8
Mar
2021

Science Policy Chat: Join Rep. Auchincloss and Me on Clubhouse Mar. 10

Science is poised for a comeback in the public mind.

Most can agree that science, after years of getting beaten up, is leading us out of the crisis. It’s a source of national competitive advantage. This creates an opportunity to double down on investments, to test new ways of working, to shake some things up that need shaking.

Mark your calendars for 7:30 pm ET / 4:30 pm PT Mar. 10 on Clubhouse. I’m happy to discuss ideas for US science policy with freshman Congressman Jake Auchincloss. I’ll interview him for the first half-hour, followed by another half-hour of audience Q&A.

Rep. Jake Auchincloss, (Democrat, Massachusetts District 4)

Rep. Auchincloss is a Democrat from the Fourth District of Massachusetts. The district extends from the Boston suburbs of Brookline and Newton to the blue-collar industrial towns that stretch to Rhode Island.

He’s an ex-Marine who commanded infantry in Afghanistan and special operations in Panama. Before being elected to Congress in November, he served on the Newton City Council.

Science runs in the family – his father, Hugh Auchincloss, is the principal deputy director to Tony Fauci at the National Institute of Allergy and Infectious Diseases. His mother is Laurie Glimcher, CEO of the Dana-Farber Cancer Institute.

Rep. Auchincloss strikes me as well-schooled on the issues and eager to learn more about biotech. He’s potentially well-positioned as a young and energetic new member of Congress who doesn’t carry some of the baggage of past partisan fights. He identifies as an “Obama-Baker” voter. He’s thinking about bipartisan issues like NIH funding, and ways to invest in young people for bio-manufacturing jobs.

If you are new to Clubhouse, it’s audio-only, invitation-only, and iPhone-only at this point. It appears to be engineered in a way that elevates substantive conversations. It’s sometimes fun. It can be spontaneous, like old-school call-in radio. I’m looking forward to trying out a forum here with Congressman Auchincloss.

For those on Clubhouse already, follow Jake Auchincloss to save this session on your calendar. If you are an active TR subscriber and would like an invitation to join, ask me luke@timmermanreport.com

See you at 7:30 pm ET / 4:30 pm PT Mar. 10 on Clubhouse.

4
Mar
2021

Mental Health: A New Frontier for Biotech

Luke Timmerman, founder & editor, Timmerman Report

Mental health problems were mounting heading into this pandemic.

Now, the challenges are bigger and coming in waves.

There’s the grief. Think about all the family and friends of the more than 520,000 people who have died.

There’s anxiety about getting infected. There’s depression, and loneliness, that stems from social distancing. Addictions to alcohol and drugs are on the rise as people seek ways to cope. Post-traumatic stress disorder is a concern among our healthcare workers. The social media platforms are designed to maximize engagement — they keep us angry and outraged and ultimately exhausted by efforts to sell us stuff.

Data are starting to tell a story.

Depression rates have tripled during the pandemic, according to one study published in JAMA in September. Suicidal thinking among young people was rising before 2020, and surged last year to the point where one in four young adults in the US contemplated suicide, according to the CDC. Heavy drinking episodes shot up 41 percent among women, according to a RAND Corp. study.

Biotech has sprung into action like never before against the virus. Incredible progress has been made there.

What can industry do about mental health?

This week, some of you may have heard my interview with Bob Nelsen of ARCH Venture Partners on The Long Run podcast. The longtime VC, known for being ahead of the curve, spoke of increasing investment in mental health. This isn’t exactly new for him. Nelsen previously invested in schizophrenia drug developer Karuna Therapeutics and depression drug developer Sage Therapeutics.

What struck me most was that Nelsen wasn’t speaking exclusively about the next Karuna and other “hard science” approaches. He also spoke of the “soft” kind of interventions that incorporate some combination of other elements like, presumably, talk therapy, cognitive behavioral therapy, more convenient access, maybe some passive data collection from smartphones equipped with useful analytical capabilities, and maybe some pharmacologic therapy. He didn’t specifically mention the term “digital therapeutics” but there’s a lot of room to re-think mental health treatment in a broader way.

Thinking about those comments, I called a friend.

D.A. Wallach is a general partner at Time BioVentures, a biotech investment firm in the Los Angeles area. He’s curious about science and startups, and a longtime TR subscriber. He’s a successful recording artist. He kindly gave me one of his unpublished songs to start The Long Run podcast in 2017.

That music still fills me with joy each episode.

D.A. Wallach, general partner, Time Bioventures

I wanted to check in with D.A. partly for his thoughts on mental health investing, but moreso for his personal experience with the system.

He suffered a death in the family last year and has sought grief counseling.

Grief, like death, is something our society doesn’t like to talk about. “Nobody knows what to say to you,” D.A. told me.

“Grief isn’t a mental illness, but it’s sort of the equivalent of a mental injury,” he added. “I’d think of it almost like rehab. If you have an injury to your leg, you go to rehab. If you have an injury to your brain, you should go to rehab.”

Like so many people in America, he discovered that it’s a lot easier to get rehab for a leg injury.

First off, it was hard to find someone qualified to talk to. It didn’t take long to figure out why. A market failure was staring him in the face.

Healthcare insurance reimbursement rates are so low in greater Los Angeles that all the best providers refuse to take insurance, D.A. said. They take cash only. Some of the best charge up to $400 an hour.

That means they end up serving primarily wealthy clientele, leaving the average and the below-average practitioners for everyone else with insurance. “You’d have to be a saint to be an incredibly talented therapist and take insurance. You’re choosing to make less money,” D.A. said.

D.A. ended up finding a counselor. He said he’s satisfied with the quality of care he’s been getting via telemedicine.

What’s gnawing him now is the broken system. Los Angeles has developed what amounts to a two-tiered system – high-quality cash-only mental healthcare for the wealthy and lower-quality, insurance-based mental healthcare for everyone else.

That might be too generous of a description. It assumes people who aren’t wealthy can even get access to mental health services at all.

Limited access is the downstream manifestation of deeper ills. Our social-cultural stigma around mental health issues feeds directly into a political system that, as a result, provides only the most parsimonious support for mental healthcare. Naturally, we are left with this narrow funnel of qualified professionals attempting to grapple with millions of people in need.

The gap is enormous. One pre-pandemic study, conducted by the Cohen Veterans Network, a national nonprofit, and National Council for Behavioral Health, attempted to get its arms around this access problem with its inaugural “America’s Mental Health” report in 2018. (Full report).

According to the report:

  • 42 percent of the population considers cost and inadequate insurance coverage as a barrier to accessing mental healthcare.
  • Nearly one in five Americans, 17%, said they have had to choose between getting treatment for a physical health condition and a mental health condition because of their insurance.
  • Almost two-thirds of Americans, 64%, who have sought mental health treatment believe the U.S. government needs to do more to improve mental health services.
  • More than one-third of Americans, 38%, have had to wait longer than one week for mental health treatments.
  • Almost half of Americans, 46%, have had to or know someone who has had to drive more than an hour roundtrip to seek treatment.

These numbers were disturbing in 2018. One year into the COVID-19 pandemic, we need an update.

Jonathan Shaywitz, psychiatrist

Jonathan Shaywitz, a board-certified psychiatrist in Los Angeles with a medical degree from Harvard Medical School, said the demand for mental health services is “the highest it has been for some time.” (If the name’s familiar, he’s the younger brother of TR healthtech columnist David Shaywitz.)

Jon Shaywitz currently handles outpatient services, as well as inpatient services at five facilities. He’s busy. Despite efficiency gains that make it easier to accommodate new patients through telemedicine, Shaywitz said the waiting list for new patients extends out for three months.

Even with increasing awareness of the need, mental healthcare still doesn’t get reimbursed at the same level as physical healthcare. As Jon Shaywitz said:

“This is an area that still needs work — while the law has attempted to create parity between physical and mental health — we are still lacking regarding parity of reimbursement for mental health. Due to the lack of procedures in mental health, our currency is time and talking and unfortunately insurance companies don’t reimburse for time/talking as they do for procedures or imaging. While some of my colleagues still do private practice, the majority are leaving practice and joining large organizations/companies (community psychiatry/Kaiser) where they are salaried and who take insurance.”

With 520,000 dead from COVID-19, how many family members and friends of the deceased out there could use some help coping with their grief? How many people could use help for depression and anxiety?

What can biotech do that might make a difference?

D.A. hasn’t yet invested in mental health, but he’s been studying the opportunities. It’s an area that can’t simply be addressed with pharmacologic solutionism, where the pill is everything, he says.

A more integrated approach that might involve some combination of tech-enabled diagnostic data, behavioral coaching, new treatments, and the empathetic touch from skilled professionals is more likely to succeed. Smoking cessation is one potential model, where the drug is just one tool. Psychedelic therapies for mood disorders are another potential arena for integrated investigation (see in-depth TR coverage of psychedelic drug R&D, September 2020).

Those of us who aren’t neuroscientists or psychiatrists or venture capitalists can do a few things, too.

We can create situations in our companies when it’s OK for people to take a break when they need it. We can lean on our health insurance providers to improve access to mental health services. We can pressure elected officials to raise awareness and provide more funding for reimbursement.

We can support more basic research, from people like Harmit Malik, a member of the National Academy of Sciences. He bravely admitted in a public forum — see below — that many scientists are struggling.  

We can make ourselves aware of the suffering of our friends and colleagues that’s often buried beneath the surface. We can choose to uplift. We can be kind.

We can do more for mental health.

TR readers can continue on for a roundup of the deals and financings and other major developments of the week in biotech.

Vaccines

Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. NEJM. Mar. 3. (Kimberly G. Blumenthal et al Mass General Brigham)

Fauci: U.S. must stick with two-shot strategy for Pfizer-BioNTech, Moderna vaccines. Washington Post. Mar. 1. (Dan Diamond)

India-based Bharat Biotech reports vaccine trial results from 25,800-volunteer study with 81 percent efficacy against COVID-19. (Bharat Biotech statement)

Science of SARS-CoV-2

High resolution profiling of MHC-II peptide presentation capacity, by Mammalian Epitope Display, reveals SARS-CoV-2 targets for CD4 T cells and mechanisms of immune-escape. BioRxiv. Mar. 2. (Jan Kisielow et al Repertoire Immune Medicines in Cambridge, Mass.)

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science. Mar. 3. (Nicholas Davies et al London School of Hygiene and Tropical Medicine)

Science Features

Data That Mattered

San Francisco-based VIR Biotechnology and GSK had some bad news from the NIH-sponsored ACTIV-3 clinical trial that evaluated its therapeutic neutralizing antibody against COVID-19 in hospitalized patients. The Data Safety Monitoring Board recommended enrollment in the drug arm be closed after seeing data “that raised concerns about the magnitude of the benefit.” There were no reported safety signals, the companies said. VIR shares fell 28 percent on the news. (NIH Statement on ACTIV-3, which includes antibodies from VIR and Durham, NC and Beijing-based Brii Biosciences.)

Financings

Cambridge, Mass.-based eGenesis said it raised $125 million in a Series C financing. The company uses CRISPR to engineer animal tissues for transplant into humans – starting with kidneys for kidney failure and islet cells for type 1 diabetes.

Foresite Capital raised $969 million in its Fund V and Opportunity Fund.

Paris-based Sofinnova Partners, a European-focused life science fund, raised a new $540 million late-stage crossover fund.

Berkeley, Calif.-based Caribou Biosciences raised $115 million in a Series C financing to use its CRISPR technology to further advance work on allogeneic, off-the-shelf engineered immune cell therapies for cancer. Farallon Capital Management, PFM Health Sciences, and Ridgeback Capital Investments co-led.

Philadelphia-based Century Therapeutics raised $160 million in a Series C financing. The company is developing induced pluripotent stem cell-derived therapies for cancer. Casdin Capital led. (Listen to Century chief strategy officer Janelle Anderson on The Long Run podcast, Aug. 2019).

Waltham, Mass.-based Morphic Therapeutic seized upon its surging stock price to put together a new offering of shares at $70 apiece. The company, the developer of oral small molecule integrin inhibitors, took home a fresh $245 million from the offering. (See Tuesday’s TR coverage of Morphic’s proof-of-concept clinical data).

San Diego-based Janux Therapeutics raised $56 million in a Series A financing led by Avalon Ventures. The company is developing “Tumor Activated T Cell Engager” technology.

South San Francisco-based Amunix Pharmaceuticals said it raised $117 million in a Series B financing led by Viking Global Investors. The company is developing protease-activated T cell engagers and cytokines for the treatment of solid tumors.

UK-based Exscientia, an AI drug discovery company, said it raised $100 million in a Series C financing that included Blackrock funds, Novo, Bristol Myers Squibb and others.

MassBio released a report this week finding that Massachusetts biotech companies raised a record-breaking $5.8 billion combined in venture capital in 2020. That shattered the previous record of $4.8 billion from 2018. A remarkable 21 biotech companies from Massachusetts alone went public last year, raising another $3.9 billion, the trade group said. (Summary and link to full report).

Access and Manufacturing

Merck, likely suffering from a bruised corporate ego after its COVID-19 vaccine candidates failed, agreed to help Johnson & Johnson manufacture its adenoviral vaccine that was just authorized for distribution by the FDA. The Biomedical Advanced Research and Development Authority (BARDA) agreed to provide $269 million to Merck to set up the necessary processes to make the J&J vaccine. President Biden later said the plan is to make enough vaccine to vaccinate all American adults by May 31. Previously, Novartis and Sanofi said they would help produce the Pfizer / BioNTech vaccine.

WuXi Apptec completed its acquisition of Oxgene, a UK-based contract manufacturer of cell and gene therapies.

San Diego and Boston-based Resilience acquired two new biotech drug manufacturing facilities. One is the 310,000-square foot landmark along the Charles River in Boston, originally developed by Genzyme and now part of Sanofi. The other is a 136,000-square foot facility in Mississauga, Ontario. Resilience said it has now assembled a network of factories with 750,000 square feet in North America. It will continue to invest in upgrading and adapting the facilities for production. (Bob Nelsen of ARCH Venture Partners, co-founder of Resilience, discussed the company in my latest Long Run podcast).

Cambridge, Mass.-based Biogen said it plans to build a new gene therapy manufacturing plant in Research Triangle Park, North Carolina. It’s planning to scale up future gene therapies for neurological disorders. Biogen plans to hire 90 new workers there, and invest $200 million.

Germany-based CureVac, a less-known mRNA vaccine and therapeutics developer, agreed to work with Novartis to help scale up production of its mRNA vaccine candidates in the second quarter of 2021. The companies said they expect to be able to make 50 million doses at a Novartis facility in Austria in 2021, and another 200 million in 2022.

Deals

Amgen agreed to pay $1.9 billion to acquire South San Francisco-based Five Prime Therapeutics, a company that’s been on a 20-year odyssey in biologic drug discovery and development. Amgen pointed to its interest in bemarituzumab, an anti-FGFR2b antibody being prepped for Phase III study in gastric cancer. (Five Prime founder Lewis T. “Rusty” Williams is a member of my Everest Base Camp trekking expedition to benefit Fred Hutch. It’s been on hold because of the pandemic, and now looks like a Spring 2022 event. Can’t wait to ask him about Five Prime on the trails of Nepal).

Takeda Pharmaceuticals took back full rights to soticlestat (TAK-935/OV935) for developmental and epileptic encephalopathies, including Dravet syndrome and Lennox-Gastaut syndrome. New York-based Ovid Therapeutics had been its development partner since 2017, and helped drive the asset through Phase II testing. To get back full global rights, Takeda agreed to pay Ovid $196 million at closing and another $660 million in milestones, plus royalties. Ovid stock, beaten down after a clinical failure with its candidate for Angelman syndrome, jumped back up 37 percent on the news that it was getting the cash infusion.

AbbVie obtained an exclusive option to acquire San Francisco-based Mitokinin once it completes IND-enabling studies. Mitokinin is developing drugs to increase the activity of PINK1 a master regulator of mitochondria. The company, spun out of work at UCSF by Nicholas Hertz and Kevan Shokat, is betting that by increasing the activity of PINK1, it can address one of the underlying problems that contributes to Parkinson’s disease. Terms weren’t disclosed. The startup was backed by Mission Bay Capital.

Santa Clara, Calif.-based Agilent Technologies agreed to pay $550 million in cash at closing, plus $145 million in milestones, to acquire Kirkland, Wash.-based Resolution Bioscience, which uses liquid biopsies and next-gen sequencing technology for the diagnosis of cancer.

The Defense Advanced Research Projects Agency (DARPA), the government agency that made a visionary investment in mRNA vaccines for pandemic preparedness in 2013, awarded a grant to Georgia Tech Research Institute to develop technology to detect SARS-CoV-2 in the air in real-time. San Diego-based Cardea Bio is a subcontractor on the deal. If successful, the detectors could conceivably be used in schools, offices, restaurants and other indoor environments where people might wonder about whether the virus is circulating.

Seattle-based Presage Biosciences said it raised $13 million in a round that included $7 million from new investors LabCorp Venture Fund, Bristol Myers Squibb, and InHarv Partners Ltd. Presage also said it established new research agreements with Merck and Maverick Therapeutics. The company uses intratumoral microdosing to evaluate several cancer drugs simultaneously in Phase O trials.

Grail, the Menlo Park, Calif.-based developer of next-gen sequencing enabled tests for early detection of cancer, said it struck an agreement with Providence, a major West Coast hospital network, to offer Grail’s Galleri test that’s scheduled to become available in the second quarter of 2021. It’s not a surprise that Providence would be an early adopter of this next-gen sequencing enabled healthcare application – it acquired the Institute for Systems Biology, led by DNA sequencing pioneer Leroy Hood, in Mar. 2016. (Read “Hood: Trailblazer of the Genomics Age”).

Our Shared Humanity

The California Life Sciences Association (CLSA) published a Racial & Social Equity Plan, which includes specific actions and a $1 million commitment over three years to get the ball rolling.

Regulatory Action

The FDA released its Data Modernization Action Plan, about 18 months in the making. There are three main elements – identifying valuable demonstration projects, developing consistent and repeatable data practices across the agency, and build up and sustain a stronger talent network (internally and with external partners). (Executive Summary)

Merck said it’s voluntarily withdrawing one of its approved indications for the PD-1 inhibitor pembrolizumab (Keytruda). It’s for metastatic small cell lung cancer. The drug was granted accelerated approval by the FDA in 2019 on a surrogate endpoint – tumor response – but full approval was supposed to be contingent on demonstrating an Overall Survival benefit. The drug failed to clear that higher bar of evidence in January 2020, and now the indication is being taken out of the prescribing label.

The FDA, in an unusual public statement, waded into a mess around Brainstorm Cell Therapeutics and its experimental NurOwn treatment for amyotrophic lateral sclerosis. The company announced Feb. 22 what looked like unequivocal bad news – that the FDA said it doesn’t have enough evidence of efficacy to submit a Biologics License Application. The company, however, appeared to muddy the waters and perhaps stir some false hope by adding that “FDA advised that this recommendation does not preclude Brainstorm from proceeding with a BLA submission.”

The FDA — under pressure for years to release full Complete Response Letters to investors, doctors and patients so that companies can’t engage in one-sided and misleading communications about new drug applications – decided to clear things up. The agency said:

Although FDA generally cannot provide confidential information about unapproved products, given the tremendous public interest in this product, we have concluded that it is important to provide high-level information about the status of the NurOwn development program.

With the recent completion of a randomized phase 3 controlled clinical trial comparing NurOwn to placebo, it has become clear that data do not support the proposed clinical benefit of this therapy. Data indicated that none of the primary or secondary endpoints were met in the group of patients who were randomized.

The agency got into some more specifics in case anyone is wondering if this is a close call, or the agency is being wishy-washy. The take-home lesson: the FDA has to step up its communications game in the age of transparency, especially with companies who are leaving people with misleading impressions.

The FDA granted a label expansion to Pfizer to start marketing lorlatinib (Lorbrena) as a treatment for patients with newly diagnosed ALK-positive non-small cell lung cancer. The FDA also converted an accelerated approval from 2018 into a full approval, based on results from the CROWN study which showed a 72 percent reduced risk of disease worsening or death for ALK-positive patients on the medicine.

Personnel File

Cambridge, Mass.-based Fulcrum Therapeutics said CEO Robert Gould is retiring at the end of March, and will remain on the board of directors and function as an advisor. The rare disease drug developer is promoting chief operating officer Bryan Stuart to president and CEO. (TR coverage of Fulcrum, Sept. 2018).

Cambridge, Mass.-based Solid Biosciences, the developer of gene therapy for Duchenne Muscular Dystrophy, said Erin Powers Brennan was hired as chief legal officer and Joel Schneider was promoted to chief operating officer.

Dilawar Syed was nominated by President Biden to be the deputy administrator of the Small Business Administration. He’s currently CEO at Lumiata, an AI-for-healthcare company.

Waltham, Mass.-based Dyne Therapeutics, the developer of treatments for muscle diseases, said it hired Wildon Farwell as chief medical officer. He was VP of neuromuscular at Biogen.

Cambridge, Mass.-based eGenesis, the CRISPR for xenotransplantation company that recently raised $125 million in a Series C financing and is almost surely getting dressed up for an IPO, hired Sapna Srivastava as chief financial officer. She previously worked as chief financial and strategy officer at Abide Therapeutics, and before that had a similar job at Intellia Therapeutics.

Chicago-based OMX Ventures, a new fund that says it’s investing in companies “at the intersection of biology, big data and engineering,” hired Jamie Kasuboski as a vice president on its team of investing professionals. Jamie previously worked at RA Capital, and Boehringer Ingelheim Venture Fund. Kevin Ness, former CEO of Inscripta, also agreed to become an advisor to OMX.

San Diego-based Viracta Therapeutics, a company working on treatment for viral-associated cancer, added Stephen Rubino and Barry Simon to its board of directors. The company also announced a series of promotions in operating roles.

4
Mar
2021

What Pharma Data Scientists Can Learn from SpaceX, Health System Barriers, & the FDA

David Shaywitz

Three quick data science items:

1) How pharma companies could engage more constructively with data scientists.

2) How health system barriers to data sharing inhibit robust evaluation of the underlying science.

3) The savvy way the FDA is thinking about data science.

  1. Learning From SpaceX

On Wednesday, Elon Musk’s SpaceX landed a prototype spacecraft vertically on the ground — a remarkable engineering accomplishment, and one with important lessons for pharma companies harboring digital aspirations.

SpaceX has been working on this vertical landing for a while. Two previous prototypes crashed to earth with spectacular explosions; even Wednesday’s successful landing was followed in minutes by another large explosion, perhaps because of a “leak in a propellant tank,” the New York Times suggested.

While presumably not pleased by these failures, Musk appeared to see them for what they were, part of the inevitable iterative learning experience that’s required for success with any new technology.

In contrast, many of the data scientists I know in pharma companies feel they have far less room for error. The institutional powers that originally hadn’t welcomed such data scientists at all now have let them in, but often under the equivalent of Dean Wormer’s “Double Secret Probation” (cue up the scene from “Animal House”). 

Many data science teams in pharma feel they have a single chance to prove themselves, and if whatever they are trying to do doesn’t work brilliantly, the data scientists worry they’ll be booted, the technology dismissed as not ready for prime time. 

This seems precisely the wrong mindset for effective technology implementation. The truth is that it takes time and engagement to figure out any new technology – to learn how to use it effectively in a particular context. The way you do this is by trying something provisionally, seeing what works and what doesn’t, making adjustments, and quickly trying again.

It’s an iterative process that allows for rapid adaptation. This allows far more agility than more classic organizational approaches that insist on the pre-specification of almost everything.

Giving new technology a single shot, and requiring perfection straight out of the gate, sets it up for failure. This sort of rigid thinking ultimately doesn’t allow pharma companies to access the power and benefits that data science and emerging technologies have to offer.

  1. Irreproducible

The core premise of science lies in its reproducibility; my description of an experiment should afford you the opportunity to evaluate my math and methods, and to obtain the same results in your own hands.

But this can be a real challenge when the underlying data aren’t shareable – as is often the case with health data studies. 

This came up most recently in a departmental journal club I attended, where a guest professor led a captivating discussion of a just-published paper (not hers) that described a particular application of EHR data. 

Towards the end of the hour, the focus turned to replication – were the raw data underlying the conclusions in the paper available for review?

Here’s what the text actually stated:

“DATA AVAILABILITY
The data used for this study are available from the [redacted] health system,
but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with the permission of [redacted] Health System.“ (redactions mine).

The way this statement was universally interpreted by 30 or so experienced attendees of this journal club was, as several people actually said, “good luck.” 

It was universally understood that no one was ever going to actually access these data. 

A couple of points: the first is that health systems typically see no upside in sharing their data. They generally only share the minimum amount possible and only after the maximum amount of duress.  Many reasons are often invoked, but a key driver is that there’s no economic incentive for health systems to share, and plenty of reasons not to (including fear of divulging information to competitors). Hence, we are stuck in something of a rut with minimal data sharing.

It’s not just health systems, however. Individual researchers tend not to be especially eager to share their data either.

This isn’t universally true, of course, and important exceptions exist. Some scientists are quite open with their data, and have laudably managed to simultaneously advance both science and their careers – the pioneering work of Daniel MacArthur on the Exome Aggregation Consortium (ExAc) comes to mind.  

Nevertheless, many investigators resist sharing “their” data – for reasons that are understandable, if perhaps not always justified. After going through the often arduous process of gathering clinical data, researchers are inclined to guard it so their own team can benefit from this intense upfront effort – a key component of the recent “data parasite” debate. Other times, researchers worry the data will be coarsely reanalyzed, perhaps without adequate understanding of relevant nuance, and legitimate conclusions called into questions by naïve, crusading, attention-seeking critics — a plausible concern.

From the perspective of many researchers, what’s the upside?  Many would say: just about none.

This situation evokes the classic academic joke in which a young faculty member is advised to study seven-year locusts – by the time the work can be called into question, the professor will have already achieved tenure!

But to the extent that conclusions drawn from health data can’t be re-evaluated by others because of issues with data access, the science may not be adequately pressure-tested, and flawed methods may remain unchallenged. 

This is bad for the discipline of health data science, and ultimately bad for patients.

  1. Good News From FDA

Finally, some welcome good news from the FDA, which just released its Data Modernization Action Plan (DMAP) – a companion to the previously released Technology Modernization Action Plan.

I was especially struck (though not surprised, given what DMAP co-author and deputy FDA commissioner Dr. Amy Abernethy has consistently preached) by the emphasis on “high value driver projects.” Dr. Janet Woodcock, acting FDA commissioner, is the other co-author.

As the document states:

“The DMAP is anchored on driver projects that help generate value while building critical capabilities. Driver projects for DMAP are defined as initiatives with measurable value that help multiple stakeholders envision what is possible, allow technical and data experts to identify needed solutions, and develop foundational capabilities. This strategy is distinctly different from focusing on data collection and then looking for questions the data can answer.” (emphasis in original).

In short, this approach gets right what so many get wrong – the importance of collecting and evaluating data with a specific purpose in mind. The intended purpose strongly influences what data are needed and the degree of subsequent validation and refinement required. 

This mindset is likely to be far more productive than approaches that robotically dump all data into some kind of lake and then proudly reports how big the lake is. 

The DMAP approach is so much savvier, and far more likely to yield meaningful results. This methodology also inherently refines the mechanism of fit-for-purpose data collection; as Dr. Abernethy has stated on a number of occasions, you don’t truly understand a dataset, including its limitations, until you really start to use it.

If FDA starts with these well-defined driver projects, and has success, then there will be more natural momentum to spread the successful practices across the agency.

The pragmatic driver project approach (versus creating a data lake upfront and hoping to figure out how to capture value later) is one that many pharma companies and healthcare organizations would do well to emulate.

3
Mar
2021

J&J Vaccine: One Dose Delivers Strong Immune Response and Protection

Larry Corey, MD

The mRNA vaccines from Pfizer / BioNTech and Moderna have understandably dominated the news, but this past week was Johnson & Johnson’s turn in the spotlight with another important contribution to the COVID-19 vaccination effort.

The FDA’s vaccine advisory committee recommended, and the FDA authorized the vaccine, based on results from the 44,000-person Operation Warp Speed–sponsored ENSEMBLE clinical trial evaluating the Johnson & Johnson (J&J) Ad26 vaccine.

This vaccine uses a different way for the spike protein transcript to be introduced into the cells. This transcript, essentially the same as with the mRNA vaccines, is carried in—not by a lipid particle encasing the RNA of the SARS-CoV-2 spike protein—but by a genetically engineered type 26 adenovirus, which has the SARS-CoV-2 spike gene encoded into it.

What happens next is similar to RNA vaccines—the spike protein is made, and the immune cells begin to recognize the new structure and initiate the process of defining anti-SARS-CoV-2 antibodies and T cells to defend against it.

The J&J vaccine has several different immunological characteristics than the RNA vaccines. The neutralizing antibody levels generated by a single dose are not nearly as high as those seen in either the Moderna or Pfizer vaccines. But the T-cell responses in the J&J vaccine, what we call cell-mediated immune responses, appear higher, especially in those we call killer T cells, or the CD8+ cytotoxic T cells, which seek out and destroy cells that are infected with the virus.

These killer T cells are an important part of the story, especially because they tend to both arise earlier and can persist at effective levels with less variation in titer than neutralizing antibodies.

Another important difference in the J&J vaccine trials is that they were designed through an international lens: J&J is a worldwide company with high production capabilities, which eases the burden of distribution. The Ad26 vaccine doesn’t have the cold-chain requirements of the mRNA vaccines and is quite stable at 4 degrees Celsius for extended periods of time.

The Ad26 vaccine platform, importantly, has a long track record and is well-known around the world. It has been used in Africa for preventing Ebola infections, in which the Ebola surface protein is placed into the Ad26 shuttle vector. The Ebola vaccine has been WHO (World Health Organization) authorized for preventing Ebola infections and has been widely administered to women of child-bearing age, pregnant women, and children. The Ad26 platform is also under investigation in elderly adults for RSV (Respiratory Syncytial Virus) infections and in Africa and South America for a preventive HIV vaccine.

The ENSEMBLE Trial was conducted in the United States, Mexico, South Africa and in South America—Argentina, Brazil, Chile, Colombia, Peru. The trial enrolled approximately 44,000 persons, of which 19,302 were in the US; 479 in Mexico; 17,426 in South America; and 6,576 in South Africa. The geographic diversity turned out to be an important feature of the data set, in the context of a pandemic virus with evolving variants becoming prevalent in different parts of the world.

The initial analysis from the J&J trial data provided an extensive look at the vaccine’s effects. More than 400 cases of COVID-19 were reported in the data set: this large data set allowed for a reliable look at the efficacy by country and region without analytical problems posed by too-small sample sizes.

Trial planning was done before the new variants were identified. Hence, it was both fortuitous and extremely lucky that within two months of identifying variants of concern, we “caught” the wave of the introduction of these variants in both Brazil and South Africa. Thus, we now have real-world data on how the B.1.351 variant that has multiple resistant mutations does against a COVID-19 vaccine with the Wuhan-like virus as the immunizing strain.

The point estimates for mild-to-moderate disease showed some difference by region—after one dose, the point estimate was 72% in the US; in Brazil, 71.5%; and in South Africa, 57.3%. This was far better than the point estimate of the AstraZeneca vaccine to the B.1.351 variant (10.1%).

Fortunately, and importantly, the efficacy against severe COVID-19 disease was high in all countries. In the United States, there was only 1 case of severe disease in the vaccine group, 7 in placebo. For South Africa, it was 4 in the vaccine group, 22 in placebo; for Colombia, 1 in the vaccine group, 11 in placebo; and in Brazil, 1 in vaccine, 8 for placebo. So, in this one trial, the J&J one-dose vaccine offered anywhere from 82% to 90% protection against severe disease. The 6 deaths from COVID-19 in South Africa were all in the placebo group.

There is a question about whether the J&J vaccine will be more effective in a two-dose formulation. We don’t know that answer yet. But for a one-dose vaccine, these data are better than I initially expected. To illustrate this, I’ll include the two Kaplan-Meier curves below, which nicely demonstrate the J&J vaccine efficacy on moderate-to-severe disease in South Africa and the disease in severe COVID-19 for the entire study.

The ENSEMBLE study outlines the complex nature of the human immune response to vaccination and the subsequent outcome.

Let’s come back to the question about what the vaccine’s effect on the immune response, and how that immune response translates into protection against severe disease.

The antibody levels with the one-dose J&J vaccine are much lower than what we see with the mRNA vaccines and yet its effectiveness against preventing severe disease—particularly against the B.1.351 South African variant—is quite similar.

Why?

What components of the immune response are central to this protection for severe disease? Antibodies? T cells? Both? These are issues we must decipher, and many of us expect that having high levels of CD8+ T cells activated to recognize the virus is an important part of the reason this adenoviral vaccine provides such excellent prevention against severe disease. It is a nice scientific problem to have, how to go from 85% to 100% efficacy.

The question in front of us today is how do we use this vaccine in our country and globally? To date, it is the only vaccine in which we have good clinical data about both its effects in mild disease as well as severe disease with the South African variant — the cause for recent concern worldwide.

The data from the two mRNA vaccines suggest that they are able to effectively handle the other emerging B.1.1.7 and the California 20.C variants in the US. It is, however, the South African variant that we are concerned about with respect to all the platforms in our current portfolio. As I mentioned earlier, the South African variant is one in which the two-dose AstraZeneca vaccine (chimp adenovirus-based vector) showed no effectiveness in reducing even mild-to-moderate disease in young, healthy South Africans. The point prevalence was 10% with the two-dose AstraZeneca vaccine versus 59% in the one-dose J&J vaccine.

Seeing the disappointing efficacy against the B.1.351 variant that was quickly evolving into the dominant local strain, the South African government—after purchasing and receiving more than a million doses of the AstraZeneca vaccine—made the decision to halt administration of the AstraZeneca vaccine to healthcare workers. Instead, South African authorities opted to work with J&J to obtain its vaccine in an expanded access program. This dynamic interaction between clinical trial data and health care policy is what all these trials have been about. It’s about following the data and adjusting accordingly.

The J&J vaccine is an extremely well-tolerated vaccine—less than 0.5% of enrollees had any grade 3 side effects. It is easy to transport and distribute without the strict cold-chain requirements. There is extensive clinical experience with pregnant women and children. Even though there is somewhat less efficacy with the J&J vaccine in preventing illness—such as a cough, fever, headache, or sore throat—than with the mRNA vaccines, the data from the J&J trial show that the severity of illness is significantly less after vaccination.

This vaccine will keep people out of the hospital, and prevent people from dying. I am gratified to see that both the FDA and CDC ACIP (Advisory Committee on Immunization Practices) advisors endorsed use of this vaccine for those 18 years of age and older. We are pushing J&J to conduct its pediatric trials expeditiously so the advantages of a one-dose vaccine can be used to help get children immunized and back to school by the fall term.

Combating this outbreak requires achieving high vaccine coverage – the percentage of the overall population that’s received a vaccine. The higher that number goes, the greater the chances are that we can stop the spread of new variants.

For all these reasons, the data support the widespread use of this vaccine in our country and around the world.

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.

1
Mar
2021

Investing in Manufacturing, Mental Health & More: Bob Nelsen on The Long Run

Today’s guest on The Long Run is Bob Nelsen.

Bob is the co-founder and managing director of ARCH Venture Partners. He’s one of the most prolific, and successful, venture capitalists in biotech history.

Bob Nelsen, co-founder and managing director, ARCH Venture Partners

Bob likes to get involved in startups in the earliest days. He is willing to stick his neck out, and generally do things that might seem weird or premature to most people at the time.

He was an early investor in gene sequencing technology with Illumina, RNA interference with Alnylam, cell therapy with Juno, and infectious disease with VIR.  

He dreams big, thinks ahead of the pack, and isn’t afraid to take big risks.

Bob was one of the first people I met when starting out covering biotech 20 years ago. I’ve interviewed him too many times to count. In 2016 when he made the Forbes Midas List, I wrote that Bob is “whip-smart, quirky, funny, profane, audacious and quotable.”

Still true. He’s always been a character, love him or hate him for whatever reason.

For this conversation, I focused mainly on what Bob and the ARCH investing team are doing with the latest fund, Fund XI. It’s a $1.85 billion colossus.

He talked some about priority indications for investment, including some new higher priorities coming out of the pandemic – especially mental health and bio-manufacturing. I didn’t ask Bob about his personal story, as others have covered it before. (Matt Herper wrote a nice profile of Bob for Forbes in 2016).

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

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The company leverages gene editing, machine learning, and automation to build platforms for science at scale. By enabling unprecedented access to cutting-edge genome engineering, Synthego is at the forefront of innovation, accelerating the development of truly engineered biology.

Synthego’s expertise in CRISPR, combined with their proprietary software and technology, means you have a trusted partner whether you are at early stages of basic research or ready to take your therapy to the clinic.

Visit Synthego.com/timmerman to learn more.

Now, please join me and Bob Nelsen on The Long Run.

27
Feb
2021

Digital Tools Helped Enable COVID-19 Vaccine Trials. What are the Lessons Learned?

David Shaywitz

Digital tools played a critical role in accelerating the development and evaluation of COVID-19 vaccines, according to leaders at the companies driving this effort. 

Speaking at a recent virtual panel discussion organized by the Galien Foundation (and available here), leaders from Pfizer, AstraZeneca, Janssen, Moderna, and the CRO IQVIA shared their experiences leveraging digital tools for vaccine development.

Data Deluge

The first striking observation was simply the staggering scale and raw intensity of the undertaking.  Pfizer’s phase 2/3 study, for example, involved around 44,000 subjects, 156 research sites in six countries – and was executed in four months. Janssen shared similar data – a 45,000 person study, which managed to recruited 3,000 subjects on a single day.

These are eye-popping figures.

The volume and velocity of trial data – far outside the norm for conventional clinical studies – presented urgent challenges to vaccine developers, who responded by leaning into existing data management platforms, and supplementing them with fit-for-purpose tools such as highly customized dashboards.  This enabled study sponsors to monitor a range of vital study parameters — including site start-up, participant diversity, data entry, and data cleaning — and where necessary, make adjustments on the fly. 

A particular challenge for COVID-19 studies was anticipating where the virus was likely to be most prevalent – regions where the impact of the candidate vaccine would be most readily ascertained.  All the companies claimed to use a range of analytic techniques and diverse data sources (such as mobility data) to identify the most promising study locations.

The “Last Mile Touch”

Another important challenge highlighted by several speakers involved the implementation of technology, the “learning curve that we had to bring our sites and investigators and staff on board,” as one leader put it. 

Some companies took to deploying “virtual study coordinators” who were “trained up on the tech” and could “bring folks up to speed with the new mobile devices, and help with the back office.” Help desks were staffed up to manage the increased call volume, and tech coordinators were also assigned to research sites. 

Takeway: Technology may be powerful, but people are required to make it effective. 

As one speaker said:

“Technology works, but actually technology had to be complemented with humans….you do need that last mile touch…one of the things we realized in the scale up is how do you bring the human and technologies together, complementing each other so that we can make sure this delivers the promise, what it’s designed for.”

Moreover, study sponsors discovered that technology wasn’t equally embraced by all participants, “some of whom will find it easier to use a tool than others.”  

Consider the question of using an electronic diary versus a paper diary.

“Sure,” a speaker suggested, “the electronic is easier for us, for many people around the world, actually putting X’s on a piece of paper is easier than finding the app on their iPhone.” 

Another speaker noted many participants “would not necessarily respond to super techie reminders,” and thus sponsors recognized the need to add “at times the human touch to really complement the technology when we need it.”

The New Normal?

The speed of COVID-19 vaccine development inevitably raises the question of whether the approaches used to accelerate the process will become standard, and represent the new normal. 

On the one hand, there was clearly the ambition to leverage the tools and learnings from the vaccine experience, as suggested by one company’s mantra, “no going back.” 

At the same time, speakers acknowledged just how exceptional these circumstances truly were – from the worldwide prevalence of disease to continuous (versus episodic) engagement with regulators, cited by all sponsors as critical to study acceleration. COVID-19 vaccine studies also operated under economics, and in the presence of resources that were far from typical.

The toll on all the people involved in executing these studies was also palpable – speakers described teams working “flat out” for months, to the point of utter exhaustion. It felt like the sort of superhuman effort that could be mustered and sustained only for a cause as cataclysmic as a global pandemic.

The ability of data platforms to support (apparently effectively) large volume COVID vaccine studies may also not speak to their ability to support the more usual trials companies sponsor, where the numbers are significantly lower, cost is a more pressing factor, and identifying and recruiting difficult-to-find subjects a recurring challenge. It will also be important to pressure-check the triumphalist story shared by these digital champions and stakeholders against reality, to the extent such an independent after-action report is possible.

Fix vs Reinvent?

Perhaps the most intriguing observation emerging from the discussion was a point made by several speakers, and elegantly summarized and extended upon by the moderator, Jessica Federer (former Chief Digital Officer of Bayer, and currently Managing Director of Huma Health):

“Something that we hear from so many pharmaceutical companies and manufacturers [is] that we’re using new technology, but we’re retrofitting our old processes and we’re trying to do the same things we’ve always done using new tech. And that clash is creating a complexity and it’s not shortening the timelines and it’s causing barriers. And the challenge for us as an industry is to  try to do new things with new tech instead of the same old ways we’ve always done it.”

This perfectly captures the challenge of technology implementation in medicine, as I’ve discussed here.  One prominent example: electronic medical records, which hew closely to traditional physician notes, in a deliberate effort to ease adoption. 

The “fix vs reinvent” tension turns out to pervade the history of technological innovation (see here), including the classic example of electrification of factories. Data suggest that electrifying legacy factories – historically built in a dense three-dimensional configuration to leverage the single source of steam power – by swapping in an electrical generator didn’t do much to goose productivity. It wasn’t until innovators completely rethought the design of the factory and developed an entirely new layout and workflow that huge productivity gains were finally achieved.

In the case of factories, innovation was spurred by the economic gains associated with improved efficiency. In medicine, the economic incentives, as Todd Park recently discussed, can be far less intuitive – perhaps the most substantial barrier faced by aspiring healthcare innovators. (Harvard’s Zak Kohane makes a similar point here).

Bottom Line

Vaccine developers leveraged digital platforms to manage the staggering data requirements and clinical trial needs. Successful implementation of new technologies required people to assist with the last mile. The exceptional global circumstances associated with vaccine development suggest we ought to exercise caution before generalizing from the experience, even as we’re inspired by the results. Coming up with novel ways to leverage technology for evidence generation, rather than adapting new technologies to established procedures, represents a future frontier; aligning economic incentives will be critical.

27
Feb
2021

AI in Healthcare: Harvard’s Zak Kohane on What Innovators Are Missing

David Shaywitz

Despite, or perhaps because, of the incessant hype, it can be difficult to assess the impact AI is actually having in medicine. 

Enter Harvard’s Zak Kohane, who in a remarkably astute recent seminar, available on YouTube, highlighted the opportunities for AI in healthcare while revealing some of the ways AI is falling short – generally by being deployed in a rote fashion that neglects the dynamics of patient care.

Kohane views medicine as “the great frontier,” with “boundless opportunity” – though he emphasizes that “the complexity and breadth of medicine require a multidisciplinary approach.”

Many data scientists, Kohane observes, are enamored of the promise of electronic health data, yet lack an intuitive understanding of the context in which these data were developed. The context is critical, Kohane emphasizes, adding that it’s essential to tease apart at least two very different dynamics captured in medical records data: the physiology of patients and the behavior of doctors.

Zak Kohane, Chair of the Department of Biomedical Informatics, Harvard Medical School

Consider the observation that a patient with a normal white blood count at 3 am has a far worse prognosis than a patient with an abnormal white blood count at 3 pm.

A tech guru to whom Kohane presented these data suggested that perhaps this reflected a circadian pattern. 

But ask any physician, and the answer is obvious: the only reason anyone would have a blood draw at 3 am would be if something was desperately wrong. In contrast, labs in the afternoon are drawn routinely, and it’s fairly common, incidentally, to see values outside the standard reference range.

Kohane cites a celebrated paper by Google demonstrating the potential of AI to predict hospital readmission rates from EHR data. But hold on for a second, he says. He then shares additional research revealing that nearly all the power from this comes from the AI learning not from the medical values in the EHR records, but rather from the pattern of tests and procedures that were performed. 

In other words, the AI is learning from the behavior of physicians as the doctors pursue diagnoses.  Kohane shares data demonstrating that when the AI is fed purely procedural information – the “chargemaster” data used for hospital billing – and has no idea what any of these tests and procedures showed, it does nearly as well as the algorithm running off all the actual EHR data, including test results.

Kohane also describes an EHR company’s proprietary algorithm that was developed during the early days of COVID-19, to predict patient deterioration. When it was subsequently tested by an independent investigator on data from a different hospital, the algorithm didn’t perform as well.

The most likely explanation, Kohane says, is also surprisingly common: the algorithm was trained on patients with different characteristics, and involved doctors who might have a different approach to treatment. 

It would have been foolish, Kohane says, to rely on such an algorithm, given how rapidly our understanding of the virus changed during the year, including both our approach to treatment and the characteristics of the patients infected. An algorithm developed in the context of one dataset could fail badly if the dataset shifts, especially if the algorithm was used reflexively, and not updated to keep up with the fast-changing circumstances.

Kohane tries more generally to moderate our expectations for AI; for example, he points out that algorithms like the one used to master chess and Go are likely to have only modest applicability to medicine. He quotes a leader in the field, Andrej Karpathy, now at Tesla, who has pointed out that these types of algorithms only work under certain conditions: when the system is deterministic and fully-observed, the action space is discrete, and we have access to a perfect simulator (e.g. the game itself) so that the effects of any action are known. 

“Unfortunately,” Kohane observers, “none of this is true of the physiology of disease course, of drug responsiveness, of surgery.”

In fact, Kohane adds ruefully, the only area of medicine where these conditions seem to hold involves reimbursement. He said he expects we will see extensive application of these sorts of algorithms — for the purpose of maximizing billing.

Nevertheless, Kohane is optimistic about the ability of AI to profoundly impact medicine and patient care. One promising application he sees is as an automated note-taker for physicians. That would free doctors up to focus on the patient, while the AI distilled and summarized the doctor’s observations, assessment, and treatment plan.

Identifying relevant disease subtypes is another potential application of AI. One particularly poignant example Kohane noted was the identification of a previously underappreciated subtype of autism with a prominent inflammatory bowel disease (IBD) component. 

Savvy analytics helped spot this pattern (which could also help form a hypothesis for further study of what the relation between these two conditions might be). Recognition of the autism/IBD association was especially meaningful to these patients and their families, Kohane explained, because it’s something a physician might otherwise miss – or misdiagnose. Many of these patients are non-verbal, he says, and when they experience gastrointestinal discomfort, their only way to respond is to act out, which is then often treated with tranquilizers – hardly the right therapy for IBD.

Yet now, thanks to data science-enabled research, Kohane says, IBD is more likely to be considered in autistic patients, leading to more appropriate diagnosis and treatment.

Moving forward, Kohane argues, requires us to explicitly recognize and separate health system dynamics and disease physiology; he adds that a third critical component will be patient-gathered data.

Perhaps the most powerful part of the talk occurs after Kohane cites several apparent examples of AI-driven successes. One approach was shown to be helpful in more rapidly weaning premature infants from ventilators. Another algorithm was used to integrate disparate info in a patient’s medical history to suggest a higher probability of domestic abuse. 

Yet, Kohane emphasizes, these are not true success stories. Yes, these results were published and shared, but the approaches were never broadly implemented – which he attributes to a failure of leadership, starting with his own.

“We need to recognize our own agency, our own ability to actually change the practice of medicine,” he urges. 

Kohane’s other advice for students and young innovators seeking to drive AI through to implementation: “Get an MBA, because business can drive this, and learn about health care policy, because what drives it in the end is money. Having business models and policy models and regulatory models is the way this is going to happen.”

Bottom Line:

The ability of AI-driven approaches to impact the care of patients will depend upon the ability of data scientists to meaningfully incorporate clinical experience and expertise. Determination, leadership — and perhaps a reasonable business plan — are required to ensure that successful AI approaches are not just published in journals but implemented, and find routine expression in the care and treatment of patients.

25
Feb
2021

Pfizer/BioNTech Ace Real-World Test, J&J Faces FDA Scrutiny, & Merck Pays Up

Luke Timmerman, founder & editor, Timmerman Report

Vaccine news keeps getting better by the day. The number of new people being diagnosed with COVID-19 has been plummeting for weeks.

That’s the good news. Read on and synthesize the most important financings, deals, and scientific developments of the week in biotech.

Vaccines

Let’s start with the best news of the week. Researchers from Israel reported on the Pfizer / BioNtech vaccination campaign in the real world – a potentially chaotic and messy situation under the best of circumstances. Even so, they found that the vaccine’s performance delivered more than 90 percent protection against severe disease after two doses. That’s no small feat, as it’s on par with what was seen in well-controlled clinical trials. New England Journal of Medicine. Feb. 24. (Ran Balicer, Ben Reis, Marc Lipsitch and colleagues).

The second-best news of the week was for the Pfizer / BioNTech vaccine among 23,000 healthcare workers in the UK. See The Lancet Preprint, Feb. 22, by Victoria Jane Hall. Sek Kathiresan, a recent guest on The Long Run podcast, succinctly summarized a key finding about the vaccine’s ability to curtail asymptomatic spread of the virus.

Some of the most vulnerable people to COVID-19 are elderly people in nursing homes. They were among the first to get vaccinated, and now we can start to see the results. Deaths in this group are coming way down. (See NYT graphic).

Cambridge, Mass.-based Moderna said in its quarterly and year-end financial report that it has advance purchase agreements worth $18.4 billion in sales for its COVID-19 vaccine in 2021.

That windfall will surely cue up critics howling about profiteering. It is a lot of money, and it’s legitimate to ask questions in good faith about what the fair price ought to be. The companies, if they are smart and thinking about the long-term, will exercise restraint on this point, as advised by John LaMattina in Forbes. Some of the insider stock sales from executives at the companies last year were ham-fisted and regrettable, and some of the corporate communications were premature and undermined public confidence.

Then again, they — Moderna and Pfizer/BioNTech — are moving heaven and Earth to scale up production (140 million extra doses for the US in 5 weeks) beyond anything previously conceivable with the new mRNA and lipid nanoparticle delivery vehicles. They have done, and are doing, herculean work everyone thought impossible a year ago. The value to the world from this vaccine vastly exceeds what we’re paying. The total, cumulative cost of COVID-19 is estimated at $16 trillion in the US by Harvard University economists David Cutler and Larry Summers. We should remember to reward and incentivize achievements of this magnitude. Our willingness to pay today supports capital investments and further incentivizes future work against SARS-CoV-2 variants and other threats like flu.

Today (Feb. 26) is the long-awaited day when the FDA advisory committee reviews the safety and efficacy profile of J&J’s adenoviral vaccine candidate for COVID-19. Reasonable people can debate the merits of the evidence, but the full protection against severe disease and death, conducted in more than 40,000 subjects around the world under fast-changing conditions against tough new viral variants – I think J&J has a compelling new tool to offer the world. Add up the practicalities of a single-shot, refrigeration-only, low-cost, scalable-to-manufacture vaccine, and you have an essential new intervention to help vaccinate a world with more than 7 billion people. (FDA briefing document). See also Derek Lowe’s positive review at In The Pipeline.

Speaking of what it will take to crush COVID-19, let’s not forget about Novavax. The little company from Gaithersburg, Maryland, left for dead not long ago, has risen from the ashes in the most spectacular “only in biotech” way. Its protein-and-adjuvant vaccine has shown 90 percent efficacy in a study of 15,000 subjects in the UK, and its 30,000-subject study has now completed enrollment in the US and Mexico. While we wait for those results with bated breath, partnerships are in place for Novavax to scale up and deliver more than 1 billion doses of its vaccine to the world. Read this inspiring WSJ story about a remarkable comeback.

Diagnostics

Seattle-based Adaptive Biotechnologies, the company that sequences B and T cells of the adaptive immune system to develop diagnostics and treatments, said this week it has started offering the first T-cell based test to tell people if they’ve had COVID-19 recently or in the further past. Adaptive is offering the test with its partner, LabCorp, which has 2,000 sites where it can take the necessary blood draw. Adaptive is seeking an Emergency Use Authorization from the FDA for the test, but is able to market its test in the meantime as a CLIA-certified lab, a company spokeswoman said.

Treatments

The WHO Solidarity Trial, a massive study of 11,000 randomized participants conducted in the frenzied early days of the pandemic, looked at a lot of different repurposed antiviral therapies. The outcomes were not good. The latest NEJM paper is withering. “These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay,” the authors wrote.

Science of SARS-CoV-2

The new tools of biology allow for incredible precision and speed. See this paper based on single-cell sorting technology used to identify the most potent neutralizing antibodies from COVID-19 survivors. “Extremely potent human monoclonal antibodies from COVID-19 convalescent patients.” Cell. Feb. 23. (Emanuele Andreano et al colleagues in Italy and London)

A couple of new variants are circulating. This time they are not being associated with some faraway place – it’s a place like many others in the US with long-festering, uncontained community transmission. “A Novel SARS-CoV-2 Variant of Concern, B.1.526, Identified in New York.” MedRxiv. Feb. 23. (Medini Annavajhala et al Columbia University). See also the latest on the CAL.20C variant, now known as B.1.427/B.1.429 and described by Carl Zimmer in the NYT.

How does the B.1.351 variant – aka the South Africa variant – appear to escape from neutralizing antibodies? An Oxford University team that did structure-function analysis on antibodies from convalescent sera and vaccine-induced antibodies found that receptor binding domain mutations provide tighter binding to ACE2. Cell. Feb. 17. (Daming Zhou et al Oxford University).

From China, researchers looked at the 501.Y.V2 variant and found no higher rate of infectivity, but they also saw a higher rate of escape from neutralizing antibodies. Again, they pointed to mutations affecting the receptor binding domain. Cell. Feb. 18. (Qianqian Li et al)

What is AI good for in the pandemic? Apparently, it’s being put to work hoovering up adverse event reports from people getting the COVID-19 vaccine to help researchers understand the real-world/real-time safety profile and put things in context. MedRxiv. Feb. 23. (Reid McMurry et al nFerence Labs)

The National Institutes of Health announced a call for scientific applications to tear into the many unknowns around Long COVID. In December, Congress allocated $1.15 billion over four years to help scientists explore what’s going on with the brain fog, fatigue, shortness of breath and other symptoms that so many people are suffering from. The scope and severity of this condition are only beginning to come into focus. Researchers at the University of Washington led by Helen Chu – who were remarkably well-positioned to respond to COVID-19 because of pre-existing infrastructure from the Gates Foundation-funded Seattle Flu Study – reported this week in JAMA on what they’ve learned about Long COVID since they pivoted in that direction in early 2020. According to 234 COVID-19 survivors who answered a research questionnaire, a full one-third (32.4 percent) reported at least one persistent symptom of COVID between 3 and 9 months after the original infection. If those numbers are a close approximation of the national incidence of Long COVID, then we are looking at an enormous toll of long-term chronic disease with perhaps 30 million cases of Long COVID (using a conservative estimate of 100 million infections).

Deals

Cambridge, Mass.-based Beam Therapeutics, the company developing base-edited gene therapies, used the leverage from its sky-high market capitalization (more than $5 billion) to acquire a little company to help with delivery. Beam agreed to pay $120 million upfront with its stock, plus another $320 million in milestones to acquire Guide Therapeutics. Guide is focused on nonviral delivery mechanisms of gene therapy, specifically with screening technology to identify lipid nanoparticles that can be delivered in vivo with “novel biodistribution and high selectivity for target cells,” the company said in a statement. Biomatics Capital, GreatPoint Ventures, and GV were the early backers of GuideTx.

Merck agreed to pay up to acquire another small company with a sky-high valuation – Watertown, Mass.-based Pandion Therapeutics. The price was $1.85 billion, or $60 a share. That’s more than double the previous day’s closing share price of $25.63. Pandion secured a $58 million Series A financing in January 2018 co-led by Polaris Partners, Versant Ventures and Roche Venture Fund. SR One and BioInnovation Capital also participated. See Timmerman Report coverage of the Series A about its approach to flip some of the learnings from immuno-oncology toward the treatment of autoimmune disease. Three years later, the company’s named lead candidate is an engineered IL-2 mutein fused to a protein backbone that’s supposed to selectively activate and expand regulatory T cells (Tregs) to tamp down overactive immune responses. Ulcerative colitis is the lead indication. Pandion also has PD-1 agonists in development for autoimmunity – obviously an area of interest at Merck, the maker of the market-leading PD-1 inhibitor for cancer.

South San Francisco-based Day One Biopharmaceuticals has told me on two occasions (the Series A financing and its recent $130 million Series B financing) that it planned to in-license another program to develop as a cancer drug specifically for kids. This week, it followed through. Day One worked with Merck KGaA to in-license pimasertib and another oral, highly-selective small molecule allosteric inhibitor of MEK 1/2, a key enzyme in the MAPK signaling pathway. Pimasertib has been through 10 clinical trials in about 900 patients with different tumor types. Day One said it believes there’s a scientific rationale to combine the MEK inhibitors with its existing pan-RAF inhibitor.

Somerset, NJ-based Catalent agreed to acquire Belgium-based Delphi Genetics, a plasmid DNA cell and gene therapy contract development and manufacturing organization. Financial terms weren’t disclosed.

Menlo Park, Calif.-based Grail agreed to work with Quest Diagnostics to collect the blood samples necessary for its Galleri product for blood-based early detection of cancer. Grail plans to start marketing in the second quarter. Quest has a network of 2,200 blood collection sites.

Financings

Waltham, Mass.-based Xilio Therapeutics, the developer of tumor-selective cancer therapies, raised $95 million in a Series C financing. Rock Springs Capital led. A tumor-selective version of IL-2, and a tumor-selective anti-CTLA-4, are being teed up to enter clinical trials in 2021.

San Diego-based Truvian Sciences raised $105 million in a Series C financing to push through to FDA approval for its benchtop blood diagnostic instrument that’s supposed to rival the capabilities central labs have for routine blood work. (TR coverage).

Cambridge, Mass.-based Orna Therapeutics raised $80 million in a Series A financing to advance work on circular RNA therapies, as opposed to the traditional linear kind. It’s based on research from the MIT lab of Dan Anderson, and was seeded and incubated by MPM Capital. (TR coverage).

Cambridge, Mass.-based Cellarity said it raised $123 million in a Series B financing to advance work on computational modeling of cell behavior for drug discovery. Flagship Pioneering founded the company, and was joined in the new round by BlackRock, The Baupost Group, Banque Pictet among others.

San Diego-based Vividion Therapeutics, the developer of precision medicines against previously undruggable targets for cancer and immune disorders, raised $135 million in a Series C financing. Logos Capital and Boxer Capital of Tavistock Group co-led.

San Francisco-based Miroculus completed a $45 million Series B round to develop lab automation tools. Cota Capital and Section32 joined the round.

San Diego-based Halozyme, the company that turns IV biologics into subcutaneous formulations, said it agreed to borrow $700 million in a convertible note offering due in 2027. The debt converts to equity if Halozyme stock reaches $77.17 a share. It’s at $47.17 now.

Beijing-based YishengBio, the developer of cancer and infectious disease therapies, raised $130 million in a Series B financing. Oceanpine and OrbiMed co-led.

Shanghai-based WuXi Diagnostics secured a $150 million Series B financing. Thermo Fisher joined the round. WuXi Diagnostics said in a statement that it is “the first platform company in China focusing on integrated diagnostics.”

FDA Leadership

Who will be the next FDA commissioner, and what will it mean for industry? The former president of R&D at Pfizer and a board member at Puretech Health looks at the contrasts between candidates Janet Woodcock and Joshua Sharfstein. Forbes. Feb. 24. (John LaMattina)

Our Shared Humanity

Too many Americans don’t learn our country’s history, and don’t want to grapple with the long-term consequences. It’s important for people to know that things like the infamous Tuskegee experiment happened. It harmed African Americans. It left an understandable legacy of mistrust.

Even those who are aware sometimes take home the wrong lesson. Tuskegee can sometimes unwittingly be used for blame-shifting onto African Americans. We would do better by acknowledging there are reasons why so many people are mistrustful of the healthcare system in the urgent now, and that racism in healthcare isn’t a thing of the past.

We would do better by asking ourselves: Are there things our healthcare systems can do to foster more trust in vaccines?

As USC social work professor Karen Lincoln put it in an interview with San Francisco public radio KQED:

If you continue to use it as a way of explaining why many African Americans are hesitant, it almost absolves you of having to learn more, do more, involve other people – admit that racism is actually a thing today.

Why might some people still be mistrustful of those urging use of the vaccine? Sadly, we have to listen to reports like this from NPR about San Francisco-based One Medical, which has allowed its well-to-do concierge medicine clients to skip ahead in the vaccine line. It’s more healthcare inequity in real-time.

Racial inequity is not a thing of the past. It’s not someone else’s problem. It will not resolve itself with time. We all pay a price for failing to fix this. Biopharma has a part to play, and some companies are busy doing the work. It will require vigilance.

Science

“Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.” NEJM. Feb. 25. (Stephen K. Brannan, Sharon Sawchak, Andrew C. Miller, Jeffrey A. Lieberman, Steven M. Paul, and Alan Breier) For the backstory on xanomeline-trospium, being developed as KarXT by Boston-based Karuna Therapeutics, listen to Karuna CEO Steve Paul on The Long Run podcast.

“Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity.” Science. Feb. 19. (David Liu et al Broad Institute and Harvard University). (See TR coverage of the latest spinout from Liu’s lab, Exo Therapeutics, December 2020).

“Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.” This is the paper describing the BMS-Bluebird cell therapy directed at the BCMA antigen. The companies are seeking FDA approval. NEJM. Feb. 25. (Nikhil Munshi et al)

“Risdiplam in Type 1 Spinal Muscular Atrophy.” Genentech’s risdiplam (Evrysdi) helped 19 of 21 infants with spinal muscular atrophy Type 1 survive without permanent ventilation. One-third of the infants, 7 out of 21, were able to sit without support for at least five seconds – not normal in the natural course of disease. NEJM. Feb. 24. (Giovanni Baranello et al FIREFISH Working Group)

Book Review

The Genome Odyssey. From Code to Clinic. WSJ. Feb. 24. (David Shaywitz)

Personnel File

Cynthia Pussinen joined Philadelphia-based Spark Therapeutics, the Roche gene therapy unit, as chief technical officer.

Heidi Hagen was named interim CEO of Boston-based Ziopharm Oncology, a cancer immunotherapy company. She replaces Laurence Cooper effective immediately. James Huang was named executive chairman. Hagen, a cell therapy expert and co-founder of Vineti, was the lead independent director at Ziopharm.

Jerry Cacia joined South San Francisco-based Graphite Bio, a gene editing company, as chief technical officer. (TR coverage, Sept. 2020)

New York-based Intercept Pharma, the NASH drug developer, said Jason Campagna, the chief medical officer is resigning effective Mar. 5.

Waltham, Mass.-based Tscan Therapeutics hired Brian Silver as chief financial officer. He will step down from the board of directors to take the operating job. He’s a former investment banker, so you can probably set you can set the over/under date for when this company goes public.

Regulatory Action

The FDA placed two Bluebird Bio clinical trials for sickle cell disease on clinical hold. It was a formality, after the Cambridge, Mass.-based company already voluntarily paused the studies after learning of two cases of patients on its treatment who developed cancer. The investigation is ongoing into what caused the cases of cancer, and whether it’s related at all to the treatment. The world of gene therapy is watching.

AbbVie won another FDA label expansion for the aging franchise of adalimumab (Humira). This one is for pediatric patients with moderate to severe ulcerative colitis.

Restoring Honest Public Discourse

While we are busy trying to crush the pandemic, we have to stitch back together the fabric of a society ripped apart by 24/7 information war.

There is such a thing as honest inquiry and debate that doesn’t devolve into ad hominem attacks and bottomless nihilism for fun and profit.

Carl Bergstrom, a University of Washington professor and co-author of “Calling Bullshit” offers a glimpse of how to dig ourselves out of this ditch. It’s OK for people to disagree. It’s OK to change one’s mind based on new data. There isn’t *always* some sinister hidden agenda or dishonest subterfuge going on with people we disagree with on one issue or another.

That’s true for COVID-19, for drug pricing, and for a thousand other issues we need to be able to think about and discuss like intelligent adults.

There has to be a way forward to discuss issues without constant thermonuclear infowarfare. I’ve seen some encouraging signs. I hope to see more. Otherwise, the infowar will never end, and no one will win.

24
Feb
2021

Comprehensive Policy for Infection: There Has Never Been a Better Time

Ankit Mahadevia, CEO, Spero Therapeutics

The suffering from COVID-19 can be measured in multiple, sobering ways:

Life expectancy in the US has fallen by a full year, according to the CDC.

The economic cost – measured in reduced gross domestic product, premature death, and long-term disability – has been estimated at $16 trillion by economists David Cutler and Larry Summers at Harvard University.

This week, the US passed the grim milestone of half a million deaths from COVID-19.

The pandemic has shaken the foundations of our society. It has forced people to question assumptions about scientific priorities to better prepare for pandemics an interconnected world.  Further, multi-drug resistant bacterial infections pose one of the major threats to global health and prosperity, and these troublesome bugs haven’t gone away.

Even so, there is reason for optimism: there has never been a better time to muster the will, resources and expertise to reduce the threat from infectious disease.   

New Opportunities in Washington

We applaud the work underway at the World Health Organization and international governments. The US, under a new Administration, is well positioned to extend its global leadership in science with short-term and long-term investments.

Scientists with knowledge of the infectious threats are in a better position to help shape policy than ever before. President Biden, in his letter to his new science advisor Eric Lander, asked him to think broadly about pandemic preparedness. That call specifically included antibiotic resistance. Lander’s work in this area will not be marginalized – he is the first science advisor to be elevated to the Cabinet.

Within Congress, a change in party leadership and a focus on broad solutions for everything from COVID-19 to immigration creates an opportunity.  Well thought-out solutions are being crafted. The PASTEUR Act, with bipartisan co-sponsorship, is one. 

PASTEUR would commit transformational, multi-hundred-million-dollar investments to support drug development against key microbial threats that are not prevalent today, but would be deadly without effective medicines. The bill changes the incentives for antibiotic developers — allowing for investment returns that aren’t based on maximizing prescribing volumes. This would be a powerful incentive for industry to develop these critical defenses, while avoiding overprescribing that undermines effectiveness over time.

Expanded Support for Innovators

New and existing organizations have stepped up to provide support for new weapons against infection. The government-supported efforts are being supplemented by the Bill & Melinda Gates Foundation, the NOVO Repair Fund, and CARB-X – as well as traditional biotech investors.

The Biomedical Advanced Research and Development Authority (BARDA) continues to support R&D for diagnostics and therapeutics for existing and emerging threats. We applaud the agency’s timely response to the COVID-19 challenge; along with continued support for defense against drug-resistant bacteria.

The AMR Action Fund is the latest player on the scene. It’s a global organization established in 2020 by more than 20 pharmaceutical companies to fund development of innovative medicines against infectious threats.

The fund recently added Henry Skinner, a former Novartis Ventures investor, as CEO. The stated plan is to begin investing this year. The pharma companies and nonprofit groups backing the AMR Action Fund agreed last week to contribute another $140 million to the more than $1 billion it had already raised for R&D against multi-drug resistant bacteria. 

Bold Strategies Are Needed…and They Already Exist     

As Operation Warp Speed has taught us, we need bold, wide-ranging strategies against fast-moving and far-reaching pathogens. Incremental policy incentives, such as targeted changes to reimbursement for therapeutics, are necessary but not sufficient.

Fortunately, more ambitious plans do exist. The PASTEUR Act is one such example. Another is the Bipartisan Commission on Biodefense’s Apollo Program.

Founded in 2014 and co-chaired by former US Sen. Joe Lieberman and former Secretary of Homeland Security Tom Ridge, the Bipartisan Commission has proposed ~$10 billion a year for a comprehensive approach to testing, tracing, and treating future pathogenic threats. Former BIO president Jim Greenwood serves on the commission, so this group at least has some industry input.

What Next?

It has been some time since the conditions were so favorable for infectious disease. The time is now to work together.

Drug developers in infectious disease continue to have a duty to choose sustainable programs that marry clinical need with commercial benefit. This creates a stable base of R&D and expertise that can respond to future threats. 

The biotech industry at large can make its priorities clear.

  1. Bold, transformative solutions that give our industry what it needs for pandemic defense.
  2. Advocate for policies that prioritize treatments against infection. We can do this through our representative organizations such as BIO.

As private citizens, we can make clear to our elected officials that we want bold solutions to make sure we don’t have another COVID-19. 

We have the technology, talented drug developers, clinicians, and public health professionals. What we need is leadership, long-term focus, and coordinated efforts against a problem that’s bigger than any one company, or any one country. If we act together behind a comprehensive plan, we’ll be in position to prevent future pandemics.

Special thanks to Aleks Engel of the NOVO Repair Fund, Tim Hunt, and the Spero team for their contributions

18
Feb
2021

Biotech as a Beacon for Youth

Luke Timmerman, founder & editor, Timmerman Report

Biotech has always depended on the ideas and energy of young people.

But it’s time to think more broadly about how biotech and young people relate.

Let’s start with young people.

Recall the column from two weeks ago, which cited a 2017 Pentagon study. That study found that a full 71 percent of Americans between the ages of 18-24 aren’t eligible to serve in the US military. Three main reasons stand out as disqualifiers – obesity, criminal records, and lack of a high school diploma.

Let that sink in for a minute.

Think about how many millions of young people whose lives were going off the rails in the 2010s, because of long-simmering societal ills.

That was clear before the pandemic.

Now, consider how many young people are struggling, especially with mental health issues exacerbated by the pandemic.

All of us need hope. This is a hard time. But young adults need to be especially optimistic when making some of the big choices in life — what career to pursue, where to live, who to marry, how to maybe someday buy a home. Maybe some young people would make different life choices, and be more attractive to employers, if they had more hope.

What does any of this have to do with biopharma?

Consider manufacturing.

We are in the early phase of a cell and gene therapy revolution.

About 900 Investigational New Drug (IND) applications for cell and gene therapies were on file with the FDA as of February 2020. More are coming. Every week, more capital flows into startups aspiring to churn out more of these valuable next-generation medicines.

The opportunity for growth is obvious. There are more than 1,000 clinical trials for cell and gene therapies that could enroll as many as 60,000 patients worldwide, according to the Alliance for Regenerative Medicine. The FDA says it anticipates approving 10-20 such cell and gene therapies per year by 2025.

Whatever the numbers are, some of these specialized therapies will pan out. Some will get FDA approved. Some will need to scale up to meet global demand.

Jobs will have to be created in specialized, customized manufacturing plants to make these cell and gene therapies. Advanced biologics aren’t going away, either. The making of these medicines can’t be completely automated, and shouldn’t be entirely shipped offshore. There are national security reasons, national competitive advantage reasons, logistical shipping reasons, and workforce development reasons to keep most of this work on US soil.

There are large swaths of the map outside of San Francisco, New York and Boston where this work can be done inexpensively.

Biotech can choose to invest in people, equipment, and places to get ready for this manufacturing boom.

Actually getting this done will require a shift in employer mindset. Not everyone needs a 4-year degree to work in a cell therapy manufacturing plant. Some of these jobs are better suited to people with 2-year community college training.

These can be high-salary/good-benefits/steady paycheck blue collar jobs. As biotech matures as an industry, it will depend on more of these jobs. When the industry invests in people to do this skilled work, it makes good long-term economic sense to pay high wages to keep people motivated and productive and loyal.

I grew up in the industrial and agricultural economy of the Upper Midwest. The high salaries and good benefits offered by companies like John Deere were considered the ticket to middle-class life. There was pride and dignity in this work for people like my Dad. He got a community college certificate to become a welder. He got a job with that skill at John Deere in Dubuque, Iowa. He thought he had it made.

He lost that job in a round of layoffs when I was in preschool.

Jobs like that today are scarce. My Dad had to reinvent himself a couple times to provide for our family.

Now I live in Seattle. It’s a tech metropolis. But before the tech boom, it was put on the map by Boeing. Tens of thousands of blue-collar, union workers built Seattle. They earned good wages and solid benefits. They took pride in work assembling “the best airplanes in the world.” That’s what Boeing commercial airplanes chief Alan Mulally, a boy from Kansas, used to say.

Like any for-profit industry, of course, biotech isn’t in the business of creating jobs just for the sake of creating jobs. But it is an industry on the upswing. It needs to think long-term about people to meet long-term business needs.

Young people seeking purpose could step up for this line of work, whether they aspire to be scientists or blue-collar machine operators.

What if biotech were to open up to more people without 4-year or advanced college degrees? What kinds of manufacturing jobs, in particular, might be doable for people with community college training? Would it make sense to invest in apprenticeship programs, and then continue to invest in training people to keep skills updated over an entire career?

Might some of these people become longtime, loyal, productive employees? Might some rise through the ranks to make even greater contributions to their companies? Might the kids of manufacturing workers grow up to be scientists and executives of tomorrow?

Biotech can be the new Boeing, the new John Deere. It will require extending a hand to young people. It will require taking chances on people who might not otherwise get one.

It will take some imagination. But the potential is clear. Biotech, as I wrote here a few weeks ago, is radiant at a dark time.

Let’s make biotech into a beacon of hope for young people.

An Ominous Development at Bluebird

Cambridge, Mass.-based Bluebird Bio, the cell and gene therapy company, is experiencing a nightmare. The company said it halted clinical trials of its Lentiglobin gene therapy for sickle cell disease after seeing a report of a patient dosed five years ago now coming down with acute myeloid leukemia. Around the same time, the company said it learned of another case of a patient getting myelodysplastic syndrome (MDS), a pre-leukemia syndrome. The company hasn’t been able to confirm whether the cancerous conditions are related to its lentiviral vector. But because that possibility can’t be ruled out, and because its only marketed therapy uses the same vector, it shut down sales and marketing of that other treatment for beta-thalassemia in Europe and the UK.

Shares in Bluebird crashed, down 41 percent in value from $45.76 last Friday to $26.95 at yesterday’s close. Many investors have to be wondering about the decision Bluebird recently announced to split into two companies – one focused on genetic diseases, and the other focused on cancer. The future for genetic diseases will hinge on what investigators uncover in days and weeks ahead about what might have caused the severe adverse events.

Analyst Raju Prasad of William Blair downgraded the stock immediately, as many investors surely aren’t going to hang around long to find out. At best, the situation means Bluebird will suffer from a significant delay. At worst, if the vector ends up looking like the culprit, it could be devastating to the company and send a chill through investor sentiment in other gene therapy companies. It’s too early to say yet what the answer will be. “While there is precedent of [sickle cell disease] patients to have an increased risk of leukemia compared with the general population, we believe the complexity of the issue is likely to lead to a thorough investigation and potentially a significant delay to trial timelines and/or change to trial design,” Prasad wrote in a note to clients.

Bluebird shares this week.

Vaccine Access and Distribution

Moderna said it expects to deliver 100 million doses of its mRNA COVID-19 vaccine to the US government by the end of March, another 100 million by the end of May, and another 100 million by the end of July. Those are faster timelines than the company had agreed to previously, and enough for this company alone to fully vaccinate almost half of the US population with a two-shot regimen. The company also agreed to provide an additional 150 million doses to the European Union, bringing the total doses ordered there to 310 million in 2021. The European Commission also secured an option for another 150 million doses in 2022. It’s all pretty breathtaking to consider, knowing the pressure to move this fast with global-scale manufacturing of a novel mRNA vaccine technology with lipid nanoparticle delivery.

Pfizer and BioNTech said they will supply 200 million extra doses of its mRNA COVID-19 vaccine to the European Union, bringing its total supply agreement there to 500 million doses. The plan is to deliver by the end of 2021. The European Commission obtained an option to request another 100 million doses. Last week, the companies said they upped their commitment to the US government by 100 million doses, bringing its total commitment to the US government to 300 million doses.

Novavax reached an agreement with GAVI to provide 1.1 billion cumulative doses of its protein-adjuvant vaccine for COVID-19 through the COVAX facility, to provide vaccine access to people in low-income, middle-income, and high-income countries. Gaithersburg, Maryland-based Novavax is working in partnership with Serum Institute of India to boost manufacturing output.

Johnson & Johnson, the developer of a single-shot vaccine for COVID-19 that’s due to go before an FDA advisory committee for review Feb. 26, is still planning to supply 100 million doses to the US government in the first half of 2021. But it’s unclear how many doses will be available in March and April, assuming it wins Emergency Use Authorization from the FDA. Tony Fauci told CNN he’s “a little disappointed” in the expected number of doses available from J&J this spring.

While the race is on to vaccinate in wealthy countries, Science magazine reporter Kai Kupferschmidt notes that not a single healthcare worker in Africa has been vaccinated, until South Africa started this week.

Science of SARS-CoV-2

Reduced Neutralization of SARS-CoV-2 B.1.1.7 Variant by Convalescent and Vaccine Sera. This study isn’t quite as bad as the headline suggests. The authors write, “widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.” Cell. Feb. 18. (Piyada Supasa et al Oxford University)

Transmission of COVID-19 in 282 clusters in Catalonia, Spain. This study shows that people with high viral loads of SARS-CoV-2 are main drivers of transmission. The Lancet. Feb. 2. (Michael Marks et al).

Densely sampled viral trajectories suggest longer duration of acute infection with B.1.1.7 variant relative to non-B.1.1.7 SARS-CoV-2. Why does the new variant seem so concerning? One reason, according to this Harvard study, is that it appears to last longer, naturally creating more opportunities for transmission. Digital Access to Scholarship at Harvard. Feb. 10 preprint. (Stephen Kissler et al)

Science

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell. Feb. 15. (Kai Wucherpfennig et al Broad Institute). Researchers at the Broad Institute analyzed tumor-infiltrating T-cells with single-cell analysis, and identified the gene that encodes for CD161 which appears on NK cells and T cells. It’s the basis for cell therapy work being done at Waltham, Mass.-based Immunitas, which raised a $39 million Series A financing in 2019. (Company statement).

Vaccines

Neutralizing Activity of BNT162b2-Elicited Serum — Preliminary Report. NEJM. Feb. 17. (Pfizer / BioNTech research teams). The mRNA vaccine showed in vitro that it can neutralize the SARS-CoV-2 virus with the B.1.351 variant to the spike protein (more widely known as the South Africa variant). (Pfizer statement).

Brazil is trying to answer one of the key outstanding questions about the COVID-19 vaccines. Do they help reduce transmission of the virus? It’s difficult to run such a study, but the Brazilians are trying a pilot project – vaccinate an entire town of 45,000 people to see what happens. (WSJ coverage).

Vaccine Hesitancy

The myth of ‘good’ and ‘bad’ Covid vaccines. This article discusses how false perceptions about the next batch of vaccines could complicate the vaccine hesitancy story, especially in communities of color. STAT. Feb. 17. (Helen Branswell)

Therapeutics

UK-based Synairgen said it started enrolling in a Phase II/III study with an inhalable interferon beta treatment for mild-to-moderate COVID-19 patients who aren’t hospitalized.

South Plainfield, NJ-based PTC Therapeutics said it started the second stage of a Phase II/III trial of an oral therapy it developed against a cellular enzyme, dihydroorotate dehydrogenase (DHODH). By targeting this enzyme instead of a protein on SARS-CoV-2, PTC hopes to inhibit viral replication and calm down the excessive inflammatory responses that result from infection. CEO Stu Peltz noted in a statement that the drug could be taken at home, as well as in the hospital, and that if it’s effective, it ought to work against wildtype virus as well as the variants.

Diagnostics

Thermo Fisher Scientific said it secured FDA Emergency Use Authorization for the TaqPath RT-PCR diagnostic test, which can tell the difference between COVID-19, Flu A and Flu B in a single sample. It’s for CLIA lab use.

Financings

New York and San Francisco-based Adjuvant Capital, founded in 2019 but quiet until this week, announced its initial $300 million fund to invest in public health needs that deliver social and financial returns. Merck, Novartis, IFC, the Bill & Melinda Gates Foundation, Children’s Investment Fund Foundation, and Dalio Philanthropies are among the LPs supporting the team led by Glenn Rockman and Jenny Yip. (TR coverage by Anika Gupta).

Cambridge, Mass.-based Centessa Pharmaceuticals raised $250 million in a Series A, to roll up 10 Medicxi Ventures-backed asset-centric virtual biotech companies into an umbrella organization. Saurabh Saha, formerly of Bristol-Myers Squibb, is the CEO, while Moncef Slaoui, the former chief scientific advisor of Operation Warp Speed, is the CSO. (Timmerman Report coverage).

Durham, NC-based Humacyte went public through a SPAC deal that brought in $255 million in cash proceeds to advance its work in making universally implantable, off-the-shelf human tissues for transplant at large commercial scale. Fresenius Medical Care, OrbiMed, Monashee Investment Management, and Alexandria Venture Investments were among the participants in the related PIPE deal.

Cambridge, Mass.-based Elicio Therapeutics, an immunotherapy company targeting the lymph nodes, raised $73 million in a Series B financing. It didn’t name the investors, but said there were “multiple strategic and international investors.”

San Francisco-based Excision Biotherapeutics said it raised $60 million to develop CRISPR-based antiviral therapies. Greatpoint Ventures led.

Cambridge, Mass.-based Immune ID raised a $17 million seed financing led by Longwood Fund, and which included Arch Venture Partners, Pitango HealthTech, In-Q-Tel and Xfund. The company is working to identify therapeutic targets based on antibody interactions that drive immune diseases.

New York and Guilford, Conn.-based Quantum Si, a proteomics company founded by Jonathan Rothberg, went public through a SPAC transaction with HighCape Capital. The deal involves $540 million of gross proceeds to the company, including a $425 million private investment in a public equity (PIPE) that included Foresite Capital Management and Redmile Group, among others.

Boston-based Gamida Cell, a cell therapy company, raised $75 million in a convertible debt offering with Highbridge Capital Management. The cash is supposed to keep the company going into the second half of 2022.

Seattle-based Ozette raised $6 million in a seed financing to advance AI for immune system monitoring. Madrona Venture Group led, and was joined by the Allen Institute for Artificial Intelligence (AI2) and Vulcan Capital.

Houston-based Iterion Therapeutics pulled in $17 million in a Series B financing led by Lumira Ventures to develop a potent and selective nuclear beta-catenin inhibitor for desmoid tumors.

Deals

Charles River Labs agreed to acquire Cognate Bioservices, a cell and gene therapy contract manufacturing organization, for $875 million in cash.

Novartis and the Bill & Melinda Gates Foundation agreed to work on a more affordable, globally accessible in vivo gene therapy for sickle cell disease. The Gates Foundation has agreed to fund “a research team within NIBR wholly dedicated to developing an approach to delivering this potential treatment.” Terms weren’t disclosed.

Cambridge, Mass.-based Cytovia Therapeutics agreed to work with Cellectis on TALEN-engineered iPSC-derived Natural Killer cell therapies. Cellectis will get either $15 million in equity in Cytovia, or $15 million in cash, by the end of 2021.

GSK and San Francisco-based VIR Biotechnology agreed to expand the collaboration that started in April 2020 to work on neutralizing antibody therapies for COVID-19. The expanded deal now includes other viral infectious diseases, including influenza. GSK will partner on development of an intramuscular injection that’s supposed to work as a universal prophylactic for influenza A, and that has completed a Phase 1 trial. Next-generation antibodies to prevent or treat flu are also part of a three-year research collaboration. GSK is agreeing to pay $225 million upfront, plus make an additional $120 million equity investment.

Eli Lilly agreed to pay $125 million upfront to South San Francisco-based Rigel Pharmaceuticals to co-develop Rigel’s receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor. The deal is global, exclusive, and covers all therapeutic indications.

San Francisco-based Nektar Therapeutics said it will receive as much as $150 million from SFJ Pharmaceuticals, a company backed by Abingworth and Blackstone Life Sciences, to develop bempegaldesleukin (BEMPEG), an IL-2 agonist in combo with Merck’s pembrolizumab (Keytruda) for head and neck cancer. Nektar will serve as the sponsor of the Phase II/III study. It has agreed to pay milestones over 7-8 years to SFJ, if it wins regulatory clearance.

Data That Mattered

Merck and AstraZeneca said they were planning to halt a Phase III trial early, at an interim analysis, because a data monitoring committee reported the drug has demonstrated superiority over placebo. The drug, olaparib, (Lyparza), is a PARP inhibitor being tested in the adjuvant setting for germline BRCA mutated, high-risk HER2 negative breast cancer after local treatment and neoadjuvant or adjuvant chemotherapy. Data will be presented at a medical meeting.

Personnel File

Sara Nayeem joined New York-based Avoro Ventures as a partner. She was previously with NEA for 12 years. She will source and manage biotech investments from early-stage to late-stage to crossover, the firm said in a statement.

Kizzmekia Corbett, the mRNA vaccine scientist at the NIH, was named to the TIME100. Read about her contribution in this essay by Tony Fauci.

Salt Lake City-based Recursion, the company using AI and other tech tools for drug discovery, hired Louisa Daniels as chief legal officer and general counsel. She was a vice president at Pfizer. (TR coverage of Recursion, Sept. 2020).

BIO hired Shaye Mandle as chief operating officer. He comes to the biotech trade association with experience in restructuring and rebranding Minnesota’s Medical Alley Association.

Westlake Village Biopartners hired Peter Calveley as chief operating officer.

South San Francisco-based Day One Biopharmaceuticals, the developer of treatments for kids with cancer, hired Charles York as chief operating and chief financial officer. (TR coverage of Day One’s $130m Series B round, Feb. 2021).

Boston-based Dewpoint Therapeutics added Regina Barzilay, Distinguished Professor for AI and Health at MIT, to its board of directors. (TR coverage of Dewpoint, Apr. 2019)

Cambridge, Mass.-based Evelo Biosciences, a microbiome-based therapeutics company, named John Hohneker to its board of directors. (The Long Run podcast with Evelo CEO Simba Gill, Nov. 2020).

Regulatory Action

Amgen said the FDA has granted Priority Review status to its application to market sotorasib, the KRAS G12C-directed small molecule drug for non-small cell lung cancer. The PDUFA review deadline is Aug. 16, but it wouldn’t be a surprise if the FDA acted sooner to approve this potentially pathbreaking medicine against one of the classic hard targets of oncology.

South San Francisco-based Cortexyme said its atuzaginstat Phase II/III trial for Alzheimer’s disease is on partial clinical hold, following an FDA review of “hepatic adverse events” – aka liver toxicity. The events were reversible and didn’t appear to cause long-term damage, the company said.

Novartis secured an expanded label from the FDA for sacubitril/valsartan (Entresto). The drug’s prescribing information is now thought to cover about 5 million of the estimated 6 million people in the US with forms of chronic heart failure.

Genomic Surveillance

The CDC, newly empowered to lead in the pandemic, pledged a $200 million “down payment” on improved genomic surveillance of SARS-CoV-2 and its increasingly troubling variants. For the world leader in genomics, this is an embarrassing late date to get moving in a nationally coordinated way to help us adapt our behavior as the virus evolves. We are sequencing fewer than 1 percent of samples, and expert say we need to get to 5 percent, and do it with samples from around the country, if we’re going to have an adequate surveillance system.

See below this Twitter exchange with a genomic surveillance expert, explaining why so little sequencing of viral samples was being done as recently as December. We late to the game, and have some serious catching up to do.

 

16
Feb
2021

Increasing Vaccine Confidence With the Tools That Got Us This Far

Michele Andrasik, PhD. Director, Social & Behavioral Sciences and Community Engagement
HIV Vaccine Trials Network; Affiliate Assistant Professor, Global Health, University of Washington

By Michele Andrasik, Sally Bock, Stephaun Wallace and Michael Ferguson

This month, when the news was full of stories of vaccine scarcity and images of long lines of people hoping to get immunized, the COVID-19 Prevention Network and Fred Hutch ran TV ads during the Super Bowl for people still hesitant about the vaccine in Washington state.

When given this rare opportunity to reach so many people, we were careful about what to say and not to say.

There was no scolding or chiding or pleading.

The narrator of the ad invites people to engage, and empowers them to come to their own conclusion. “You may still be doubtful. That’s OK. We can work together to get answers to your questions,” the narrator says.

Why seek to build more demand during a vaccine shortage?

In one word: equity.

COVID-19 vaccinations in Washington state began on Dec. 14. As of Feb. 8 — 56 days later — a little over 10% of Washington state residents received their 1st dose and slightly less than 3% were fully vaccinated.

The large majority of those who have gotten their first shot (66.6%) and who have gotten fully vaccinated (65.8%) are White.

Only 18% of individuals initiating vaccinations are from BIPOC communities. The people who are suffering disproportionately from the pandemic are also less likely to get the vaccine.

For BIPOC communities hardest hit by COVID-19, vaccination rates are disturbingly low, particularly among Native Hawaiian/Pacific Islander (0.5% of the vaccinated population), American Indian/Alaska Native (2.2%), Black/African American (2.2%), Hispanic/Latino/a (4.7%) and Asian Americans (8.3%).

Although Black, Indigenous and People of Color (BIPOC) represent 34.6% of the total population of Washington state, as is the case nationally, these groups carry the greatest COVID-19 burden, representing 52% of all COVID-19 cases, 47% of COVID-19 hospitalizations and 29% of COVID-19 deaths.

Among BIPOC communities, the Hispanic/Latino/a community is most disparately impacted by COVID-19, representing 32% of all COVID-19 cases, 24% of hospitalizations and 12% of deaths. 

The rates are also disproportionately high among Asian, Black, Native Hawaiian, Pacific Islander, American Indian and Alaska Native communities. These rates are likely higher as testing is limited across the state and a significant number of confirmed cases, hospitalizations and deaths are missing racial and ethnic information. 

What does it take to build trust and confidence in vaccines?

The creative strategy behind the vaccine confidence campaign is to validate the questions and concerns of the hesitant, and to empower people to get back to the things COVID-19 has taken away—gathering with family and friends, freedom from masks and worry about the virus, and reopening businesses.

But ads alone won’t build confidence. It takes open and transparent dialogue, hearing from trusted messengers, and assurance that the research behind the vaccines is thorough and that people that look like them have been part of it.

The campaign is supported by a website — PreventCovidWA.org — to continue the dialogue. It uses an integrated media strategy with animated videos breaking down the science behind the vaccines, “Ask An Expert” videos featuring the diverse physicians and researchers who led the Phase III vaccine trials, and testimonials from people who volunteered for studies and people who have been vaccinated.

With deep listening through digital channels and on-the-ground community engagement, the content is dynamic. It’s responsive to community conversation as the scientific narrative unfolds and changes and new and novel misinformation and myths arise.

These aren’t just strategies suggested by audience research. These are the strategies the COVID-19 Prevention Network (CoVPN) has been developing and refining since spring 2020 when it began preparing for Phase III COVID-19 vaccine trials. Those studies were conducted at unprecedented speed and scale and with some of the highest representation of BIPOC people ever.

Pivoting to the pandemic

The CoVPN was formed in April 2020. Tony Fauci turned to the clinical trial networks the NIH had established for HIV/AIDS and charged them with conducting large scale Phase III trials for COVID-19 vaccines being developed under what came to be called Operation Warp Speed.

One of those leaders was Larry Corey, renowned virologist, head of the HIV Vaccine Trial Network and past president and director of Fred Hutch. We were well-positioned for this work based on years of experience in HIV vaccine trial work.

Immediately, the HIV Vaccine Trials Network (HVTN) Community Engagement and External Relations teams began reaching out to longstanding community partners to learn more about the impact of COVID-19 in their respective communities, to better understand COVID-19 fears and uncertainty, and to identify what information was needed to ensure that communities had the resources they needed to make informed decisions about participation in the vaccine trials in the short term and vaccine acceptability and uptake in the long term. 

Priority populations — older adults (65+), Black, Latino/a/Hispanic, Indigenous and People of Color — have been the focus of these efforts for months. Strong community partnerships — rooted in bidirectional communication, trust and reciprocity — were the cornerstones of the plan.  

A few weeks into the new CoVPN efforts, a strategic communications and marketing effort was launched to extend out from the community-based work. A creative partnership was formed among CoVPN leadership and the agencies Socialisssima and Sam Bonds Creative, who brought their deep expertise in BIPOC consumer mindsets to develop a mass media campaign that was both national and localized.  

The community engagement plan focused on increasing awareness and knowledge. We sought to build trust by lifting up the voices of people with lived experiences. Our community-based researchers listened carefully to the concerns being raised. The campaign sought to address the common fears, uncertainty, isolation, mistrust and misinformation by offering hope, a way to end the uncertainty and a call to action.

The Super Bowl ad reflects this emphasis — it features real people who might look like you and have questions and concerns. Those questions and concerns are dealt with respectfully.

People working to build vaccine confidence in Washington state. From left to right: Sally Bock, senior director, marketing, CoVPN; Stephaun Wallace, director of external relations, CoVPN; Michael Ferguson, director of marketing, CoVPN; Norberto Zylberberg, founder, Socialisssima; Sam Bonds, principal, Sam Bonds Creative

Lessons from clinical study recruitment

All of these efforts to engage community built a strong foundation for the Washington state effort.

Then we got a bit lucky.

When our CBS affiliate reached out on short notice with available Super Bowl commercial space, we were able to produce a strategic and emotionally on-target 30-second Public Service Announcement in just days.

Of course, a Super Bowl ad is just one opportunity to spread the word. We also partnered with the Washington State Department of Health to develop a user-friendly vaccination website specific to Washington state – PreventCovidWA.org – where people from across the state can obtain information about available vaccines, hear testimonials from people who participated in the vaccine trials and from people who have been vaccinated, and schedule a vaccination appointment. 

Partnering with community and working together, with all members providing direction and guidance, is what ensured equity and inclusion in the COVID-19 vaccine clinical trials.

This approach worked before – it is what made the vaccine trials as diverse as they were.

It IS the same approach that will help us achieve equity and inclusion in this vaccination campaign.

For more information on the PreventCovidWA campaign, check Instagram and Facebook.

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