Focus: Blue-blooded crabs at heart of pharma dispute on drug testing
01/08/2019 07:00
* Horseshoe crab blood used in medical safety tests
* Hundreds of thousands of the crabs are bled a year
* Lonza pushes for adoption of synthetic alternative
* Comes amid pressure from conservation activists
* Charles River says more scrutiny needed of new method
By John Miller
ZURICH, Aug 1 (Reuters) - If you've received a vaccination,
hip replacement or chemotherapy without suffering toxic shock,
chances are you've benefited from a vast bloodletting of
horseshoe crabs.
Every year, fishermen net hundreds of thousands of the
creatures off the U.S. East Coast and in Asia before their
prized milky-blue blood is drained for use in medical safety
tests.
Swiss biotech Lonza LONN.S and U.S.-based Charles River
Laboratories CRL.N are the biggest suppliers of crab
blood-based endotoxin tests, which detect bacterial
contamination in intravenous drugs and medical implants.
They are now at odds over the future of this testing, as
Lonza urges adoption of a synthetic alternative called
recombinant Factor C (rFC), amid pressure from wildlife
campaigners and worries about supply reliability.
Meanwhile Charles River, which is still studying rFC, argues
moving too quickly could compromise patient safety.
There's much at stake - for both companies, the industry
and, of course, horseshoe crabs, a 450-million-year-old species
that's more closely related to scorpions than crustaceans.
Endotoxin tests number 70 million annually and are rising.
If rFC gains traction, it could re-shuffle winners and losers in
the global market for such testing that is seen growing about
13% a year to close to $700 million in annual revenue by 2021
and $1 billion by 2024, according to market researchers.
For Lonza, whose internal testing growth estimates are more
modest, the risk is that the synthetic method won't catch on,
hurting efforts to capitalise on a $460 million investment it
made in 2006 when it bought the technology along with a peer's
biological businesses.
Conversely, Charles River risks becoming a laggard if the
technique wins wide acceptance.
PHARMACOPOEIA PUSH
The leading U.S. pharmaceuticals standards organisation,
U.S. Pharmacopoeia (USP), which publishes a compendium of drug
information, told Reuters it was pressing ahead to recognise
synthetic tests as comparable to crab blood-based ones.
"There is a consensus on moving forward and USP is fully
committed," said Fouad Atouf, USP's Science-Global Biologics
head.
"Making sure all the stakeholders are on board and all the
data has been collected is what's happening right now," he said,
with proposed revisions recognising rFC due around September for
public consultation.
That coincides with a push by USP's European counterpart in
Strasbourg, to recognise rFC. Japan is also working on the
issue.
France's Biomerieux BIOX.PA and Germany's privately held
Haemochrom Diagnostica, which have versions of rFC, are also
eager to see pharmacopoeias act.
Lonza said its rFC product, PyroGene, now accounts for less
than 5 percent of its endotoxin test sales but sees fortunes
changing as global pharmacopoeias act.
"We would hope to see around 10% by 2021," Lonza said.
It has won a big customer for PyroGene: Eli Lilly's LLY.N
migraine medicine Emgality last year became the first rFC-tested
drug to win U.S. regulatory approval.
Roche ROG.S and Bayer BAYGn.DE told Reuters they were
also considering rFC.
'UNACCEPTABLE RISK'
Charles River insists additional scrutiny is necessary
before rFC technology wins equal standing.
Companies pushing rFC must prove it can detect endotoxins in
the real world, not just the manufactured strains used so far in
studying the synthetic agent, said John Dubczak, Charles River's
microbial solutions manager.
"A move by the pharmaceutical industry towards current rFC
methods is premature," said Dubczak, adding more data is needed.
Lonza points to analyses by multiple drugmakers
demonstrating rFC was comparable to the crab-blood tests in
ensuring drugs were contaminant-free.
To be sure, Lonza has no plans to stop bleeding crabs, since
many existing medical products will continue to be tested with
traditional methods, it said.
The industry predicts the global crab blood-based test
market will also expand in the next few years.
But Lonza is counting on rFC emerging as a new pillar of its
testing business, contributing to its goal of more than 7
billion Swiss francs ($7.1 billion) in group annual revenue by
2022, from 5.5 billion francs.
NATURE'S INGENUITY
Horseshoe crabs' copper-rich blood has helped them survive
since before the dinosaurs in brackish coastal waters by
clotting around endotoxins, the potentially dangerous molecules
found in cell walls of bacteria like E. coli.
Scientists harnessed nature's ingenuity, using crab blood to
make so-called amebocyte lysate endotoxin tests which, by the
1970s, began displacing tests on rabbits that were injected with
medicine then monitored for fever.
However, concerns have since escalated over wildlife
conservation and the supply chain's reliability.
In Asia, where horseshoe crabs are also eaten by humans, the
tri-spine species is listed by the International Union for
Conservation of Nature as at risk of extinction. Two other
species are also imperilled.
Glenn Gauvry, director of the Delaware-based Ecological
Research and Development Group which focuses on horseshoe crab
conservation, said Asian crabs destined for dinner tables were
first "rented" to biomedical companies for bleeding.
Gauvry contends the biomedical industry is perpetuating
consumption of crabs in Asia and contributing to their decline.
Lonza does not harvest Asian crab blood.
Charles River, which does, said it followed local rules.
"Horseshoe crab blood is collected only to a point where the
crab naturally stops bleeding," Dubczak said, adding its Asian
suppliers and local governments were responsible for ensuring
crabs were released into "waters of appropriate salinity".
RUFA RED KNOT
Studies paint a mixed picture of the blood harvest's effects
on U.S. East Coast horseshoe crabs, hundreds of thousands of
which are also killed annually for bait or caught incidentally
by commercial fishermen hunting other marine species.
Those caught by Lonza, Charles River and Associates of Cape
Cod, owned by Japan's Seikagaku Corp 4548.T , are drained of
about a third of their blood, then returned alive to the sea.
An Atlantic States Marine Fisheries Commission report from
May indicates current harvest levels "appear to be sustainable".
Additionally, a recent U.S. Geological Survey study found
bled crabs' survival rates may exceed those of non-bled crabs in
New Jersey's Delaware Bay.
However, previous studies found anywhere between 4% to 30%
of bled crabs may die prematurely, prompting pressure on the
biomedical industry, largely out of concern for shorebird
populations that rely on crab eggs.
Advocates including the Audubon Society became increasingly
vocal when the rufa red knot, which eats crab eggs on stopovers
at Delaware Bay, was listed as threatened under the U.S.
Endangered Species Act in 2014.
"That was the tipping point," said Jay Bolden, an Eli Lilly
biologist whose hobby as a birdwatcher spurred him to champion
his company's switch to rFC that he believes will ensure
supply-chain reliability.
"If it got really serious, and they said nobody could touch
the horseshoe crabs because they have to rebuild the red knot
population, that was going to be significant."
Lilly has shifted three of eight global drug manufacturing
sites to rFC testing and is more than halfway to its goal of 90
percent rFC testing by 2020, he added.
"Until the global pharmacopoeias revise the test method to
recognise rFC as on par with crab blood-based tests, we can't
just make the change for medicines that are already on the
market," Bolden said.
"When that happens, then we can change over that final 10
percent."
(Reporting by John Miller; Editing by Michele Gershberg and
Pravin Char)
((J.Miller@thomsonreuters.com; +41 58 306 7734; Reuters
Messaging: j.miller.thomsonreuters.com@reuters.net))