Actelion
Hier schon mal ein Vorgeschmack auf die Almorexant-Ergebnisse:
Actelion: almorexant's ongoing clinical trial design against Ambien sets high bar as targeted mechanism of action may hinder efficacy - experts
2009-10-22 Pharmawire
Intelligence Details
Actelion's (PINK:ALIOF) head-to-head study comparing insomnia drug almorexant against Ambien is considered "bold," several experts noted. Almorexant’s more targeted mechanism is promising, but it may be difficult to demonstrate efficacy compared to a well-established agent like Ambien, they said.
Almorexant is an oral orexin receptor antagonist that acts by producing a transient, reversible blockade of the orexin receptors, OX1 and OX2. According to the website clinicaltrials.gov, the agent is currently being studied in a multi-center, randomized, placebo-controlled, active reference, parallel-group, polysomnography trial to evaluate the safety and efficacy of a 16-day oral administration of ACT-078573 in adults with chronic primary insomnia.
Almorexant, Ambien (zolpidem) and placebo are being studied in the three arms of the trial.
It is too early to determine if a targeted agent like almorexant will have an advantage over a more broadly acting agent like Ambien, according to Dr David Neubauer, the associate director of the Johns Hopkins Sleep Disorder Center. Almorexant’s mechanism on the orexin system is greatly different compared to any other agent in primary chronic insomnia, and it is targeted and rather appealing, Neubauer said. At the same time, chronic insomnia is a complex problem involving multiple metabolic and endocrine changes that cannot be traced back to a single pathology, he added.
Almorexant is a very interesting medication, but it is too early to determine whether or not the agent will be successful, Neubauer said. Many of the agents used to treat primary chronic insomnia are me-too drugs, so it is encouraging that there is an agent with a novel mechanism in development, he noted. "The physician community is very excited about the data that has been available so far, but it is too early to determine if the drug works," he added.
While it is known that the orexins are involved in the pathology of primary chronic insomnia, their exact role is unclear, an investigator noted. It is clear that acting on orexins is manipulating a system that is involved in sleep and wakefulness, but the relationship between sleep and orexins is limited, he said. In addition, data on the long-term effect of stimulating the orexin receptors is lacking, he added.
“There is an upside and a downside to specificity,” said Dr Gary Richardson, an expert in sleep disorders at the Henry Ford Hospital in Detroit. Takeda's (TYO:4502) Rozerem (ramelton) is the only agent for insomnia that has a different mechanism of action and is more specific and has less side effects, but there is a trade-off in response, Richardson noted. It is unclear if there is an orexin hyperactive type of insomnia, Richardson noted. Still, he said he believes that Rozerem was a very good agent.
"We are very happy with the results," said a second clinical investigator on the ongoing clinical trial. The investigator noted that not many patients who are treated with almorexant wake up in the middle of the night, and patients do not seem to have headaches in the morning. The investigator agreed, however, that Ambien is a very strong comparator and noted that somewhere around 60-70% of the overall patient population responds to treatment with Ambien. "I think that this is a good drug, and will be a better drug than the benzodiazepines," the investigator said.
"Neurologists who treat insomnia frequently say that the only agent that is more effective than 10mg of Ambien is 20mg of Ambien," Richardson said. It is likely that Ambien is more effective than most agents for sleep disorders because the drug acts on multiple pathways, and the clinical trial design set a really high bar for demonstrating efficacy, Richardson said. "I would suggest that Ambien should not be the efficacy comparator. A drug like Takeda’s Rozerem would be a better comparator for efficacy," he said.
Ambien is a prescription agent that is used for the short-term treatment of insomnia. The drug is a short-acting nonbenzodiazepine hypnotic that works by potentiating gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. The agent has a short-half life (two to three hours) and it generally works within 15 minutes.
The study design could also set a high bar because the European approval mechanism is more advanced compared to the United States, Richardson suggested. It is unethical to conduct a placebo controlled trial when there are effective drugs on the market for primary chronic insomnia.
Ambien is one of the better agents that could be used to treat sleeping disorders, and patients generally respond to it after a week of treatment, noted Dr Christina Calamaro, an assistant professor at the University of Maryland School of Nursing in the department of family and community health. A targeted mechanism is very promising because the agent will likely lack side effects, Calamaro said. "Primary chronic insomnia" is a blanket term and there is a lack of biomarkers to help find those who will respond to an agent targeting orexins, she added.
Ambien is a very popular agent, and it is effective in helping patients fall asleep more rapidly, Neubauer agreed. He noted that Ambien helps patients fall asleep more rapidly than other agents, so there is value in using it in the experimental arm of the trial.
The trial design is very “bold” in testing almorexant head-to-head with Ambien as well as placebo, the first investigator said, adding that this specific clinical trial design would encourage companies to move away from “me-too drugs.” If Actelion could demonstrate that almorexant has greater efficacy in prolonging sleep duration, then it has the potential to be a “grand slam,” he noted. He added that “sleep maintenance” is a problem with Ambien, and it is the main area where a novel agent could succeed in showing benefit because there is an unmet need for this problem. There is a big concern that many patients feel “hung-over” after being treated with the benzodiazepine class, he noted.
The primary outcome of the trial is studying the change in latency to persistent sleep (LPS) and the change in wake after sleep onset (WASO).
by Klara Czobor