Novel Insights on Orexin Receptor TAK-994 and its Discontinued Narcolepsy Study

Elena Koundourakis, PhD

Narcolepsy type 1 (NT1), a neurological sleep disorder, is characterized by excessive daytime sleepiness, cataplexy, and disrupted nighttime sleep. Those living with this sleep disorder may also experience other symptoms such as hypnagogic/hypnopompic hallucinations and sleep paralysis, as well as a high risk of obesity.¹

Findings from a recently published phase 2 study (NCT04096560) assessing TAK-994 (Takeda), an investigational orexin receptor agent, showed greater improvements on measures of sleepiness and cataplexy compared with placebo over 8 weeks in a cohort of patients with NT1.² Although the trial yielded positive efficacy results, treatment with the therapy was associated with hepatotoxic effects, which led to discontinuation of the study.³

Elena Koundourakis, PhD, head of orexin franchise development at Takeda, recently had a conversation with NeurologyLive® to discuss how the company’s promising trial results despite discontinuation. She also talked about the implications these findings using the orexin receptor type 2 (OX2R) agonists for the future of narcolepsy therapy and other sleep disorders. In addition, Koundourakis spoke about how the company is advancing its OX2R agonist portfolio, and the potential of these drug applications for medical treatments.

NeurologyLive: Among the phase 2 findings, what stands out?

Elena Koundourakis, PhD: In July 2023, we published findings in the New England Journal of Medicine of a phase 2 study of our discontinued TAK-994 program in patients with NT1. These data represent the first-ever clinical data to be published of an oral orexin agonist in NT1.

The trial was stopped because of hepatotoxicity and consequently, the TAK-994 program was discontinued for further development. While the severe adverse events that led to the program’s discontinuation were disappointing, the study demonstrated statistically significant improvement in daytime wakefulness and weekly cataplexy rates were reduced or abolished at all doses compared to placebo over a period of eight weeks in patients with NT1.

Although the phase 2 trial was not designed to compare the efficacy of TAK-994 with that of other narcolepsy medications, the improvements in average sleep latency on the Maintenance of Wakefulness Test (MWT) were of greater magnitude than improvements observed with currently available agents. After 8 weeks of TAK-994 therapy, sleep latency on the MWT was above the normal threshold for most patients and similar effects were observed for the Epworth Sleepiness Scale. While not tested in this trial, these findings may have implications for quality of life, work productivity, and patient safety (notably, driving risk).

As this field of study progresses, the data from this study are of critical importance as they indicate orexin receptor 2 (OX2R) as a potential biologic target for future development, further demonstrating the need for additional studies with new well tolerated OX2R agonists. We are applying these learnings as we look to advance our portfolio of OX2R agonists as quickly as possible.

What are the implications of these results for patients with narcolepsy in terms of treatment?

As the first-ever clinical data to be published of an oral orexin agonist in patients with NT1, the TAK-994 results indicate OX2R as a promising novel biologic target for the future development of NT1 treatments and other sleep wake disorders. There is significant unmet need for patients with narcolepsy. Current therapies only manage excessive daytime sleepiness and cataplexy and require patients to take several different therapies to address the multitude of symptoms they experience. NT1 is caused by severe loss or absence of the neuropeptide orexin, also known as hypocretin. Unlike current treatments which are designed to address partial symptoms of the disease, OX2R agonists target the underlying cause of the disease, which as these results demonstrate, led to statistically significant improvement in daytime wakefulness and weekly cataplexy rates were reduced or abolished.

What are the next steps in terms of research in this area?

We are leveraging our deep knowledge of orexin biology to advance the research and development of a first-in-class, multi-asset orexin agonist portfolio across a broad array of indications both within and beyond hypersomnia including:

• TAK-861, an oral OX2R agonist being evaluated in phase 2 trials for the treatment of NT1 and narcolepsy type 2 (NT2), for which we expect a readout in the first half of Takeda’s 2024 fiscal year.
• In addition to TAK-861, Takeda anticipates filing an IND for a next-generation oral OX2R agonist by the end of Takeda’s 2023 fiscal year.
• Danavorexton(TAK-925), an intravenously administered OX2R agonist that previously provided proof of concept of the mechanism in NT1, NT2, idiopathic hypersomnia (IH), excessive day time sleepiness in obstructive sleep apnea (OSA), and opioid induced respiratory depression. Leveraging the proof of concept we achieved in areas outside of wakefulness, we are further investigating the use of OX2R agonists in respiration such as postanesthesia recovery, where danavorexton is being investigated in a phase 2 trial in patients with moderate to severe OSA undergoing general anesthesia.

How did preclinical data contribute to the program?

The preclinical study for danavorexton (TAK-925) was the first study to provide proof of concept of the OX2R mechanism in hypersomnias, demonstrating an increase in wakefulness in non-human primates and healthy individuals during their sleep phase. Danavorexton was also shown to effectively promote wakefulness at night in individuals with a normal orexin system suggesting that activation of OX2Rs represents a promising therapeutic approach for the treatment of excessive daytime sleepiness that is not associated with orexin deficiency, including individuals with NT2.

It was this early research that catapulted our discovery efforts and led to the development of what is now a first-in-class, multi-asset orexin agonist portfolio across a broad array of indications both within and beyond hypersomnia.

In animal models of narcolepsy, danavorexton showed potent wake-promoting effects and suppression of cataplexy, that was proved in patients with NT1 in clinical trials. Our preclinical studies also found that danavorexton may increase respiratory function and can improve post-anesthesia recovery. These data supported the decision to conduct clinical studies evaluating the use of danavorexton in opioid induced respiratory depression.

Transcript edited for clarity.

REFERENCES
1. Evans R, Kimura H, Nakashima M, et al. Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals. J Sleep Res. 2023;32(5):e13878. doi:10.1111/jsr.13878
2. Dauvilliers Y, Mignot E, Del Río Villegas R, et al. Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1. N Engl J Med. 2023;389(4):309-321. doi:10.1056/NEJMoa2301940
3. The New England Journal of Medicine Publishes Data from Phase 2 Study of First Oral Orexin Receptor 2 Agonist TAK-994 in Patients with Narcolepsy Type 1. News Release. Takeda. Published July 26, 2023. Accessed October 3, 2023. https://www.businesswire.com/news/home/20230725117944/en/The-New-England-Journal-of-Medicine-Publishes-Data-from-Phase-2-Study-of-First-Oral-Orexin-Receptor-2-Agonist-TAK-994-in-Patients-with-Narcolepsy-Type-1