Can Takeda Help Treat Narcolepsy?

Sleep-wake disorders come in various forms, and with various symptoms – from sporadic and inadvertent sleepiness, to vivid dreams, hallucinations, and cataplexy, a sudden and debilitating loss of muscle tone. Conventional study methods and treatments are burdensome, slow, and have largely been ineffective. Now, Takeda is developing a small molecule compound targeting the loss of orexin – the neurotransmitter that controls sleep and wakefulness in the brain. With accelerated data through the use of at-home wearable devices, and lessons learned from a previous iteration, Elena Koundourakis, Head of Takeda’s Orexin Franchise Development and Neuroscience Programs and Portfolio Strategy, is excited about bringing hope and peace of mind to patients.

What can you tell us about Tak-861?
 

TAK861 is our lead orexin receptor-2 agonist, which is enrolling patients in phase III trials. Phase IIb data in narcolepsy type one (NT1) showed the potential to provide transformational efficacy. NT1 is arguably the most severe strain of narcolepsy and is caused by a loss of orexin neurons, and low levels of orexin neuropeptides in the brain and cerebrospinal fluid.

Companies have been working for many years to discover and develop a therapeutic that has the ability to restore what is missing by modulating the orexin receptor 2. It's been very difficult!

Takeda had been working in this space for some time, leveraging capabilities with similar receptors such as ramelteon, which is indicated for insomnia. Our first oral orexin receptor agonist was TAK-994, which we progressed up to phase IIb. Unfortunately, there were three cases of hepatotoxicity, so we stopped. The efficacy data, however, were groundbreaking (published in NEJM, July 2023) so we switched our resources and knowledge to TAK-861, moving it very quickly to the same point.

We’re very excited about the profile thus far. The dose feels right because it's enough to keep you awake during the day, but not so much that it keeps you awake at night. In the morning, you get up and you're ready to go. You have to take the drug every day and it does not cure the disease per se; you have to keep taking it to have a sustained effect, but we’re excited to give patients their lives back. Data show that it can also improve secondary symptoms such as cataplexy.

How did you bring wearable technology into clinical trials for this drug?
 

The idea for a wearable came from a collaboration with Beacon Biosignals, which is a company that has validated an at-home sleep device – a “Dreem” headband – that tracks sleep patterns. It was originally designed to improve diagnosis rather than monitor outcomes; however, we’re now using it to find a way to better diagnose or predict sleep-wake disorders, such as narcolepsy.

One of the barriers to diagnosis for this type of disorder is that the patient has to go to a sleep lab for a traditional polysomnography (sleep study). There are not many of these, it’s a burden for people to attend, and there is also a lack of physicians properly trained to suspect and diagnose narcolepsy. In contrast, a condition like obstructive sleep apnea is diagnosed much more because it can be done at-home. We wanted an at-home test that could alleviate the burden of sleep labs and provide insights earlier.

How can wearable technology help improve drug development?
 

One aspect is a greater understanding of the journey to diagnosis, which will help drug developers confirm whether a patient is an NT1 patient. Unlike other sleep-wake disorders, NT1 in polysomnography has a very distinct sleep architecture and, therefore, presents itself very well for interventions. Wearable technology makes the process easier, and we have access to academic collaborations, patient databases, and algorithms that we can use to correlate with the patterns of the patients to offer a more certain diagnosis and differentiate from others. We can do so much more for patients with sleep-wake disorders if we have more reliable tools. All the effort going into digital technologies and AI carries the goal of maximizing data and incorporating it into product development.

We also want to expand the use of the compound beyond NT1 and leverage Orexin effects in multiple bodily functions, such as respiration and metabolism. We are looking into obstructive sleep apnea as one of the sleep wake disorders that overlaps with narcolepsy and often masks its diagnosis. If we can include the use of wearables to access the type of data that we hope we can, we can provide a set of solutions for patients with multiple sleep wake disorders.

How could TAK-861 compare with other treatments, such as psychotherapy?
 

NT1 is caused by a loss of orexin neurons and is not something that therapists can address. The disease comes with many symptoms from excessive daytime sleepiness and cataplexy, to vivid dreams, hallucinations, and disrupted night-time. Co-morbities such as depression and anxiety are very common for these patients, who also suffer from cognition issues, like brain fog. TAK-861 is a low-dose solution with very few side effects thus far and we are very, very pleased with it! We believe we can treat the main symptoms and the underlying pathophysiology.

As we progress in our regulatory interactions, we're getting great feedback and support –. The patient now has a choice between living a long life with a debilitating disease, and a therapy the likes of which nobody has had before. Tak-861 is the difference between a lot of drugs that treat a little bit of the wakefulness, and a single drug that helps with all the symptoms. But before I get too excited we need to get through phase III and make sure the data are as strong as they are at phase II. Let’s get through the regulatory process! Right now though, I think this drug certainly has the potential to transform the way this disease has been looked at.

What does the future look like for sleep-wake disorder patients now that this drug is in development?
 

Patients have been waiting a long time for progress in this area. We created the buzz from the TAK-994 trial and we learned from it. Excitement in the field is high, and the hope of patients is inspiring. Let’s recruit for our phase III studies as efficiently as we can and bring it to the finish line! We do not intend to fall asleep on the job. We want to continue to provide hope and change the way these disorders are treated.