Efficacy and improved tolerability of Hypericum perforatum extract, WS 5570, compared to paroxetine in patients with moderate to severe depression

Depression is the most common mental disorder worldwide affecting around 120 million people globally. The depression market is the largest segment of the CNS market with global sales of US$15.5 billion in 2003 although this figure is dropping as generic equivalents of past blockbusters are launched. Although the depression market has matured, key areas of unmet clinical need will have to be addressed in order to drive further growth of the market. These include improvements in the safety/tolerability of drugs. Extracts from St. John' s wort (Hypericum perforatum) offer competition to synthetic antidepressants and are frequently used particularly in European countries. German phytomedicine company, Dr. Willmar Schwabe Pharmaceuticals has developed an H. perforatum extract, WS 5570, of highly reproducible stability and purity. This extract has already been shown to be significantly superior to placebo in a large clinical trial. Now Schwabe researchers report data from a phase III double blind study showing that WS 5570 is at least as effective as clinical doses of paroxetine in patients with moderate to severe depression. Moreover this efficacy is achieved with few adverse effects.

Depression is the most common mental disorder worldwide. It is estimated that 5.8% of men and 9.5% of women will experience a depressive episode in any given year. The lifetime risk of developing major depression is 10-25% for women and 5-12% for men. Globally, around 120 million people suffer from depression and the WHO predicts that depression will become the leading cause of disability by the year 2020.  Depression costs the an estimated US$44 billion each year.

Paralleling the high incidence of depression and related costs is a massive market for therapeutic agents.  The depression market is the largest segment of the CNS market with global sales of US$15.5 billion in 2003. The dynamics of the marketplace are however changing as patent expiries hit past blockbusters and as new classes of drugs such as the selective noradrenaline reuptake inhibitor, Cymbalta (Eli Lilly), and new formulations of drugs such as the 5-HT1A antagonist, Wellbutrin XL (GSK), are launched.

As physicians continue to increasingly prescribe generic antidepressants the market is expected to decrease by -21.5% to $13.5 billion by 2011. Lilly’s blockbuster antidepressant Prozac (fluoxetine) was particularly hard hit and its sales fell at unprecedented speed following the loss of exclusivity in the in August 2001. At one time Prozac brought in approximately $2.7 billion in annual sales for Eli Lilly and was the fourth largest-selling medication in the .  Within weeks of the first generic fluoxetine being released by Barr Laboratories the majority of patients had switched from Prozac. GlaxoSmithKline’s Seroxat/Paxil (Paroxetine), a second SSRIs has also been extensively used in the treatment of depression and has a similar efficacy, safety and tolerability profile to that of fluoxetine. Again showing similarities to  Prozac, Seroxat/Paxil has suffered from generic competition and although it briefly assumed the top spot in the antidepressant class following the genericization of fluoxetine, the launch of generic paroxetine in 2003 led to a decline in sales.

Although the depression market has matured, key areas of unmet clinical need will have to be addressed in order to drive further growth of the market (see the depression section of our feature CNS Drug Discoveries: What the future holds). These include improvements in the efficacy, speed of onset, safety/tolerability of drugs and a reduction in remission rates and relapse/recurrence.

One class of therapeutic agents that is challenging the antidepressant class includes various extracts from wort (Hypericum perforatum).  This class generated sales worth $86 million in the US market in 2000, and today, preparations based on H. perforatum extract are among the most widely prescribed drugs for depression in many European countries, particularly in Germany where some sources claim that it is prescribed four times more often than fluoxetine. With the increased use of H. perforatum there has been concern over the rigor with which some Wort extracts are being purified.  To address this situation German phytomedicine company, Dr. Willmar Schwabe Pharmaceuticals employ proprietary technology to ensure the purity and stability of their H. perforatum extract WS 5570.

Extract of Hypericum perforatum ( wort) is more effective than placebo in the treatment of mild to moderate major depression and as effective as several tricyclic antidepressants or fluoxetine. Furthermore, in clinical practice, hypericum extract is better tolerated than synthetic antidepressants, and this may be particularly helpful in severe depression with its high risk of chronicity.  The efficacy of hypericum extract has not however been established in patients with severe depression.

In their recent BMJ paper, Szegedi et al report the results of a study sponsored by Schwabe Pharmaceuticals and designed to compare the efficacy and safety of hypericum extract WS 5570 with paroxetine in patients with moderate to severe depression.

Results from this 6 week study demonstrated that WS 5570 is at least as effective and better tolerated than standard treatment with paroxetine in the treatment of moderate to severe major depression. The randomised, double-blind, reference-controlled, multicenter phase III clinical trial reports that WS 5570 produced a significantly better improvement in patients as measured using the Hamilton Depression Rating Scale (HAMD) when compared to paroxetine. Although a similar percentage of WS 5570- and paroxetine-treated patients demonstrated a response, WS 5570 induced remission in 50% of patients compared with 35% for paroxetine. Of interest this difference was evident even though patients were allowed to double their treatment dose in the absence of a response after 2 weeks.  The adverse event incidence with WS 5570 was 71% lower than with paroxetine.  Of particular note paroxetine was associated with diarrhea in 18% of patients compared to only 10% in WS 5570-treated patients.  Similar reductions in the incidence of nausea, dry mouth and dizziness were also observed.

This study is important for two reasons.  Firstly it demonstrates that WS 5570 is at least as effective as SSRIs in the treatment of major depression irrespective of the severity of the depression.  Secondly WS 5570 can achieve this efficacy with fewer side-effects than established antidepressants, a key finding given the chronicity of depression.

Source: LeadDiscovery-TherapeuticAdvances