Up all night to make a new drug for narcolepsy

Narcolepsy is not simply feeling sleepy all the time. It is a chronic neurological disorder where people do feel excessive daytime sleepiness, but they often also experience sudden muscle weakness called cataplexy, fragmented sleep, and sleep paralysis.

The Head of Orexin Franchise Development, Neuroscience, and Portfolio Strategy at Takeda, Elena Koundourakis, oversees the development of the oral orexin agonist TAK-861 for narcolepsy type 1.

Credit: Takeda

“Narcolepsy is a rare disease,” said Elena Koundourakis, the Head of Orexin Franchise Development, Neuroscience, and Portfolio Strategy at Takeda. It can sometimes take people as long as 15 years to receive a narcolepsy diagnosis, which already is an optimistic estimate, she added.

The most common form of the condition is narcolepsy type 1 (NT1), in which people have a deficiency in the neurotransmitter orexin. Normally, neurons in the hypothalamus produce orexin, which at high levels helps keep people awake and at low levels leads to rapid-eye-movement sleep. In NT1, it’s not clear why orexin levels are reduced. The immune system may mistakenly attack and destroy orexin-producing neurons, and there is also evidence that people may be genetically predisposed to the condition (1).

The team at Takeda recently developed a molecule that aims to activate and restore orexin signaling in people with narcolepsy. Koundorakis led the recent Phase 2b clinical trial of the first-in-class oral orexin agonist TAK-861. With a mechanism that targets the source of the condition, TAK-861 could be an exciting new option for managing this challenging condition.

What motivated Takeda to pursue orexin as a treatment for NT1?

Researchers in Japan and at Stanford University first found that loss of orexin caused NT1. This discovery led to interest in how to restore orexin signaling. Takeda became interested in this space because we have laboratories in Japan and are very close with the academic institutions where much of this research occurred. Japan also has a high incidence of sleep-wake disorders, so that was another factor. We had worked on other neurological drugs, so we had the technical expertise to advance these therapies more accurately than others.

What makes orexin agonists different from other therapeutics?

There are medicines available on the market that can help manage some NT1 symptoms; for instance, amphetamines can help patients stay awake, and antidepressants can help with cataplexy. But, of course, not all people have the same degree of disease severity and symptoms. Many patients end up taking a lot of drugs together, which is not ideal. We found that 80 percent of these NT1 patients who take multiple medications still complain about their symptoms. To treat the disease optimally, a drug should improve all of the symptoms. The orexin agonist provides an opportunity to treat the underlying pathophysiology of the disease. It addresses the disease on a molecular level. We hope that we will eventually provide a medication to patients where they don’t have to worry about taking multiple drugs.

How do orexin agonists work?

When the neurons are lost in NT1, the receptors stay somewhat intact. They are intact enough for an orexin agonist to find and configure the receptor to restore the proper downstream signaling and wakefulness. We found that through these phenomena, orexin agonists not only restore wakefulness but also relieve all of the other NT1 symptoms. We saw that patients had almost no cataplexy attacks. We even heard patients say that their dream architecture changed. Basically, people said that they started feeling normal.

What challenges did Takeda face in developing orexin agonists?

The first modality we used for the proof-of-concept was TAK-925. This was the first direct orexin agonist. It was an IV formulation that we made in 2014. At that time, we were already working on an oral formulation, which was easier for patients to take. This was TAK-994. Because the mechanism of action for this drug was unknown, the Food and Drug Administration regulators wanted long-term safety data on it.

I have been around for a long time, and we don’t get to work on things like this very often in life. Everyone on our team knows it’s special, and we treasure every second of this.
- Elena Koundourakis, Orexin Franchise Development

In the first 16 weeks of the Phase 2 clinical trial, we had our first case of severe liver toxicity (2). We thought that it would be just one case, but then two weeks later, there was a second case. Within one month, we had three cases of liver toxicity. This was terrible, and we couldn’t move forward with this compound. But fortunately, we had TAK-861 in a Phase 1 trial for NT1 at the same time. Drug development is a tough place to be, so you have to be prepared for that. So, we shifted the entire army of people working on TAK-994 to TAK-861. Two years later, we were at the same place as TAK-994 was when it stopped (a Phase 2 trial for TAK-861), which is very expeditious.

How did the patients react to stopping the TAK-994 trial?

We had incredible testimonials from patients on the TAK-994 trial. They basically asked to be back on the trial despite the liver toxicity cases because they found their lives back, and then suddenly we pulled the rug out from under their feet. They understood that we didn't do this lightly because this was a serious setback, but they told us that they felt so good when they were on the drug. When we started with TAK-861, we were agonizing over if it was going to be as good as TAK-994. That kept me up for many nights because we almost had it right. I was like, “Are we going to have a second drug that’s going to be as good?” Well, guess what, it’s better.

What makes TAK-861 better than TAK-994?

TAK-861 acts like TAK-994, but we can give it to patients at much lower doses. It’s more potent and has a very nice pharmacokinetic profile. Basically, it allows orexin to rise to a normal level during the day, but at night, the levels persisted because of the drug’s long half-life. It mimics the natural fluctuation of orexin. Patients had an incredible experience. It worked for the critical symptoms of wakefulness and cataplexy, and it improved all functional outcomes in other areas such as depression, anxiety, and cognition, which we captured through quality-of-life questionnaires.

How did you feel when you saw these TAK-861 clinical trial results?

Drug development relies on patients coming to our trials. When we had these three serious toxicity cases that led us to discontinue the trial for so many people — I will speak personally — I felt responsible for that. There is no other way to put it. This intense sense of purpose and commitment to the patients really kept us going. Now, we go to the conferences and hear people saying that they got their lives back; there is nothing more rewarding for me and the team. I have been around for a long time, and we don’t get to work on things like this very often in life. Everyone on our team knows it’s special, and we treasure every second of this.

This interview has been condensed and edited for clarity.

Correction (December 3, 2024): This article previously included an incorrect statistic of the prevalence of narcolepsy as well as an incorrect characterization of Takeda's involvement in the initial stages of narcolepsy research. These have been removed from the text.