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.

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. 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.

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.