Actelion
So langsam sickert immer mehr durch von den Ergebnissen der Almorexant-Studie:
Actelion: almorexant's mechanism on orexin receptors could improve sleep maintenance, reduce hangover effect seen with other agents - experts
2009-10-26 Pharmawire
Intelligence Details
Actelion's sleep aid almorexant's mechanism targeting orexin receptors is likely to improve sleep maintenance and reduce the hangover effect seen with other agents, several experts interviewed for this article agreed.
However, they noted that the drug will need to improve co-morbid symptoms to capture a greater portion of the market, since there are so many agents available to treat insomnia.
Almorexant is an oral orexin receptor antagonist that acts by producing a transient, reversible blockade of the orexin receptors, OX1 and OX2.
This news service previously reported that the ongoing clinical trial of almorexant sets a high bar by using Ambien as the comparator agent. Dr Gary Richardson, a sleep expert at the Sleep Disorders and Research Center at the Henry Ford Hospital in Detroit, said that for approval, a novel agent will have to shorten the time to fall asleep and also decrease the time that someone spends awake. However, even though it will be challenging for almorexant to improve upon Ambien, all experts interviewed mentioned that in terms of sleep maintenance and next-day effect almorexant has an advantage.
There is evidence from knockout models in mice that targeting the orexin system is involved in sleep maintenance, according to an almorexant clinical investigator based in the United States. He noted that Ambien (zolpidem) – an agent that is associated with sleep maintenance concerns in some patients – has actions on the GABA receptor complex that avoid the orexin system altogether. “When you get off the Gabba receptor complex, you are not faced with the same type of adverse events,” the investigator said.
The investigator said that acting on the orexin receptor complex promotes sleep maintenance. The greatest value in almorexant’s mechanism of action is that it has the ability to produce therapeutic effects without touching the GABA receptors, the investigator said. Acting on the GABA receptors could give rise to impairment in psychomotor functioning, lead to postural instability, as well as affect anterograde memory, he said. However, the investigator declined to comment on whether almorexant significantly improved symptoms of middle of the night awakening compared to Ambien, in light of the upcoming study results.
A second clinical investigator, who is involved in the European arm of the ongoing trial, noted that almorexant decreases middle of the night awakening and improves next-day impairment.
The data shows that orexins play a role in sleep maintenance and even increase Stage III-IV sleep, according to Dr Paul Doghramji, a family physician at Collegeville Family Practice in Pennsylvania. At least 60% of patients have trouble falling asleep, and for insurance company reimbursement purposes sleep maintenance is an important endpoint to improve, Doghramji said.
Still, he added that even though the improvement in sleep maintenance and Stage III-IV sleep is impressive, but the agent will have to improve quality of life parameters to really capture a large portion of the insomnia market. Many patients with primary chronic insomnia are plagued by depression, psychiatric ailments, and a variety of medical problems; it would be useful if almorexant actually improves upon these endpoints, he added.
Doghramji noted that it is now clear that almorexant significantly improves sleep maintenance over placebo, but he questioned whether the drug improves sleep maintenance compared to drugs such as Sepracor's (NASDAQ:SEPR) Lunesta. He noted that Ambien is a good drug, but Lunesta would set the highest bar in terms of showing a benefit in sleep maintenance.
However, Dr Alexandros Vgontzas, the director of the sleep research and treatment center in the department of psychiatry at Penn State College of Medicine in Hershey, disagreed and said that Ambien is a good comparator. He noted that Ambien’s lack of effect on daytime functioning will be able to show if almorexant has an impact on daytime functioning.
Dr Martin Scharf, the director of the Tristate Sleep Disorders Center in Cincinnati, Ohio, who is also an investigator on the ongoing clinical trial, noted that there is an unmet need to treat patients who have middle of the night awakening. Available data suggests that patients with narcolepsy are deficient in orexins, so adding an orexin receptor antagonist may help improve sleep maintenance, Scharf said. He cautioned, however, that there is data lacking to suggest that a patient with insomnia has excess orexins; all that is known so far is that a system that is involved in sleep and wakefulness is being manipulated, he said. He declined to provide further comment on almorexant because the trial is still ongoing.
The goal of therapy with almorexant is to determine if the drug can improve sleep quality, leave a patient feeling rested the next day without a hangover, and be safe without impairing cognition, noted Dr Christina Calamaro, an assistant professor at the University of Maryland School of Nursing's department of family and community health. If almorexant can be even more specific in mechanism of action to the parts of the brain that control sleep, then it could avoid the side effects of Ambien, Calamaro noted.
Improving Co-Morbid Behaviors
Doghramji said that for approval, Actelion will have to demonstrate that almorexant improves some parameters of sleep such as next-day function, and the time that it takes patients to get to sleep. He noted however that the insomnia market is crowded with agents, and that Actelion will have to show an improvement in the co-morbid disorders associated with insomnia – such as depression and anxiety – to capture a greater market share.
Dr David Neubauer, associate director of the Johns Hopkins Sleep Disorders Center, said the available research data regarding almorexant is preliminary, but he does not believe the medication would lead to daytime cognitive impairment. Still, he said it will be more challenging to show that the drug significantly improves daytime functioning. While there are concrete numbers available to demonstrate improvement on sleep, he said it is difficult to select the correct parameter of daytime functioning to measure.
Richardson also agreed that in addition to decreasing the time it takes to fall asleep and the number of times patients wake up in the middle of the night, the drug will have to improve other co-morbidities of sleeping disorders. Shortening the time it takes for a patient to fall asleep is not the only measure that needs to be improved, he added.
The primary outcome measure of the ongoing clinical trial measured the change in latency to persistent sleep (LPS) and the change in wake after sleep onset (WASO).
by Klara Czobor
