In December 2004, however, the FDA approved Lunesta (eszopiclone) as the first hypnotic that can be taken over long periods for both sleep onset (difficulty falling asleep) and sleep maintenance (waking in the night or too early in the morning). Lunesta, previously known as Estorra, is a single isomer version of zopiclone, marketed outside the US by sanofi-aventis as Imovane; it was never launched in the US. Sepracor licensed the rights to the S isomer from Aventis heritage company Rhone-Poulenc Rorer, paying $5 million in 1999. When Sanofi-Synthelabo acquired Aventis in 2004, it divested its rights to Pall, which will receive single-digit royalties on Lunesta’s sales from Sepracor.
The isomer differs in that it does not have a ‘hangover’ effect and the incidence of nocturnal awakenings is less; it also causes fewer anticholinergic side-effects, such as dry mouth. Moreover, it has a longer duration of action (six hours sleep), compared with other hynoptics, which offer three. Lunesta is a Schedule IV controlled substance, but is not a narcotic or a benzodiazepine, and can be used in elderly patients at the lower two of the three available doses.
Global sales of hypnotics/sedatives (ATC class N5B)
12 months to March 2005
Source: IMS MIDAS
Until the launch of Lunesta, the global insomnia market was dominated by sanofi-aventis’ Ambien/Stilnox (zolpidem), which had sales in excess of $2 billion and a 56% share of the N5B ‘Hypnotics/Sedatives’ class, according to IMS MIDAS data, in the 12 months to March 2005. With sales ranging from $125-85 million, the other leading sleeping pills are Lendormin (brotizolam), from Boehringer Ingelheim; King’s Sonata (zaleplon); Pfizer’s Halcion (triazolam); and Imovane. Most of these are prescribed for only 7-10 days continuous use. IMS data shows that the global hypnotic market was worth $3.8 billion in the 12 months to March 2005, and saw 11% growth in fixed-rate US dollar terms.
Many other products are used off-label for the treatment of insomnia, including antidepressants, antipsychotics and tranquilisers, for example trazodone – possibly owing to the limitations on prescribing specific hypnotics for chronic use.
A nascent blockbuster…?
After its first month on the US market, Sepracor’s pill had almost a 10% share of new prescriptions for insomnia - making it one of the industry’s most successful launches; analysts believe its annual sales could eventually exceed $1 billion, although by July there were signs that its share of new prescriptions was flattening. Most of the patients appeared to be switching from Ambien, but many analysts believe Lunesta will also grow the overall insomnia market. Sepracor backed the launch with a $60 million direct-to-consumer advertising campaign, including late night adverts on television to catch potential users. Although Sepracor has not ruled out a future alliance, at present it is marketing the drug independently, with 1,250 sales representatives.
This stance may have to change when new products from the likes of Pfizer and Merck & Co join the market, but Sepracor received a boost later in April 2005 when the FDA ruled that sanofi-aventis’ Ambien CR, a controlled-release version of Ambien, was only ‘approvable’; the agency raised issues about the drug delivery mechanism. Ambien loses US exclusivity in October 2006 (though it may receive a six-month paediatric extension), and sanofi-aventis is also hoping that Ambien CR will have a broader label. The French giant is confident that it will be able to launch the new formulation in the summer of 2005, but in the meantime has intensified its efforts to secure Ambien’s sales; in the first half of 2005, they rose 9% to €670 million. King and Elan are also developing an extended-release formulation of Sonata.
Sepracor is currently studying Lunesta in patients with depression (including in combination with Prozac/fluoxetine), obstructive sleep apnoea, pain associated with rheumatoid arthritis, and women in perimenopause or menopause – all conditions associated with the development of insomnia. Lunesta may also have potential in other conditions, including generalised anxiety disorder, schizophrenia and dementia. Moreover, Sepracor claims that Lunesta is cost effective, saving a health plan with 100,000 members $588,000 a year. Nevertheless, US consumer group Public Citizen criticised the price of Lunesta and said the FDA had approved the product despite a concern about cancer risks.
...but Takeda soon steals the limelight
Unfortunately for Sepracor, Lunesta soon had to move over to make room for Takeda’s Rozerem (ramelteon), approved by the FDA in July 2005. It has the advantage of being the first sleeping aid that is not classified as a scheduled drug by the US Drug Enforcement Administration, having demonstrated no potential for abuse. Takeda also notes that it is the first prescription insomnia medication with a novel therapeutic mechanism of action in 35 years: Rozerem affects the melatonin receptors, rather than GABA. Like Lunesta, Rozerem can be used long term, though it has been associated with changes to testosterone and prolactin levels.
It is due to be launched in the US by the end of September 2005, and is indicated for patients who have difficulty falling asleep – a narrower label than Lunesta’s. Takeda has boosted its US sales force by 500 reps, to 1,800, and analysts are predicting peak sales of up to $900 million. It will be the first product the Japanese firm launches independently in the US, having previously utilised TAP, its joint venture with Abbott. Takeda is planning to study the use of Rozerem in other CNS disorders, including Alzheimer’s disease and depression.
The major competitors
|
Ambien |
Lunesta |
Rozerem |
indiplon |
gaboxadol |
|
| Status |
Marketed |
Marketed |
Approved |
Pending FDA approval |
Phase III |
|
Owner |
sanofi-aventis |
Sepracor |
Takeda |
Neurocrine Biosciences, Pfizer |
Lundbeck, Merck & Co |
|
Mechanism of action |
imidazopyridine (GABA omega-1 sites) |
GABA modulator |
melatonin MT1/MT2 agonist |
GABA-a modulator |
GABA-a agonist |
|
Comments |
Standard product may lose US exclusivity in October 2006, controlled-release version expected 2H05 |
First hypnotic that can be taken long term, for both sleep initiation and maintenance |
The first non-scheduled hypnotic |
Has both immediate- and modified-release capsule and tablet formulations |
Doesn’t affect REM sleep, induces and maintains sleep |
Next to the market, possibly in mid-2006, should be Neurocrine Biosciences’ indiplon. Originally developed by Wyeth and licensed to DOV, this is due to be co-promoted by Pfizer, which is likely to try and out-gun sanofi-aventis, Takeda and tiny Sepracor. Neurocrine submitted NDAs for both tablet (modified-release to maintain sleep) and capsule (immediate-release to induce sleep) formulations of indiplon in late 2004, but there were problems navigating the electronic document. The capsule NDA was thus re-submitted in April 2005 and the tablet NDA in May. Indiplon will be of use in both adult and elderly patients, and analysts believe it too could have blockbuster potential.
Further behind is Lundbeck’s gaboxadol, which is being co-developed by another US big-hitter, Merck & Co. This could reach the market in 2008. It selectively binds to the alpha 1 subunit of the GABA receptor and is described as a “selective extrasynaptic GABA-a agonist”. Initial data suggests that gaboxadol may differentiate between non-REM and REM sleep, resulting in better next-day performance. As generic zolpidem will be available when gaboxadol is launched, Lundbeck and Merck will have to demonstrate a significantly improved side-effect profile in order to win market share.
The hypnotics market is certainly due to enter an exciting period, with novel products fighting for space on cost-controlled formularies with cheap generics. As so many companies are now involved, DTC activity and ‘disease awareness’ campaigns are likely to feature highly, as marketing companies promote the individual virtues of their products. Whether minnow Sepracor can successfully see off the sharks and ride this wave of interest is yet to be seen.
This article was written by Selena Class, Deputy Executive Editor of IMS Company Profiles.
Much of the information was sourced from IMS Knowledge Link, which integrates detailed data from a number of publications covering sales, R&D, news, patents and strategic issues on a single website. The extensive coverage includes more than 2,000 of the top pharmaceutical and biotechnology companies as well as 300 therapeutic areas and 38 countries. For more information, visit imsknowledgelink.com or contact Stephanie Earle via e-mail or +44 207 393 5757.