It’s not often that a pharmaceutical executive discusses a competitor’s success. Alkermes Chief Operating Officer Blair Jackson not only talks about it openly, he cheers it.
Alkermes’s scope in neuroscience is expanding to sleep science, and the Dublin-based company is developing a drug that addresses the same central nervous system target as an experimental Takeda Pharmaceutical pill on track for an FDA submission. Regulatory approval would make Takeda’s drug first in this new class of medicines, marking the new first new mechanism of action for a narcolepsy medicine in years. Takeda projects its pill could reach up to $3 billion in peak global revenue. Jackson expects an FDA approval will be followed by strong commercial uptake from a narcolepsy community eager for a new way to treat the sleep disorder.
“I think it’s going to launch really, really well,” Jackson said in an interview during the recent J.P. Morgan Healthcare Conference in San Francisco. “My expectation is that they’re going to really do a lot to educate this patient population on this [drug] class. And that’s going to benefit us, of course, as we come in with what we think is a better embodiment of that treatment.”
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Neuroscience research has found that the excessive sleepiness experienced by narcolepsy patients is driven by deficiency of orexin, a peptide that activates pathways in the brain that regulate the sleep/wake cycle. The Alkermes narcolepsy drug, alixorexton, is an oral small molecule designed to target and activate the orexin 2 receptor. Alkermes is developing this once-daily pill for both narcolepsy type 1 (NT1), in which excessive sleepiness is also accompanied by sudden events of muscle weakness called cataplexy, and the rarer narcolepsy type 2 (NT2), which does not have cataplexy. An estimated 80,000 Americans have NT1 or NT2, but the condition is also believed to be underdiagnosed, so the market for new narcolepsy drugs could be larger.
Alkermes has positive Phase 2 results for alixorexton in both NT1 and NT2. The company plans to begin a Phase 3 study this year. But Alkermes will have a commercial presence in the narcolepsy market soon. After a short bidding war with Lundbeck, Alkermes is acquiring Avadel Pharmaceuticals and its commercialized narcolepsy drug, Lumryz, for $2.37 billion. Avadel shareholders approved the acquisition last week. Jackson said the transaction is expected to close in the current quarter. When the M&A deal was first announced last October, Leerink Partners analyst Marc Goodman said in a research note that Avadel helps Alkermes by bringing to the company a profitable drug as well as commercial infrastructure that will support alixorexton. Jackson echoes those points.
“We’re going to be immediately now in front of those sleep doctors talking to them about Lumryz — we’re there before Takeda,” Jackson said. “It means we don’t have to build out our commercial engine in the sleep space. We can use theirs as our launch platform. And then it enhances our revenue and our profitability.”
In addition to excessive daytime sleepiness, narcolepsy also leads to difficulty sleeping at night. Lumryz, part of a class of medicines called oxybates, works as a central nervous system depressant. Taken at bedtime, the Avadel drug helps patients sleep uninterrupted at night. By contrast, Alkermes’s alixorexton is taken once in the morning and is intended to help patients feel more awake during the day. For some narcolepsy patients, both drugs could be appropriate, Jackson said.
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Takeda leads the class of orexin agonists with oveporexton. Last September, Takeda reported statistically significant and clinically meaningful Phase 3 data for its narcolepsy drug. Two doses of this twice-daily pill were tested; Takeda said it will seek FDA approval of both to give physicians and patients more dosing flexibility. Oveporexton was only tested for NT1; another Takeda orexin agonist is in development for NT2 as well as a different sleep disorder called idiopathic hypersomnia. Other companies developing orexin receptor-targeting drugs include Centessa Pharmaceuticals, which is in Phase 2 testing, and Eisai, which is in Phase 1.
Jackson contends alixorexton’s formulation as a once-daily pill is an advantage and the company aims to offer a range of doses for patients who may need higher dosing. Another potential advantage is the opportunity to address a broader swath of patients. While Takeda’s oveporexton was only developed for NT1, alixorexton’s clinical program spans both NT1 and NT2 as well as idiopathic hypersomnia. That’s key because the cataplexy that distinguishes NT1 from NT2 is a spectrum that can make it challenging to diagnose between the two types of narcolepsy, Jackson said. Securing approval in idiopathic hypersomnia is important because there are fewer drugs available for patients with this sleep disorder.
One of the concerns surrounding alixorexton is reports of visual disturbances, such as blurry vision. Jackson said these problems happened in a few instances for the highest dose tested and the side effect was transient, lasting from five to 20 minutes and then going away. When these problems happened, they continued only for the first few times a patient took the drug. Jackson said visual disturbances are a class-wide effect. Takeda reported that vision problems in its studies were low and equally balanced across treatment and placebo arms. The more common side effect for orexin agonists is frequent urination. In alixorexton’s clinical testing to date, Jackson said this side effect was mild and did not led to discontinuation of the study drug.
Alkermes aims to build on its research in narcolepsy by bringing orexin receptor modulation to other indications. The orexin system affects several different areas of the brain, and the mechanism that drives wakefulness is different than the one that drives fatigue, Jackson said. Depending on the indication, drugs for other disorders could differ in dosing and potency. The Alkermes pipeline includes ALKS 4510 for fatigue in two neurological disorders, Parkinson’s disease (PD) and multiple sclerosis (MS). ALKS 7290 is being developed for attention deficit hyperactivity disorder. Both are in Phase 1 testing.
“PD and MS fatigue is kind of the wedge into the broader fatigue space because there’s a whole host of areas within neurodegen and other areas where fatigue is prominent,” Jackson said. “I think you can imagine things like cancer fatigue, people who have severe fatigue after their treatment. These are all things that are open for investigation as we move forward.”
Photo by Alkermes