In a phase 2 trial involving patients with narcolepsy type 1, Takeda’s orexin receptor 2 (OX2R) agonist TAK-994 demonstrated statistically significant improvements in wakefulness and reduced weekly cataplexy rates compared to placebo but was associated with hepatotoxic effects, according to data published in The New England Journal of Medicine. 

“Although this study was not designed to compare TAK-994, the first-in-class oral OX2R agonist, with other narcolepsy drugs, its effectiveness on objective measures of wakefulness, self-reported assessment of daytime sleepiness, and frequency of cataplexy was impressive. However, TAK-994 was associated with hepatotoxicity; therefore studies with new well-tolerated OX2R agonists are strongly requested,” says Yves Dauvilliers, MD, director of the Sleep-Wake Disorders Center in the department of neurology at Gui de Chauliac Hospital, Montpellier, France, and one of the study’s principal investigators, in a release.

The TAK-994-1501 Phase 2 Study

Patients aged 18-65 years with confirmed narcolepsy type 1 were randomly assigned to twice-daily oral TAK-994 30, 90, 180 mg, or placebo.

The primary endpoint was the change in mean sleep latency in minutes on the Maintenance of Wakefulness Test from baseline to week eight. Secondary endpoints included change in Epworth Sleepiness Scale score, weekly cataplexy rate, and treatment-emergent adverse events. Patients completing the phase 2 treatment period were eligible for inclusion in an extension trial. 

Limitations of the trial are that it was terminated early, the number of participants was small, and there was substantial dropout and missing data. The trial was prematurely terminated due to hepatotoxicity in several patients, and this agent will not go forward as a treatment for narcolepsy but may indicate a biologic target for future development. Another Takeda oral OX2R agonist is being evaluated in two phase 2, randomized, double-blind, placebo-controlled trials for the treatment of narcolepsy.

Efficacy Results

Of 73 patients enrolled, 17 received TAK-994 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo.

  • Primary endpoint results: Changes in mean sleep latency on the Maintenance of Wakefulness Test to week eight were available in 56% of patients, with least square means of -2.5 minutes for placebo, 23.9 minutes, 27.4 minutes, and 32.6 minutes for the three doses respectively; P<0.001 for all comparisons.
  • Secondary endpoint results: Changes in Epworth Sleepiness Scale to week eight were available in 58% of participants with least square means of -2.1 for placebo, -12.2, -13.5, and -15.1 for the three doses respectively. Week eight weekly cataplexy rates were available in 53% of participants, with weekly incidence rate estimates of 5.83 for placebo, 0.27, 1.14, and 0.88 for the three doses respectively.

After eight weeks of TAK-994, sleep latency on the Maintenance of Wakefulness Test was above the normal threshold (>=20 minutes) for most patients. Similar effects were observed for the Epworth Sleepiness Scale.

Safety Results

Forty-four (79%) patients treated with TAK-994 had adverse events; the most common were urinary urgency or frequency. More patients experienced treatment-emergent adverse events with TAK-994 than with placebo, with a greater number and severity of treatment-emergent adverse events observed with higher TAK-994 doses. Most treatment-emergent adverse events were mild in severity. 

Eight patients exceeded predefined alanine transaminase and/or aspartate transaminase thresholds for subject discontinuation, including three cases meeting Hy’s law criteria, indicating drug-induced hepatotoxicity and leading to the early termination of the trial. No specific risk factors were identified. The current hypothesis is that TAK-994 associated drug-induced liver injury is caused by reactive metabolites and is unlikely to be an on-target effect of OX2R activation as orexin receptors are not expressed on human hepatocytes or on most immune cells.

“As leaders in orexin research and development, Takeda is committed to applying our learnings from the TAK-994 trial and our deep and growing understanding of orexin biology as we drive forward the research and development of multiple orexin assets. We would like to thank the patients, caregivers and investigators who participated in the TAK-994 clinical trials and are committed to continue developing and delivering transformative treatments to people living with narcolepsy and other hypersomnolence disorders. Takeda is also exploring other indications that could benefit from this mechanism,” says Sarah Sheikh, MSc, BM, BCh, head of neuroscience therapeutic area unit at Takeda, in a release. 

Orexin programs in development include the oral OX2R agonist TAK-861, currently being evaluated in two phase 2 trials for the treatment of narcolepsy type 1 and narcolepsy type 2, and danavorexton (TAK-925), an intravenously administered OX2R agonist being investigated in a phase 2 study of people with obstructive sleep apnea after general anesthesia.

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