The Quinism Foundation Shares its Concerns with Theranexus Regarding its Drug Candidate THN201

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Mefloquine, a Component of TNH201, May Cause Neuropsychiatric Adverse Effects Including Cognitive Dysfunction and Nightmares That May Last Years After Use

The Quinism Foundation has sent correspondence to Mathieu Charvériat, Scientific Director and Deputy Chief Executive Officer of Paris-based Theranexus, sharing its concerns regarding its drug candidate THN201, a combination of donepezil and mefloquine, which aims to treat neurocognitive disorders in Alzheimer’s disease.

“Adding mefloquine to an Alzheimer’s drug is like adding gasoline to a fire extinguisher,” said Remington Nevin, MD, MPH, DrPH, executive director of The Quinism Foundation. “This effort at drug repurposing raises significant safety concerns, and particularly in light of existing warnings for use of mefloquine, should attract further scrutiny by drug regulators.”

According to European, U.S., and Canadian drug regulators, mefloquine may cause neuropsychiatric adverse effects that may persist years after use [1]. Drug regulators at the European Medicines Agency (EMA) have concluded that there is sufficient evidence "supporting a causal relationship between mefloquine and the occurrence of long lasting and even persistent neuropsychiatric effects" and have speculated that these are due to "permanent brain damage." The EMA has noted that no risk factors could be identified for this effect, and that for this reason "only the advice—to stop taking mefloquine if neuropsychiatric reactions or changes to their mental state occur can be given as a precautionary measure." [2]

“The EMA has since required the mefloquine product documentation be updated with a boxed warning," explained Dr. Nevin, “cautioning that when used for the prevention of malaria, mefloquine is to be discontinued at the onset of symptoms of insomnia, abnormal dreams, nightmares, acute anxiety, depression, restlessness or confusion, which, in the EMA’s language, ‘have to be regarded as prodromal for a more serious event’.”

“The ‘more serious event’ that may occur with use of mefloquine can include lasting and disabling nightmares and neurocognitive impairment,” said Dr. Nevin.

In a double-blinded randomized trial of mefloquine 250 mg weekly versus chloroquine, poor concentration was reported by 5% of mefloquine users, versus only 1% of chloroquine users [3]. In a double-blinded randomized trial of mefloquine 250 mg weekly versus atovaquone-proguanil, concentration impairment requiring discontinuation of the study drug was reported in 0.6% of mefloquine users, versus 0% of atovaquone-proguanil users [4]. In a follow-up study of those who had reported cognitive dysfunction with use of mefloquine, fully one-third reported this symptom lasting over three years after use [5].

Recent research also confirms that nightmares and other abnormal dreams affect nearly 1 in 7 of those exposed to mefloquine for the prevention of malaria [4], and that more than 1 in 5 of those who complain of nightmares report this symptom lasting as long as three years after use [5].

“The last thing a family member would want is for their loved one to suffer the remainder of their lifetime from horrific nightmares and worsened cognitive impairment as a result of their use of a study drug," said Dr. Nevin. "Yet this is precisely what may happen with attempts to use mefloquine to treat Alzheimer’s disease."

In its correspondence, The Quinism Foundation encouraged Theranexus to immediately review its clinical protocols for the testing of THN201 to ensure that possible adverse effects from mefloquine will be properly recognized and reported.

“We would encourage you to specifically inquire of your subjects prior to every dose of the study drug if they are experiencing symptoms of abnormal dreams, nightmares, insomnia, anxiety, depression, restlessness, or confusion,” wrote Dr. Nevin. “If your subjects cannot respond reliably to this question, the drug should be immediately discontinued. If, for whatever reason, they report these or other psychiatric symptoms, these should be considered prodromal to a more serious event, and the drug should be similarly immediately discontinued”.

“While we recognize that subjects enrolled in a trial for Alzheimer's disease may already be experiencing such symptoms,” wrote Dr. Nevin, “it is this very fact that will typically preclude their safe use of the medication. Mefloquine is, notably, contraindicated for use in chemoprophylaxis among those with pre-existing psychiatric disturbances, including Alzheimer's disease, among whom the reliable recognition of prodromal symptoms poses significant challenges.”

About The Quinism Foundation

The Quinism Foundation, founded in January 2018, in White River Junction, Vermont, promotes and supports education and research on chronic quinoline encephalopathy, a disease caused by poisoning of the brain and brainstem by quinoline drugs, including mefloquine and tafenoquine.

Dr. Nevin is a board-certified occupational medicine and preventive medicine physician and former U.S. Army medical officer and epidemiologist. He is author of more than 30 scientific publications on malaria and the quinoline antimalarials, including “A serious nightmare: psychiatric and neurologic adverse reactions to mefloquine are serious adverse reactions," published in the journal Pharmacology Research and Perspectives (https://doi.org/10.1002/prp2.328).

1. Nevin RL. Implications of Changes to the Mefloquine Product Monograph. Canadian Journal of Hospital Pharmacy. 2017;70(4):323-324.
2. European Medicines Agency. Updated PRAC Rapporteur Assessment Report on the Signal of Permanent Neurologic (Vestibular) Disorders with Mefloquine. EMA/63963/2014. January 31, 2014.
3. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Tropical Medicine and Parasitology. 1993;44(3):257-265.
4. Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clinical Infectious Diseases. 2001;33(7):1015-1021.
5. Ringqvist Å, Bech P, Glenthøj B, et al. Acute and long-term psychiatric side effects of mefloquine: A follow-up on Danish adverse event reports. Travel Medicine and Infectious Disease. 2015;13(1):80–88.
6. Tickell-Painter M, Maayan N, Saunders R, et al. Mefloquine for preventing malaria during travel to endemic areas. The Cochrane Database of Systematic Reviews. 2017;10(10):CD006491.

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