeza), a monoclonal antibody directed at ANGPTL3, as a treatment for homozygous familial hypercholesterolemia – a rare genetic disease that results in elevated cholesterol levels and raises the risk of heart attack, stroke and death. A couple days earlier, Regeneron won FDA clearance for cemiplimab-rwlc (Libtayo), a PD-1 inhibitor for advanced basal cell carcinoma for patients who have previously gotten a hedgehog pathway inhibitor, or for whom that kind of medicine isn’t appropriate.

The FDA’s Oncologic Drugs Advisory Committee voted against approval of Merck’s PD-1 inhibitor pembrolizumab (Keytruda) as a neoadjuvant treatment for high-risk, early-stage triple-negative breast cancer in combination with chemotherapy after surgery. The data were premature, leaving the door open to a future reconsideration.

Personnel File

Cambridge, Mass.-based Surface Oncology promoted Robert Ross to president and CEO. He was previously chief medical officer. Current CEO Jeff Goater will remain chairman of the board.

South San Francisco-based Cortexyme, the developer of a treatment for Alzheimer’s disease, promoted Chris Lowe to chief operating officer and chief financial officer.

Cambridge, Mass.-based Synlogic named Lisa Kelly Croswell to its board of directors. She is senior vice president and chief human resources officer for Boston Medical Center Health System.

Cambridge, Mass.-based Dewpoint Therapeutics named Joel Sendek as its chief financial officer. He was previously CFO at Sema4.

San Francisco-based Lyell Immunopharma, a developer of T cell therapies for solid tumors, hired Charlie Newton as chief financial officer. He was previously with BofA Securities as a healthcare investment banker.

Vancouver, BC-based AbCellera, the antibody discovery company, promoted Ester Falconer to chief technology officer. She was previously head of R&D.

Eli Lilly said Anat Ashenazi has been promoted to chief financial officer, replacing Josh Smiley, after learning of “an inappropriate personal relationship between Mr. Smiley and an employee.”

Los Altos, Calif.-based Retrotope, a company working on degenerative diseases, said Rick Winningham has been named its new chairman of the board. He’s the chairman and CEO of Theravance Biopharma.

Gilead’s Kite Pharma cell therapy unit said Frank Neumann has joined as senior vice president and worldwide head of clinical development. He replaces Ken Takeshia, who is leaving the company at the end of February.

Cambridge, Mass.-based Gemini Therapeutics hired Brian Piekos as chief financial officer. The company is working on precision medicines for age-related macular degeneration.

Berkeley, Calif.-based Caribou Biosciences, a CRISPR genome editing company focused on CAR-T and CAR-NK cell engineering, hired Jason O’Byrne as chief financial officer. He was previously SVP of finance at Audentes Therapeutics.

UK-based Exscientia, an AI pharmatech company, named Elizabeth Crain to its board, along with Ben Taylor, the company’s chief financial officer.

Deals

Gilead Sciences and its partner, Belgium-based Galapagos NV, said they are shutting down the Phase III trials of ziritaxestat in patients with idiopathic pulmonary fibrosis. A Data Safety Monitoring Board recommended the trials be halted. The latest failure comes after another Gilead / Galapagos partnered program, filgotinib for rheumatoid arthritis, was rejected by the FDA. The partnership was originally valued at $5 billion in 2019.

Dallas-based Taysha Gene Therapies announced a pair of research collaborations with the Cleveland Clinic and University of Texas-Southwestern to further develop AAV vectors to carry mini-gene payloads for epilepsy and other CNS diseases. Terms weren’t disclosed.

AbbVie agreed to work with Berkeley, Calif.-based Caribou Biosciences on CRISPR-based genome editing programs for CAR-T cell therapies. Caribou is pocketing $40 million upfront.

8
Feb
2021

A Single Shot for Heart Disease: Sekar Kathiresan on The Long Run

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08 Feb 2021

Today’s guest on The Long Run is Sek Kathiresan.

Sek is the co-founder and CEO of Cambridge, Mass.-based Verve Therapeutics.

Sekar Kathiresan, co-founder and CEO, Verve Therapeutics

Verve is using genome editing technology in a bold fashion. Its idea is to develop a one-and-done shot that essentially would prevent cardiovascular disease in adults. Its plan is to start out with a group of patients at very high risk of cardiovascular disease, and potentially broaden the availability of the treatment later.

The treatment, which uses a newer-generation editing technique known as base editing, takes aim at a gene called PCSK9. Scientists have long for a long time that if you knock out the activity of this gene out, you can dramatically reduce LDL cholesterol and reduce the risk of heart attack, stroke and death from cardiovascular disease. Verve’s technology aspires to do this with a single shot.

The company has shown some pretty compelling data that this approach works in monkeys, and the effects are holding up after 6 months of follow-up.

Sek is a native of India, and immigrated to Pittsburgh in elementary school. He got a broad-based education there, including a bachelor’s degree in history, that he says served him well before he became a physician and scientist and entrepreneur. I think you’ll enjoy Sek’s story.

Now, before we get dive in…a word from the sponsor of The Long Run.

Synthego is a genome engineering company that enables the acceleration of life science research and development in the pursuit of improved human health. The company leverages machine learning, automation, and gene editing to build platforms for science at scale. With its foundations in engineering disciplines, the company’s platforms vertically integrate proprietary hardware, software, bioinformatics, chemistries, and molecular biology to advance life sciences from basic research through therapeutic development programs. By providing commercial and academic researchers, and therapeutic developers with unprecedented access to cutting-edge genome engineering products and services, Synthego is at the forefront of innovation in engineered biology.

To learn more, visit Synthego.com/timmerman

If you click there, you’ll learn about Synthego and help Timmerman Report along the way, so what’s not to like?

Now, please join me and Sek Kathiresan on The Long Run.

7
Feb
2021

The Variants Ratchet Up the Pressure

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07 Feb 2021

Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University

The biggest questions at this moment in the pandemic concern emerging variants.

Over the past two weeks in preprint publications, we have learned:

  • Viral antigen tests remain effective in their ability to detect cases of COVID-19 driven by new variants. New objective comparisons of viral antigen tests: Clinitest; RAY Crispr; Panbio.
  • Good news: Israel is the first real-world example of what we can expect from a mass vaccination campaign. Beginning Dec. 20 with the Pfizer / BioNTech mRNA vaccine, 89% of Israelis 60 and over had either recovered or been vaccinated through Feb. 2: early returns show 41% fewer cases, and ~50% lower mortality in that age group.
  • Single dosing of the Pfizer / BioNtech mRNA vaccine is a viable strategy in a supply-constrained world, even though the vaccine was developed to boost immunity in a two-dose formulation. For people who already have some natural immunity from a prior COVID-19 infection, a single vaccine dose could be advisable.
  • Many scientists are evaluating what the emerging strains of SARS-CoV-2 mean for control of the pandemic.
Key remaining questions include:
  • What strains are we most worried about and why?
  • Can previously infected COVID recovered individuals be re-infected by these new variants?
  • Do they threaten to derail our current testing strategies, treatment protocols, and vaccine effectiveness?
  • What should we do about them?
What strains are we most worried about and why?

A word on biology: all viruses evolve new point mutations (aka variants) all the time, and the vast majority of these reduce strain fitness. Fitness means that a particular strain outcompetes all others to become the dominant source of infection in a region. A particular strain’s fitness may be based on spreading faster or more easily and/or because it is better at escaping the immune system. 

Both of these aspects are concerning, but as we get better at countermeasures (antibody treatments and vaccines), it is immune escape that most threatens to derail our hopes for beating the epidemic.  Fitness results from the net benefit of all the underlying positive, neutral and beneficial mutations that have evolved and are packaged with a “headline” mutation. 

We tend to focus on single point differences within a strain. Currently, the greatest concern stems from the E484K mutation, (found in COVID-19 samples from South Africa and Brazil). The next most concerning mutation is known as N501Y (first identified in the UK, but present in South African, Brazilian and US strains also). In distant 3rd place, we there’s the Y453F mutation (the Danish mink strain). These new mutations have now all combined with the D614G mutation, which became the globally dominant form of SARS-CoV-2 in February 2020. 

It can be misleading to focus on single headline mutations only. For example, see a small study in the UK that found that the Pfizer/BioNTech vaccine, originally developed based on the genetic code of SARS-CoV-2 from Wuhan in January 2020, was equally effective in neutralizing a modified strain containing only the 3 key UK mutations (N501Y; A570D; del69/70).

That sounded good at first glance. But when faced with all 23 mutations present in the wild type UK B.1.1.7 variant, the Pfizer / BioNTech vaccine was 3.9x less neutralizing. Of course, we know that even a reduction of this magnitude is still highly effective in mitigating or protecting from the disease for most cases, but we do not know how much of an immune response is enough to protect individuals, or whole populations, from illness.

Carefully controlled lab tests of new viral variants against the vaccines are essential, but can be only directional guides to what might happen in the real clinical world. Unfortunately, the strains that embed the variants of most concern, are now spreading around the world and appear to be fueling recent growth waves of COVID-19, especially in the UK. 

We are in a scramble to figure out what they mean against a background of limited but growing scientific data. There is evidence that N501Y accelerates transmission by 50-70% (10x greater affinity to the ACE2 receptor on human cells reduces the viral load necessary for successful infection). Plus, early data on N501Y indicates that it also contributes to more serious disease and immune escape. E484K appears to drive immune escape more strongly than N501Y, making the combination present in the South African strain of great concern.

If we have a circulating variant that is more transmissible, causes more severe illness, and is more able to escape vaccine-induced immune responses – then we are truly up against a much more formidable virus.

Can recovered people be re-infected by the new variants?

Until the E484K variant was identified, the answer was no.Now that we see E484K containing strains in both South Africa and Brazil, the early answer appears to be yes. Before the emergence of the E484K variant, there was a consensus that for all but the immune-compromised, natural infection protected against reinfection for at least 6 months or longer. Reinfection cases had been documented, but at very low rates (e.g. 0.16% of previously COVID positive UK health workers). 

Most concerning is the emergence of a second — more lethal — wave of infection in Manaus, Brazil. The experience from Manaus implies novel spike variants can re-infect those who have recovered from the strains circulating in early 2020. Manaus is an isolated community of 2 million in the Amazon rain forest, where effective control had been achieved by May 2020. By mid-December, an estimated 76% of the population had been previously infected and was presumably COVID-immune.

But that turned out to be an illusion. In January, a more transmissible and virulent strain (P.1, a derivative of the B.1.1.28 Brazil strain) was identified, supported by a case investigation of a patient who had recovered in late March but became reinfected in December. Data are preliminary and limited, but highly suggestive that the new strain in Brazil can overcome immunity gained from previous SARS-CoV-2 infection.

Do they threaten to derail our current testing strategies, treatment protocols, and/or vaccine effectiveness?

Individual test effectiveness will have to be continuously monitored for evasion, but none of the known variants have yet had a significant impact on test accuracy since most (all of the rapid antigen tests) detect the abundant nucleocapsid protein and its mRNA. Almost none target the mutated spike regions, and very, very few focus on the spike region alone.

Variants do threaten the highly specific monoclonal antibody-based therapies. The antibodies most effective at neutralizing the virus are those directed at very specific epitopes within the receptor binding domain of the spike protein. This is a small region, and is where the variants of most concern reside. There is evidence that the SARS-CoV-2 virus is able to generate variants to escape focused antibody therapies, but since very few of these have been used clinically to date, emerging strains must have been able to develop current immune mitigation strategies (e.g. E484K) even under the much wider pressure of the immune response to natural infection. 

Current vaccines are all designed to focus on the most effective aspects of response to natural infection i.e. to the spike protein, and so there is a parallel threat that the virus will be able to evolve further escape variants as vaccination is rolled out, and puts greater pressure on the virus to adapt or die. 

Notably, Israel is providing early data that vaccines will retain substantial effectiveness – the dominant strain in Israel is becoming the UK B.1.1.7 strain, and vaccine effectiveness is already apparent, but at lower levels than in clinical trials. 

The faster we vaccinate, the less opportunity there is for escape adaptation to occur and spread.

What should we do about emerging mutations?

We need to proactively adapt our vaccine portfolio to the strain mutations that are rapidly emerging and becoming dominant, while remaining vigilant that testing targets do not mutate away from current probes and primers.

For now, it appears that current vaccines still have adequate, albeit reduced, efficacy in the face of emerging variants. However, time is not on our side – in the year it has taken for science to deploy vaccines against the original Wuhan sequence, the virus has evolved 4 novel mutations. Taken together, these mutations substantially enhance transmissibility and virulence. 

We have the ability to keep up, but only if we adopt a flu-vaccine-like timetable. In early 2020 Moderna, among others, developed their first vaccine candidate 4 days after publication of the SARS-CoV-2 genome on Jan. 12; two months later an improved candidate was beginning Phase I/II trials. The FDA granted an Emergency Use Authorization on Dec. 18.

This is light speed by the standards of prior novel vaccine approvals – a 10-year timeframe reduced to 10 months. Shortening traditional approval timelines, for new mRNA vaccine variations designed against the new variants, will be absolutely essential. A further reduction to 10 weeks or less is required to counter emerging mutations.

Safety is less concerning since vaccines will utilize unchanged packaging – this is akin to a slight modification like we see with flu vaccines each year. No major 30,000-volunteer study will be needed to demonstrate safety and efficacy. Variants require minimal changes to vaccine payloads, and testing targets. Efficacy can be monitored post-launch in a Phase IV manner since it will be reasonable to expect only improved efficacy from including novel point mutations in payload design.

The FDA sees the need for urgency. On Feb. 4, the FDA issued a statement on accelerated timetables for confronting the emerging variants – “We do not believe that there will be the need to start at square one with any of these products” (i.e. tests, therapies and vaccines). Few specifics were included, but keeping up with the variants means not only quickly adapting our vaccines, but also enhancing variant surveillance, evaluation and communication.  

We should not underestimate the degree of culture change required of both regulators and risk managers at vaccine companies if an adequately speedy response is to be successful. It’s a serious challenge. There’s no time to waste.

5
Feb
2021

Scientists Love Data – And Data Reveal Most People Prefer Anecdotes

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05 Feb 2021

David Shaywitz

The unreasonable effectiveness of personal narrative – and what it means for persuasion and health

The goal of “alternative facts,” is “to flood the zone with sh*t,” as former Trump advisor Steve Bannon notoriously explained to the author Michael Lewis. The idea is to persuade us it’s just too difficult to know what to believe about anything. 

This “manufactured nihilism,” as Vox’s Sean Illing memorably described it, enables us to default to our own instincts and inclinations. If you’re inclined to believe that COVID is a hoax, say, the consequences can be lethal.

Manufacturing nihilism isn’t a heavy lift: as economist Tim Harford reviews in his new book, The Data Detective, lots of behavioral research suggests we’re easily persuaded to doubt information we don’t want to believe.

For instance, when the tobacco industry was initially attacked after robust clinical data demonstrated their product was deadly, for instance, it launched a deliberate public relations campaign to muddy the water. The facts were uncertain, the companies argued.

Many dedicated smokers, sadly, were all too eager to believe this fundamentally bogus message.

*****

As if facts weren’t in enough trouble already, new research, published in January in Proceedings of the National Academy of Sciences (PNAS), demonstrates that when it comes to moral or political issues, we are more likely to respect an argument based on personal experience than one rooted in data. 

“In moral disagreements,” the authors report, “experiences seem truer than facts.” 

They continue,

“Across many studies, basing one’s stance on personal experiences (versus facts) seems to make people appear more rational to opponents.  We suggest that this effect is because personal experiences are unimpugnable; first-hand suffering may be relatively immune to doubt.”

Especially as a scientist, it’s hard not to feel demoralized by these results. A cornerstone of science is the importance of not confusing anecdotes with data – you can actually buy a “scientist shirt” on Amazon bearing the motto, “The plural of anecdote is not data.” 

Yet now scientists have data demonstrating that anecdotes tend to be more persuasive.   

Adding insult to injury, the final experiment reported by the researchers compared a subject’s reactions to: 

  • a layperson sharing a personal anecdote
  • a scientist reporting data
  • and a layperson reporting facts

The result?

“[P]articipants saw the personal experiences of the layperson as the ‘truest,’ followed by the scientific research, and then facts provided by a layperson. That people see one person’s anecdotal experience as truer than the conclusion of scientific research is striking.”

Striking, and also scary, because it means truth is effectively defined by the most compelling personal story.

*****

In The Black Swan, Nassim Taleb introduces us to “narrative fallacy,” a cognitive deception “associated with our vulnerability to overinterpretation and our predilection for compact stories over raw truths.”

It’s hardly news that we are drawn to stories, of course. But motivated by behavioral researchers such as Daniel Kahneman, we’ve started to quantify the remarkable strength of this attraction, and to reach for a more productive response than casual despair.

The power and relatability of anecdote might be used to bridge divergent perspectives, the authors of the January PNAS paper write, noting their results can be read as offering guidance for engaging those who are on the opposite side of fraught issues.

Rather than trying to lead with facts, the authors suggest, “personal experiences might be deployed early in conversations to first build a foundation of mutual respect, and then facts could be introduced as the conversation moves to policy specifics.”   

A similar strategy was used in the 2020 election by Republican Voters Against Trump (RVAT), which sought to encourage GOP defections not by presenting data on, say, the deficit under Trump or the number of lives lost to COVID, but rather, by letting people tell their own stories. RVAT encouraged disaffected Republicans to upload raw video selfies – relatable and compelling personal stories about why they opposed Trump. RVAT would then curate and promote the best videos, in hopes that these personal anecdotes would resonate with other disaffected Republicans. 

*****

It’s hard – especially as a scientist – to escape the sense that persuasion should be based on a common set of facts and shared standards for evaluation – the premise of the scientific method – rather than accessible anecdotes. Yet at a time when a quarter of unvaccinated adults say they don’t want to get immunized, and most Republican voters continue to insist the election was stolen – it’s clear that facts alone aren’t cutting it.

Purists may need to take a page from the RVAT playbook, and lean into personal narratives to convey the vital lessons suggested by the data.

Perhaps some Republicans would be moved by the raw, personal stories of Trump-leaning state election workers — ordinary people — who describe their own, meticulous efforts to ensure the vote was free and fair, even if they were disappointed by the outcome. 

Similarly, efforts to encourage vaccination will need to go beyond the recitation of the (extraordinarily reassuring) safety and efficacy data, especially given the tendency of any rare adverse event to be widely publicized by the media and amplified by critics. 

To counter this, a marketing expert advised in a recent New England Journal of Medicine,

“[V]accine communications teams should proactively spread their own ‘cases’ in addition to statistics. News briefings or websites could include real individual success stories — a Georgia family going out for ice cream after being vaccinated, perhaps, or Indiana retirees joyfully visiting neighbors 10 days after receiving the vaccine. Such stories, however banal, can help counteract the shock value of a few bad-effect stories.”

At best, these approaches are likely to change only a few minds. It’s notoriously difficult to move people off the comfort of their prior assumptions. 

But even a few percentage points can make a big difference, both in deciding a close election and in blunting the spread of a deadly contagious virus.

If leaning on stories feels unseemly or unscientific, remember that if you want to persuade skeptics, the data are clear: in a world of alternative facts, the personal narrative is king.

4
Feb
2021

The Insurrectionist and the Visionary

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04 Feb 2021

Luke Timmerman, founder & editor, Timmerman Report

One photograph captured our contradictions on Jan. 6.

There was the man carrying the Confederate flag where it had never flown before – inside the US Capitol.

A violent mob, carrying symbols like that and worse, sought to assassinate elected officials and overthrow our democracy. They were sent there by other elected leaders who were telling lies.

It was horrific.

But look closer at the photo. There’s a portrait on the wall of a true American visionary — Justin Smith Morrill.

Kevin Seefried holds a Confederate flag outside the Senate Chamber during a riot in the U.S. Capitol on Jan. 6. (Associated Press)

Who?

US Rep. Morrill, from Vermont, was a founding member of the Republican Party. His signature achievement was the Land Grant College Act of 1862, also known as the Morrill Act. The law allowed proceeds from federal land sales to benefit states. The states, the ones still in the Union at the time, could use the bounty to start up technical and agricultural colleges. The law contained a community outreach component, and Reserve Officer Training Corps (ROTC) programs for decentralized military training across the states.

The bill had stalled for years in Congress, but was finally passed at the height of the Civil War. It was signed into law by President Abraham Lincoln.

This turned into one of the best investments in American history. MIT, Cornell University, the University of Wisconsin-Madison, University of California-Berkeley, and Michigan State University are a few of the outstanding education and research centers that owe their existence to this act (see map). Years after the war, former Confederate states were able to participate, as were the Historically Black Colleges and Universities.

Institutions established under the Morrill Act of 1862, and its subsequent expansions in 1890 and 1994.

 

These institutions, more than 150 years later, are integral parts of the country we inherited. The land grant universities are engines of research, teaching, education, community outreach, and economic development in all 50 states. They created — and continue to create — a national talent pool for science, engineering, and agricultural disciplines.

This investment, more than any single initiative, set the stage for the US to build the world’s leading network of research universities. When the NIH and NSF and Defense Department research agencies hit their stride after World War II, they were positioned to send grant dollars flowing through this pre-existing network.

It was like running semi-trucks full of equipment down an Interstate highway that someone had already thought to build.

The knowledge-based industries the US dominates today – tech and biotech – can trace their origins to this series of investments.

Yes, it’s hard to be a determined optimist these days. It’s hard to think about investing big for the future in a country this divided. We have 450,000 dead in the pandemic, and more than 3,000 deaths a day. Millions more are suffering mentally, physically, economically, and spiritually. We must vaccinate about 80-90 percent of a nation of 330 million people, jump start the world’s largest economy, and get serious about creating a more fair, decent and humane society. Then we have to confront the threat of future pandemics, and get serious about climate change.

But look at what Justin Smith Morrill and his contemporaries were up against. They had to win a brutal war that left 700,000 dead, while holding the Union together, ending slavery, rewriting the Constitution with the 13th, 14th and 15th amendments, and sending in federal troops to enforce the rule of law in the former Confederate states.

Even with so many fires to put out at once, the leaders in that generation thought in expansive terms.  

We are at our best when thinking along these lines. We have reason to believe it can be done, even under the hardest of circumstances.

  • We won World War II, and in the process, built an enduring competitive advantage in science and technology
  • The US government conceived and executed on the Apollo program during the civil unrest of the 1960s
  • We used federal research funding, through DARPA, to catalyze the development of the Internet
  • We spearheaded the Human Genome Project, accelerating the biotech revolution
  • We invented COVID-19 vaccines from scratch, with government researchers and industry partners working together, in less than 12 months
  • We have the world’s best health agencies – the NIH, FDA and CDC. These are the exemplars every other country either aspires to copy or follow. Despite recent blunders, this is still true.

For Republicans who may be skeptical of those agencies above, take a look at our national security apparatus.

For instance, in October 2013, the Defense Advanced Research Projects Agency (DARPA) made a $25 million grant to a little startup called Cambridge, Mass.-based Moderna Therapeutics. The objective was to support mRNA vaccine development for pandemic preparedness.

I interviewed CEO Stephane Bancel. At the time, I wrote:

“By making this grant, [DARPA] is betting on what could become a superfast, cheap, and unusually adaptable method for fighting today’s known pandemic threats, and the unknown threats of the future.”

The US government was prescient. Moderna wouldn’t be where it is today without DARPA and the NIH supporting it every step of the way.

So what can we do now, besides the obvious things the President and leaders in Congress are working on?

  1. We can triple the NIH budget over the next decade. This would be a strategic investment at a moment of biomedical possibility, and it would be done at a scale that is beyond the scope of any entity other than the US government.
  2. We can shake up the FDA. It needs to be restored as the world’s best public health regulatory agency, one that thoughtfully facilitates the creation of safe and effective medicines that unleash human productivity. Here, the industry has a clear voice through renegotiating the Prescription Drug User Fee Act (PDUFA), that comes due in September 2022. Let’s re-think regulatory frameworks for things like master protocols and adaptive designs. Let’s invest in studying technology-enabled biomarkers from real-world experience of patients who carry smartphones, as part of a push to reinvent the R&D enterprise with leaner and meaner clinical trials. If we’re willing to spend some money, and able to attract the right leadership, we’ll create an FDA that can operate at the speed and scale necessary to keep up with industry, and keep up with health needs.
  3. We can build up our community colleges with programs in advanced biologics manufacturing, where there’s a need for domestic skilled labor. If we’re serious about filling a pipeline with people who seize these opportunities, we’ll bolster our support for K-12 public schools.

Our failure to invest in young people is mind-boggling.

Consider a 2017 report from the Pentagon. It says that 71 percent of Americans ages 18-24 are ineligible to serve in the US military primarily because of three reasons: obesity, failure to graduate from high school, or a criminal record.

“This is a very real risk to our national security,” said Steve Doster, Pennsylvania State director of Military Readiness for Council for a Strong America, told the York Daily Record in 2019.

It’s also a sign of a country struggling with apathy. Our young people are yearning for purpose and hope. We’ve seen in other countries what happens when young people are hopeless. They turn to violent extremism, or surrender, living in fear of authoritarian leaders.

Biotech, as I wrote here last month, is shining with possibility amid the darkness. It’s one of the bright spots in the US. It’s why I think this industry needs to shine that light as far and wide as possible.

Those of you in industry can share the wonder and joy of discovery, especially with underserved communities that are full of untapped human potential. If kids in middle school and high school knew a fraction of what’s happening in biomedicine today, and they could pursue advanced study without taking on a mountain of debt, they’d tune in. (Life Science Cares is a terrific organization that connects biotech companies with nonprofit partners that advance education, and anti-poverty work.)

Too many people have given up on the American dream. We need to shake off the malaise. We should know our history, and never forget where our amazing scientific enterprise comes from.

 

Science of SARS-CoV-2

  • Single Dose Administration, And The Influence Of The Timing Of The Booster Dose On Immunogenicity and Efficacy Of ChAdOx1 nCoV-19 (AZD1222) Vaccine. Preprints with The Lancet. Feb. 1. (Merryn Voysey et al University of Oxford – Oxford Vaccine Group)
  • Learning the Language of Viral Evolution and Escape. Science. Jan. 15. (Brian Hie et al at MIT)
  • SARS-CoV-2 Infects and Replicates in Cells of the Human Endocrine and Exocrine Pancreas. Nature Metabolism. Feb. 3. (Janis Muller et al)
  • Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. The Lancet. Feb. 2. (Denis Logunov et al)
  • Age groups that sustain resurging COVID-19 epidemics in the United States. Science. Feb. 2. (Melodie Monod et al Imperial College London)
  • Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response. Cell Host and Microbe. Jan. 29. (Jing-wen Lin et al)

Vaccines

Access and Distribution

Genomic Surveillance

Features

Personnel File

Merck CEO Ken Frazier announced he plans to retire June 30, 2021 after a decade in the job. He will continue as executive chairman. Robert Davis, the current CFO, will become president in April and CEO on July 1 as part of the transition process. (See Matt Herper’s STAT article on Frazier’s career).

Merck said Stephen Mayo, a professor of biology and chemistry at Caltech, is joining the board of directors Mar. 15.

Ramona Sequeira, president of Takeda Pharmaceuticals USA, is the new chair-elect of PhRMA. She will be the first woman to serve as chair of PhRMA. She will replace Eli Lilly CEO Dave Ricks in that role next year. Novartis CEO Vas Narasimhan was elected to serve as PhRMA board treasurer.

Germany-based Merck KGaA said Rehan Verjee, the president of EMD Serono and head of innovative medicines, is leaving the company for a new job to be announced. He’s being replaced by Andrew Paterson.

South San Francisco-based Twist Bioscience, the DNA synthesis company, announced a series of promotions. Siyuan Chen was promoted to chief technology officer and Aaron Sato was promoted to chief scientific officer. Paula Green was promoted to senior vice president of human resources, and Angela Bitting joined the company as senior vice president of corporate affairs.

Cambridge, Mass.-based Scholar Rock announced a string of promotions, including Gregory Carven’s promotion to chief scientific officer.

Cambridge, Mass.-based Revitope Oncology, a cancer immunotherapy company, added Louis Lange to its board of directors. He’s a general partner at Asset Management.

Cambridge, Mass.-based TCR2 Therapeutics named Shawn Tomasello to its board. She has a 35-year track record in commercial operations and medical affairs, including time at Pharmacyclics, Celgene and Genentech.

Cambridge, Mass.-based Moma Therapeutics named Asit Parikh as its new CEO. It’s a precision medicine company backed by Third Rock Ventures.

Burlingame, Calif.-based Lyra Health, the provider of mental health care benefits for employers, added Danielle Gray to its board of directors. She is senior vice president, chief legal and administrative officer for Blue Cross and Blue Shield of North Carolina.

Katie Porter’s Swing-and-a-Miss

Rep. Katie Porter of California is a smart progressive and a formidable prosecutor. I cheered when she grilled former Celgene CEO Mark Alles about that company’s unjustifiable price increases for Revlimid. He deserved a public dressing down after getting wealthy while running the company into the ground. Rep. Porter is channeling much of the frustration people have with our current form of capitalism, which punishes people who follow the rules and rewards the lying, cheating and stealing.  

But Rep. Porter issued a 16-page report on mergers and acquisitions in biopharma late last week that was an oversimplified rant that won’t do anyone any good. She called it a “bombshell” report on how M&A stifles innovation.

This report is actually a swing-and-a-miss.

Porter used the Amgen-Immunex acquisition of 2002 as a case study. I covered the Amgen-Immunex deal day-by-day for The Seattle Times. It was a fascinating, nuanced story. Porter’s team interviewed a number of former Immunex employees. They rightly complained about how the vibrant scientific culture at Immunex got smothered. But Porter missed some crucial context to understand the situation. She failed to mention that Immunex screwed up manufacturing. It couldn’t make enough etanercept (Enbrel) to meet the demand from rheumatoid arthritis patients. They left tens of thousands of patients in the lurch, struggling in pain. That fiasco depressed its stock, making it vulnerable to takeover.

Amgen, arrogant and stifling as it was in many ways under CEO Kevin Sharer, was able to fix the manufacturing supply problem in short order. Patients were better served by having Enbrel in its hands. And Amgen, over time, was able to combine some IP with Immunex that led to the development of denosumab (Prolia) for osteoporosis and (Xgeva) for bone metastases.

In the big picture, is M&A good for innovation? I’m no fan of megamergers like BMS-Celgene, because they create organizations so big it’s hard for anyone to do nimble, innovative work. But most deals aren’t like that. Often, but not always, a new product is better off in the hands of a big company. Small companies and their investors also need to know there’s a strong incentive, a pot of gold at the end of the rainbow, if they’re going to invest and do the risky, innovative work in the first place. As John LaMattina rightly pointed out in Forbes, the Pfizer / BioNTech partnership in mRNA vaccines is a great example of different kinds of players playing to their respective strengths. Neither the big company or the small company could have made the vaccine alone. It took both entities, working together, to pull off that historic feat.

The Federal Trade Commission needs to have clear and consistent criteria for when to bring antitrust cases, like when a merger is really about snuffing out competition or depressing innovation to protect an existing franchise. FTC prosecutors need to exercise good judgment on when to take action. Members of Congress should provide oversight and accountability.

Rep. Porter, instead of painting in broad brushstrokes about the ills of M&A, would be wise to leave this work to the FTC. We don’t need more complex issues like this reduced into dumbed-down left-right food fights. That sort of thinking has done a lot of damage already.

Deals

Jazz Pharmaceuticals agreed to pay $7.2 billion to acquire London-based GW Pharmaceuticals, the marketer of cannabidiol oral solution (Epidiolex) for epileptic seizures. The deal includes $200 a share in cash and $20 in Jazz ordinary shares.

Gilead Sciences agreed to work with Gritstone Oncology to use the smaller company’s vaccine technology to work on an HIV cure. The plan is to develop a prime-boost product “comprised of self-amplifying mRNA (SAM) and adenoviral vectors, with antigens developed by Gilead.” Gritstone is getting $30 million in cash and $30 million in an equity investment from Gilead.

South San Francisco-based Veracyte agreed to acquire San Diego-based Deciphera Biosciences for $600 million — $250 million in cash and up to $350 million in stock. The deal strengthens Veracyte’s position in genomic diagnostics for cancer, and provides a foothold in another biotech talent pool.  

GSK and Germany-based CureVac agreed to work together on multi-valent mRNA vaccines for COVID-19, which hopefully will be able to address multiple variants in a single vaccine. The deal is worth 150 million Euros, and GSK said it will support manufacturing of 100 million doses in 2021.

Horizon Therapeutics agreed to acquire Gaithersburg, Maryland-based Viela Bio for $3.05 billion or $53 a share.

Bristol-Myers Squibb agreed to in-license a COVID-19 treatment composed of two monoclonal antibodies from Rockefeller University. The dual antibody treatment is designed as a longer-lasting subcutaneous formulation, that is supposed to be more suitable to give to non-hospitalized patients than earlier antibodies that are given intravenously.

Redwood City, Calif.-based Coherus Biosciences paid $150 million upfront to Shanghai Junshi Biosciences to obtain US and Canada rights to a late-stage PD-1 inhibitor, toripalimab. Coherus also obtained an option to Junshi’s TIGIT and IL-2 drug candidates that could be used in combination.

A group of more than a dozen pharma R&D leaders have formed a new COVID-19 R&D alliance.

Financings

ARCH Venture Partners raised a new fund with $1.85 billion to create and finance new biotech startups. ARCH listed a long list of interests for this new fund — infectious disease, mental health, immunology, oncology, neurology, manufacturing, clinical trials, anti-aging medicines, genomic and biological tools, data sciences, and ways of reimagining diagnostics and therapies. 

Abingworth raised its 13th biotech fund, Abingworth Bioventures 8, with $465 million to invest. It has already made three investments in the new fund, including one in gene therapy company Atsena (profiled in TR, December 2020)

Seattle-based Sana Biotechnology raised $588 million in an IPO of 23.5 million shares at $25 a share. Initial valuation: $4.9 billion. The cell therapy company is still in preclinical development. It’s the largest preclinical stage IPO ever. Shares climbed another 40 percent in first-day trading to close at $35.10.

Boston and Rockville, Maryland-based Sensei Biotherapeutics, a cancer drug developer, raised $133 million in an IPO at $19 a share.

Watertown, Mass.-based EyePoint Pharmaceuticals raised $100 million in an IPO at $11 a share. The company is developing a treatment for the wet form of age-related macular degeneration.

23andMe, the consumer genetics company, went public through a SPAC sponsored by Richard Branson’s Virgin Group. The deal comes with $759 million of proceeds ($509 million in cash, plus a $250 million private placement), and pegs the company’s enterprise value at $3.5 billion.

Blacksburg, Virginia-based Landos Biopharma raised $100 million in an IPO priced at $16 a share. It’s working on treatments that work on novel mechanisms for autoimmune diseases. The lead candidate is for ulcerative colitis and Crohn’s disease, and targets the LANCL2 pathway.

Biogen said it’s issuing $1.75 billion in debt.

Billerica, Mass.-based Quanterix, which does digital biomarker analysis for precision health, raised $200 million in a stock offering.  

Redwood City, Calif.-based Revolution Medicines raised $261 million in a stock offering at $45 a share.

Lexington, Mass.-based Kaleido Biosciences raised $60 million in a stock offering at $11.50 a share.

Regulatory Action

Biogen and Eisai said the FDA has extended its review of the Alzheimer’s drug aducanumab by another three months, to a review deadline of June 7.

The FDA cleared tepotinib (Tepmetko) from Merck KGaA as a new treatment for metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

RIP

Dr. Emil Freireich, a pioneer of treatments for children with leukemia, died at age 93. (USA Today obituary)

Andrew Brooks, the Rutgers scientist who developed a quick saliva-based test for COVID-19 in the early days of the pandemic, died of a heart attack at 51.

1
Feb
2021

2021: The Rise of the Variants

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01 Feb 2021

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

This column will have a “glass half full / glass half empty” feeling for many readers, I fear.

Before diving deep into the troubling emergence of highly transmissible and virulent SARS-CoV-2 variants, a couple of brief reminders:

  • Immunology is very complicated: for the uninitiated, please read this (always impeccably well written) piece by Ed Yong in The Atlantic.
  • We still lack *a lot* of information about the virus and the immune response to it. We don’t yet know the relative role of antibody vs. T-cell responses in long-term protection against the virus. We don’t yet know whether vaccinated people are still capable of transmitting the virus to others. We know barely anything yet about the phenomenon some call “Long COVID.”

Science is moving very fast indeed, and it must continue at this relentless pace because we still have much to learn.

To drive this point home, allow me to relay a personal anecdote. I was asked to opine if it was safe for a pregnant woman (friend of a friend) to receive one of the mRNA vaccines currently being distributed in the US (she is in her third trimester). After many obvious and obligatory caveats (I am not an MD, and *definitely* not an ob/gyn, nobody should listen to me for medical prescriptions, etc etc), I mentioned that, yes, mRNA vaccines do elicit a strong immune response (the main goal with any vaccine), but that I suspect the potential risk of harm to the fetus was indeed very low (though not zero).

Two days later, WHO issued guidance “recommending generally against the use of the vaccine during pregnancy except for those at high risk of exposure or having a severe case”… Indeed, neither the ModeRNA nor the Pfizer/BioNTech mRNA vaccines have been tested so far in this population (there are plans to do so shortly). If I could print here the faceplant emoji, I would.

The WHO guidance isn’t based on any data from vaccine trials, as far as I can tell, but more out of an abundance of caution. That said, this is not straightforward, since pregnant women appear to be at higher risk of contracting severe cases of COVID-19 as well as (possibly) having a higher risk of preterm delivery (incidentally, the CDC has maintained that pregnant women should get vaccinated).

So, we still have a lot to learn. And we need to remain humble about how much we still do not (yet) know.  

Some Good News

In the US, after the rise in cases and fatalities derived from Thanksgiving and Christmas mingling, we seem to be turning the corner (all the graphs below from @COVID19Tracking). It’s yet another reminder that strict Non-Pharmaceutical Interventions (NPIs) — that we knew worked 100 years ago — are still effective in preventing viral spreading via the respiratory route (see, for example, how flu transmission has basically been wiped out this season).

As you can see, cases / hospitalizations are coming down (though from what is an exceedingly high level): cases are definitely trending down and are ~40% below the recent peak in early-to-mid January; hospitalizations are also ~30% down from peak. Tragically, deaths remain extremely elevated at >3,000/day, and will continue to be for several (2-3) more weeks: yet another reminder that deaths are a lagging indicator resulting from infections that occurred ~4-6 weeks prior. The country will soon surpass the sober milestone of >500,000 overall fatalities.

That said, we should expect COVID-19 deaths to begin trending down soon-ish (never soon enough), assuming we continue to behave responsibly (more on this later). Encouragingly, the US administration communication policy has taken a U-turn versus the previous one (even the CDC, under new leadership, has *finally* issued a mask mandate for people using planes, trains and other public transportation).

Another, unabashedly positive piece of news: we now have positive results from two more vaccines, J&J’s and Novavax’s. This is in addition to a slew of data showing several antibodies (from Lilly and Regeneron: alone and in combination) are also extremely effective at preventing deaths and reducing hospitalizations, or in reducing overall infections within the first week, with 100% prevention of symptomatic infections.

At least one study (Regeneron’s) shows markedly decreased levels / duration of viral shedding in the asymptomatic infections that occurred in the treatment group. Of course, these antibodies need to be given at the right time, prior to hospitalization, and that’s a tricky thing for an intravenous medication (though subcutaneous formulations are in the works). But still, these are important medicines.

In case it needed to be said (again), the biotech / pharma industry is rallying at unprecedented scale and speed to provide a solution to this pandemic. What are GameStop or AMC doing in comparison??

For how I see future treatment regimens (vaccines vs antibodies vs antivirals etc), I will direct you to the “Forecasts” section of this column (at the end).

Back to the (new) vaccine data: I would like to make several (non-mutually exclusive) observations (starting with the inevitable request to compare the different vaccine results):

  1. As eloquently said by Kai Kupferschmidt (@kakape), as well as several other commentators, it is really not possible to compare vaccine efficacy (mRNA-based vs Novavax or J&J) with the data at our disposal (so, please: stop asking!): the mRNA vaccines were tested early on, in places lacking the variants which are circulating right now. Had they been tested in those conditions, results might look different (or perhaps much the same: we really don’t know). The headline vaccine efficacy rates that you read in the news (50% vs 80% vs 95%, say) relates to the protection conferred against infection: however, what matters *most*, as Dr. Ashish Jha (dean of Brown University’s School of Public Health) rightly said recently to the NYT: “I don’t actually care about infections. I care about hospitalizations and deaths and long-term complications.” Which brings me to:
  2. In the >70,000 people having received one of these 5 vaccines in controlled clinical trials, *including in geographies where the new variants are present / spreading*, as far as I can tell, there have been 0 hospitalizations / fatalities from COVID (as well as, and this bears repeating, 0 fatalities from the vaccine): basically, ALL of these vaccines work very well in preventing deaths and even severe illness (these events are measured after vaccines have had a chance to work, typically 14 days after the first shot). Even after you receive a vaccine (lucky you, BTW), you should still endeavor to behave responsibly: we do not yet know if a vaccinated person could continue spreading the infection once contracted (I know, I already said that not half a page ago, but it is worth repeating). For an example on vaccine protection, check out this thoughtful Twitter thread from Helen Branswell at STAT News on the J&J vaccine.  
  3. In an immunologically naïve population to this virus, administration of *any* efficacious vaccine helps to increase overall population immunity. Looking at the severe manufacturing / supply chain limitations to make vaccines available to the entire world’s population, it is extremely encouraging to see the entire pharmaceutical industry joining forces to bring more manufacturing capacity online (to name but a few examples, Novartis will assist in manufacturing Pfizer/BioNTech vaccine, Bayer just announced a collaboration to increase Germany-based CureVac’s mRNA vaccine supply in 2022, etc.). I will continue to state that *everybody / everywhere should get vaccinated as soon as feasible, with whatever vaccine* available in their locale. This is also extremely important in limiting the emergence / spread of new variants (see, again, below): as Dr. Anthony Fauci just stated, “the fundamental principle of getting people vaccinated as quickly and as efficiently as you possibly can” is because it’s the “best way to prevent the further evolution of any mutation”.
Some Very Concerning News: Viral Variants Emerging

The table below (source: https://cov-lineages.org/global_report.html) shows some information about the currently-known viral variants that are spreading in different geographies: for the non-geeks/amateur virologists amongst you, B.1.1.7 is the “UK variant”, B.1.351 is the “South African variant”, and P.1 is the “Brazilian variant”.

You have likely been hearing about those variants quite a bit, so will spare you a lengthy and geeky discussion. If you really want to go deep into the rabbit hole, this thread from eminent virologist Florian Krammer (@florian_krammer) does a pretty amazing job.

Here are some broader thoughts that should worry you, hopefully arranged in some sort of logical order:

  1. First and foremost, this pandemic is happening in unprecedented conditions. As I discussed recently with a friend from the pandemic response frontline, there is likely no precedent to this in humanity’s history: with so many individuals infected at the same time, and with widely available mass transportation / (fast) travel amongst regions / continents. As a (very rough) calculation, there have been ~100M confirmed infections to date worldwide. Knowing that there was very little diagnostic capacity (criminally so in the US) in the early phases of the pandemic, and that it is still the case in large countries / continents (there is practically 0 screening ongoing in India and the African continent, for example), it is probably safe to assume >500M people have been infected in the course of the last 10 months or so (out of a global population of ~8 billion). Worryingly, there seems to be evidence that people can be re-infected with some of the new variants (see Novavax results in South Africa and Brazil data below).
  2. The UK variant, for example, is very transmissible indeed (we do not yet know about the others, but I suspect they are too): starting from a “Wild Type” virus isoform that already has an R0 well in excess of 2 (vastly exceeding flu), B.1.1.7 seems to add an additional 40-60% increase in infectiousness. For a viral pandemic spreading at an exponential rate, adding a compounding 40%+ increase in transmissibility is scary. The UK variant has so far managed to colonize the landscape wherever it is present in a very short time (the curves for diffusion of that variant in Ireland and London are practically vertical). This leads to a much higher number of infected individuals in a shorter period of time, thereby leading to (many) more hospitalizations / fatalities. Hospitals simply cannot keep up with a virus that spreads this fast. The data on disease severity with this variant aren’t yet conclusive, but it appears (caveat emptor applies here) that this variant does not seem to cause more severe disease per se: so, perhaps this variant has evolved to increase the amount of viral shedding after infection.
  3. As of this writing, 11 cases of the South African variant have been discovered in England as well, without any direct links to its country of origin. And we are only aware of it because England is responsible for ~50% of all viral genomes sequenced to date! Not to state the obvious, but the fact that the variant was originally discovered in samples from South Africa, does not mean it *started or even stayed* in South Africa. So it’s a bit misleading or unfair to call it the “South Africa variant.” Just as the first variants of the virus arrived in the US from multiple countries, not just from China, the South African variant has likely been circulating in Africa and other countries for a while. Banning travel from Brazil, South Africa, and England like the US did on Jan 26 to limit variant transmission is helpful, but you need to assume that these variants have already been spreading quite widely in the US in the meantime. Very few countries, with the exception of the UK as stated, are properly tracking these variants with the right sequencing / surveillance efforts: which, in the case of a country as technologically advanced and wealthy in the US, is another example of failed leadership.
  4. Incidentally, “vaccine nationalism”, while understandable, is ultimately self-defeating and dangerous: prioritizing vaccine supplies to developed / rich countries and letting the virus continue to expand and mutate in developing countries will condemn us to endless cycles of epidemic localized flare-ups (with associated lock-downs etc) and having to continuously play catch-up by having to adjust vaccine composition and booster shots. It’s in everyone’s interest to vaccinate as much of the world as possible, as fast as possible.
  5. All the variants (particularly so for the South African and Brazilian variants), have a large number of mutations, several of which are shared. “Immune escape” studies have not yet been performed against the Brazilian variant: however, a number of clinical studies and preclinical experiments (too long to list here) have been performed against the South African variant. These studies strongly suggest that variant has evolved to “evade” the immune system (or, at least, a part of it): see, for example, for the Regeneron antibody cocktail, and for the recent Novavax results. The Novavax results are quite interesting (in a horror-movie kind of way): they report that >50% of UK cases resulted from the B.1.1.7 variant (did I not say it was very transmissible?). Looking at their trial results in South Africa, 90% of the cases in trial were caused by B.1.351, and vaccine efficacy in preventing infection there dropped to 49% (remember what I said above about how efficacy is measured in these trials, though). That strongly suggests: a) the virus variants are evading the immune system, and b) “prior infection with #COVID19 may not protect against subsequent infection by the South Africa escape variant”, as mentioned by the Novavax press release. Likewise, ModeRNA showed a 6.4x drop in neutralization against the South Africa variant in their publications.
  6. Now for the really scary stuff: as highlighted in this Lancet article, in Manaus (Brazil, in the Amazon forest), blood donor data “indicated that 76% … of the population had been infected with SARS-CoV-2 by October, 2020… The estimated SARS-CoV-2 attack rate in Manaus would be above the theoretical herd immunity threshold (67%), given a basic case reproduction number (R0) of 3.4”. However, even after this much progress toward herd immunity, there was a substantial, abrupt increase in COVID-19 related hospital admissions in Manaus during January 2021 (while, after the previous epidemic peak of late April, 2020, hospitalizations had remained stable / fairly low from May to November, despite the relaxation of COVID-19 control measures during that period). The paper is worth a full read, but I would indicate here that a) the P.1 lineage was first discovered in Manaus; b) this variant reached a high frequency (~40%) in viral genome samples from COVID-19 cases in December, 2020, but was absent in samples collected between March and November; c) the P.1 variant shares several independently acquired mutations with B.1.1.7 and B.1.325 circulating in UK and South Africa.
Forecasts
  1. I believe the virus is here to stay (see Pfizer CEO’s interview with Bloomberg BusinessWeek). We messed up: early on, we should have gone for *maximum* suppression of the spreading, like China did, instead of this endless whack-a-mole cycle of lock-downs / reopenings. Masks should have been (and still should be) mandatory. And I mean, N95 masks: the new variants make fabric masks almost (not entirely) useless.
  2. That said, currently available (for those of you lucky enough) vaccines seem to protect strongly against severe disease, even from some of the new variants. We have other tools that are also reducing disease severity in at-risk populations (antibodies and, it is to be hoped, orally-available antivirals). There, we also messed up: funding went mostly and foremost towards vaccines, neglecting antivirals, diagnostic capacity (more on this below) and increasing manufacturing of material needed for non-pharmaceutical interventions (masks etc).  
  3. Therefore, the first order of business is to continue to massively expand manufacturing capacity and ensure everybody is vaccinated (including in developing countries) as soon as possible. One scenario I am extremely concerned by, especially in 3-4 months as we enter spring in developed countries in the Northern Hemisphere, is the one highlighted by Prof Drosten from Charite in Berlin: namely, that “once the elderly and (maybe) part of the at-risk groups have been vaccinated, there will be immense economic, social, political and perhaps also legal pressure to end the (restrictive) corona measures. And then, huge numbers of people will become infected within just a short amount of time….” Politicians and lobbyists / interest groups are not very well equipped to listen to public health advice in a pandemic, especially after one exhausting year of isolation for the elderly and at-risk groups.
  4. However, vaccines will perhaps, if not very likely, not be enough. We need to stop thinking of them as the silver bullet, and start thinking of them as a (necessary, invaluable) weapon in the armory. Many other weapons need to be developed and improved. If any of you has any political connections, please spread this far and wide:
    1. A comprehensive, clear communication policy continuously explaining that non-pharmaceutical interventions are effective (even against the new variants);
    2. Prepare the research / development / regulatory / manufacturing / distribution infrastructure for the potential scenario of yearly COVID vaccinations (like for flu, and perhaps even combining it with flu); and
    3. Very importantly: we need to stop flying blind: we need to step up genomic surveillance of viral spreading, at the community level (sewage wastewater testing, for example) as well as at the individual level (people need to be able to get fast and reliable, PCR-grade testing at airports and other potential transportation hubs).

I leave you with a mixed message: it is stunning what human ingenuity has achieved in such a short period against this pandemic. Vaccines (and other pharmaceutical interventions) are a necessary, but not sufficient component of the effort to overcome it. Public health measures, improvements in logistics / vaccine distribution, broad / fast genome surveillance, and many other measures are also necessary.

That’s because — and it pains me to say this — this pandemic really is but a dress rehearsal. Viruses and other infectious diseases are humanity’s oldest and strongest enemy.

We need to win this battle and prepare for the inevitable, bloodier wars that are surely coming.

Postscript

[Added: 9 am ET Feb. 2] Within hours after this column went to “print,” there is now evidence that the UK variant B.1.1.7 has picked up the E484K mutation (linked to some degree of ability to evade the immune system in the South African and Brazilian variants):  and for a more thoughtful / full thread, please check out this from @kakape. This is pure speculation at this stage, but it feels sensible to infer that this viral mutation confers an evolutionary advantage in populations with some degree of existing immunity (UK, South Africa and Brazil were hit extremely hard in the first wave of infections in the Spring of 2020).

I will leave you (again) with this quote from Kai Kupferschmidt: “this virus is telling us again and again, that it will gladly take any opportunity we allow it of spreading and replicating to evolve and make our lives even harder.”

In retrospect, I now wish that the entire planet would have gotten into a synchronized and strictly enforced lockdown for 3 weeks or so in early March…

31
Jan
2021

The Evolving Virus Against the Vaccines

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31 Jan 2021

Larry Corey, MD

For about a month, we were lulled into thinking we had turned the corner and were winning the battle against the virus.

With 95% effectiveness in preventing COVID-19 illness and nearly 100% efficacy in preventing severe disease, we just needed to mass produce these wonderful mRNA vaccines developed by Pfizer / BioNTech and Moderna. Then we could bring an end to this nightmare in a few months.

This illusion can now be called a delusion. We are in a new phase.

Our South African brethren have pointed the way. They had the foresight to set up a genomic surveillance system in a systematic, regionalized way to see how the virus was mutating day by day. This is the way molecular epidemiology and pandemic control should be undertaken.

What they’ve learned has been disturbing. They detected incredibly sudden changes in the virus’s mutational pattern. These were not single nucleotide changes of little consequence. These were multiple sudden changes to the viral RNA code that caused significant structural alterations to several areas of the spike protein on SARS-CoV-2. This has set off alarms in the scientific community. The spike protein is the structure that makes the vaccines work.

The changes we’ve witnessed were in regions of SARS-CoV-2 that were stable over the past year. The mutations were particularly concerning because they affect the Receptor Binding Domain (RBD), which defines the part of the spike protein where the virus attaches to the ACE2 receptor in human cells.

The current vaccines elicit neutralizing antibodies to the Receptor Binding Domain. Some of these mutations look so unusual, that scientists began to wonder whether the antibodies induced by the original vaccines can still bind and neutralize as intended. Might this new Receptor Binding Domain structure resist all neutralizing antibodies, from either natural infection or from vaccine-induced immunity? We’ve had to ask and answer that question. There are also changes to the viral RNA that encodes for another area we call N-terminal domain (NTD) that we don’t really understand.

The South Africans reported these changes first to the United Kingdom (UK), because the predominant strains circulating in South Africa in the early parts of the epidemic were similar to the most common one in the UK. It’s no surprise the two countries have similar viral strains, as there is considerable international travel between the two countries.

Once informed of the new strain from South Africa, now known as B.1.351,  UK molecular biologists started to look harder at strains circulating in their own country. They found a new variant that was starting to sweep over the country, called B.1.1.7. That new variant has driven a second wave of infection.

The second wave is worse than the first, as seen by increased rates of transmission and increased rates of hospitalization in the UK. This variant had one of the mutations in the RBD part of the genome, the one that appears associated with increased replication in the nose and transmission to other people, but fortunately not the changes that alter the neutralizing antibodies.

Very quickly, scientists put two and two together. The virus was evolving more rapidly than previously detected. Changes were occurring across two behavioral characteristics. And, the changes to these two characteristics were being detected in the same virus.

We have seen variations pop up over the past year. In June, we had a variation in the US where the original strain from Wuhan was overtaken by what we call the D to G614 strain; that’s what is mainly circulating here now. This strain also increased attachment to the ACE2 receptor, but the newer F105Y mutation enhances these characteristics even more and facilitates an even greater rate of spread.

This B.1.1.7 variant, commonly referred to as the UK variant, has now spread throughout Europe, and is being increasingly recognized in the US. The CDC predicts that this strain, with its evolved advantages, will become the predominant form of the virus circulating in the US over the next few months.

The B.1.351 variant, widely known as the South African variant, also has the increased transmissibility stemming from the mutation in the F105Y gene. But that’s not all. The South African variant has a couple more nasty mutations, one called E484K, that is associated with escape from an important neutralizing epitope that most people have after contracting COVID-19. That neutralizing epitope  is also found on antibodies induced by vaccination. This escape mutation on the part of the virus has been seen in other unrelated strains, so it seems to be a frequent way the virus tries to use to escape from people who have acquired immunity. So, people who have been infected with prior strains and developed immunity to those prior strains appear to be at an increased risk of re-infection with the B.1.351 variant.

We call this escape from neutralization or adaptive immune escape from the virus’s point of view.

This is what RNA viruses do. Influenza does this; HIV does it too.

In retrospect, we were a bit naïve about SARS-CoV-2, thinking that because this subgroup of coronaviruses edits its mutations more efficiently, we might escape from having lots of different strains. But natural selection is very powerful, as Darwin taught us. We have had more than 100 million confirmed cases of COVID-19 worldwide thus far, and the real number is certainly much, much bigger. When a virus spreads to this many hosts, this fast, it creates a lot of opportunity for the virus to adapt against the natural selection pressure placed on it by the human immune system.

The bad news is that we continue to give the virus opportunity to adapt. We’re tired of social distancing. Not everyone wears masks. We have limited supplies of vaccine at the moment. So, we find ourselves in a situation where mathematically, this pandemic is not going to stop anytime soon.

What do we do about it? This week brought us data that says we don’t have to panic. We do really have evidence that our current tools are going to be OK. Moderna reported that its vaccine, in lab tests, continued to produce robust neutralizing antibodies against the B.1.1.7 variant. The Moderna vaccine produced 6-fold lower titers of antibodies against B.1.351, but those antibody levels that are still higher than what are typically seen in cases of natural infection. Importantly, the nature of the mRNA technology makes it possible for Moderna to make a new mRNA construct very quickly to educate the immune system against this new B.1.351 variant, and that new “updated” vaccine can be tested in a small, fast clinical trial to validate its use as a “booster.”

Scientifically, this is the good news. But it’s only a piece of the puzzle. We have to create strategies to get us back up to the optimal state. This means vaccinating everyone globally as fast as possible. What impacts one of us impacts all of us, including here in the US. Ongoing community spread anywhere with this virus means it can spread everywhere in our interconnected world.

Besides findings from lab tests, we now have hard clinical evidence that our current vaccines will work as well against the UK variant as they have for the variants circulating in the US. The best evidence of this is a 14,500-person clinical trial of the Novavax vaccine which showed a 90% efficacy rate in a UK study where the UK variant constituted 30% to 40% of the strains circulating at the time of the trial. The antibody concentration from this two-dose vaccine is pretty similar to what we saw in the Moderna and Pfizer vaccines. Several scientific teams have now shown that sera from people vaccinated with either of these vaccines also neutralize the B.1.1.7 isolate as well as the isolate from Wuhan. That’s good news.

More importantly, we got data from the Johnson & Johnson (J&J) vaccine trial out of South Africa on Friday. We were lucky. We didn’t know when we conducted the J&J trial that there would be marked viral strain differences between South Africa and the US. In fact, when I worked with the company to design the trial, the reason we went to South America and South Africa for an international trial was because J&J is a global company and they wanted a globally developed vaccine. Their vaccine is also tailor-made for global vaccination efforts, since it can be given in a single shot, and shipped to remote parts of the world with standard refrigeration – no need for deep freeze.

My network was already working with J&J on their experimental HIV vaccines and we had great investigators in both South Africa and South America who were tackling the COVID-19 epidemic and wanted to help. We were conducting so many vaccine trials in the US, we felt we could distribute some of the work internationally and everyone would benefit. At the time these decisions were made last summer, we didn’t realize how fortuitous this decision would be. A month ago, after the South Africans noted that the B.1.351 variant was the main circulating strain in the country, we got nervous about whether the vaccine would be effective against this tough new variant.

Fortunately, this anxiety was alleviated when the data arrived from the 43,000-volunteer global trial. The J&J vaccine protected against hospitalization and death in 88% of the enrollees in South Africa! There were zero deaths in the vaccine group; six in the placebo group in South Africa. Overall, the vaccine was 57% effective against moderate and severe disease in South Africa.

The efficacy number in the US was 72%; in Brazil, 71%. Worldwide, the numbers worked out to 66 percent protection against moderate and severe disease.

Yes, we do have an 18% to 20% difference in the effectiveness in the J&J vaccine by region, and this is some source of concern. And I will add that the Novavax vaccine, which was shown to be 90% effective in the UK, showed 55% protection in South Africa. So, here too we saw a reduction in efficacy.

But to put it in perspective: What’s more important, do we develop these vaccines to reduce the frequency and severity of sore throats and cough? Or do we develop vaccines to prevent us from getting hospitalized, being put on supplemental oxygen, put on a ventilator, or dying?

I think all of us would take a vaccine that prevents us from dying, even though it might still mean a case of COVID-19 with a sore throat and a headache and body aches for a couple days. I’d take that deal.

In my next blog, I’ll talk more about the J&J vaccine and where it fits in the vaccine response in the US and globally. We need a bit more data to become public before we tackle this task. There are lots of opinions here and there’s nothing wrong with that. But it’s been a very good week. We now have two new safe and effective vaccines—Novavax and J&J. That can be nothing but great news.

As in all science, all good clinical trial outcomes lead to more good questions that we’ll need to answer to bring an end to this pandemic.

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.

28
Jan
2021

Ideas for an FDA Reboot

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28 Jan 2021

Luke Timmerman, founder & editor, Timmerman Report

The FDA needs to get healthy, and fast.

Its credibility as the world’s No. 1 science-based regulator of food and drugs has been tarnished.

From the start, it had to play catch-up on RT-PCR diagnostic tests in the wake of CDC’s epic screwup. Partly to make up lost ground, it swung open the floodgates for antibody tests. A Wild West debacle ensued. Then came hydroxychloroquine (caving in with a premature Emergency Use Authorization, followed by the embarrassing withdrawal when failure was obvious). Then came the convalescent plasma fiasco.

It’s painful to write those words.

Throughout, there was a failure of leadership to level with citizens and clearly communicate the rationale for its decisions in real-time.

Even when FDA staff were inspired to burn the midnight oil to make sure we got vaccines without delay, and the news was good, the agency was tainted. It wasn’t able to speak with the gravitas needed to shore up confidence in therapies and vaccines. Too many people came away thinking FDA was a bunch of bureaucrats or political hacks, cutting corners, probably engaged in skullduggery.

Anyone who gives a damn about healthcare, and about biopharmaceutical innovation, ought to care about restoring the FDA as the world’s leading scientific regulator. We all ought to focus our prying, skeptical eyes on the agency to hold it accountable and keep it on its toes. But we shouldn’t go overboard into bottomless cynicism.

So, today I’d like to propose a few bold ideas to help the FDA get back on its feet.

  1. Move out of the Washington, DC area. The FDA doesn’t need to be headquartered in Washington, any more than the US Mint. The FDA has about 11,000 employees in 8 million square feet of space. The scientific review teams can do their jobs anywhere – and it’s preferable to do it in a quiet place free from excessive influence from Congressmen, hacks in the White House, or industry lobbyists pushing their own special interest.

By moving out of the Washington, DC metro area, the federal government could reap a real estate windfall. The FDA has valuable land that could be redeveloped by private developers of mixed-use business and residential properties. FDA could take the windfall proceeds and build a reimagined, tightly integrated campus in the middle of the country on cheaper land.

I’m thinking of a place like Wichita, Kansas (pop. 390,000) or Tulsa, Oklahoma (pop. 402,000). These cities offer low cost of living and high quality of life. They have diverse demographics with White, Black, Hispanic and Native American populations that closely reflect the population of the country as a whole. The FDA, operating down the street from healthcare providers in a place like this, could test out lots of cool new initiatives in a “real world” healthcare setting. Done right, the FDA could gain valuable insights into how to operationalize things like telemedicine for clinical trials, remote patient monitoring and more.

A move could also refresh the agency’s staff, by clearing out some people ready for early retirement, and providing an opportunity for an influx of new talent attracted to work on hard challenges. These people could be good scientific citizens in their communities. They would be parents of kids in local schools, and neighbors to ordinary people. FDA staff could weave themselves in with local schools that don’t get enough exposure to the wonders of 21st century medical science.

  1. Double the budget over five years. The FDA has always had to struggle for resources. When it succeeds, no one notices. It doesn’t get to bask in the glory of discovery like the NIH. Its public health mission sometimes puts it crosswise with powerful constituents, like drugmakers or tobacco companies or Big Agriculture. The FDA doesn’t have a lot of natural allies in Congress who understand or enthusiastically support its multi-faceted work. Its budget, at a requested $6.1 billion for 2021, is peanuts for an agency that regulates one-fourth of the economy. How is it supposed to monitor manufacturing facilities and supply chains around the world to keep us safe from contaminated or counterfeit medicines?

For almost 30 years, the agency has long been kept on a tight leash with Congressional appropriations, and has been forced to rely increasingly on industry user fees. That’s one way to be penny-wise. But it also creates a financial dependence on industry, and a closeness that can sometimes get a little too close in ways that are subtle and hard to quantify. I think there’s a place for user fees in the FDA budget, but the lion’s share ought to come from us, the taxpayers. Either we as taxpayers think this work is important, or we don’t. If the COVID-19 pandemic has taught us a few lessons, one is the importance of an independent, nimble, science-based FDA.

With more pandemic threats looming and so many groundbreaking biopharma products coming down the pike, we need to double the budget just to keep with the anticipated demands on this stretched agency. Pay raises should go to agency veterans who have gone above and beyond.

  1. Draft a New Commissioner for the Moment. The FDA acting commissioner is Janet Woodcock. She’s an agency veteran, knows where all the bodies are buried, is a steady hand, and a serious person who knows medical evidence inside and out. She’s thoughtful about how the agency needs to modernize (see this 2017 NEJM editorial on master protocols to generate high-quality medical evidence). She has a backbone, standing with career staff in September against political hacks in a strong USA Today editorial. Woodcock cares about patients through her work on personalized medicines.

But at a moment when the agency needs to restore public trust, and break out of some of limited thinking of the past, it needs a commissioner with excellent communication skills and a vision for a 21st century FDA. The next FDA commissioner needs to communicate to the public and advocate passionately with leaders on Capitol Hill and the executive branch. Scott Gottlieb was skilled at this part of the job, and understood how to strike the balance of protecting public health while facilitating quality development of new products. Margaret Hamburg, who made a great impact as commissioner, wasn’t the kind of public spokesperson the agency needs now.

I’m thinking of someone to lead the FDA who has public health experience, who believes in the FDA mission to the bone, who can communicate scientific risk / benefit equations to a Nobel laureate or your grandma, and who doesn’t have too many industry conflicts. I could imagine a few excellent candidates.

Amy Abernethy, deputy commissioner, FDA

How about Bob Wachter of UCSF, one of the most trenchant observers of the pandemic response? Or Julie Gerberding, a former CDC director and now an EVP at Merck with tons of experience in communications? Or Anna Barker, a National Cancer Institute veteran and now the chief strategy officer at the Ellison Institute for Transformative Medicine at USC? Or FDA deputy commissioner Amy Abernethy, who’s spearheading a futuristic data science initiative, and who has credentials from academia (Duke) and industry (Flatiron Health).

Or maybe bring Gottlieb into the Biden Administration, even though he’s a Republican? He’d have to quit his board activities, and work for a Democratic administration, but that would be one way to show that the FDA isn’t a partisan institution.

  1. Get Ahead of the Trends with PDUFA VII. The Prescription Drug User Fee Act, the governing compact that has set the terms of engagement between industry and FDA since 1992, is renewed and updated every five years. The current iteration of PDUFA is due to expire in September 2022. It may seem far off, but now is the time when behind-the-scenes negotiations between industry and the agency pick up. The industry and agency will have to discuss fundamentals like fee rates, support for new initiatives, and allocating resources to keep up with the agency’s mission.

The FDA is staring at a mountain work ahead on cell and gene therapies. About 900 gene therapy INDs were in the pipeline as of February 2020. Former FDA commissioner Gottlieb and Peter Marks, head of the Center for Biologics Evaluation and Research, forecasted in 2019 that if current trends continue, the FDA will have to be in position to approve 10-20 cell and gene therapies a year by 2025.

The FDA has to staff up with people in CBER to keep up with the anticipated workload. This unit of FDA, remember, has been running at full tilt all year.

Besides the obvious need for more staff, there’s always a need to stay current with information technology, and lab technology tools, to keep up with an industry that is well-funded and moving faster than ever. The agency also needs resources for staffing up far-flung field offices so it can adequately do facility inspections, especially with the vast array of generic drug facilities around the world, and the boom in biologic manufacturing here and abroad. If we don’t make this investment, we can expect a slowdown in approvals — an abundance of innovations that can’t get all the way to people. It would be an “innovation pile-up” reminiscent of a Third World country.

If we’re smart, we’ll invest now to get ahead of the curve of the needs for CBER, while also preparing for healthcare and biopharma changes. Consider the FDA’s data science initiatives led by deputy commissioner Amy Abernethy. Or, consider master protocol study designs that could cut down on some of the waste that bogs down clinical trials today.

Neglecting the basics of how we gather medical evidence comes with a cost. There were too many small, single-site, investigator-sponsored studies in this pandemic – small and crappy trials. The FDA is the one agency that can take the lead on demanding new standards, but it needs strong leadership and  adequate funding.

It’s easy to overlook the FDA. It’s easy to criticize. Often, we’re right when we do.

But the FDA also needs our support. It deserves our most creative, constructive ideas on how to fulfill its mission. We shouldn’t take it for granted. The pharmaceutical industry wouldn’t be worth much if it were to wither on the vine.

We can’t allow that to happen. I don’t think it will. Let’s revitalize the FDA, and put it in position to be great at what it does for the next 100 years.

The Evolving Virus
  • Manaus Is Collapsing Again. CNN. Jan. 28. (Matt Rivers)
  • Manaus, the Amazonian City of 2 Million That Hatched the Brazil Variant, Has Been Crushed By It. Washington Post. Jan. 27. (Terrence McCoy and Heloísa Traiano)
  • Three-quarters Attack Rate of SARS-CoV-2 in the Brazilian Amazon During a Largely Unmitigated Epidemic. Science. Jan. 15. (Lewis Buss et al)
  • Virus Variant First Detected in South Africa Now Detected in US for First Time. Associated Press. Jan. 28. (Mike Stobbe and Michelle Liu)
  • UK Variant May be More Deadly. BBC. Jan. 22. (James Gallagher)
SARS-CoV-2 Characteristics
Vaccines
  • Gaithersburg, Maryland-based Novavax reported that its protein-based vaccine candidate was 89 percent effective in a Phase III study in the UK that enrolled 15,000 participants. Jan. 28. (Novavax statement)
  • Tracking COVID-19 Vaccines Across the US. NIH Director’s Blog. Jan. 28. (Francis Collins)
  • Merck Ends COVID-19 Vaccine Development Because of Insufficient Immune Response; Continues COVID-19 Therapeutic Work. Merck Statement. Jan. 26.
  • Moderna Vaccine Retains Neutralizing Antibody Production Against B117, but Less Robust Defense Against B.1.351. Moderna Now Working on a New Construct for Booster Vaccine Against B.1.351. Jan. 25. (Moderna statement).
  • mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. BioRxiv. Jan. 25. (Kai Wu et al, Moderna and National Institute of Allergy and Infectious Disease).
  • Pascal Soriot, CEO of AstraZeneca, Interview With La Repubblica. “There Are a Lot of Emotions on Vaccines in EU.” Jan. 26.
  • As Virus Grows Stealthier, Vaccine Makers Reconsider Battle Plans. NYT. Jan. 25. (Denise Grady, Apoorva Mandavilli and Katie Thomas.)
Collateral Damage of the Pandemic
The Infodemic
  • Anti-Vaccine Activists Peddle Theories That Covid Shots Are Deadly, Undermining Vaccination. Kaiser Health News. Jan. 25. (Liz Szabo)
Treatments for COVID-19
  • Efficacy of Colchicine in Non-Hospitalized Patients with COVID-19. MedRxiv. Jan. 27. (Jean-Claude Tardif, Nadia Bouabdallaoui, Philippe L L’Allier et al at Montreal Heart Institute)
  • Full-Dose Blood Thinners Decreased Need for Life Support and Improved Outcome in Hospitalized Patients. NIH statement on three trials. Jan. 22. (National Institutes of Health)
  • Lilly, Vir Biotechnology and GSK announce first patient dosed in expanded BLAZE-4 trial evaluating bamlanivimab (LY-CoV555) with VIR-7831 (GSK4182136) for COVID-19. Jan. 27. (GSK statement)
  • Lilly’s neutralizing antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) together reduced risk of COVID-19 hospitalizations and death among COVID-19 patients considered high-risk. The BLAZE-1 trial found that in 1,035 high-risk patients, there were 11 events (2.1 percent) in patients taking therapy and 36 events (7.0 percent) in patients taking placebo. There were 10 deaths total in the study — all of which were in the placebo group.
Market Chaos

The GameStop retail shareholder attack against hedge funds of Wall Street has prompted a lot of bewildered hot takes. As someone who formerly covered biotech stocks for Bloomberg News, I have some sympathy for the little guy who always gets screwed by the big guys. It’s been going on far too long (for just one example in biotech, see my “Selling Drug Secrets” investigation for The Seattle Times in 2005). At the simplest level, this retail shareholder rebellion makes some sense in a world that’s come unglued and where it appears there are no consequences for people who incite society-wide lawbreaking and mayhem. But when you open a Pandora’s Box of lawlessness and bottomless cynicism and too many people don’t know what’s true and don’t care, terrible damage gets done to innocent victims.

Look at Vir Biotechnology. The San Francisco-based developer of infectious disease therapies scored a fundamental win this week with its hepatitis B treatment. The stock skyrocketed to a high of $135 this week, before falling to as low as $51. There’s no fundamental reason for this much volatility. It had good news for hepatitis B, and some more good news for its combo therapy partnership on COVID-19 with Lilly and GSK. Apparently, part of the volatility can be explained because there’s a large percentage of shareholders who have a short position in the company based on a belief that it’s overvalued for its COVID-19 therapeutic antibody work. It’s fine for people to argue about valuations in the market – that’s what the market is supposed to do. But I think most people would also agree that we don’t want to have a system where it’s fun and profitable to launch manipulative attacks – bearish or bullish – to settle scores against Hedge Fund Bad Guys, if it means companies tackling the world’s biggest health challenges become collateral damage.  

Our Shared Humanity

  • Rob Perez on His Big Idea That Might Change the World. Authority magazine. Jan. 26. (Fotis Georgiadis)

Worth a Listen

RIP

Kirk Raab, the former CEO of Genentech, died from complications of COVID-19. He was 85.

Deals

San Francisco-based Verana Health struck an agreement with Janssen Pharmaceuticals to curate real-world evidence for data analysis to inform R&D in ophthalmology and urology. Terms weren’t disclosed. (TR coverage of Verana, July 2018)

Data That Mattered

Takeda Pharmaceuticals said that its experimental drug mobocertinib, an oral tyrosine kinase inhibitor, showed positive results in a Phase I/II trial of non-small cell lung cancer patients with EGFR Exon20 insertions. Researchers reported a 35 percent overall response rate, in patients who had previously worsened after platinum-based chemotherapy. Data were presented at the World Conference on Lung Cancer.

Amgen’s sotorasib, the oral KRAS G12C inhibitor, generated an overall response rate in 37 percent of patients with advanced lung cancer, according to data presented at the World Conference on Lung Cancer.

Genentech’s faricimab met the primary endpoint of in a pair of Phase III studies of patents with the wet form of age-related macular degeneration. The Genentech medicine is a bispecific antibody aimed at angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). The drug, administered every 16 weeks, was found non-inferior compared with Regeneron’s aflibercept (Eylea).

Personnel File

San Diego-based Cidara Therapeutics, the developer of antifungal and antiviral therapies, named molecular biologist Bonnie Bassler of Princeton University and Carin Canale-Theakston, founder and CEO of Canale Communications, to its board of directors.

Seattle-based Umoja Biopharma, an in vivo immunotherapy company, added Rob Glassman to its board of directors. He has been a vice chair at Credit Suisse since 2015.

Philadelphia-based Tmunity Therapeutics, the developer of T-cell therapies for solid tumors, said Jeff Leiden has become its new chairman of the board. Leiden is executive chairman of Vertex Pharmaceuticals.

San Diego-based ViaCyte, a regenerative medicine company, named Michael Yang as President and CEO. Brittany Bradrick was promoted to COO and CFO, and Steve White was named chief technology officer.

Financings

Waltham, Mass.-based Tscan Therapeutics raised $100 million to advance T-cell receptor engineered T-cell therapies for cancer. BlackRock and RA Capital Management participated.

Cambridge, Mass.-based Nuvalent raised $50 million in a Series A financing from Deerfield Management to work on kinase inhibitors for treatment-resistant cancers.

Seattle-based Lumen Bioscience received funding from CARB-X worth up to $14.5 million to develop orally available monoclonal antibody cocktails for serious diarrheal diseases.

Redwood City, Calif.-based Seer, a proteomics company, said it’s raising $251 million in a stock offering at $67 a share.

Germany-based CureVac, a mRNA therapeutics and vaccine developer, raised $450 million in a follow-on stock offering.

Israel and Palo Alto, Calif.-based Ukko raised $40 million to combat food allergies. Leaps by Bayer led.

Regulatory Action

Alameda, Calif.-based Exelixis won FDA clearance for cabozantinib (Cabometyx) in combo with nivolumab (Opdivo) as a first-line treatment for patients with advanced renal cell carcinoma.

24
Jan
2021

What’s Your DEQ? Why Data Empathy Is Essential For Health Data Impact

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24 Jan 2021

David Shaywitz

“Their story — yours, mine — it’s what we all carry with us on this trip that we take, and we owe it to each other to respect our stories and learn from them.” — Dr. William Carlos Williams to Dr. Robert Coles, from Coles’s “The Call of Stories.”

The term “data empathy” is on the verge of entering the mainstream.  It’s about time.

At least in print, the concept of “data empathy” was introduced in a 2014 paper by James Faghmous and Vipin Kumar, on climate science. One of the most significant challenges of working with “big data,” the authors write, is that, “with large datasets where one measures anything and everything, it can be difficult to understand how that data were collected, and for what purpose.”

This matters, the authors eloquently argue, in the most important sentence of the paper: 

“Every dataset has a story, and understanding it can guide the choice of suitable analyses.” 

This understanding, the broader contextual background surrounding the data collection and analysis, is termed “data empathy.”

There are two important reasons to seek out the story behind data, continue Faghmous and Kumar:

“[F]irst, understanding how the data are generated, their purpose, and generation processes will guide your investigation. Second, understanding the inherent biases in the data gives you the chance to correct them or adjust your results and recommendations.”

Yes, yes, a thousand times yes.

The most significant challenge faced in learning from “big data” in health is the disconnect between those generating the data and those trying to apply analytics to learn something from these data. Nearly everything worthwhile in health is complicated and messy, from biology to healthcare delivery (see here, here, here).

It’s appealing (for some) to imagine the intrinsic messiness can be offset by data volume or smart analytics, or that if you just stick all your assorted information in a giant digital vat, you can generate brilliant insights simply by letting data geeks, AI, or both, push and pull at it until it’s tortured into submission.  

Bashing at data you don’t deeply understand is futile at best, and often dangerously misleading, because you can always calculate something. The question is whether what you’re doing is meaningful or simply digital onanism.

I’ve recently discussed in TR why learning from EHR data, challenging under the best of circumstances, requires a sophisticated understanding of the local clinical practices associated with the data you’re examining; absent this knowledge, your conclusions are likely to be naïve, misguided, and quickly dismissed.

This has profound implications for healthcare and pharma organizations building out data science teams, as so many are right now. To cut to the chase: unless you recognize the foundational importance, as an organizing principle, of data empathy, and select your team with this vital and often elusive capability in mind, you’re going to have a really difficult time both gaining critical organizational traction and delivering meaningful insights. You will risk being regarded as just the innovation flavor of what promises to be a very short moment. 

Many supposedly brilliant data scientists, arriving with impeccable technology credentials (think “best of the best of the best, sir”), have enjoyed remarkably short tenures in healthcare organizations – attributable, I’d argue, to a low DEQ – data empathy quotient.

Conversely, leaders who’ve most effectively marshaled health data science to solve organizational challenges – Dr. Amy Abernethy’s work at Flatiron obviously comes immediately to mind – have extremely high DEQs. Other conspicuous examples of high DEQ at work include Dr. Omri Gottesman’s early contribution to Regeneron’s data integration platform, and Dr. Griffin Weber’s work in the academic sector.

The integrative ability at the heart of data empathy must reside in and reflect the philosophy of the entire data science team, as well as be embodied by the team’s leadership. The data science team must recognize, and must, critically (this is the biggest challenge), persuade the organization that data scientists do not and will not succeed by staring at a computer screen and delivering insights on datasets they’ve been handed.

The organization must not be conditioned to expect this over the transom approach, either. Instead, skilled data scientists work closely and collaboratively with front-line colleagues, including physicians and drug developers, who are generating the data, and with colleagues who are seeking greater insight from the data (the two groups might not be the same, but could be).

The point is that whether in a pharma company or a healthcare system, only by deeply understanding the nuance of how the data were generated, and having a sense of the anticipated use — and by being innately curious about both — can health data scientists function effectively, and deliver relevant results and meaningful insights. 

Fortunately, there are at least two reasons for real hope: first, data scientists, as I’ve described in both a recent Wall Street Journal book review and in TR, are increasingly attuned to the shortcomings in their datasets, and are (now) exceptionally attuned to issues of bias and equity. The idea that even – especially – large datasets need to be scrutinized with particular care is now dogma among leading data scientists, who recognize data doesn’t exist, and can’t be assumed to exist, on some pure, objective plane. The increased attention to how data are generated will be especially valuable for healthcare data science.

Second, and perhaps most importantly, there are ever-more inquisitive physicians and biomedical scientists who are captivated by, and often trained in, data science. I grew up running gels in traditional wet labs (how quaint), but today’s inquisitive physicians and scientists are as likely to be crunching data at multiple desktop monitors.

These emerging health data scientists are more apt to recognize that all data aren’t equally suitable for all analyses, and to realize how important it is, as you’re collecting and organizing your data, to have a clear sense of what sort of things you hope to learn from it. Done right, in collaboration with providers and scientists who are closest to the problems, it’s possible to create a positive feedback loop in which data scientists get more clarity on the problems to solve, and front-line stakeholders appreciate the insights and values high DEQ data scientist teams can bring.

Bottom line

The successful application of data science to healthcare delivery and drug development requires a high DEQ, an awareness of, and innate curiosity around the context in which data are generated. Data science teams in healthcare organizations foundationally require data empathy. The increased humility and self-reflection within the field of data science, and the increased focus of inquisitive biomedical researchers on data science questions, both represent hopeful signs for the future of health data science.

21
Jan
2021

A Bold Idea for the NIH

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21 Jan 2021

Luke Timmerman, founder & editor, Timmerman Report

Too many people don’t believe anymore in the American dream.

But if you can’t dream big, you can’t accomplish big things.

Today, I’d like to propose a bold idea for the future of biomedical research.

Let’s triple the National Institutes of Health budget over the next decade.

Impossible? Hear me out.

We know the NIH, with a $41.7 billion a year budget, is a force for human health and the economy. It has catalyzed the economy for decades.

Think about the Human Genome Project. Criticized as a costly boondoggle in the 1990s, it morphed into a seed investment for the ages. It cost $3.8 billion between 1990-2003. What did we get? Through 2010, the estimated economic impact was $796 billion, according to Battelle.

That’s $141 of economic activity for every $1 invested by the US government. That’s right — a 141x return on investment!

The dividends don’t stop there. That calculation was made in 2010. Biotech would be in the dark ages today without that DNA code on every desktop, and the ability to sequence DNA at high speed and low cost. You can draw a straight line between that catalytic investment by the US government (and to a lesser extent the UK, France, Japan and others), and biopharma’s invention of mRNA vaccines for COVID-19.

That is one success story. There are many others.

The NIH, composed of 27 institutes, supports the best work in cancer, infectious disease, neuroscience, mental health and other fields.

Ordinary citizens in the US have no idea that our taxpayer dollars can have this kind of impact. They have no idea that when we send our $41.7 billion to Washington for the NIH, 85 percent of that money comes right back to the states that are home to so many vibrant universities.

People have no idea that the NIH money is divvied out on a competitive, merit-based grant review system. Often, they are surprised to learn it doesn’t go in the pocket of some Congressman’s son-in-law.

They have no idea that the institutes themselves are led and staffed by brilliant hard-working people like Tony Fauci. They are surprised to learn he’s more than a good talker on TV. They are surprised to learn he got his job because he was the 13th most cited scientist in the world from 1983-2002.

People have no idea that you and me — the US taxpayer — are by far the most powerful investors in biomedicine. No country in Europe invests at this magnitude. China? It has ambition. But it envies the NIH system, seeks to copy it, and knows it has a long way to go.

Citizens in the US tend to have an exaggerated view of what billionaires like Bill Gates and Warren Buffett can do. Drinking from the poisoned chalice of political entertainment media for far too long, we’ve internalized the idea that government is full of screw-ups, and business titans like Gates and Buffett are the true wellsprings of science and innovation.

Generous as they are, their impact pales by comparison to the US taxpayers. The Bill & Melinda Gates Foundation, the world’s largest philanthropy, invests $5 billion a year across all its programs that include education, global development and global health. The NIH pumps $41.7 billion into biomedical research alone for the American people. The Gates Foundation knows this, and it’s why they are always talking about partnerships. They know the NIH is the beating heart of biomedical research.

We as a country just don’t fully appreciate what a gem we have in the NIH.

In my state of Washington, the late Sen. Warren Magnuson brought home the bacon that built the University of Washington Health Sciences Center and the Fred Hutchinson Cancer Research Center. These are sparkling stars in my community, and in the global scientific enterprise.

Sen. Magnuson operated in the optimistic post-WWII era, guided by FDR’s science advisor, Vannevar Bush. It’s worth re-reading that seminal document “Science, the Endless Frontier.”

It’s worth noting that in 1945, when Bush wrote that visionary document, we hadn’t even discovered the double helix structure of DNA.

So what could we do with a reinvigorated NIH?

A couple thoughts:

  1. A new NIH intramural campus, located West of the Mississippi. The NIH campus in Bethesda, Maryland currently has about 6,000 research scientists. I’m thinking of a new 5,000 or 6,000-scientist campus in a Midwestern or Western city. It could be an attractive place for young families, a place with affordable housing, cultural amenities, existing biomedical building blocks, and good transportation bones to handle an influx of newcomers. St. Louis would work. It’s the home of Washington University in St. Louis, it’s the Gateway to the West, and a major American city that has lost 65 percent of its population since its peak in 1950.

Why do this? Planting a major research stake in the ground, outside of Washington DC, New York, San Francisco or Boston could have multiple benefits. We would get good bang for our taxpayer investment, with lower operating and capital expenses. A new NIH campus would spur surrounding economic development with housing, transportation, small business. It would send a powerful cultural message that this 21st century industry creates shared prosperity, not just prosperity for a few coastal cities.

Putting an NIH campus in St. Louis would give young scientists a place to spread their wings and get established – where they could make the same wage as in a place like Bethesda but where their salary would support a higher standard of living. Not only that, but a fresh new campus would create some healthy competition for Bethesda, and help bust out of moldy Groupthink patterns of thought.

A St. Louis NIH campus could attract fresh new thinkers. I’m reminded of Nobel Laureate Mario Capecchi, who left Harvard University to go to the University of Utah to get away from some of the suffocating aspects. At Utah, free to do his own thing, he invented knockout mouse technology. (Capecchi, by the way, is a Holocaust survivor, and orphan, who found refuge in the US. He’s a poster boy for immigration reform, but that’s another column.)

  1. Build up four new cornerstone institutes of the NIH. We could support areas that need more basic research. I’m thinking of a reborn National Institute of Infectious Disease ($5.8 billion annual budget), a beefed-up National Institute of Mental Health ($2 billion), and a more generously funded National Institute of Neurological Disorders and Stroke ($2.4 billion). The “allergy” part of Fauci’s group at NIAID could be reorganized under a new, independent National Institute of Immunology. This is worth housing in an independent institute because immunology is so full of possibility, and we need more young people growing up in the field.

Why do this? These institutes are traditionally underfunded, especially compared with the big dog at NIH – the National Cancer Institute ($6.6 billion annual budget). But look at the future of disease burden. There’s SARS-CoV-2 and flu and malaria, TB and HIV. Then depression and anxiety and schizophrenia and bipolar disorder. Then Alzheimer’s and Parkinson’s and multiple sclerosis.

We’re talking about diseases affecting tens of millions of people worldwide.

Biopharma invests little in these areas because these fields are less mature than cancer, and because there’s less government-funded basic research to build on. There simply are not a lot of promising, short-term angles for industry R&D to attack. That was true for cancer in 1970. But then President Nixon and leaders in Congress (including Sen. Magnuson) made a big bet on the National Cancer Institute. That investment is paying dividends today.

This week, while mulling the state of our divided country, I listened to a podcast with former Sen. Bill Frist (listen here). He’s a Republican from Tennessee, a heart surgeon by training. NIH director Francis Collins was his guest. Frist, reminiscing about the Human Genome Project, marveled at how it came in ahead of schedule and under budget.

Then he asked Collins about the NIH budget.

Collins rattled through the basics. The NIH budget doubled in a bipartisan push from 1998-2003. Then things stalled. Only one-fifth of grant proposals get funded, leaving a lot of worthy projects on the cutting-room floor, Collins said. By 2015, Congress took notice, setting aside cash for “inflation-plus 5 percent” budgets. Collins sounded happy with this progress.

Certainly, “inflation plus 5 percent” is better than the 25 percent annual budget cuts that President Trump proposed. Congress, wisely, overruled him.

Francis Collins, NIH director

But we can do better than “inflation plus 5 percent.” We are in a biology renaissance. The needs for human health are enormous, and growing. The US government is by far the most powerful force in the world for this kind of catalytic investment. The NIH is capable of creating entirely new industries, like genomics.

With NIH as the foundation, along with a vibrant biotech industry, the US should be able to create hundreds of new drugs and diagnostics and vaccines over the next 100 years. We have a generation of talented young people that are yearning for purpose and meaning in work.

Let’s shake off the cynicism, pessimism and stale thinking that has infected our country in recent years.

Let’s triple the NIH budget. Let’s continue to lead the world in biomedical research.

 

Vaccines
  • Moderna on Track to Make 100 Million Doses of Vaccine by End of March, CEO Says. WSJ. Jan. 19. (Peter Loftus)
  • Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science. Jan. 21. (Kate Bubar et al)
  • How Fast Can Vaccination Make a Difference? Look at Israel. The Economist. Jan. 23.
  • Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine. JAMA Insights. Jan. 21. (Tom Shimabukuro, Narayan Nair)
  • SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn. Annals of Internal Medicine. Jan. 19. (Mark Connors, MD, Barney S. Graham, MD, H. Clifford Lane, MD, Anthony S. Fauci, MD)
  • Let’s Not Forget, We Have a Phase III COVID-19 Vaccine Readout Coming Soon from J&J.
Science of SARS-CoV-2
  • SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. BioRxiv. Jan. 19. (National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa team)
  • Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells. Science Immunology. Jan. 21. (Anthony Kusnadi et al)
  • Sex Differences in Immune Responses to COVID-19. Science. Jan. 22. (Takehiro Takahashi and Akiko Iwasaki)
  • Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19. JAMA. Jan. 21. (Robert L. Gottlieb et al)
  • The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome. PNAS. (Brett Finlay et al)
  • mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. BioRxiv. Jan. 15. (Zijun Wang et al)
  • Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study. The Lancet Immunology. Jan. 18. (Fang Li et al)
Public Health
  • Outgoing CDC Director Warns We’re Heading Into the ‘Worst of it.’ NPR. Jan. 15. (Mary Louise Kelly)
  • Europe’s Growing Mask-Ask: Ditch the Cloth Ones for Medical-Grade. Washington Post. Jan. 20. (Loveday Morris)
Features
  • Another Way to Protect Against COVID-19, Beyond Masking and Social Distancing. Indoor Humidity. Scientific American. Jan. 19. (Akiko Iwasaki)
  • Patients Fend for Themselves To Access Touted Antibody Therapeutics. Kaiser Health News. Jan. 20. (JoNel Alecia)
  • Rogue Antibodies Could Be Driving Severe COVID-19. Nature. Jan. 19. (Roxanne Khamsi)
Policy & Politics
  • A ‘Tsunami of Randoms’: How Trump’s COVID Chaos Drowned the FDA in Junk Science. Vanity Fair. Jan. 19. (Katherine Eban)
  • Signs of Hope in Joe Biden’s Science Advisor. The Bulwark. Jan. 16. (David Shaywitz)
  • National Security Directive on United States Global Leadership to Strengthen the International COVID-19 Response and to Advance Global Health Security and Biological Preparedness. WhiteHouse.gov. Jan. 21. (The White House)
  • New CDC Director Pledges to Speed Vaccination, Restore Trust in Agency. WSJ. Jan. 19. (Betsy McKay)
  • COVID-19 Vaccine Leaders Waited Months to Approve Distribution Plans. WSJ. Jan. 15. (Betsy McKay, Rebecca Ballhaus and Stephanie Armour)
  • Mark Cuban Is Going to Help Pharma’s Image. Forbes. Jan. 19. (John LaMattina)
Our Shared Humanity
  • If You’re Offered a Vaccine, Take It. NYT. Jan. 21. (Melinda Wenner Moyer)
  • Ideaya, Spelman College Team Up to Provide Young African-American Women a Steppingstone to Biotech Careers. FierceBiotech. Jan. 19. (Amirah Al Idrus)
Financings

Cambridge, Mass.-based Beam Therapeutics, the developer of DNA base editing for drug development, raised $260 million in a stock offering at $93 a share. The developer of this early-stage technology is now valued at more than $5 billion. It has been buoyed in part by intriguing results by one of its partners, Verve Therapeutics, which uses base-editing for a single-shot gene therapy that has shown an ability to lower cholesterol in non-human primates.

Speaking of base-editing, Cambridge, Mass.-based Verve Therapeutics raised $94 million in a Series B venture financing led by Wellington Management and co-led by Casdin Capital. The company plans to enter the clinic in 2022 with its gene-editing therapy aimed at PCSK9 for patients with heterozygous familial hypercholesterolemia. It’s a genetic disease that causes extremely high levels of cholesterol that raises the risk of heart attack, stroke and death. (Listen to CEO Sek Kathiresan on an upcoming episode of The Long Run podcast).  

South San Francisco-based Vera Therapeutics, the developer of treatments for autoimmune and inflammatory diseases, raised $80 million in a Series C deal. Abingworth led. The company is developing atacicept, in-licensed from Merck KGaA, and is being run by a team of drug developers formerly with Gilead Sciences.

Plymouth Meeting, Penn.-based Inovio, the DNA vaccine developer, raised $150 million in a stock offering at $8.50 a share.

South San Francisco-based CytomX Therapeutics, the developer of antibody drugs for cancer, raised $100 million in a stock offering at $7 a share.

Cambridge, Mass.-based Editas Medicine, the genome editing therapeutics company, raised $231 million in a stock offering at $66 a share.

Waltham, Mass.-based Dyne Therapeutics raised $168 million in a stock offering at $28 a share. The company is developing treatments for muscle diseases.

Durham, NC-based Chimerix raised $100 million in a stock offering at $8.50 a share.

Bothell, Wash.-based Athira Pharma raised $90 million in a stock offering at $22.50 a share. It’s working on small molecule drugs for neurodegenerative diseases.

San Francisco-based Invitae said it’s raising $400 million in a stock offering to support its genetic testing.

Lexington, Mass.-based Aldeyra Therapeutics raised $75 million in a stock offering at $9.50 a share. It’s working on immune-mediated diseases.

Cambridge, Mass.-based Syros Pharmaceuticals raised $75.6 million in a stock offering at $14 a share. It’s working on medicines based on controlling gene expression.

Cambridge, Mass.-based TCR2 Therapeutics, the developer of T-cell therapies for cancer, raised $140 million in a stock offering at $30.50 a share.

Cambridge, Mass.-based Fulcrum Therapeutics raised $44 million in a stock offering at $11 a share. (TR coverage of Fulcrum, September 2018).

San Diego-based Plexium raised $35 million in a Series B financing to develop protein degrading drugs. Lux Capital and Pivotal BioVentures led, with participation from The Column Group.

Deals

South San Francisco-based Twist Bioscience, the DNA synthesis company, struck a pair technology partnerships. One, with Serotiny, allows it to make Chimeric Antigen Receptors for CAR-T cell therapies. Another deal with Applied StemCell provides access to Chinese Hamster Ovary cell technology for making antibody therapeutic candidates.

Emeryville, Calif.-based Gritstone Oncology, a personalized neoantigen therapeutics developer, secured a licensed from the La Jolla Institute for Immunology to incorporate additional epitopes into a new SARS-CoV-2 vaccine candidate, potentially making it harder for the virus to develop escape mutations. The National Institute for Allergy and Infectious Disease and Bill & Melinda Gates Foundation are supporting the work.

Servier and MiNA Therapeutics agreed to work together on small activating RNA therapies for neurological diseases.

Thermo Fisher Scientific agreed to acquire Mesa Biotech for $450 million in cash upfront. The small company does PCR point of case testing for infectious diseases.

Eli Lilly agreed to work with Netherlands-based Merus on T-cell engaging bispecific antibodies for cancer. Merus will get $40 million in upfront cash, plus a $20 million equity investment from Lilly.

Personnel File

Eric Lander, the leader of the Broad Institute, was appointed to be science advisor to President Joe Biden, and head of the Office of Science and Technology Policy. The OSTP was also elevated to a Cabinet-level position, increasing the clout of science in the new administration. Read Biden’s letter to Lander, filled with questions on important scientific matters for the years ahead. (Science coverage)

BIO CEO Michelle McMurry-Heath announced her new team, and leadership structure.

Cambridge, Mass.-based Foundation Medicine said CEO Cindy Perettie is moving over within the Roche group of companies to lead the Molecular Lab Solutions business at Roche Diagnostics in Pleasanton, Calif. Brian Alexander, the chief medical officer, will lead Foundation Medicine until a permanent CEO takes over at Foundation Medicine.

Bristol-Myers Squibb’s head of hematology, Nadim Ahmed, left the company after the company failed to win FDA approval of its liso-cel CD-19 directed cell therapy by Dec. 31. Reported by FiercePharma.

Cambridge, Mass.-based Cerevel Therapeutics, the developer of drugs for neurodegenerative diseases, named Deval Patrick and Deborah Baron to its board of directors.

South San Francisco-based Trishula Therapeutics named Anil Singhal as its new CEO. The company is developing a CD39-directed antibody for cancer.

San Diego-based Avidity Biosciences, the developer of antibody-oligonucleotide drugs, named Michael Flanigan as its chief technical officer.

Cambridge, Mass.-based Black Diamond Therapeutics named Kapil Dhingra to its board of directors.

Regulatory Action

Daiichi Sankyo and AstraZeneca won FDA approval for fam-trastuzumab deruxtecan-nxki (Enhertu), a treatment for locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Janssen Pharmaceuticals won FDA approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) for newly diagnosed light chain amyloidosis. It’s a subcutaneous form of Darzalex.

Merck won FDA approval for vericiguat (Verquvo) for heart failure patients.

Tweetworthy

Science is back in the saddle, and serious people are back in charge at the top of the US government. Thank God.

19
Jan
2021

Gene Editing for Transplants and Cell Therapy: Luhan Yang on The Long Run

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19 Jan 2021

Today’s guest on The Long Run is Luhan Yang.

Luhan is the founder and CEO of Hangzhou, China-based Qihan Biotech.

Luhan Yang, founder and CEO, Qihan Biotech

Qihan is using genome editing technology to engineer pigs with organs that can be safely transplanted into humans. This is what scientists call xenotransplantation. The concept has been around a long time, but new CRISPR-based gene editing technologies make it more feasible to overcome some of the challenges, including the likelihood that the human immune system will reject an organ transplant from a pig. If this turns out to be feasible at scale – still a big IF – then Qihan could be position to tackle the shortage of available organs for transplant.

Besides xenotransplantation, Qihan is also seeking to leverage its precise gene editing capabilities to engineer off-the-shelf, allogeneic cell therapies that won’t be rejected by the immune system.

Luhan is a native of China, and one of the leaders in CRISPR gene editing. She made her name in George Church’s lab at Harvard, and was the first author on a landmark paper in Science in 2013 that was the first demonstration that CRISPR could make precise gene edits in mammalian cells. She went on to co-found Cambridge, Mass.-based eGenesis to advance the xenotransplantation application of CRISPR, before leaving the US to take the helm of Qihan in China.

Luhan is a bright young scientific entrepreneur, in the hunt for the first big medical applications of a groundbreaking technology. I think you’ll enjoy this conversation.

Now, please join me and Luhan Yang on The Long Run.

17
Jan
2021

Two Doses or One? Let’s Stick To the Data

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17 Jan 2021

Chris Beyrer, MD, MPH, Desmond Tutu Professor in Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health

With COVID-19 surging and a chaotic political situation, we still have reasons to consider ourselves fortunate.

We have two safe and effective COVID-19 vaccines authorized for emergency use by the U.S. Food and Drug Administration. While the rollout has been frustratingly slow thus far, these vaccines and others under study hold our best promise of pandemic control.

Both products, the Pfizer-BioNTech and the Moderna vaccines, are based on novel mRNA technology, and both were shown to be highly effective in large clinical trials in preventing COVID-19 illness and severe COVID-19 disease.

Larry Corey, MD, leader of the COVID-19 Prevention Network (CoVPN) Operations Center; Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division, Fred Hutch

Both were studied as two-dose regimens. The Pfizer vaccine is given as two doses 21 days apart, and the Moderna vaccine is given as two doses 28 days apart.

The two products work remarkably similarly as two-dose vaccines. 

With both vaccines, the goal was to be well above the antibody levels of persons who recovered from the natural SARS-CoV-2 infection. Essentially, we were aiming to show that vaccines could trigger the production of even more antibodies than the body would normally produce from a natural infection.

That is exactly what we saw with these vaccines.

The Phase I trials showed it took two doses of mRNA to get above these natural levels. This is the basis for the two-dose regimens that were eventually tested, and shown to be so effective at preventing illness. 

Both scientific papers on the Pfizer/BioNTech and Moderna vaccines show the vaccines appear to start working 10-12 days after the first dose. These trends, which show protection for people on vaccine compared with people who got a placebo, are extended out for the next four months.

Over time, protection increases. The data after 21 days for the Pfizer vaccine or after 28 days for the Moderna vaccine, however, show the results of the second dose, since everyone in these trials received two doses.

Since no large trials have been run with a single dose, we simply don’t know how effective a single dose might be.

There’s a reason why the first big trials looked at two-doses, not just one. Vaccine regimens are selected based on empirical studies of immune responses, first in animals, and then eventually, if the products pass safety and immune response tests, in human volunteers.

Both the dose (how much of a vaccine is given) and the regimen (one, two, or three doses, and how far apart) are carefully selected based on these kinds of studies. Then, we go into the field with our best estimate of dose and regimen, and study how the vaccines work in real people with real exposures to the diseases we are trying to prevent.

In the case of the mRNA COVID-19 vaccines, we studied two-dose regimens, spaced by 3 or 4 weeks. That is what we know from the data from the vaccine efficacy trials.

That said, we are learning more about these products every day. Safety data continue to be gathered. Each day, we understand more about the ‘real world’ logistical challenges of using these products.

The pressure to get more people immunized is driving some decision-makers to move toward single-dose use, or to stop withholding vaccines – as U.S. Department of Health and Human Services Secretary Alex Azar announced last week – which has an impact on the certainty of available second doses for all who have had their first doses.

President-Elect Joe Biden has also stated he would press for release of all available doses and no longer hold back vaccine doses to make certain that everyone who got a first dose will be able to get the second dose on schedule. Neither is suggesting that one dose is enough – but both approaches are gambling that product manufacturing will keep up with demand, and that by extension it would be acceptable to have some persons vaccinated with second doses after longer windows than the current FDA-approved 21 or 28 days.

To be clear, the findings from the clinical trials in tens of thousands of volunteers is that these vaccines work as two-dose regimens with tight time intervals between doses.

Everything else is speculation.

Until we have the empirical evidence to suggest it would not reduce safety or efficacy to make a change in the dosing and regimen, two spaced doses are what has shown such high efficacy.

While there is urgency to accelerate the COVID-19 vaccine rollout, and to immunize more Americans who want and need these vaccines, there are real risks to the effectiveness in changing anything about their current recommended and authorized use.

A corollary of the two-dose response to the mRNA vaccines that is also increasingly being asked is how closely to 21 or 28 days does one need to be to give the second dose? The answer is another unknown. But in general, waiting for a boost is often associated with higher responses.

So getting a boost at 2 months, while unproven, would compare well with other vaccine platforms and will likely be able to spur the kind of antibody production we know is sufficient to protect against illness. The key issue with delaying the second vaccination is really how good, and how long, a first vaccination alone will work. That answer is unknown. Getting the second dose, from a policy point of view, is imperative.

With the AstraZeneca-Oxford vaccine candidate, the trials in the US, UK and elsewhere have also studied two-dose regimens. This two-dose regimen was what the UK approved for Emergency Use Authorization in December. But again, some decision-makers in the UK are pressing to deliver this product as a single-dose vaccine.

The argument from policymakers is that a single-dose represents a reasonable trade-off. If you give a single dose to a larger percentage of the population, it might be better at blunting the spread of the pandemic than giving a two-dose regimen to a smaller group of people.

But this too is a problematic framing of the issues.

We don’t know that one dose is effective, or for how long. Having a large number of people partially protected, particularly during periods of high COVID-19 transmission, could end up benefiting variants of the viruses that can bypass the weak or partial protection from incomplete immunizations.

The combination of partial protection, and loosening of social distancing precautions, could end up undermining the effort to control the pandemic. A decision of this gravity has to be made based on empirical data from human vaccine trials, not on modeling or other speculative approaches, and certainly not on political considerations or expediency. 

The current COVID-19 vaccines that we have developed so quickly are precious resources. We must use them wisely and protect their efficacy. This calls for fidelity to the science, ongoing and rigorous research, and the great patience that COVID-19 has demanded of us all.

We need to ramp up immunizations as quickly as is humanly possible, and we need to get many more vaccines into people’s arms. But for a two-dose vaccine regimen, that means getting two doses, spaced apart as our data suggest, to ensure that people are truly protected.

Chris Beyrer, MD, MPH is the Desmond Tutu Professor in Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health. A professor of Epidemiology, Nursing, and Medicine, he now serves as Senior Scientific Liaison to the COVID-19 Vaccine Prevention Network, and as co-editor of this blog series.

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 U.S. 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.

14
Jan
2021

Our Communities, and Biotech, Need Local Journalism

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14 Jan 2021

Luke Timmerman, founder & editor, Timmerman Report

National traumas force us out of our comfort zones. They can force us to search, to ask new questions, to think deeper about our world.

This week, my first real journalism job came to mind.

One day, when I expressed surprise to my editor in Madison, Wisconsin that the tiny Grand Forks Herald in North Dakota had won the Pulitzer Prize for Public Service for its coverage of a 100-year flood, he said:

“One of the great things about journalism is that you can look at newspapers in all 50 states, and there are editors there who know their communities, know all the elected officials, have institutional memory,” he told me. “Every one of these places has the potential, under the right circumstances, to win a Pulitzer.”

“Then I guess we just need a natural disaster to hit Madison,” I joked.

Twenty years later, I see this conversation in a different light. My editor was telling me something important. Maybe more important than he and I realized at the time.

The newspaper industry was the primary fact-gathering engine of American journalism and the town hall for political discourse. Newspapers were the thing, for more than 200 years, that set the agenda for conversations across the country. These community organs, in the second half of the 20th century, were especially profitable and stable. Radio, TV, and everyone else followed the lead.

Newspapers often had local owners and publishers with backbones, editors who had seen and heard it all, and a small group of tireless young reporters working for starvation wages (watch “Spotlight” with Michael Keaton and Mark Ruffalo to get a feel).

Newspapers were a carefully curated bundle of news, information you could use, sports, entertainment. The content was meant to appeal at least a little to everyone in the community – there’d be something from last night’s city council meeting, high school sports recaps, and human-interest features about the local Girl Scout troop fundraiser. There was the crime blotter, the weather, and what our US Senator might have said about dairy policy that week.

Occasionally, we would dig up a scandal about a crooked local politician. The ensuing outrage would force change, like a resignation.

Maybe even more important than what we did publish was what we chose NOT to publish. When a neo-Nazi skinhead or some other extremist called to complain, or wrote a racist letter to the editor, we tossed that in the trash. Before we did, we might turn to a colleague and say “can you believe this guy?”

Seven days a week, with metronomic consistency and community sensibility, the family newspaper arrived on the doorstep.

As a newspaper reporter, I got to learn about the community, and on better days, hopefully helped the community better understand itself. In the newsroom, we kept ourselves and our viewpoints out of our copy. It was our job to gather the facts, lay them out in the proper context, and let the readers decide. We weren’t in the entertainment business. We were trying to make the important stuff interesting to read for a busy reader who might give us 5-10 minutes out of their day.

Today, local newspapers are dead, or shells of their former selves. Most of the jobs are gone. The Internet enabled a great “unbundling.” For most surviving newspapers, ownership is distant, usually some nameless private equity firm fixated on cost-cutting. Communities now get hardly any real news about what’s happening close to home. If they do, it’s not always from people committed to traditional standards of fairness and accuracy.

There’s no more town square, no campfire to sit around and tell each other stories.

It would be a mistake, of course, to indulge in too much sepia-toned nostalgia about local newspapers. These newspapers sometimes would write in hackneyed cliches, show bad judgment, or blow things out of proportion on slow news days. They’d make errors. Sometimes the editorial board would endorse a certain politician, and readers would seethe. Old white men were in charge, and they were too often blind to racial and ethnic injustices.

Imperfect as these outlets were, they were bound by facts and ethics and professional codes of judgment. They were staffed by people who loved their communities.  

Now, instead of relying on local newspaper bundles, news has been both nationalized and fragmented into ever-narrower niches. There are bright spots on today’s Internet, but a serious information seeker has to do a lot of work to find the signal and avoid the noise.

There’s no mystery tens of millions of Americans believe false conspiracies such as QAnon, or that the Presidential election was stolen.

The Internet, over the past 20 years, has come to be dominated by outrage, cable TV infotainment distractions, and partisan rat poison that’s been algorithmically jackhammered into our minds. Opportunists know this, and have seized the advantage. In a pandemic, when millions of people are isolated and genuinely stressed, it adds up to a frightening level of mass radicalization.

As we come to terms with what we have wrought, I’d like to try to think big and bold about better ideas for how we communicate. Local communities, long considered an afterthought, deserve to be brought back in to the conversation.

Biotech, this includes you. Biotech is a thriving industry in the US for many reasons. Strong local communities are one reason. This industry has taken root in local clusters like Boston, San Francisco, San Diego, Seattle, Raleigh-Durham, Washington DC, New York / New Jersey.

Local newspapers are integral parts of those communities. In the early days of biotech – the Boston Globe, San Francisco Chronicle, Seattle Times, San Diego Union-Tribune among others – helped educate the public and tell the stories of this nascent industry. First-generation executives running companies like Genentech, Amgen, Biogen and Genzyme understood this. They read, and spoke with, their hometown papers in addition to the financial press. Their employees read these papers, and so did elected officials that biotech companies wanted to keep in touch with. (I remember ex-Amgen CEO Kevin Sharer calling my cell phone more than once to complain about my coverage in The Seattle Times).

We all live in local communities, and benefit from local investments. Subscribing to your local newspaper is one such small investment.

If a newspaper is too old-school for you, there is a new generation of online outlets – text, audio, and sometimes video. The important thing is to support outlets committed to traditional values of the journalism craft. There’s The Frisc and KQED in San Francisco, Crosscut and KUOW in Seattle, and the Texas Tribune, to name a few. ProPublica, the investigative journalism outlet, is expanding into regional communities. Each place does good work that could help stitch back together the bonds that hold our communities together. It won’t happen overnight, but it’s worth doing.

If we don’t get to work on repairing our democracy, our institutions, our social bonds, our communities, then we all have a lot to lose.

I’ll leave you with a quote from Thomas Jefferson on press freedom. It’s about more than just free speech, and more than just newspapers. The newspaper itself isn’t the important part — it’s the need for a shared set of facts, a shared reality, from which citizens could educate themselves to hold government accountable and make wise decisions in a representative democracy.

Jefferson said:

“The people are the only censors of their governors: and even their errors will tend to keep these to the true principles of their institution. To punish these errors too severely would be to suppress the only safeguard of the public liberty. The way to prevent these irregular interpositions of the people is to give them full information of their affairs thro’ the channel of the public papers, & to contrive that those papers should penetrate the whole mass of the people. The basis of our governments being the opinion of the people, the very first object should be to keep that right; and were it left to me to decide whether we should have a government without newspapers or newspapers without a government, I should not hesitate a moment to prefer the latter. But I should mean that every man should receive those papers & be capable of reading them.”

Responding to Insurrection

The Biotechnology Innovation Organization said it would pause all political giving, as many trade groups have done, in the wake of the insurrection against Congress incited by President Trump. BIO’s statement  noted that the industry is based in science, and that “it is very concerning that some elected leaders last week chose to ignore facts and embrace widely discredited conspiracies.” It’s a start. I want to see the industry issue a permanent ban against funding members of Congress that supported the violent mob insurrection.

Financings

The Rockefeller Foundation said it made a $30 million advance market commitment to support COVID-19 testing to help safely reopen communities. The deal enables Thermo Fisher Scientific to move buy necessary supplies, in $30 million chunks at time, with guaranteed demand.

South San Francisco-based DiCE Molecules raised $80 million in a Series C financing led by RA Capital. The company is developing small molecule drugs based on a DNA-encoded library. The lead program is a first-in-class attempt at an oral small-molecule aimed at IL-17, an inflammatory cytokine that’s been well-validated by injectable biologic drugs for psoriasis, psoriatic arthritis and other autoimmune diseases.

Baltimore-based Delfi Diagnostics raised $100 million in a Series A financing to advance a pan-cancer early detection test. OrbiMed led.

Boston-based Atalanta Therapeutics started up with $110 million to develop RNA interference therapies for neurodegenerative diseases. The company said it has partnerships with Biogen and Genentech. Alicia Secor is the CEO.

Cambridge, Mass.-based Vedanta Biosciences, the microbiome therapeutics company, secured a $25 million investment from Pfizer. The company plans to use the cash to advance a Phase II study of a treatment for inflammatory bowel disease.

Cambridge, Mass.-based Generation Bio raised $225 million in a stock offering at $24.50 a share. The company is working on non-viral delivery of gene therapy. (TR coverage, August 2020).

Boston-based Valo Health raised $190 million in a Series B financing led by Public Sector Pension Investment Board. It’s using machine learning for drug discovery.

New York-based Lexeo Therapeutics, a gene therapy developer, raised $85 million in a Series A financing co-led by Longitude Capital and Omega Funds.

San Francisco-based Earli raised $40 million in a Series A financing to advance its platform for early cancer detection. Khosla Ventures led.

Seattle-based Altpep raised $23 million in a Series A financing led by Matrix Capital Management. It’s working on treating amyloid disorders. David Goel of Matrix, Joel Marcus of Alexandria Real Estate Equities, and Chad Robins of Adaptive Biotechnologies are on the board of directors.

Waltham, Mass.-based Mana Therapeutics said it raised a $35 million Series A financing to develop off-the-shelf allogeneic cell therapies for cancer. Cobro Ventures and Lightchain Capital co-led.

Seattle-based Sana Biotechnology, the cell therapy company led by former Juno Therapeutics executive Steve Harr, filed an S-1 prospectus to raise up to $150 million in an IPO.

Monmouth Junction, NJ-based Elucida Oncology raised $44 million in a Series A-1 financing.

Red Bank, NJ-based Provention Bio raised $100 million in a stock offering at $16 a share to continue work on immune-mediated diseases.

Chatham, NJ-based Tonix Pharmaceuticals raised $40 million in a registered direct offering.

Deals

Tarrytown, NY-based Regeneron Pharmaceuticals said the US government agreed to purchase up to 1.25 million more doses of its therapeutic antibody cocktail for non-hospitalized COVID-19 patients. The deal is worth up to $2.625 billion.

Beijing and Cambridge, Mass.-based BeiGene formed a partnership with Novartis to further develop and commercialize a PD-1-directed antibody therapy for cancer. BeiGene is getting $650 million upfront.

Cambridge, Mass.-based Bluebird Bio said it will spin off its oncology business into a new company, while the original company will focus on severe genetic diseases. Nick Leschly will be CEO of the oncology newco, and executive chairman of Bluebird Bio.

Seattle-based Adaptive Biotechnologies, which does sequencing of immune system B and T cells for diagnostic and therapeutic applications, struck a deal with AstraZeneca that combines the company’s sequencing and mapping capabilities to map T-cell receptors (TCRs) to antigens, across AstraZeneca’s oncology portfolio. Adaptive didn’t disclose specific financials, but said it will receive quarterly payments plus sequencing and data mapping fees.

Cambridge, Mass.-based KSQ Therapeutics agreed to work with Takeda on novel immuno-oncology therapies. KSQ stands to collect up to $100 million in upfront and preclinical milestones. (See TR coverage of KSQ, October 2017).

Ann Arbor, Mich.-based Evoq Therapeutics formed a deal with Amgen to work on autoimmune therapies. The little company stands to collect up to $240 million in upfront and milestone payments.

Germany-based Boehringer Ingelheim struck a deal with Enara Bio, a UK-based company working on cancer antigen discovery. The upfront payment was undisclosed, but Enara said it stands to collect up to 876 million Euros in milestone payments.

Cambridge, Mass.-based Biogen, the developer of treatments for Alzheimer’s disease, agreed to team up with Apple to use the Apple Watch and iPhone to collect digital biomarker data on cognitive performance for a multi-year observational study starting in 2021.

Menlo Park, Calif.-based Grail, the developer of a methylation-based test for early detection of cancer, formed collaborations with Amgen, AstraZeneca, and Bristol-Myers Squibb. These deals are focused on detecting Minimal Residual Disease, in patients who have been treated for cancer, and might have lingering malignancies not easily seen with other measurements. Separately, Grail said it plans to introduce its Galleri early-detection test before the end of June.

The Broad Institute, Verily and Microsoft said they are working together to expand Terra, a platform the Broad and Verily have been working on for some time, and which they described as “secure, scalable, open-source platform for biomedical researchers to access data, run analysis tools and collaborate.” The new partnership brings Microsoft’s cloud, data and AI technologies to the table.

Vaccines
  • Biden Will Release Nearly All Vaccine Doses, in Break With Trump Administration that Had Been Holding Back 2nd CNN. Jan. 8. (Sara Murray)
  • J&J Single-Dose Vaccine Candidate Phase I/II Data Published in New England Journal of Medicine. Jan. 13. (NEJM article and J&J statement).
  • Moderna Says it Believes It Can Update its Vaccine Without a Big New Trial. Tech Review. Jan. 13. (Antonio Regalado)
  • Messenger RNA Vaccines Against SARS-CoV-2. Cell. Jan. 13. (Eric Topol)
Science
  • Immune determinants of COVID-19 disease presentation and severity. Nature Medicine. Jan. 13. (Peter Broddin)
  • Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal of Experimental Medicine. Jan. 12. (Eric Song et al)
Rebuilding
  • The CDC was damaged by marginalization and politicization. This is how Biden can fix it. NBC News. Jan. 14. (Four former CDC directors)
  • As CDC Director, I’ll Tell You the Truth. NYT. Jan. 11. (Rochelle Walensky)
The Viral Evolution Story
  • Pfizer / BioNTech Vaccine Appears Effective Against Mutation in New Variants. Jan. 8. (Reuters)
  • Still going to the grocery store? With new variants spreading, it’s probably time to stop. Jan. 14. Vox. (Julia Belluz)
  • We lost to SARS-CoV-2 in 2020. We Can Defeat B117 in 2021. STAT. Jan. 9. (Kevin Esvelt and Marc Lipsitch)
  • Why Epidemiologists Are So Worried About the New Variants. Vox. Jan. 8. (Brian Resnick)
  • Germany Plays Catch-Up in Bid to Monitor Coronavirus Mutations. Reuters. Jan. 14. (Ludwig Burger)
  • How Worried Should We Be About SARS-CoV-2 Mutations? Timmerman Report. Jan. 14. (Mara Aspinall)
  • Genomic characterization of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. Virological.org. Jan. 12. (Nuno Faria et al CADDE Genomic Network)
SARS-CoV-2 Features
  • After aborted attempt, sensitive WHO mission to study pandemic origins is on its way to China. Science. Jan. 13. (Kai Kupferschmidt)
  • COVID Reinfections Are Unusual, But Can Still Help Spread the Virus. Nature. Jan. 14. (Heidi Ledford)
Science Features
  • An Algorithm May Soon Help People Make Babies. Future Human. Jan. 13. (Emily Mullin)
  • COVID Measures Also Suppress Flu – For Now. Science. Jan. 15. (Kelly Servick)
Our Shared Humanity
Biotech Strategy
Personnel File

Janet Woodcock, the veteran FDA leader, is expected to be named acting FDA commissioner in the Biden Administration. Joshua Sharfstein is reportedly a leading contender for the top job, according to BioCentury.

Moncef Slaoui, the leader of Operation Warp Speed, is resigning. He will reportedly be available as a consultant to the Biden Administration for about four weeks.

Andy Slavitt, the former acting CMS director under President Obama, will join the Biden Administration as a COVID-19 advisor. He’s been the host of the excellent “In the Bubble” podcast this year.

A former Merck cancer researcher was arrested and charged in federal court with theft of trade secrets.

Cambridge, Mass.-based Beam Therapeutics, the DNA base editing company, named Kate Walsh to its board of directors.

Stamford, Conn.-based Sema4 hired William Oh as chief medical science officer. He was most recently Chief of the Division of Hematology and Medical Oncology at the Mount Sinai Health System and Deputy Director of The Tisch Cancer Institute.

Data That Mattered

BioMarin said it met all primary and secondary endpoints in a Phase III study of its gene therapy for hemophilia A, evaluated for one year. The FDA has held up that product candidate, asking for more follow-up data.

Cambridge, Mass.-based Verve Therapeutics, the developer of gene editing therapies for cardiovascular disease, released updated data from non-human primates which said its experimental therapy was able to reduce LDL-cholesterol levels for six months after a single infusion. The treatment targets the PCSK9 gene, in a lipid nanoparticle delivery package. (Learn more in a few weeks, as CEO Sek Kathiresan is an upcoming guest on The Long Run podcast).

14
Jan
2021

How Worried Should We Be About Emerging Strains of SARS-CoV-2?

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14 Jan 2021

Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University

All virus strains mutate continuously. That’s normal. There’s nothing inherently concerning about that word, “mutation.”

Unless, of course, the mutations give an evolving virus new properties that make it more transmissible or more pathogenic. That’s trouble.

The news has been worrisome in recent weeks with reports on the B.1.1.7 strain first detected in the UK, and other new strains of SARS-CoV-2, such as the E484K strain first identified in South Africa.

Before getting into the particulars of those new strains, let’s go over some background. Large numbers of silent mutations are accumulated over time with all viruses. These silent mutations, which don’t cause meaningful change in the clinical sense, are helpful to us because they create a viral fingerprint. This unique code can be used to track the spread of particular versions over time and by geography — the data that tells us how and where a particular virus emerged. 

When a mutation persists and grows as a cause of infection there are two possible reasons: pure chance — that mutation just happened to be in the right place at the right time (aka founder effect); or, more worryingly, because it is more virulent or fitter than its ancestors. The vast majority of mutations do not persist, but a very few do, and when that happens, we have to quickly figure out how concerned to be, and what to do to outmaneuver the fast-spreading virus.

All mutations that are incorporated into virus strains that spread out geographically and grow faster than their predecessors are a “smoking gun”. This is exactly what has happened in the United Kingdom over the past three months and may be happening again in South Africa. The most recent analysis of the UK strain (B.1.1.7; aka VOC-202012/01; aka 20B/501Y.V1) combines prior laboratory findings (Scott 2020) and animal data (Gu 2020) that the N501Y spike enhances the critical spike protein’s ability to bind its human receptor (ACE2).

This finding has serious real-world implications. We see it in the recent explosive growth of UK cases of this strain (rapidly approaching complete dominance). The conclusion is that the UK strain is 50% to 75% more infective than the earlier strains in circulation, boosting its reproduction number Rt from ~1 towards 2.

At the very least, that means that the clock has sped up, and our time window to react effectively is closing. We must dramatically speed up our response – more and more frequent testing; better mask/distance/ventilation/handwashing compliance; faster vaccine roll-out than achieved to date.

The UK and South Africa strains are not the first major variant strains we have faced, but they are the most serious – direct evidence we are living on borrowed time. There have been four major strains of concern since early 2020: the D614G mutation in February; the UK strain in September; the Danish Mink crisis in November; and in December – the South Africa strain (E484K). Each strain is comprised of a number of variants, what follows is a brief summary of the key mutations believed to underly our greatest threat:

February – variant D614G

Extensive in-vitro and mouse work (Plante 2020) confirmed that this strain was more highly transmissible than the original Wuhan strain, most likely because this specific mutation created a more “open” and therefore more infective spike protein. This mutation is now globally dominant as a result and is the common ancestor of more recent strain emergence, against which they are evaluated.

September – UK strain N501Y spike variant

The UK has a national and comprehensive sequencing initiative (the US has a decentralized approach). Ironically, this greater effort at genomic surveillance in the UK may amplify concern in the absence of good data elsewhere. Since its identification in the UK, many other countries, including the US, have found it locally.

This strain comprises 17+ protein-altering variants, six of which are in the Receptor Binding Domain (RBD) of the spike protein, one of which (N501Y) is known to increase virus binding affinity and infectivity. Highly specific monoclonal antibodies may show less therapeutic binding and may be less effective.

The vast majority of new cases in London and the south east UK are of this strain. Higher rates of infection in children are being reported. Population transmission fitness is about 47-75% greater. Spike-based PCR tests are reporting spike negative results, and this is being used as a biomarker of strain prevalence. It is unlikely this strain is dominating only by chance. 

November – Danish Mink Y453F variant (aka “Cluster 5”)

It is a little unfair to label this the Danish strain since it was also found in Dutch, Spanish, Swedish and US mink. Among the four spike mutations comprising this strain, Y453F was found (Scott 2020) to be second only to N501Y in ability to enhance spike binding. There is no evidence that this strain is either more severe or transmissible. No increase in human cases accompanied the emergence of this strain, so the current hypothesis is that its emergence is more likely a chance-driven event. However, it is most concerning since an animal-to-human pathway (i.e. via mink) is a potential avenue for further threatening mutations to arise.

December – South Africa strain E484K and K417N plus N501Y (aka 501.V2; aka B.1.351)

The least is known about this strain, which has only recently been identified. It consists of 21 mutations, nine of which are in the spike protein. It appears to share the UK strain’s greater transmissibility, but this has not been reliably quantified, and there is no evidence today of enhanced severity.  However, this is the strain which presents the most concern with respect to the current vaccines, given in-vitro studies have suggested some decreased efficacy of neutralizing antibodies in the presence of the E484K mutation (Weisblum 2020; Adreano 2020)

Although we have very limited reliable data on which to evaluate the impact of each of these individual strains, action cannot wait.

Specifically, there are five areas of concern.

Will these emerging variants:

  1. Make tests less accurate, threatening our ability to contain the pandemic?
  2. Make the COVID-19 pandemic worse by increasing cases and deaths?
  3. Make emerging treatments ineffective?
  4. Make vaccines ineffective?
  5. Make the vaccination threshold for achieving herd immunity higher?

The best current answers are:

  1. Make tests less accurate? No for antigen tests because all antigen tests cleared via the FDA’s Emergency Use Authorization target the abundant N (nucleocapsid) protein, not the spike protein. PCR and serology tests are more vulnerable since they rely on short stretches of RNA for primers and probes, or limited antigen protein segments, respectively, either one of which may by rendered less effective in the face of novel mutations. However, only a very few target spike RNA at all, and those that do sample additional regions and genes in combination (e.g. Thermo-Fisher Taqpath PCR assay). Few manufacturers publish which antigens are utilized in serology tests –  so more investigation is needed to determine the efficacy of serology assays. Overall, PCR and antigen based active-disease testing is likely minimally affected.
  2. Increase cases and deaths? Almost certainly. None of the known variants have been shown to increase case fatality rates (CFR, percent of infected who die). However, if the greater transmissibility of UK variant associated mutations is confirmed, then the resulting rise in new cases will threaten to overwhelm hospital capacity at an even faster rate, which will lead to more total deaths.
  3. Render treatments Ineffective? Convalescent serum — less likely; monoclonal antibodies — some yes. Convalescent serum has a broad spectrum of antibodies, and although its utility may be limited, it is less likely to be affected than cloned single epitope monoclonals if directed at epitopes directly modified by the new variants. It’s worth noting here that the Regeneron antibody cocktail was specifically designed to hit two epitopes, making it more difficult for the virus to evolve an escape mechanism.
  4. Will vaccines remain effective? Yes, current vaccines are likely still effective. Both currently authorized vaccines in the US invoke immunity against the entire spike protein, i.e. polyclonal responses, so a few changes among all 1,273 amino acids in the protein are unlikely to reduce vaccine effectiveness. Recent unpublished work (Xie 2021) confirms that the Pfizer vaccine (BNT162b2) raises comparable levels of antibodies to the N501Y mutated (Y) virus as to the prior (N) virus. Testing of the Moderna vaccine is underway. All our current data comes from laboratory work on single mutations. It is possible that a novel group of mutations (e.g. the South Africa strain) may have the potential to enable immune escape by the strain. The good news is that even if current vaccines do need to be modified, a new generation of mRNA vaccines can be quickly created (months not years) to adapt.
  5. Will increased vaccination be needed? Likely yes. Achieving herd immunity – the ultimate objective of pandemic control – is a function of both viral contagiousness and vaccine efficacy.[1] If more transmissible strains become widespread, the proportion of global population vaccination required for herd immunity increases, and with it the number of vaccines that must be distributed and administered. The SARS CoV2 vaccine roll-out has to be even quicker and broader than has been previously assumed, and we are falling behind even those more modest expectations. Time is not on our side.

Mara Aspinall is co-founder and managing director of BlueStone Venture Partners and a professor of the practice, biomedical diagnostics, at Arizona State University.

 

[1] Herd immunity for highly contagious measles requires 95% of children to receive the 97% effective vaccine; but for the less contagious influenza, herd immunity is achieved with only 50% being vaccinated with at most a 60% effective vaccine (e.g. the 2010/11 season) or 80% for more typical 30-40% effective annual vaccines.

13
Jan
2021

The Politics of Speaking Up

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13 Jan 2021

Paul Hastings, CEO, Nkarta Therapeutics; vice chair, BIO

We thought we had lived through the most difficult year of our lives in 2020, from the deadly COVID-19 pandemic to the delusional and autocratic ambitions of a sitting President of the United States.

Then we were shocked once more, by deadly mob violence and ominous threats of more to come at the U.S. Capitol in the days before the inauguration of a new President.

The social fabric of our country is in bad shape. Our sense of shared values as a country seems to have gone missing. Many of us in the biotech community were stunned in 2020 to learn that we had to FORCE many people to become educated about the novel coronavirus, including basic mitigation strategies such as social distancing and mask wearing.

These are common-sensical, even self-evident, concepts to those of us who embrace material reality and scientific facts. Even today, with 381,000 Americans dead from COVID-19, we still see certain lawmakers who refuse to wear masks in Congress. Last week, in a shocking display of arrogance, ignorance or callous disregard for their fellow citizens, some of them insisted on remaining maskless while in secure holding rooms at the Capitol. They were there as a safety precaution, after hundreds of unmasked thugs illegally entered the Capitol in a grotesque and seditious act of political violence.

Then, shortly afterwards, still without regard for the gravity of this attack on our democracy, many of these same elected officials immediately resumed their attempt to overturn the outcome of a free election. Their speeches on the House floor were filled with the very same repeated lies that brought the angry mob into the heart of the Capitol.

The treachery and immorality of these actions will haunt our nation for many years to come.  

I’ve noticed that few CEOs, industry leaders, or trade associations are speaking up loudly about this cataclysm. WHY? The facts are clear, our moral compass is intact. Our democracy is at stake. It is time for leaders to LEAD. Our employees are looking to us to help lead the way back to normalcy, so we can focus on our crucial mission of delivering vaccines and therapeutics to the patients who need them. The US provides us with a vibrant, free operating environment to do all the things we do. When our country is in peril, our industry is in peril.

This week, I was surprised to hear from a group of folks concerned about making a public statement about the insurrection. Comments about the atrocities at the capital could anger the California Republican congressional delegation, and we can’t “afford” that.

Really? We, as an industry, should cower on the sidelines and avoid saying anything of substance about a violent mob attack on our democracy, because doing so might anger an elected official? I know professional politicians on both sides of the aisle, and I do not fear angering them. Neither should any self-respecting life science leader or citizen.

If one thinks attempting to overturn a free and fair election with violent insurrection is wrong, and anti-American, one should say so. I do think it is wrong, and anti-American.

If a person, president or otherwise, incites the kind of violence we have seen, that act demands accountability. Actions have consequences. Lawmakers should apply those consequences, period. Our democracy is at stake. Without a democracy, nothing else matters.

Paul Hastings is President and CEO of Nkarta Therapeutics and Vice Chairman of the Biotechnology Innovation Organization.

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