By Sree Roy
Narcolepsy pharmacotherapies have existed in the US prescription drug market for decades. However none have targeted the orexin (hypocretin) system, even though it lies at the root of the neurological sleep disorder.
But several biopharmaceutical companies are actively pursuing drug candidates that target the orexin system, meaning that within the next year or two, an orexin system-focused drug may become an option for people with narcolepsy.
Sleep Review spoke to a research and development (R&D) executive at one such company, Alkermes, at SLEEP 2024. Here are the highlights of our conversation.
Interest in Orexin 2 Compounds
“As we understand the pathophysiology of diseases like narcolepsy type 1 [NT1], what we realize is these patients have a deficiency of orexin-producing neurons,” says Craig Hopkinson, MD, executive vice president of R&D and chief medical officer at Alkermes. “So designing agents that can really address that underlying low orexin tone has been a focus and what has driven a lot of the excitement in the space.”
ALKS 2680 is the company’s novel, investigational oral orexin 2 receptor (OX2R) agonist. It is about 5,000-fold times more selective for orexin 2 over orexin 1 and about 10-fold more potent than the naturally occurring neuropeptide. “One of the big challenges…is you want to be selective for orexin 2 over orexin 1,” Hopkinson says. “What’s limited companies in the space are challenges around chemistry. Other programs have run into problems with liver toxicity and other problems. What we’ve focused on is using advanced medicinal chemistry to get that optimized profile.”
ALKS 2680 Design
Alkermes’ goal is to develop an orally bioavailable compound suitable for once-daily morning dosing with a high potency and acceptable safety profile that can address excessive daytime sleepiness, as well as the quality and duration of wakefulness. “Even though we’re going for once-daily dosing, we want to have an effective on-period of eight to10 hours, after which it will drop below the concentration threshold for efficacy,” Hopkinson adds.
The idea is to mimic the orexin cycle of healthy people. That is, a period of wakefulness followed by a bout of normal sleep. “That was our design hypothesis, and so far we’re excited by what’s emerging from our data,” Hopkinson says.
Its phase 1 studies indicate that people with narcolepsy type 2 (NT2) need a higher dose than those with NT1. According to Hopkinson, this is because the NT1 population has an absolute deficiency of orexin tone versus the relatively more normal orexin tone of people with NT2, who “have orexin deficiency, but they are less sensitive to orexin than the NT1 population,” Hopkinson says. “The sensitivity is what’s leading to the high doses.”
Measuring Improvements in Narcolepsy Symptoms
Phase 1
Alkermes presented phase 1b, proof-of-concept study data as a late-breaking abstract at SLEEP 2024. The trial measured improvement in narcolepsy symptoms using the Maintenance of Wakefulness Test (MWT), which, though not widely used clinically, is a focus of regulatory agencies.
In people with NT1, treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in mean sleep latency on the MWT, with a mean change from baseline versus placebo of 18.4 minutes at 1 mg, 22.6 minutes at 3 mg, and 34.0 minutes at 8 mg. Placebo treatment resulted in an about 1.4-minute reduction in mean sleep latency from baseline. Before treatment with ALKS 2680, these patients had a mean sleep latency on the MWT of about six minutes.
The study also analyzed the change from baseline on the subjective Karolinska Sleepiness Scale as an exploratory endpoint. The average score at baseline was approximately 7 (with 1 being “extremely alert,” 9 being “extremely sleepy,” and 5 being “neither alert nor sleepy”). ALKS 2680 showed improvements of 2 to 3 points in self-reported alertness between 1 and 8 hours, indicating clinically meaningful improvements.
Dose-Response
The “very clear” dose responses in the NT1 participants at the 1, 3, and 8 mg doses “were both clinically and statistically meaningful in terms of the change from baseline versus placebo,” Hopkinson says. “Each dose actually separated statistically, and we felt the improvement in the sleep latency was reflective of a clinically meaningful outcome for each of those doses as well.”
A very clear, statistically and clinically meaningful dose response was also seen in NT2 participants, who were studied at doses of 5, 12, and 25 mg.
It was “pretty exciting,” Hopkinson adds, that when the baseline is taken into account in the observed data, the MWT scores normalize.
Phase 2
Doses for NT1 patients for the now-recruiting phase 2 trial will be 4, 6, and 8 mg and, for NT2 patients, 10, 14, and 18 mg.
The primary endpoint is a change in mean sleep latency on the MWT from baseline to week six. Key secondary endpoints include the Epworth Sleepiness Scale and weekly cataplexy rate. Investigators will also explore polysomnography data for possible sleep quality assessments.
“What are the patient-reported outcomes that are important? We built a number of those into our phase 2 program,” Hopkinson says, including the Karolinska Sleepiness Scale and the Narcolepsy Severity Scale. “The focus is which ones are most important coming out of phase 2 and then to select phase 3 endpoints to reflect the patients’ experience.”
Safety Profile
Since several orexin system-focused drugs have reported concerning adverse events in their clinical trials (including hepatotoxic effects in a Takeda trial and visual disturbances in a Jazz Pharmaceuticals trial), Sleep Review asked about adverse events reported so far in Alkermes ALKS 2680 trials.
Alkermes focused on the metabolic profile of the drug candidate preclinically, fully characterizing the identified metabolites and their reactivity. “We are confident in the metabolic profile of the drug at this point,” Hopkinson says.
The phase 2 trials found:
- ALKS 2680 was generally well tolerated across all doses tested in patients with NT1. Most treatment-emergent adverse events were mild in severity, transient, and self-resolving (with one moderate case of nausea in a participant who was in a fasting rate that resolved with food intake). There were no severe adverse events. Adverse events observed in >1 patient were insomnia, pollakiuria, salivary hypersecretion, decreased appetite, dizziness, and nausea.
- There were no serious adverse events reported or treatment-emergent adverse events leading to study drug discontinuation in patients with NT1. There were no drug-related, treatment-emergent, clinically meaningful changes from baseline in laboratory values at any dose. No cardiovascular safety signals were identified in vital signs or electrocardiogram parameters.
“In the NT2 and [idiopathic hypersomnia] studies, once again we saw insomnia, increased urine production, and some dizziness. Once again, predominantly mild adverse events, self-resolving,” Hopkinson says. “We did see one moderate in each of those two groups at the high dose of 25 mg; that was moderate pollakiuria.”
The urinary adverse events do not suggest any tie-in to hepatoxicity, Hopkinson says. “It’s increased frequency, not increased volume of urine production,” he says.
According to Hopkinson, Alkermes is monitoring for visual adverse effects. “We saw one photophobia in NT2 population at the high dose, which occurred about one hour after dosing and disappeared within two hours,” he says. “The other one was a visual disturbance in [idiopathic hypersomnia], once again a high dose and an hour after dosing and disappeared within an hour of appearing.
“So far, our profile is what we view to be acceptable, predominantly mild episodes at this point.”
Next Steps for Orexin System-Based Drugs
These results are promising, but it will still be some time before any drugs targeting the orexin system will be indicated for people with narcolepsy. In the case of Alkermes, its phase 2 study is expected to be completed in July 2025. Other drugs that seek to remedy the underlying pathophysiology of narcolepsy are also on the horizon. The next few years will likely be an exciting time.
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