Targeting orexin: the future of narcolepsy treatments 

A consistent sleep schedule of going to bed and waking up each day allows the body to rest and helps maintain optimal brain function, physical health, and emotional stability. But for people with narcolepsy, staying awake can be a struggle. And as there isn’t a cure yet to treat narcolepsy, there is a need for more therapies. There are a few new narcolepsy treatments being tested in the clinic, and recently, some of them have made promising strides. But how far along are they?  

New narcolepsy treatments: Alkermes’ reports positive results for alixorexton  

Irish biotech Alkermes was the most recent to report encouraging results in the clinic. Its drug candidate alixorexton addresses orexin deficiencies. Orexin is a neuropeptide – a chemical messenger that is released by neurons – strongly linked to wakefulness and regulating sleep-wake transitions. When enough orexin is not being made in the body, it can lead to narcolepsy. 

Alixorexton is an orexin 2 receptor agonist, part of a new class of investigational medicines designed to stimulate the orexin system, explained Craig Hopkinson, chief medical officer (CMO) and executive vice president of Research and Development at Alkermes. Alixorexton is being tested for narcolepsy type 1, which, unlike narcolepsy type 2, is characterized by a symptom called cataplexy, a sudden, temporary loss of muscle control. 

“People with narcolepsy type 1 have a loss of orexin neurons, thought to be caused by an autoimmune response, so there is clear biologic rationale for the use of an orexin agonist in this patient population,” Hopkinson told Labiotech. 

The topline phase 2 study results revealed that the once-daily therapy met the primary endpoint across all doses tested and demonstrated statistically significant, dose-dependent improvements compared to placebo in wakefulness on the Maintenance of Wakefulness Test (MWT) – a measure of the ability to stay awake during the day. Alixorexton was generally well tolerated at all doses tested, according to a press release. 

Improvements in other symptoms such as fatigue and cognition were also measured. 

“While excessive daytime sleepiness and cataplexy are the hallmark symptoms of narcolepsy type 1, many patients also experience other symptoms, such as fatigue and cognitive dysfunction, which can disrupt their lives. The exploratory patient-reported outcomes we observed with alixorexton in Vibrance-1 study after six weeks are compelling, with robust and consistent improvements compared to placebo on outcomes related to disease severity, fatigue, and cognition,” said Hopkinson. 

As currently approved treatments for narcolepsy focus on treating specific symptoms like excessive daytime sleepiness and cataplexy, Hopkinson believes that “there is a persistent need for new therapies, as patients continue to experience a range of symptoms that impact their daily lives.” 

He added: “Orexin 2 receptor agonists have the potential to transform the standard of care and be the first disease-modifying treatments for people with narcolepsy.” 

Soon, alixorexton will press forward with phase 3 studies to address narcolepsy type 1, while continuing its phase 2 trials in narcolepsy type 2 and idiopathic hypersomnia – a condition that causes people to be excessively sleepy during the day. 

Will Takeda’s oveporexton hit the market soon? 

Alixorexton is challenging Takeda’s oveporexton, but the pharma giant might be a few steps ahead. It recorded two phase 3 wins this month with oveporexton, another orexin receptor 2 (OX2R) agonist. By stimulating OX2R, it is meant to restore signaling, thereby promoting wakefulness and reducing abnormal rapid eye movement (REM) sleep. 

In a normal sleep cycle, people enter REM sleep after at least an hour. That’s when most people do their dreaming. However, in people with narcolepsy where sleep is fragmented, the boundaries between wakefulness and sleep are less distinct, according to a report by the National Institute of Neurological Disorders and Stroke. So, these people are more likely to enter REM sleep much quicker, often within 15 minutes of falling asleep. The report also added that patients can experience muscle weakness or dream activity of REM sleep while they are awake.   

So, that’s why cutting down on REM sleep is crucial, and drugs like alixorexton and oveporexton aim to tackle it.  

Takeda’s oveporexton met primary and secondary endpoints in two phase 3 randomized, double-blind studies where they achieved statistically significant improvement compared to placebo. These endpoints measured wakefulness, excessive daytime sleepiness, cataplexy, the ability to maintain attention, overall quality of life, and daily life functions. 

“The comprehensive assessments from our phase 3 studies build on the transformative results we saw with our phase 2b study, with most participants reaching normative ranges and reporting clinically meaningful improvement across a broad range of symptoms at the end of the 12-week treatment period,” said Andy Plump, president of research and development (R&D) at Takeda, in the press release. “The positive results also reinforce the continued momentum for our late-stage pipeline, which we believe will deliver value to the patients we serve around the world.” 

The OX2R agonist has already racked up Breakthrough Therapy designation for the treatment of excessive daytime sleepiness in narcolepsy type 1 from the U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation of China’s National Medical Products Administration. Takeda now seeks to submit a New Drug Application with the FDA, putting it next in line in the narcolepsy treatment market. 

“We are thrilled to reach this pivotal milestone for the oveporexton program,” said Christophe Weber, president and chief executive officer at Takeda. Oveporexton takes the lead on Takeda’s orexin agonists pipeline. It is also evaluating TAK-360 for narcolepsy type 2, idiopathic hypersomnia, and other conditions implicated in orexin signaling. 

However, Alkermes’ Hopkinson explained that in narcolepsy type 2, targeting the orexin system may address excessive daytime sleepiness across these sleeping disorders whether or not deficient orexin signaling is the underlying cause of disease. 

“The biology of narcolepsy type 2 is less clear, and researchers are still trying to uncover the underlying pathophysiology for this sleep disorder,” said Hopkinson. 

New drugs for narcolepsy: Centessa’s orexin agonist to present phase 2 results 

Meanwhile, Centessa’s ORX750 has been creeping up closely behind Takeda’s oveporexton. Like oveporexton, ORX750 is an OX2R agonist, and it is being assessed for narcolepsy 1 and 2 and idiopathic hypersomnia. As the British-American company gears up to present phase 2 results, phase 1 data was presented at the American Academy of Neurology Annual Meeting in California in April.  

The data showed that sustained effects were observed in the 5 mg dose cohort throughout the eight-hour period post dosing. The main factors that were measured were mean sleep latency – the speed of falling asleep – on the maintenance of wakefulness test and in Karolinska Sleepiness Scale (KSS) scores, compared to placebo. The KSS scale is a self-report on a patient’s sleepiness. On average, it takes people with narcolepsy fewer than eight minutes to fall asleep, according to a report by Cleveland Clinic. 

Last year’s interim phase 1 results propelled the ongoing phase 2a studies. It was found that 2.5 mg dose restored normative wakefulness with a mean sleep latency of 32 minutes as measured by the maintenance of wakefulness test, a step up in narcolepsy.  

“ORX750 is progressing in the phase 2a CRYSTAL-1 study and is on track with patient data expected across all three indications this year. Given the unmet patient need for new treatment options, the team is intensely focused on execution to carry this momentum forward into registrational studies as quickly as possible.” said Saurabh Saha, CEO of Centessa, in a press release in May. 

New research related to narcolepsy

• Narcolepsy Type-I Vaccine – University of Helsinki
• A Novel Mouse Model for the Study of Narcolepsy and Orexin System Function – Nagoya University

Axsome tests controversial reboxetine in narcolepsy study 

As drug developers are invested in OX2R agonists, Axsome has other plans to address narcolepsy. It is revamping the controversial drug reboxetine to treat the rare sleep disorder. Formerly owned by Pfizer, reboxetine was initially developed as an antidepressant, but then a damning study by scientists in Germany exposed the pharma giant for underplaying its risk in 2010. While it was found that reboxetine, known by its brand name Edronax in Europe, worked no better than the placebo for major depressive disorder, Axsome is now reviving the drug to work against narcolepsy, and this time in the U.S. 

Dubbed AXS-12, in phase 3 trials, the drug significantly reduced the frequency of cataplexy attacks compared to placebo. In fact, 72% of the patients achieved at least a 50% improvement in cataplexy after a month and an 82% reduction at six months. It also led to improvement in cognition as well as narcolepsy overall. When excessive daytime sleepiness was assessed, 84% of patients who were given the medicine saw an improvement after a month, and 78% after six months.  

Moreover, some patients who switched to placebo after being given AXS-12 experienced the worsening of cataplexy, compared to those who continued with AXS-12, whose cataplexy attacks decreased. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, pointed out in the press release that the therapy “has the potential to rapidly and durably ameliorate one of the most debilitating symptoms for patients, cataplexy, while also reducing the severity of excessive daytime sleepiness and improving cognition and overall function.” 

Beating depressants and stimulants: are orexin agonists up to the task? 

While there is optimism in the therapeutic space at present, Jazz has been left behind in the ongoing race to broaden treatment options for narcolepsy. Two years ago, the Irish biotech paused the development of its orexin-2 receptor JZP441, owing to safety concerns. Now, it has been caught up in an antitrust case for its FDA-approved narcolepsy drug, Xyrem, which is made of sodium oxybate, a central nervous system (CNS) depressant. A CNS depressant, colloquially known as a ‘downer,’ is meant to slow down brain activity. 

London-based Hikma Pharmaceuticals has accused Jazz of scheming to delay the commercialization of a generic version of Xyrem. Jazz is now paying $145 million as part of a settlement.  

While a long road lies ahead for drug developers to bring these therapies to people with narcolepsy, the recent developments are promising. For instance, Irish company Avadel Pharmaceutical’s Lumryz, also made of sodium oxybate, had a bumpy ride to get to where it is now. It was struck down by the FDA back in 2022 over patent issues but was then greenlit in 2023 to treat cataplexy in patients with narcolepsy. Avadel also won an exclusivity battle that Jazz brought to a U.S. court. Jazz claimed that Lumryz was encroaching on its drug Xywav’s – a low-sodium alternative to Xyrem – seven-year market exclusivity, but the court quashed the claim last month. 

As orexin receptor agonists pick up speed in the clinic, they will be competing against downer drugs like Xyrem and Lumryz as well as stimulants such as Provigil and Nuvigil – both acquired by multinational pharmaceutical Neuraxpharm in January. But as Hopkinson pointed out that this novel class of drugs goes beyond targeting the hallmark symptoms for people who experience a range of narcolepsy symptoms, they sure look promising.