Study slams single-isomer antidepressant
older pharmaceuticals by developing new versions based on just one
of the two optical isomers of the active compound, a process known
as racemic switching. But critics suggest that this often does not
improve the properties of the drug enough to justify a premium
price.
A study of Lundbeck's escitalopram, the active isomer in its Cipramil (citalopram) antidepressant, is the latest to poke holes in this argument.
In the January issue of the journal Psychotherapy and Psychosomatics, Staffan Svensson of the Department of Clinical Pharmacology of Sahlgrenska University Hospital of Goteborg, Sweden, and colleagues challenge Lundbeck's claims that escitalopram has more efficacy and a faster onset of effect than citalopram.
They reviewed trial reports obtained from Lundbeck and the Swedish drug regulatory authority. The trials consisted of a pooled analysis of 1,321 patients from one unpublished, one partly published and one published eight-week trial, as well as a 24-week trial with 357 patients published as a poster. The studies compared escitalopram with placebo and/or citalopram in outpatients aged 18 years who met specified criteria for depression.
The advertising claims are not justified, they say because they are based on secondary outcomes, do not use intent-to-treat analyses (in which all patients in the study are assessed, whether or not they remain on treatment) and use arbitrarily defined subgroups which in any event provide inconsistent results. Methodological flaws in the trials could account for the differences found, they said.
"Even if the differences claimed were real they appear too small to justify higher prices. On the evidence available to us the manufacturer's claims of superiority for escitalopram over citalopram are unwarranted," the conclude.
The Swedish and Danish drug regulatory authorities reached similar conclusions in assessments of the new drug, and this highlights the need for wider dissemination of national authorities' statements to other countries affected by the European Union's mutual recognition procedure, they note.
And it seems that Lundbeck may also be finding it hard to persuade doctors about the value of escitalopram. In November, the Danish company issued a profit warning after it emerged that sluggish sales of the new version would not counteract the effect of generics on its patent-exposed parent product.
Despite this, there is still ample evidence that in come cases selection of the right optical isomer can lead to a better, safer product. AstraZeneca is one company that has successfully improved on an original product - the gastrointestinal drug Prilosec/Losec (omeprazole) - and in so doing defended a valuable franchise. The key was the launch of the left-handed (s) isomer of omeprazole, sold by AstraZeneca as Nexium (esomeprazole).
Losec alone achieved sales of $5.6 billion (€4.47bn) in 2001 but, despite patent expiries led to generic competition in a number of markets, the franchise has continued to grow. While other top-selling products have seen up to 85 per cent of their sales eroded within a year of going off patent, combined sales of Losec and Nexium reached $6.6 billion in 2002.
In Nexium's case, there was a clear benefit of the single-isomer drug over its parent. Losec suffered from a lot of variability between patients in terms of its metabolism, so a range of different doses were need to find the optimal level for control. Nexium offers improved bioavailability, higher potency and less variations between individuals compared to Losec, and this translates to improved efficacy.
Other racemic switches have not been so successful. Eli Lilly and Sepracor hoped to develop a single-isomer version of the blockbuster antidepressant Prozac (fluoxetine) but dropped the programme after it emerged that the new version had more side effects than the racemate.
