China’s state-run Xinhua News Agency reports that
healthcare providers at Wuhan’s Jinyintan Hospital will begin treating
the first group of severe coronavirus cases with Gilead Sciences’ (GILD-2.2%) remdesivir tomorrow. A total of 761 patients will receive therapy.
Chinese authorities have OK’d the start of clinical trials.
The United States’ expected “export boom” to China in the aftermath
of the Phase 1 trade deal will be delayed, as China battles the rapidly
spreading coronavirus, White House economic adviser Larry Kudlow said on
Tuesday.
Chinese factories, cities and transport links are shut as Beijing
fights the spread of the virus, dampening domestic demand for everything
from oil to consumer goods.
Under the trade deal, Beijing agreed to boost its U.S. purchases by
$200 billion over two years, a massive increase that many analysts said
was overly ambitious before the virus emerged. PURCHASE TARGETS
In the text of the agreement, Beijing has pledged https://www.reuters.com/article/us-usa-trade-china-details-factbox/whats-in-the-us-china-phase-1-trade-deal-idUSKBN1ZE2IF
to buy $76.7 billion of additional U.S. goods and services, on top of a
2017 baseline, in the 12 months that started Jan. 1, 2020, although the
agreement doesn’t formally take effect until Feb. 15, 2020.
It specifies an additional $123 billion in Chinese purchases for the second year, 2021.
Included in the first-year target are increases of $32.9 billion in
U.S. manufactured goods purchases, $12 billion for agricultural
products, $18.5 billion for energy and $12.8 billion for services.
The deal deliberately does not spell out when during the year these
goods should be purchased, in part because Beijing insisted that market
demand dictate purchase timing.
It says, “The Parties acknowledge that purchases will be made at
market prices based on commercial consideration and that market
conditions, particularly in the case of agricultural goods, may dictate
the timing of purchases within any given year.”
The deal text contains a disaster clause, yet to be formally invoked
by Beijing, to allow for delays: “In the event that a natural disaster
or other unforeseeable event outside the control of the Parties delays a
Party from timely complying with its obligations under this Agreement,
the Parties shall consult with each other.” CONSULTATIONS
The form these consultations should take is not specified in the text.
Enforcement of the agreement relies heavily on a bilateral process,
with each side setting up an enforcement office to monitor compliance
with the deal and to field complaints from companies or other parties.
Any disputes in implementing the terms of the agreement, including
meeting China’s purchase targets, will progress up a chain of officials
over a 90-day period, from the working level, to vice ministers and
ultimately to U.S. Trade Representative Robert Lighthizer and Chinese
Vice Premier Liu He.
If a dispute cannot be resolved, the complaining party can levy tariffs in proportion to the damage caused by complaint.
China, however, would be prohibited from responding in kind to any
punitive U.S. tariffs. Beijing’s only recourse in that cause is to quit
the agreement.
Lighthizer has said the structure, which includes twice yearly
consultations with Liu, is aimed at resolving any disagreements
bilaterally. He has eschewed third-party dispute resolution mechanisms
in trade agreements.
The USTR “has not received any requests from China’s government to
discuss changes in China’s purchase commitments due to the coronavirus
outbreak,” a spokeswoman said.
The Trump administration considers trade and the coronavirus separate
issues, White House senior adviser Kellyanne Conway said Wednesday. In
the public health meetings she has been in, she said she’s never “heard
the word trade mentioned a single time.”
With wide swaths of China’s economy on lockdown, implementation of
the trade deal “will take a back seat” said Wendy Cutler, a former
deputy U.S. trade representative.
“The best thing the United States can do at this point is be
compassionate and recognize this and accept it, and not make abrasive
comments on what we expect,” Cutler told a trade conference in
Washington.
Cutler said that it is unlikely that virus-prompted delays would let
China “off the hook” for its purchase agreements, and Washington and
Beijing would find a way forward.
“There is a heavy incentive on both sides for this agreement to work,” she said.
German sportswear company Adidas on Wednesday said it was temporarily shutting a “considerable” number of its stores in China due to the coronavirus outbreak.
The company said the fast-spreading virus was having a negative
impact on its business but added that it could not yet assess to what
extent.
Adidas has about 12,000 outlets in China, including franchise stores.
Adidas saw sales growth slow to 11% in China in the July-September period from 14% in the second quarter.
Several retailers have warned that coronavirus is taking its toll, including Nike Inc and Hugo Boss, which have both closed some stores in China.
Adidas’s German rival Puma said that factories will remain closed until Feb. 10.
“We have so far not been informed of any production or shipment
delays. A number of stores – both owned and operated and partner stores –
remain closed for the time being due to local regulations”, a Puma
spokesman said.
“It is too early to comment on the effects of these closures”, he added.
The group cancelled or postponed all Puma events in China in February
including training and marketing meetings and put travel restrictions
in place. Its Shanghai office remains closed until February 9.
Interleukins IL-33 and IL-5 are major culprits in the inflammatory
responses associated with asthma. But researchers at Albany Medical
College just found that leveraging the ability of these two signaling
molecules to link to a type of immune cell in the brain might alleviate
age-related cognitive decline and help treat neurodegenerative diseases.
The class of immune cell is called group 2 innate lymphoid cells (ILC2s). In a new study published in the Journal of Experimental Medicine,
the scientists reported that treating old mice with IL-33 to activate
ILC2 or use IL-5—which is a product of ILC2 activation—improved
cognition among the animals.
In healthy mice, ILC2s were recently found in the meninges—the
membranes that line the skull and enclose the brain and spinal
cord. These cells were shown to be activated and help healing after
spinal cord injury. “However, whether ILC2s also reside in other parts
of the central nervous system, and how they respond to aging, was
unknown,” Qi Yang, the new study’s co-corresponding author, said in a statement.
Yang and colleagues examined the brains of mice of different ages.
They found that in aged mice, ILC2s made up about 50% of all immune
cells in a complex cerebral structure called the choroid plexus. But
there were only a few in young mice. An analysis of choroid plexus
tissue also revealed that ILC2s exist in large numbers in elderly
people.
Choroid plexus produces cerebrospinal fluid and acts as a barrier
that blocks toxins from entering the central nervous system. It’s close
to the hippocampus, a part of the brain that’s crucial to learning and
memory functions.
ILC2s in aged mice brains were largely inactive. To determine whether
they would be able to proliferate, the researchers treated mice with
IL-33, a known ILC2 activator. As a result, the ILC2s significantly
expanded, and the researchers noted that they expressed high amounts of
Ascl2 and Hif1a, the transcription factors that promote the renewal and
survival of neurons. ILC2s in older mice also survived longer than did
those in younger rodents.
What’s more, aged mice that received pre-activated ILC2 or IL-33
showed significantly enhanced performance in tests that measured the
animal’s cognitive functions, such as spatial memory, the team reported.
“Together, these data provide direct evidence that activated ILC2 can
improve the cognitive function of aged mice,” the researchers wrote in
the study.
The team went on to examine the specific effector molecules by which
activated ILC2 work to improve cognitive function. They tried giving the
mice either IL-5 or IL-13, two signaling molecules ILC2s produce. While
IL-13 has been shown to promote spatial learning and memory in young mice, IL-5’s effects on cognition were unknown.
Surprisingly, it was IL-5, not IL-13, that improved elderly animals’
performance in tests. The team found that treatment with IL-5 increased
neurogenesis and reduced neuroinflammation, which probably explains why
they showed better cognitive function.
Neurodegenerative diseases and age-related dementia represent huge
unmet medical needs, so scientists have been searching for new pathways
to combat them. A team led by Brown University scientists previously
found that widely used HIV drug lamivudine might be repurposed
to treat age-related disorders by limiting the activity of a virus-like
mechanism that gives rise to an inflammatory immune response.
In 2018, a collaboration between the University of Virginia and Virginia Tech found that
meningeal lymphatic vessels, which connect the brain and the immune
system, could be targeted for Alzheimer’s and age-related dementia.
The Albany Medical College team believes ILC2s in the aged brain are
also promising targets for treating age-related cognitive decline and
neurodegenerative diseases.
“Our work has thus revealed the accumulation of tissue-resident ILC2
cells in the choroid plexus of aged brains and demonstrated that their
activation may revitalize the aged brain and alleviate aging-associated
cognitive decline,” said Yang. https://www.fiercebiotech.com/research/alleviating-age-related-cognitive-decline-by-activating-immune-cells
The FDA designates Alector’s (ALEC+6.8%)
AL101 for Fast Track review for the treatment of patients with
progranulin gene mutations causing frontotemporal dementia (FTD).
Phase 1-stage AL101 is a human monoclonal antibody designed to restore progranulin levels in the central nervous system. Progranulin is
a pleiotropic (produces more than one effect) protein that plays key
roles in inflammation, neurodegeneration, tumorigenesis and other
processes.
Mutations in the encoding gene that reduce
progranulin levels are associated with increased risk of developing
Alzheimer’s and Parkinson’s diseases.
Fast Track status provides for more frequent
interaction with the FDA review team and a rolling review of the
marketing application.
The novel coronavirus arrived at Regeneron Pharmaceuticals’ sprawling campus like any other parcel.
Inside a cardboard box, shipped to the company’s scientists, was a
small tube. And inside it was a fragment of genetic code belonging to
2019-nCoV, the infectious agent that has killed more than 400 people
since the start of the outbreak in China. Because it was just a snippet
of the full genome, the virus wasn’t actually infectious.
It also wasn’t hard to obtain. The sender was one of the many vendors
that will whip up synthetic genomes for a fee — a process that, for
biotech companies, has become nearly as commoditized as food delivery.
“You can’t get it on Amazon,” Christos Kyratsous, the company’s vice
president of infectious disease research, said with a smile, “yet.”
What happens with the virus now is still very much a story being
written. Like a number of other biopharma companies, Regeneron’s
response to the outbreak has been rapid. Vir Biotechnology, a startup
based in San Francisco, is also working to develop a treatment. Johnson
& Johnson and others are hoping to develop vaccines. The drug maker
Gilead Sciences has already shipped an investigational medicine to China
to see if it might work against the virus.
Despite the response, developing drugs or vaccines during an outbreak
can be tortuous, and the early science usually provides only the barest
clues to whether or not further work will yield success. If history is
any guide, most of the efforts launched in recent days will ultimately
fail — for any number of reasons. Christos
Kyratsous, Regeneron vice President of infectious disease research and
viral vector technologies, in one of the company’s labs. Erica Yoon for STAT
One of them is that what works in lab mice often fails in actual
people. But that’s where Regeneron — a $38 billion company that crafted a
treatment for Ebola virus — believes it has a leg up.
Decades ago, the company set out to bend the curve of drug
development by genetically engineering a mouse to have a fully human
immune system. That means if you inject it with a foreign agent, it’ll
generate human antibodies to fight the perceived infection. One of those
antibodies became Dupixent, Regeneron’s multibillion-dollar eczema
drug, and another grew into Libtayo, the company’s recently approved
cancer immunotherapy.
Now, Regeneron is betting its mice can come through in 2019-nCoV.
The process began last month, when scientists in China sequenced the
virus and uploaded their findings to an open-source archive. Back in
Tarrytown, Regeneron scientists copy-pasted it into genome analysis
software and began poring over the sequence in search of the key that
2019-nCoV uses to unlock and infect human cells.
Much like the pandemic pathogens SARS and MERS, each individual virus
of 2019-nCoV relies on a surface “spike” protein to bypass cellular
defenses — and cause infection. Any eventual treatment would have to
stop that protein from reaching its target.
So Regeneron homed in on the snippet of the virus’ genome that
encodes for spike, which boiled down to about 10% of the roughly 30,000
base pairs that make up 2019-nCoV, said senior R&D specialist
Kristen Pascal. And then it placed its order. A small portion of a reference sequence of the full coronavirus matched alongside two actual DNA samples sequenced by Regeneron. Erica Yoon for STAT
About a week and a half later, the tube came in the mail and
Regeneron’s scientists cleared their calendars. Over the course of some
long days and an unobserved weekend, they cloned the spike-producing
code and used it to “decorate” the surface of some otherwise harmless
particles, Kyratsous said. That created a pseudo-virus that would mimic
2019-nCoV’s cell-penetrant biology but leave out its ability to
replicate and cause illness.
And that’s where the mice come in. Regeneron’s scientists are
currently at work immunizing them with the spike-coated pseudo-virus,
generating antibodies that will interrupt the coronavirus from breaking
into cells.
The process will take weeks and likely result in thousands of
antibodies with slight variations, Kyratsous said. Once it does,
Regeneron will host an internal bake-off, screening each antibody to
isolate only the most potent.
The winners will get tested against animal models of 2019-nCoV, but first they have to grow.
“The day we decide on a lead antibody, that’s the day we can get
started,” said Hanne Bak, head of Regeneron’s preclinical manufacturing
division.
Downstairs from some of the labs at Regeneron is an on-site
manufacturing operation, a biotech brewery where row after row of
gleaming bioreactors house the genetically modified cells that churn out
therapeutic antibodies.
There, scientists will thaw out a vial of frozen cells and put them
into an oscillating machine called a wave bioreactor, which rocks back
and forth like it’s trying to coax the cells to sleep. From there the
antibody factories move through ever-larger bioreactors, a weekslong
process that produces enough drug product for the requisite animal
studies.
If any 2019-nCoV antibodies graduate to clinical trials, the saga
continues at Regeneron’s upstate manufacturing facility, which is
outfitted with the scale necessary for making human drugs.
In the end, the company hopes to have a handful of antibodies that can be packaged as a cocktail. Bioreactors at Regeneron’s manufacturing site in Tarrytown. Erica Yoon for STAT
“You want antibodies that bind to the same target but don’t compete
with each other,” Kyratsous said. “If you use more than one antibody,
you increase the chances your treatment will still work as the virus
evolves.”
Regeneron took the same approach the last time it broke the glass on
its outbreak-response process, an experience that both lends hope to the
2019-nCoV effort and underlines why pandemics can be perilous for drug
development.
In 2014, as Ebola ravaged West Africa, Regeneron employed its
chimeric mice to come up with antibodies against the virus. About 10
months later, with the support of the federal Biomedical Advanced
Research and Development Authority, Regeneron had come up with EB3, a
three-antibody cocktail ready for human testing.
But the world wasn’t ready for Regeneron. The outbreak had subsided by late 2015, leaving EB3 on the shelf.
Three years later, when the virus flared up in the Democratic
Republic of Congo, Regeneron shipped out doses of EB3 for a landmark
clinical trial. The results were dramatic: About 65% of patients who got
Regeneron’s one-time therapy survived their infections, compared to 33%
in the outbreak overall.
The speed and efficacy of EB3 is what Regeneron hopes to replicate in
2019-nCoV, even if there’s little hope for return on its investment. As
with Ebola, BARDA is supporting the latest effort, and Regeneron is
aiming to replicate that 10-month time frame. But just like last time,
the outbreak’s uncertain future could render a treatment unnecessary by
the time it’s ready for use. And even if the coronavirus persists, the
unpredictability of drug development could leave Regeneron with nothing
to show for its efforts.
“This is not a profit-driven endeavor,” Kyratsous said. “We never
start a project here by saying, ‘Oh, my God, this is a great commercial
opportunity. Let’s do it.’”
As the new coronavirus spreads, health-tech startups with medical
chatbots are scrambling to update their algorithms to screen feverish
and coughing Americans and advise whether they should be evaluated for
infection with the virus.
So far, these artificial intelligence-powered chatbots are turning up
lots of people with the flu. That’s unsurprising at this time of year.
It speaks to the small number of coronavirus cases in the U.S. — and how
hard it may ultimately be for AI systems to differentiate among the
myriad pathogens that cause the same flu-like symptoms that a mild case
of the new virus appears to cause.
The apps don’t appear to have been involved in turning up any
patients who actually have the 2019-nCoV coronavirus — there have been 11 confirmed cases
in the U.S. to date — nor is it clear whether any patients flagged by
the chatbots have even proceeded to undergo lab testing. One company,
98point6, said it has contacted the Centers for Disease Control and
Prevention about two suspected cases it turned up, but neither of those
patients were ultimately isolated or referred to get testing for the new
virus.
Still, the companies say, they’re offering people reassurance and
helping them get treatment — while keeping them out of the waiting rooms
of overwhelmed clinics and urgent care centers. And if the coronavirus
spreads more widely in the U.S., these companies could be poised to play
a more prominent role in triaging suspected cases.
The AI systems — which are part of a burgeoning industry meant to
offer patients remote care and automate rote aspects of a traditional
clinical visit — generally interview patients via text message, asking
them questions about their symptoms. When patients report flu-like
symptoms such as cough, shortness of breath, and fever, the chatbots are
now asking pointed follow-up questions related to the coronavirus,
which originated in China and has infected more than 24,000 people
there. Those questions include: Have you traveled to China recently? Or
have you been around someone who has?
The companies say the updates to their algorithms are based on
guidance that the CDC has issued to health care professionals about the
criteria that should prompt a patient to be evaluated for infection with
the virus. That guidance is online, and patients who are worried about possibly being infected can easily access it. So why, then, are these chatbots necessary?
“We think we can really help direct people to the right care at the
right time and give them quality information as it relates to this
problem,” said Dr. Brad Younggren, chief medical officer at 98point6. He
added: “We can keep them from going into an environment to be tested,
when maybe testing isn’t necessary.”
The app-based coronavirus screenings being promoted by health-tech
companies supplement the in-person screenings being conducted in
airports, clinics, and emergency rooms across the country.
Only in 260 cases to date
have U.S. patients been escalated to get lab testing through the CDC —
until Tuesday, the only way to get an infection confirmed in the U.S.
When patients have met criteria for getting tested, local physicians
have taken a sample — involving nasal and throat specimens, as well as
the patient’s blood serum — and shipped it to the CDC’s headquarters in
Atlanta. On Tuesday, the Food and Drug Administration cleared the CDC’s test for wider use, and CDC plans on quickly rolling it out to state health departments and international partners.
Seattle-based 98point6 offers virtual primary care visits via its
apps to patients in the U.S. Patients begin chatting with an AI before
getting handed off to a physician who continues the conversation via
text message. Patients can pay out of pocket for the visit — annual
subscriptions start at $20, plus $1 for each encounter — or their
employer or health plan may cover the cost.
98point6 went live with its coronavirus screening on Jan. 24 — just a few days after the first U.S. coronavirus case
was confirmed, in a Washington man who had recently traveled to Wuhan,
China, where the outbreak originated. The startup has updated its
algorithm several times since then, Younggren said. An update last week
added fever to the list of patient-reported symptoms that triggers
questioning about travel history to China.
In the two instances when a 98point6 physician has contacted the CDC
about suspected coronavirus cases, the agency advised that those
patients did not need to be tested or isolated. In each case, the
physician then telephoned the patient to let them know they weren’t at
risk.
Bright.md, a Portland, Ore., startup that sells care automation
software to health systems, went live with its own coronavirus screening
on Jan. 29. Its product uses AI to conduct remote interviews with
patients.
“We felt like that was an important aspect of helping our delivery
system partners manage both risk and exposure — but also public
concern,” said Dr. Ray Costantini, Bright.md’s CEO. So far, he said,
that’s mostly meant “making sure that all of those patients who do have
flu symptoms get treated appropriately and effectively and quickly to
minimize exposure for the more common condition that really is a much
bigger risk to population health and people’s well-being.”
When Bright.md’s AI interviews raise a red flag for a possible
coronavirus case, the software automatically arranges for the patient to
have a video encounter with a physician at the health system. The 15
health systems in the U.S. and Canada that use Bright.md’s software
sometimes let their patients use the system for no additional cost, or
charge them a fee of up to $35 per visit.
In the U.S., fear about the coronavirus may be spreading faster than the virus itself.
So when Buoy Health, a Boston-based startup that offers an AI-powered
symptom checker, added a coronavirus tool to its platform on Tuesday,
it did so with the goal of correcting misinformation, said Andrew Le,
Buoy’s CEO and co-founder.
After users enter symptoms into the latest version of the Buoy app,
it asks if there’s a specific diagnosis they’re worried about. As soon
as a user starts typing “coron…,” for example, the word “coronavirus”
appears. Tapping the word prompts the app to ask about relevant symptoms
and risk factors, all of which Buoy took from the CDC guidelines.
Depending on their answers, users will get directed to one of two
paths: high or low risk for coronavirus. High-risk consumers are advised
to head to an emergency room — and are told to call beforehand to give
the facility the chance to prepare.
“We see patients every three seconds,” said Le. “We have the
potential here to help identify outbreaks before people get to the
hospital.”
As part of its more long-term efforts to address coronavirus, Buoy is
also partnering with a HealthMap — a disease detection project run by
researchers from Boston Children’s Hospital — to help map any potential
clusters of the new illness. If Buoy and HealthMap were to document a
grouping of coronavirus-like symptoms in one location, for example, they
could alert public health officials and hospitals.
“We’re trying to match what’s happening in the world with what’s happening on the ground,” Le said.
