TAKEDA: TAK-375
TAKEDA: TAK-375
ТАК-375 is a melatonin receptor agonist that is in phase III trials in the US and Europe and phase II development in Japan for the treatment of primary insomnia and circadian rhythm sleep disorders. Results from early stage trials suggest that TAK-375, under development by TPNA for chronic and transient insomnia, is a highly selective ML-1 receptor agonist. The ML-1 receptor is a key mediator of natural sleep and may be an important new target for sleep agents. According to the results of phase II trials presented in June 2003 at the annual meeting of the Associated Professional Sleep Societies, TAK-375 showed a statistically significant improvement in sleep parameters with no significant adverse events.
The most common treatments for insomnia are benzodiazepines. These drugs work by binding to gamma-aminobutyric acid (GABA) receptors in the brain, resulting in stimulatory effects on GABAergic transmission and hyperpolarization of neuronal membranes. This mechanism has been shown to confer sedative, anxiolytic, muscle relaxant and anticonvulsant properties. Benzodiazepines have been widely used since the 1960s and their popularity is due to their good efficacy and side effect profiles, and because they are safe to use at high doses. Nevertheless, patients can become psychologically dependent on benzodiazepines and there are additional risks of tolerance and withdrawal side effects. Moreover, benzodiazepines can disturb sleep patterns.
The launch of second-generation hypnotics such as Sanofi-Synthelabo's Ambien (Zolpidem) has had a significant impact on the insomnia market. Ambien achieved sales of $1.4bn in 2002, after the former Pharmacia transferred its rights to the product to Sanofi-Synthelabo at the beginning of the year. These therapies are short-acting non-benzodiazepines that can induce sleep with fewer side effects than benzodiazepines. They also have fewer morning side effects, such as sedation and memory loss (although these can occur to some degree).
Although the market for the treatment of chronic insomnia has considerable potential, TAK-375 is at a disadvantage compared with two pipeline drugs that will reach the market first: Pfizer/Neurocrine's indiplon and Sepracor's Estorra (eszopiclone). With strong trial data and the marketing power of Pfizer behind it, indiplon is expected to be a key growth driver in the insomnia market. These new drugs are clearly being targeted at the elderly patient segment, which has the highest patient population (responsible for around 50% of total treatments in the insomnia market). This segment is dominated by the need for drugs that can provide a safe profile in the context of chronic use and low levels of drug-drug interaction.
Antidepressants and anxiety drugs are being used off-label in place of insomnia drugs, as non-benzodiazepine sleep drugs are tightly regulated, given the potential for abuse, and because chronic use has not been evaluated in clinical trials. Physicians are more concerned with the safety of insomnia products than with the lack of efficacy of using antidepressants/anxiety treatments in insomnia. Gaining a chronic use label from the FDA could drive market growth, as the drugs could be used longer term.
TAK-375 is predicted to reach the US market in 2006 at the earliest, since it has only recently entered phase III trials. If launch occurs in this year, first-year sales of $80m are forecast, rising to S224m by 2008.
Tags for articles:
takeda
tak-375
melatonin receptor
associated professional sleep societies
benzodiazepines