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Backed by five pharma giants and a crew of Penn superstars, a startup uses mRNA to create in vivo CAR-T — with a pro at the helm

Earlier this year, Jonathan Epstein and other scientists at Penn published a paper in Science that spelled out the intriguing results of a mouse study….

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Earlier this year, Jonathan Epstein and other scientists at Penn published a paper in Science that spelled out the intriguing results of a mouse study. Using CD-5 targeted lipid nanoparticles, the tiny vehicles used to carry messenger RNA, they were able to reprogram T lymphocytes into CAR-Ts in vivo, in the body. Trained to recognize fibrotic cells specifically in the heart, the scientists involved were able to restore cardiac function in mice.

Jonathan Epstein

While still very much at the preclinical stage, the tech comes with some disruptive potential applications in oncology and fibrosis — plus some — and a group of experienced biotech investors has crafted a biotech startup designed to pilot it into the clinic. After VCs planted the initial $63 million seed round, a group of Big Pharmas has come in to help with a $102 million Series A. And they’ve recruited a high-profile CEO to captain the venture, plucking her off the beach shortly after her last effort recently sank beneath the waves of a storm-tossed Nasdaq.

This new enterprise, dubbed Capstan, is the brainchild of some of the world’s top cell therapy and mRNA specialists at Penn. The biotech has gathered a who’s who in these fields to help godfather the venture, including:

  • Carl June and Bruce Levine, two cell engineering experts who played a big role in developing Novartis’ gen-1 CAR-T.
  • Drew Weissman and Hamideh Parhiz, who have been working on mRNA and lipid tech.
  • Jonathan Epstein, chief scientific officer for Penn Medicine and author of the mouse study in Science, and Haig Aghajanian, now VP of research at Capstan.
  • Ellen Puré and Steven Albelda are focusing on immunology and fibrosis.

Laura Shawver has jumped aboard as CEO, just weeks after her last biotech — Silverback — was relegated to reverse-merger material when the pipeline imploded at a time the markets are ruthless when it comes to R&D failure. And she’s skippering a crew that is after another white whale.

“To me,” Shawver tells me, “it’s as if the Covid-19 vaccine and cell therapy had a baby and this is what they produced.”

“Covid-19 vaccine taught us you could deliver a messenger RNA payload in a lipid nanoparticle. It would be translated into a protein that had a biological consequence,” she adds. “And cell therapy has taught us that if you can ex vivo activate T cells to recognize a tumor antigen and put them back that you can cure some people with certain cancers. Really just marrying the two together makes all the sense. It’s a huge opportunity for patients to have a more convenient treatment. And the breadth of the platform is quite broad.”

With a scientific foundation like Capstan’s, money has not been a major issue. Novartis Venture Fund, OrbiMed, RA Capital and Vida Ventures put up the $63 million stealth round last fall. Then Pfizer Ventures led the $102 million A round with Leaps by Bayer (seemingly game for anything likely to inspire a tech revolution), Eli Lilly, Bristol Myers Squibb, Polaris Partners and Alexandria Venture Investments jumping in alongside the seed crowd for the launch money.

Silverback may have proved to be a bust, but in this business, if you survive long enough, there are plenty of thrills and spills in line for everyone. Before Silverback, Shawver’s recent track record also includes Synthorx, the IL-2 play that Sanofi snapped up for $2.5 billion, though that’s proved troublesome. And along the way, Shawver has earned a rep for an upbeat even-handedness in just about any situation.

Rajul Jain

“She’s a very steady hand,” says Rajul Jain, the managing director of Vida and part of the former Kite CAR-T crew that helped create the venture outfit, which has been a key player in the cell therapy 2.0 field. And Jain believes Shawver’s broad experience in launching a biotech will be essential in the years to come.

Capstan originally got started as Teefib, a very low-profile June (et al) spinout initially focused on CAR-T for fibrosis, which Jain and the Vida crew watched from the sidelines for a couple of years. Then the scope and tech broadened. Vida came in on the seed round in late 2021, knowing that there are some major challenges ahead as Capstan works on payloads and targeting.

Getting the right payload, in sufficient size, and then steering it to the right cell in humans, represents a major challenge for Capstan, Jain notes.

“The biggest technological barrier will be around the RNA itself,” he says. “It’s going to be getting enough of the RNA into the T cell when we give this ultimately in human. When we describe what is the problem we hope that Capstan is on a path to solving, the hardest problem would probably be that one.”

Adrian Bot

Shawver will start out in her new gig with 45 staffers, including Adrian Bot, the former CSO at CAR-T pioneer Kite, along with chief technology officer Priya Karmali, who’s worked for years in the lipid nanoparticle field. They initially got started primarily in Philadelphia, close to Penn, then added a San Diego facility.

They’ll be focused on what could be considered the third generation of cell therapies with a second-gen mRNA strategy. Along the way from the birth of these technologies, there have been some huge challenges.

Priya Karmali

“People have been trying to do this for a very long time,” Shawver says. And there’s still a long way to go.

“How do you get RNA into the right cells?” Shawver asks. “You have to change the structure of RNA, you have to code it into a lipid nanoparticle. Of course we also decorate that lipid nanoparticle with a targeting moiety or antibodies to get it to specific cell types.”

But Capstan’s founding scientists were the leaders in making it all work, initially. And now they’ll help lead the charge for something new and better — provided it works. And that fits neatly into Shawver’s life’s work.

“Whatever I’ve chosen to do throughout my career, whether it worked or hasn’t worked, has been to always make meaningful differences for patients with serious diseases,” says Shawver.

Whether it was the early days of precision medicine, novel targets, I/O, “the goal has been the same.” And now the opportunities to do something big are better than ever.

“Everybody can see the stage has been set, the field is moving, the innovation is here to bring what cell therapy brought to people,” says Shawver. “But more broadly in a more convenient way in a cost that is more accessible and bring them to patients who can’t access these things today. So I’m certainly excited about this opportunity.”

Long sabbaticals just aren’t her style.

“I would be bored,” she said with a laugh. “If I took time off, in two days’ time I’d say, oh my gosh, why am I doing this?”

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International

The next pandemic? It’s already here for Earth’s wildlife

Bird flu is decimating species already threatened by climate change and habitat loss.

I am a conservation biologist who studies emerging infectious diseases. When people ask me what I think the next pandemic will be I often say that we are in the midst of one – it’s just afflicting a great many species more than ours.

I am referring to the highly pathogenic strain of avian influenza H5N1 (HPAI H5N1), otherwise known as bird flu, which has killed millions of birds and unknown numbers of mammals, particularly during the past three years.

This is the strain that emerged in domestic geese in China in 1997 and quickly jumped to humans in south-east Asia with a mortality rate of around 40-50%. My research group encountered the virus when it killed a mammal, an endangered Owston’s palm civet, in a captive breeding programme in Cuc Phuong National Park Vietnam in 2005.

How these animals caught bird flu was never confirmed. Their diet is mainly earthworms, so they had not been infected by eating diseased poultry like many captive tigers in the region.

This discovery prompted us to collate all confirmed reports of fatal infection with bird flu to assess just how broad a threat to wildlife this virus might pose.

This is how a newly discovered virus in Chinese poultry came to threaten so much of the world’s biodiversity.

H5N1 originated on a Chinese poultry farm in 1997. ChameleonsEye/Shutterstock

The first signs

Until December 2005, most confirmed infections had been found in a few zoos and rescue centres in Thailand and Cambodia. Our analysis in 2006 showed that nearly half (48%) of all the different groups of birds (known to taxonomists as “orders”) contained a species in which a fatal infection of bird flu had been reported. These 13 orders comprised 84% of all bird species.

We reasoned 20 years ago that the strains of H5N1 circulating were probably highly pathogenic to all bird orders. We also showed that the list of confirmed infected species included those that were globally threatened and that important habitats, such as Vietnam’s Mekong delta, lay close to reported poultry outbreaks.

Mammals known to be susceptible to bird flu during the early 2000s included primates, rodents, pigs and rabbits. Large carnivores such as Bengal tigers and clouded leopards were reported to have been killed, as well as domestic cats.

Our 2006 paper showed the ease with which this virus crossed species barriers and suggested it might one day produce a pandemic-scale threat to global biodiversity.

Unfortunately, our warnings were correct.

A roving sickness

Two decades on, bird flu is killing species from the high Arctic to mainland Antarctica.

In the past couple of years, bird flu has spread rapidly across Europe and infiltrated North and South America, killing millions of poultry and a variety of bird and mammal species. A recent paper found that 26 countries have reported at least 48 mammal species that have died from the virus since 2020, when the latest increase in reported infections started.

Not even the ocean is safe. Since 2020, 13 species of aquatic mammal have succumbed, including American sea lions, porpoises and dolphins, often dying in their thousands in South America. A wide range of scavenging and predatory mammals that live on land are now also confirmed to be susceptible, including mountain lions, lynx, brown, black and polar bears.

The UK alone has lost over 75% of its great skuas and seen a 25% decline in northern gannets. Recent declines in sandwich terns (35%) and common terns (42%) were also largely driven by the virus.

Scientists haven’t managed to completely sequence the virus in all affected species. Research and continuous surveillance could tell us how adaptable it ultimately becomes, and whether it can jump to even more species. We know it can already infect humans – one or more genetic mutations may make it more infectious.

At the crossroads

Between January 1 2003 and December 21 2023, 882 cases of human infection with the H5N1 virus were reported from 23 countries, of which 461 (52%) were fatal.

Of these fatal cases, more than half were in Vietnam, China, Cambodia and Laos. Poultry-to-human infections were first recorded in Cambodia in December 2003. Intermittent cases were reported until 2014, followed by a gap until 2023, yielding 41 deaths from 64 cases. The subtype of H5N1 virus responsible has been detected in poultry in Cambodia since 2014. In the early 2000s, the H5N1 virus circulating had a high human mortality rate, so it is worrying that we are now starting to see people dying after contact with poultry again.

It’s not just H5 subtypes of bird flu that concern humans. The H10N1 virus was originally isolated from wild birds in South Korea, but has also been reported in samples from China and Mongolia.

Recent research found that these particular virus subtypes may be able to jump to humans after they were found to be pathogenic in laboratory mice and ferrets. The first person who was confirmed to be infected with H10N5 died in China on January 27 2024, but this patient was also suffering from seasonal flu (H3N2). They had been exposed to live poultry which also tested positive for H10N5.

Species already threatened with extinction are among those which have died due to bird flu in the past three years. The first deaths from the virus in mainland Antarctica have just been confirmed in skuas, highlighting a looming threat to penguin colonies whose eggs and chicks skuas prey on. Humboldt penguins have already been killed by the virus in Chile.

A colony of king penguins.
Remote penguin colonies are already threatened by climate change. AndreAnita/Shutterstock

How can we stem this tsunami of H5N1 and other avian influenzas? Completely overhaul poultry production on a global scale. Make farms self-sufficient in rearing eggs and chicks instead of exporting them internationally. The trend towards megafarms containing over a million birds must be stopped in its tracks.

To prevent the worst outcomes for this virus, we must revisit its primary source: the incubator of intensive poultry farms.

Diana Bell does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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NY Fed Finds Medium, Long-Term Inflation Expectations Jump Amid Surge In Stock Market Optimism

NY Fed Finds Medium, Long-Term Inflation Expectations Jump Amid Surge In Stock Market Optimism

One month after the inflation outlook tracked…

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NY Fed Finds Medium, Long-Term Inflation Expectations Jump Amid Surge In Stock Market Optimism

One month after the inflation outlook tracked by the NY Fed Consumer Survey extended their late 2023 slide, with 3Y inflation expectations in January sliding to a record low 2.4% (from 2.6% in December), even as 1 and 5Y inflation forecasts remained flat, moments ago the NY Fed reported that in February there was a sharp rebound in longer-term inflation expectations, rising to 2.7% from 2.4% at the three-year ahead horizon, and jumping to 2.9% from 2.5% at the five-year ahead horizon, while the 1Y inflation outlook was flat for the 3rd month in a row, stuck at 3.0%. 

The increases in both the three-year ahead and five-year ahead measures were most pronounced for respondents with at most high school degrees (in other words, the "really smart folks" are expecting deflation soon). The survey’s measure of disagreement across respondents (the difference between the 75th and 25th percentile of inflation expectations) decreased at all horizons, while the median inflation uncertainty—or the uncertainty expressed regarding future inflation outcomes—declined at the one- and three-year ahead horizons and remained unchanged at the five-year ahead horizon.

Going down the survey, we find that the median year-ahead expected price changes increased by 0.1 percentage point to 4.3% for gas; decreased by 1.8 percentage points to 6.8% for the cost of medical care (its lowest reading since September 2020); decreased by 0.1 percentage point to 5.8% for the cost of a college education; and surprisingly decreased by 0.3 percentage point for rent to 6.1% (its lowest reading since December 2020), and remained flat for food at 4.9%.

We find the rent expectations surprising because it is happening just asking rents are rising across the country.

At the same time as consumers erroneously saw sharply lower rents, median home price growth expectations remained unchanged for the fifth consecutive month at 3.0%.

Turning to the labor market, the survey found that the average perceived likelihood of voluntary and involuntary job separations increased, while the perceived likelihood of finding a job (in the event of a job loss) declined. "The mean probability of leaving one’s job voluntarily in the next 12 months also increased, by 1.8 percentage points to 19.5%."

Mean unemployment expectations - or the mean probability that the U.S. unemployment rate will be higher one year from now - decreased by 1.1 percentage points to 36.1%, the lowest reading since February 2022. Additionally, the median one-year-ahead expected earnings growth was unchanged at 2.8%, remaining slightly below its 12-month trailing average of 2.9%.

Turning to household finance, we find the following:

  • The median expected growth in household income remained unchanged at 3.1%. The series has been moving within a narrow range of 2.9% to 3.3% since January 2023, and remains above the February 2020 pre-pandemic level of 2.7%.
  • Median household spending growth expectations increased by 0.2 percentage point to 5.2%. The increase was driven by respondents with a high school degree or less.
  • Median year-ahead expected growth in government debt increased to 9.3% from 8.9%.
  • The mean perceived probability that the average interest rate on saving accounts will be higher in 12 months increased by 0.6 percentage point to 26.1%, remaining below its 12-month trailing average of 30%.
  • Perceptions about households’ current financial situations deteriorated somewhat with fewer respondents reporting being better off than a year ago. Year-ahead expectations also deteriorated marginally with a smaller share of respondents expecting to be better off and a slightly larger share of respondents expecting to be worse off a year from now.
  • The mean perceived probability that U.S. stock prices will be higher 12 months from now increased by 1.4 percentage point to 38.9%.
  • At the same time, perceptions and expectations about credit access turned less optimistic: "Perceptions of credit access compared to a year ago deteriorated with a larger share of respondents reporting tighter conditions and a smaller share reporting looser conditions compared to a year ago."

Also, a smaller percentage of consumers, 11.45% vs 12.14% in prior month, expect to not be able to make minimum debt payment over the next three months

Last, and perhaps most humorous, is the now traditional cognitive dissonance one observes with these polls, because at a time when long-term inflation expectations jumped, which clearly suggests that financial conditions will need to be tightened, the number of respondents expecting higher stock prices one year from today jumped to the highest since November 2021... which incidentally is just when the market topped out during the last cycle before suffering a painful bear market.

Tyler Durden Mon, 03/11/2024 - 12:40

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Spread & Containment

A major cruise line is testing a monthly subscription service

The Cruise Scarlet Summer Season Pass was designed with remote workers in mind.

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While going on a cruise once meant disconnecting from the world when between ports because any WiFi available aboard was glitchy and expensive, advances in technology over the last decade have enabled millions to not only stay in touch with home but even work remotely.

With such remote workers and digital nomads in mind, Virgin Voyages has designed a monthly pass that gives those who want to work from the seas a WFH setup on its Scarlet Lady ship — while the latter acronym usually means "work from home," the cruise line is advertising as "work from the helm.”

Related: Royal Caribbean shares a warning with passengers

"Inspired by Richard Branson's belief and track record that brilliant work is best paired with a hearty dose of fun, we're welcoming Sailors on board Scarlet Lady for a full month to help them achieve that perfect work-life balance," Virgin Voyages said in announcing its new promotion. "Take a vacation away from your monotonous work-from-home set up (sorry, but…not sorry) and start taking calls from your private balcony overlooking the Mediterranean sea."

A man looks through his phone while sitting in a hot tub on a cruise ship.

Shutterstock

This is how much it'll cost you to work from a cruise ship for a month

While the single most important feature for successful work at sea — WiFi — is already available for free on Virgin cruises, the new Scarlet Summer Season Pass includes a faster connection, a $10 daily coffee credit, access to a private rooftop, and other member-only areas as well as wash and fold laundry service that Virgin advertises as a perk that will allow one to concentrate on work

More Travel:

The pass starts at $9,990 for a two-guest cabin and is available for four monthlong cruises departing in June, July, August, and September — each departs from ports such as Barcelona, Marseille, and Palma de Mallorca and spends four weeks touring around the Mediterranean.

Longer cruises are becoming more common, here's why

The new pass is essentially a version of an upgraded cruise package with additional perks but is specifically tailored to those who plan on working from the ship as an opportunity to market to them.

"Stay connected to your work with the fastest at-sea internet in the biz when you want and log-off to let the exquisite landscape of the Mediterranean inspire you when you need," reads the promotional material for the pass.

Amid the rise of remote work post-pandemic, cruise lines have been seeing growing interest in longer journeys in which many of the passengers not just vacation in the traditional sense but work from a mobile office.

In 2023, Turkish cruise line operator Miray even started selling cabins on a three-year tour around the world but the endeavor hit the rocks after one of the engineers declared the MV Gemini ship the company planned to use for the journey "unseaworthy" and the cruise ship line dealt with a PR scandal that ultimately sank the project before it could take off.

While three years at sea would have set a record as the longest cruise journey on the market, companies such as Royal Caribbean  (RCL) (both with its namesake brand and its Celebrity Cruises line) have been offering increasingly long cruises that serve as many people’s temporary homes and cross through multiple continents.

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