Takeda halts TAK-994 narcolepsy treatment development due to hepatotoxicity concerns


Takeda’s pioneering Phase 2 trial of TAK-994, a potential treatment for narcolepsy type 1 (NT1), came to an abrupt halt due to hepatotoxicity concerns, according to a report published in The New England Journal of Medicine. This marks the termination of the TAK-994 program, despite the promising results of the oral orexin agonist on narcolepsy symptoms.

“The challenges of treating narcolepsy, a chronic neurologic disorder caused by a severe deficiency of orexin, are significant,” stated Yves Dauvilliers, a key investigator in the TAK-994 study. He went on to remark on the lack of therapies addressing the root cause of narcolepsy, and acknowledged the substantial effects of TAK-994 on wakefulness, daytime sleepiness, and cataplexy despite its association with hepatotoxicity.

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The terminated TAK-994-1501 Phase 2 study involved narcolepsy type 1 patients aged 18-65 who were administered varying doses of TAK-994 or a placebo. Notable endpoints included measures of sleep latency, Epworth Sleepiness Scale score, weekly cataplexy rate, and treatment-emergent adverse events. Despite promising results, the trial had to be prematurely discontinued due to liver toxicity in several patients.

Takeda terminates TAK-994 program after uncovering hepatotoxicity in Phase 2 Narcolepsy study

Takeda terminates TAK-994 program after uncovering hepatotoxicity in Phase 2 Narcolepsy study. Photo courtesy of Lombroso/Wikimedia Commons.

Out of 73 participants, 56% demonstrated improvements in sleep latency, while 58% showed better Epworth Sleepiness Scale scores. Moreover, the weekly cataplexy rate decreased among 53% of the participants. However, safety concerns overshadowed these positive results, with 79% of the patients experiencing adverse events. Severe liver toxicity prompted the trial’s early termination, with no specific risk factors identified.

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Sarah Sheikh, Head of Neuroscience Therapeutic Area Unit at Takeda, stated that the company remains dedicated to their orexin research and development endeavors. Takeda is currently conducting two Phase 2 trials for another oral OX2R agonist, TAK-861, and is investigating danavorexton (TAK-925) in a Phase 2 study for individuals with obstructive sleep apnea following general anesthesia. Takeda’s commitment to these projects underscores their resolve to develop treatments for narcolepsy and other hypersomnolence disorders.

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