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.
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)
