Orexin Innovation

Researchers have identified orexin-producing neurons as master regulators of neuronal signaling that govern sleep-wake transitions.

Takeda is the first pharmaceutical company to investigate a selective orexin-2 receptor (OX2R) agonist in clinical trials in healthy volunteers and in persons with excessive daytime sleepiness (EDS). The unmet needs of persons living with EDS fuel our mission to develop transformative therapies. We are partnering with those affected by EDS, along with the scientific and medical community, to improve the understanding of EDS across a number of disorders. Clinical trials evaluating the safety and tolerability, pharmacokinetics and pharmacodynamic effects of orexin 2 agonists are underway.

Loss of orexin neurons in the brain is strongly linked to narcolepsy type 1 (NT1), a chronic sleep disorder characterized by EDS and a sudden loss of muscle control (cataplexy). Those with NT1 experience difficulties in nearly every aspect of their lives, often leaving them feeling frustrated and misunderstood from this “invisible disease.” An OX2R agonist could provide ‘orexin replacement’ in people living with NT1 and may result in restoration of the downstream signaling cascade, reducing disease-specific symptoms, and giving back a sense of control to persons with this condition.

Preclinical studies in normal mice and monkeys and clinical studies in healthy human subjects have found that an OX2R agonist increases wakefulness during normal sleep time. This suggests that an OX2R agonist may help improve wakefulness in other conditions, beyond NT1. These conditions may include other disorders associated with EDS, such as idiopathic hypersomnia (IH) and obstructive sleep apnea (OSA).

SPARKLE 1501 for Narcolepsy Type 1

The SPARKLE 1501 Study is a phase 1 study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising oral doses of TAK-994 in subjects with Narcolepsy Type 1 (NT1).

Investigational Study Drug

Study drug icon

TAK-994 is a first-in-class, orally available, OX2R-selective agonist being developed for the treatment of narcolepsy.

Study Rationale

Rationale icon

The available nonclinical information and emerging clinical safety, tolerability, and pharmacokinetic profiles of single doses of TAK-994 in healthy subjects support this study in persons with NT1. Nonclinical pharmacology studies of narcolepsy in a mouse model showed that wake-promoting effects of TAK-994 were observed following chronic dosing for up to 14 days. Cataplexy episodes were also suppressed by TAK-994 in this mouse model.

Randomization

Randomization icon

Up to 3 dose cohorts will be enrolled, with 18 NT1 patients in the first two dose cohorts and 36 NT1 patients in the last cohort. Each cohort will be randomized in a ratio of 2:1 to receive TAK-994 or matching placebo orally as a tablet formulation.

Key Eligibility Criteria

Eligibility icon
  • Males and females aged 18 to 65 years (inclusive)
  • Body mass index (BMI) of ≤32.0 kg/m2
  • Blood pressure (BP) <140 mmHg (systolic) and <90 mmHg (diastolic). Subjects may have a history of hypertension and be on antihypertensive medication treatment as long as the BP meets these criteria.
  • Diagnosis of NT1
  • ESS score ≥10 at screening
  • HLA-DQB1*06:02 haplotype positive
  • ≥4 episodes of cataplexy/week reported during the screening period before washout of medications used for the treatment of narcolepsy.
  • Willing to discontinue all medications used for the treatment of NT1 during the screening period

ClinicalTrials.gov Identifier

NCT04096560

Download Factsheet

SPARKLE 2001 for Obstructive Sleep Apnea with Excessive Daytime Sleepiness

The SPARKLE 2001 study is a phase 1b study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of 2 single IV infusion doses of TAK-925 in adults who have been diagnosed with obstructive sleep apnea (OSA) and who are experiencing excessive daytime sleepiness (EDS).

Investigational Study Drug

Study drug icon

TAK-925 is a first-in-class OX2R-selective agonist. Preclinical studies in normal animals found that TAK-925 increased wakefulness during their normal sleep time. The TAK-925-1002 clinical trial also showed that TAK-925 increased wakefulness in sleep-deprived healthy adults. This suggests that TAK-925 may show arousal effects in hypersomnolent states, whether or not due to orexin deficiency.

Study Rationale

Rationale icon

Preclinical studies in normal animals found that TAK-925 increased wakefulness during their normal sleep time. The TAK-925-1002 clinical trial also showed that TAK-925 increased wakefulness in sleep-deprived healthy adults. This suggests that TAK-925 may show arousal effects in hypersomnolent states, whether or not due to orexin deficiency. Hence, this phase 1b study will enroll adult patients with EDS associated with OSA and who have OSA diagnosed according to the International Classification of Sleep Disorders-3 (ICSD-3) criteria with current use of continuous positive airway pressure (CPAP).

Randomization

Randomization icon

Approximately 42 patients will be randomized. Eligible subjects will be randomized to 1 of 6 sequence groups. After randomization, each subject will be dosed in 3 treatment periods according to the order defined by the sequence group into which he/she is randomized.

Key Eligibility Criteria

Eligibility icon
  • Males and females aged 18 to 67 years old
  • A diagnosis of OSA with current use of CPAP
  • Complaint of EDS despite “consistent use” of CPAP as defined by machine tracking time
  • Does not have other comorbid sleep disorders or clinically significant nocturnal hypoxemia
  • ESS score ≥10 at screening with or without stimulants
  • Willing to discontinue medication used for the treatment of EDS prior to randomization
  • Regular bedtime between 2100 and 2400 as verified by history; regular time in bed averaging between 7.5 and 9.0 hours/night; gets at least 6.5 hours/night on average of sleep, as defined by approximately 7 days of actigraphy supported by a sleep diary completed at least 1 week before Study Day -2
  • Average (of 4 sessions) baseline MWT sleep latency less than or equal to 20 minutes and no single session has a sleep latency of greater than 30 minutes as determined by the site investigator

ClinicalTrials.gov Identifier

NCT04091425

Download Factsheet

SPARKLE 2002 for Idiopathic Hypersomnia

The SPARKLE 2002 study is a phase 1b study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single IV infusion of TAK-925 in IH patients.

Investigational Study Drug

Study drug icon

TAK-925 is a first-in-class OX2R-selective agonist. Preclinical studies in normal animals found that TAK-925 increased wakefulness during their normal sleep time. The TAK-925-1002 clinical trial also showed that TAK-925 increased wakefulness in sleep-deprived healthy adults. This suggests that TAK-925 may show arousal effects in hypersomnolent states, whether or not due to orexin deficiency.

Study Rationale

Rationale icon

Results from Study TAK-925-1002 in sleep-deprived subjects suggest that there may be potential benefit of TAK-925 in other patient populations who have EDS associated with primary sleep disorders that are not associated with orexin deficiency, including patients with IH. There are no medications approved for the treatment of IH, and current therapies are used-off label. These therapies often have limited effectiveness in improving EDS. Hence, in this proposed phase 1b study, adult patients diagnosed with IH according to the International Classification of Sleep Disorders-3 (ICSD-3) criteria will be evaluated.

Randomization

Randomization icon

Up to 40 eligible subjects will be randomized to 1 of 2 sequence groups. After randomization, each subject will be dosed in 2 treatment periods according to the order defined by the sequence group he/she is randomized.

Key Eligibility Criteria

Eligibility icon
  • Males and females aged 18 to 75 years old
  • A diagnosis of IH as verified by medical records
  • Onset of hypersomnia between 10 and 30 years of age
  • Does not have other comorbid sleep disorders or clinically significant nocturnal hypoxemia
  • Body mass index (BMI) of 18 to 38.5 kg/m2 inclusive
  • ESS score ≥11 at screening
  • Willing to discontinue medication used for the treatment of EDS prior to randomization

ClinicalTrials.gov Identifier

NCT04091438

Download Factsheet