Merck accused of downplaying early evidence of drug’s brain impact
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[June 26, 2023]
By Robin Respaut and Dan Levine
(Reuters) - An early magazine advertisement for Merck’s breakthrough
asthma and allergy medicine, Singulair, featured a happy child, hanging
upside-down from a tree. Asthmatic kids could now breathe easier, the
text assured, and side effects were “usually mild” and “similar to a
sugar pill.”
When the drug launched in 1998, its label said the drug’s distribution
in the brain was “minimal,” with no mention of psychiatric side effects.
Merck’s early safety claims later faced intense scrutiny amid reports
over two decades that patients, including many children, had died by
suicide or experienced neuropsychiatric problems after taking the drug.
The FDA in 2020 ordered its most serious warning, known as a “black
box,” on Singulair’s label. And Merck now faces a raft of lawsuits
alleging it knew from its early research that the drug could impact the
brain and that it minimized the potential for psychiatric problems in
statements to regulators.
The lawsuits cite the research of Julia Marschallinger, a cell biologist
who has studied the drug along with colleagues at the Institute of
Molecular Regenerative Medicine in Austria. That team found in 2015 that
the drug’s distribution into the brain was more significant than its
label described. The FDA cited Marschallinger’s work when it ordered
Singlair’s black-box warning label.
In its original patent for Singulair, Merck cited other applications for
the drug, beyond asthma and allergies, including as a treatment for
“cerebral spasm,” a neurological condition. Lawsuits filed against Merck
cite this 1996 patent as evidence of Merck’s knowledge of the drug’s
potential brain impacts.
Merck declined to comment for this report.
When Merck first sought FDA approval for Singulair, an FDA analyst,
relying on company assertions, said in 1998 that “only a trace amount”
of the drug could be found in the brain, federal documents show. The FDA
said Merck’s data showed the presence of the Singulair “declined over
time” in all tissues.
Marschallinger and her colleagues in Austria came away with a different
finding when they reviewed Merck’s original research and did some of
their own. They started looking at Singulair as a potential dementia
treatment in 2011. They became interested in that prospect in part
because of the reports of psychiatric side effects, such as depression,
agitation or hallucinations, from patients and medical providers. While
troubling, the side effects showed the drug might affect the brain. The
researchers wanted to understand if it could benefit older patients with
dementia.
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![](../images/062623PIX/health23.jpg)
Jan Gilpin poses with a bottle of the
asthma and allergy drug Singulair, first prescribed to her son when
he was three-years-old, at her home in Newton, Massachusetts, U.S.,
June 21, 2023. REUTERS/Brian Snyder
![](http://archives.lincolndailynews.com/2023/Jun/26/images/ads/current/heartlandcollege_lda_060123.jpg) In 2014, the scientists in Austria
reanalyzed Merck’s original animal studies and noticed the drug
decreased almost everywhere in the body 24 hours after dosage – but
not in the brain, where it increased over this period, surpassing
the amount in both the blood and the lungs. She reported finding a
“substantial amount” of the drug had reached the brain, in contrast
to Merck’s description of the brain distribution as “minimal.”
The FDA said Merck’s original animal studies were “quite limited and
cannot provide any definitive information about the montelukast
levels and activity in the brain.” The agency acknowledged that its
reviewer’s description that drug levels declined over time in all
tissues “did not fully reflect the data.”
As for Marschallinger’s finding that a “substantial amount” of the
drug had reached the brain, the FDA called it “a subjective
characterization that is not necessarily incompatible with the
‘minimal’ descriptor in other contexts.” The researchers’ 2015
study, the FDA said, provided additional evidence that the drug
reached the brain but did not show any specific harm.
Marschallinger said it would have been logical for the FDA to
require Merck to investigate the brain impacts more thoroughly once
reports of mental-health problems emerged.
“The FDA could have asked Merck to repeat the experiment or do it
for an even longer period of time,” Marschallinger said. “It’s not
hard to do this.”
(Reporting by Robin Respaut and Dan Levine; editing by Janet Roberts
and Brian Thevenot)
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