[Ip-health] FT - The Big Read: The global hunt for a coronavirus drug

Thiru Balasubramaniam thiru at keionline.org
Thu Mar 26 14:26:08 PDT 2020


The Big Read Drugs research
The global hunt for a coronavirus drug
With a vaccine up to 18 months away, drug companies are testing existing
virus treatments

Hannah Kuchler in New York, Kana Inagaki in Tokyo and Sarah Neville in
London 16 HOURS AGO

It was Friday March 13 when doctors at the largest healthcare provider in
New York City decided to take the search for a coronavirus drug into their
own hands. Many of their Covid-19 patients were not getting better — and
some were getting worse.

Two of the hospitals’ scientists each called their contacts at US biotech
companies Gilead Sciences and Regeneron to offer to test their potential
treatments: an antiviral called remdesivir and an anti-inflammatory called
Kevzara, developed for Ebola and rheumatoid arthritis respectively.
Clinicians, researchers and regulators rushed to set up the clinical
trials, which usually take months, and just four days later two patients
took their first doses of the experimental drugs.

“The patients were very, very sick,” says Kevin Tracey, president of the
Feinstein Institute, the research arm of Northwell Health. “Everybody just
rolled up their sleeves and said we’re facing a crisis and the patients
need this. After 30 years of doing research, it was one of the proudest
days of my life to know patients were getting treated with these drugs that
may help them.”

The hospital hopes the drugs will stop the replication of the virus and
reduce the inflammation in the lungs of the patients.

As the pandemic spreads — recorded cases have more than doubled over the
past week to over 460,000 on Wednesday, with more than 20,000 deaths — no
one can afford to wait the 18 months it might take to find a vaccine.
Northwell is one of many hospitals across the globe running clinical trials
on drugs that were developed for other diseases, from Ebola to malaria to
arthritis, but that early studies suggest could offer some hope to Covid-19

Doctors are desperate for evidence of what works. In the next month, they
will learn more as some important trials in China are due to publish
preliminary results.

Yet the desire from politicians and investors for a miracle cure has led to
a maelstrom of misinformation about drugs to treat the virus. Just as
Northwell was dosing its first patients, President Donald Trump said the US
Food and Drug Administration had approved the antimalarials chloroquine and
hydroxychloroquine for use against Covid-19. This turned out to be not
true, with fatal consequences for some. The FDA was actually just
collecting evidence on whether it worked.


Scientists are investigating three main types of drugs. The first are
antivirals to stop the virus from replicating. Treatment guidelines
compiled by the Chinese government during the outbreak include HIV drug
combination Kaletra, which US biotech AbbVie recently waived its patents on
so it can be made available as a generic; antimalarials such as
chloroquine, which generic drugmakers are gearing up to manufacture at
scale; and favipiravir, an anti-flu drug from Japan’s Fujifilm.

The second category is anti-inflammatories that treat the lungs after the
immune system is overwhelmed. Regeneron and Sanofi have partnered on
Kevzara, while Roche has started a trial on Actemra, approved for use on
rheumatoid arthritis in 100 countries.

The third group are antibody-based treatments, derived either from
recovered Covid-19 patients or developed in labs, to be given to the
seriously ill or as a temporary prophylactic for healthcare workers. Eli
Lilly has paired up with Canadian start-up AbCellera to work on antibodies
developed from one of the first US Covid-19 patients, while Japan’s Takeda
is developing a new drug derived from the blood plasma of others who have
survived the virus.

Analysts are eagerly awaiting data from early trials into remdesivir, an
antiviral drug that the California-based biotech group developed for Ebola.
It has also been shown to work against other coronaviruses in animal
studies. Umer Raffat, a biotech analyst at US bank advisory firm Evercore,
says evidence could be published in the next couple of weeks.


“This is a fight against time. We need to move as fast as possible,” he
says. “We have no idea what works or does not at this point. There are zero
therapies specifically against coronavirus.”

Timing will be crucial. A study published last week of the HIV drug
combination was dismissed as disappointing, but survival rates were better
when patients had taken the antiviral drug earlier in the disease.

The antimalarial chloroquine does have two clear advantages over
remdesivir: it is a generic, so is likely to be far cheaper; and it is a
pill, when remdesivir is delivered by an intravenous infusion, so would
probably need to be given in hospital. But studies in France and China,
hailed by Mr Trump, are small and did not follow the recommended protocols
of a randomised control trial, designed to prevent bias. A study in China
released on Tuesday found the drug had no impact.

Early results from clinical trials in China fuelled enthusiasm for a second
antiviral — favipiravir — after reports of faster recovery times for
patients that took the drug. Junji Okada, president of Fujifilm Toyama
Chemical, the unit that produces the branded version Avigan, says the
company is responding to a flood of inquiries from across the world.

“Our sense of mission became bigger and bigger as it became clear that
Avigan may be effective,” Mr Okada says. “We have made the preparations so
that we can increase production if needed.”

Kimiyasu Shiraki, an emeritus professor at the University of Toyama who was
involved in Avigan’s early development, says studies show that the drug
does not generate an Avigan-resistant virus that could make it less
effective in the long term: “This suggests Avigan could treat the first to
the last patient with the same efficacy during the epidemic.”


AbCellera was working on a test project on influenza with the US Defense
Advanced Research Projects Agency when Covid-19 emerged — so it rapidly
switched to preparing their antibody-finding platform for the new virus.
They took blood samples from one patient and generated almost 6m immune
cells for antibodies, using an AI-based platform that can screen down to
the individual cell and allows them to find more antibody-secreting cells.
Researchers have narrowed it down to the 500 most potent against Covid-19
and partnered with Eli Lilly for the first human trials of the drug by July.


Another obstacle is that all the drugs being tested have potentially
serious side effects: remdesivir may cause liver damage, Avigan can cause
birth defects, and Regeneron and Sanofi’s Kevzara works by suppressing the
immune system — but it could potentially go too far.

Rajeev Venkayya, president of Takeda’s vaccine business, says the industry
is facing a new challenge. “It is unprecedented,” he says. “[But] what is
very different is the opportunity we have with the tools and technologies
that can help us to address this in ways that we didn’t have in the past.”

Drugmakers face similar challenges to vaccine developers: by the time they
have the evidence they need, the new virus may have disappeared. But at
least it is now clear that Covid-19 is likely to be a longer-term problem.

“When it becomes a global health crisis, it is easy for companies like us
to make decisions to invest . . . There is a concern for wellbeing,
patients, society,” says Dr Skovronsky. “But when it first emerges and
there are five or 10 patients, is it worth spinning out incredible
resources and financial costs when you’ll never get repaid if the virus is
successfully contained?”

Even if a drug succeeds, there will be political pressure to price it
affordably. Rising Pharmaceuticals, a generic maker of chloroquine, almost
doubled the price to $7.66 per 250mg pill in the US in January, as the
coronavirus outbreak raged in China. This month, as the crisis hit the US,
it cut the price to its previous level.

AbbVie, maker of the HIV drug combination, will allow generics makers to
manufacture the drug, relinquishing its intellectual property claims, in a
move that should make it cheaper.

But Gilead initially took a different approach: it won the right to extend
its intellectual property rights for remdesivir by using an “orphan drug
designation” in the US. The rule was designed to encourage drugmakers to
make treatments for rare diseases, further fuelling criticism of the
industry’s pricing policies. Ellen ’t Hoen, director at non-governmental
organisation Medicines Law & Policy, called it “the most blatant abuse” of
the act. But on Wednesday Gilead asked the FDA to rescind the application
citing the “urgent public health needs posed by the Covid-19 pandemic.”


The main options


Drugs designed for treatment of Ebola, HIV, flu and malaria. They try to
stop the replication of coronavirus by interfering with enzymes that help
it copy itself and spread. They are believed to be most useful in the
earlier stages of the disease. The virus uses similar machinery to copy
itself as Ebola, giving some experts hope that Gilead’s Ebola drug
remdesivir may help patients.


Designed for conditions such as arthritis. Several groups are investigating
the potential of IL6 inhibitors, which lower the production of inflammatory
proteins called cytokines. They are most useful in the latter stages of the
disease, when some patients suffer from acute respiratory distress syndrome
because their immune systems are overwhelmed.


Drugs derived from Covid-19 patients’ immune response. They reproduce the
antibodies of patients’ immune systems to support people with less robust
responses. Plasma from recovered patients is being infused into the
seriously ill. But drugmakers aim to refine the process, strengthening the
potency of the antibodies or creating artificial ones that will be more

Some believe the pharmaceutical business model simply does not work for
pandemics, because the diseases will always compete for resources with
blockbuster drugs that people take for years. Emergent Biosolutions takes a
different approach: it specialises in making “rescue therapies” for
unlikely events, selling the only antidotes to smallpox, anthrax and
botulism to US and allied governments to stockpile in case of bioterrorism.
It is now working on an antibody treatment for Covid-19.

“What differentiates us from just about any other pharma company is that
they want an immediate return, very quickly within six to 12 months, and we
take a little bit of a longer view,” says Robert Kramer, chief executive of
the Maryland-based speciality pharmaceuticals company.


Additional reporting by Wang Xueqiao in Shanghai

Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International
41 22 791 6727
thiru at keionline.org

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