H. Lundbeck A/S - Depression

According to the WHO, depression is the fourth largest cause of the global health burden. The prevalence of depression is increasing, and the WHO estimates that depression will become the second largest cause of the global health burden by 2020.

Lundbeck's defined goal is always to be able to offer patients the best drugs for the treatment of depression disorders.

Since the 1950s, Lundbeck has conducted research in, and developed drugs for, the treatment of depression. Lundbeck was one of the first companies to market a tricyclic antidepressant. Lundbeck was also a front-runner in its development of citalopram, which was one of the first SSRIs. The compound citalopram – also known under the brand names Cipramil®/Celexa™ - has made Lundbeck a key player in the global market for antidepressants. Following the launch of the second generation SSRI Cipralex®/Lexapro™ (escitalopram), Lundbeck is set to further consolidate its position in the antidepressant market.

Lundbeck's ambition is for escitalopram to become the most widely prescribed antidepressant in the world by 2005.

Drugs in clinical development

Compound	Activity	Indication	Development stage	Registration application	Expected launch
Escitalopram	SSRI	Social anxiety disorder	III	2003	2004
Launched drugs
Compound	Activity	Indication	Trademark	First registration	Approved, no of counries
Escitalopram	SSRI	Depression, panic disorder	Cipralex®, Lexapro™, Sipralexa®, Sipralex®	2001	30
Citalopram	SSRI	Depression, panic disorder	Cipramil®, Seropram®,
			Cipram®, Celexa™	1989	82
Flupentixol+melitracene	Typical anti-psyc. + TCA	Mild depression	Deanxit®	1971	31
Melitracene	TCA	Depression	Dixeran®	1968	4
Nortriptyline	TCA	Depression	Noritren®, Nortrilen®, Sensaval®	1963	30
Amitriptyline	TCA	Depression	Saroten®, Sarotex®, Redomex®	1961	34
Lofepramine	TCA	Depression	Tymelyt®	1976	7
Flupentixol	Typical antipsyc.	Mild depression, schizophrenia and other psychotic disorders	Fluanxol®, Fluanxol Mite®, Depixol®	1965	67

Having introduced Cipralex®/Lexapro™ in 2002, Lundbeck continues to invest heavily in research into depression disorders.

At the end of 2002, Cipralex®/ Lexapro™ had been approved in Argentina, Austria, Belgium, Brazil, Bulgaria, Croatia, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Iceland, Ireland, Israel, Italy, Latvia, Lithuania, Luxembourg, Mexico, New Zealand, Norway, Portugal, Slovakia, Spain, Sweden, Switzerland, the UK, and the USA –corresponding to more than 90% of the global market for depression therapies. Lundbeck expects to obtain approval for escitalopram in a number of other countries in 2003.

In 2002, Lundbeck commenced marketing activities in Switzerland, Denmark, the UK, Latvia, Sweden, Estonia, Austria, Ireland, and the USA. Marketing activities will commence in the other countries as soon as marketing approvals have been issued and subsidy negotiations with the respective authorities have been finalised.

Common symptoms of depression include:

Low mood
Loss of pleasure or interest
Loss of energy or increased tiredness

Furthermore, at least two of the following concomitant symptoms must be present:

Loss of self-confidence or self-esteem
Feelings of self-reproach or guilt
Thoughts of death or suicide
Disturbed thoughts or concentration
Restlessness or behavioral inhibition
Sleep problems
Disturbed appetite or weight loss/gain

The symptoms may also occur in non-depressed individuals, for example, in connection with death in the family or relationship problems.

Depression can strike anyone, but certain social and biological factors make some people more predisposed to the disease than others. Depression is partially hereditary and may occur without an external cause.

However, in patients with a biological predisposition to depression, the disease may also be triggered by stressful events such as the death of a close relative, unemployment, loneliness or other social impacts. Serious diseases such as heart diseases, stroke, cancer, Alzheimer's disease and Parkinson's disease may be aggravated by a concurrent depression.

Anxiety is a frequent problem for depressed patients, and more than 95% of all depressed patients suffer from anxiety. Conversely, it is likely that 20-65% of patients suffering from anxiety are also depressed.

Anxiety conditions are described as:

Generalised anxiety disorder (GAD), in which the patient is in a continuous state of anxiety.
Generalised panic disorder (PD), in which the patient is overcome by sudden and unexpected anxiety attacks.
Agoraphobia – fear of going outside the home unaccompanied by others.
Social anxiety disorder (SAD) - anxiety in social situations, for example at work, in public transportation, shopping centres, parties, etc.
Obsessive-compulsive disorder (OCD)
Generally obsessive state resulting in obsessive thoughts.
Generally compulsive state resulting in compulsive actions.
Post-traumatic stress disorder (PTSD)
Anxiety in response to stress, crisis.

Depression is a disorder that has been known and addressed by philosophers and physicians throughout the ages. Numerous mythological, religious and literary writings in both Hellenic, Arabic, Indian and Western cultures describe depressed individuals; for example in Shakespeare's famous plays, in which both Hamlet and Macbeth obviously suffer from depression. Throughout history, depression has been known in the medical literature, from Greece, India and Southeast Asia. Depression research gathered momentum in the 19th and 20th centuries, but as early as the 4th century BC, Hippocrates described melancholy and depression, as did Robert Burton in his "Anatomy of Melancholy" in 1621. Some of the greatest individuals in history suffered from depression, including Abraham Lincoln, Theodore Roosevelt, Ludwig van Beethoven, Edgar Allan Poe, and Mark Twain.

Stages of the disease

Stage	Symptoms
Mild depression	The patient is in a worse mood than usual, has difficulty in sleeping and performing a job, and generally lacks energy.

Moderate depression	The patient is constantly sad and has lost interest in everything that surrounds him. Greatly reduced ability to concentrate, difficulty in making it through the day. The patient may also lose his sexual desire, suffer from a lack of appetite and lose 5-10% of his body weight.
Severe depression	The patient comes to a complete standstill, cannot cope with any activity or social gathering. The symptoms are the same as for mild and moderate depression, but more pronounced. Loss of appetite and thirst may endanger the patient's life, and the patient may become psychotic and start to hallucinate. There is an increased risk of the patient committing suicide

Marie-Louise:
"Being in a big black hole". That is a fitting description of how many depressed patients experience periods of depression.

In my case, however, it is more than just a fitting description – it is literally how I feel when I suffer from depression.

In fact, I don't exactly remember afterwards what happened during my depression. It is like being in a mist, a dream – or rather a nightmare. Or the feeling of having a high fever and being in a state between dream and reality. I don't remember afterwards what happened during my depression. But I do remember what the black hole feels and looks like:

When I'm in my black hole, I'm on an English moor. I don't know why, but an English moor in rainy weather is about the darkest thing I can imagine. This is perhaps rooted in the fact that I grew up in England and attended English schools and that an old black-and-white movie about the Hound of the Baskervilles lies buried in my conscience.

Anyway, my black hole is found far out on a wet, English moor. It's the middle of the night; it's raining and pitch dark. The walls of the hole are made of lava sand, I think, or rather some black sand that collapses every time I try to crawl out. I sit at the bottom of this black hole – in the rain and dark.

But the worst thing isn't that it's cold, wet, dark and impossible to crawl out! The worst thing is that I don't want to crawl out. I have no energy left but to sit there at the bottom.
I have given up.

The image on the left:

The arrows in the brain indicate the nerve paths, which play a crucial role when a person is afflicted with depression. A synapse is the cleft (contact site) between two nerve cells

The right hand images:

Synapse in an untreated depressed patient whose serotonin activity is lowered, leading to reduced stimulation of the nerve cell to the right.
Synapse with normal serotonin activity in a patient who has received SSRI treatment, which increases serotonin activity within the synapse.

Physiological changes in the brain
Depression involves an imbalance in serotonin metabolism in the brain.

Serotonin acts as a signaling compound by transmitting nerve impulses from one nerve ending to another; too little serotonin can trigger depression.

Antidepressants such as citalopram and escitalopram increase the amount of serotonin in the synapse between the nerve endings, by preventing the compound from being taken up into the neurones. An antidepressant using this mode of action is called an SSRI (selective serotonin reuptake inhibitor).

Lundbeck's R&D activities
In spite of the good treatment options available for depression today, one third of all depressed patients still do not respond to the drugs currently available in the market. Furthermore, there is a great need for developing medication that offers a faster onset of action than the existing drugs. Lundbeck's research projects focus partly on traditional modes of action, such as the adjustment of serotonin and noradrenaline levels in the brain, and partly on new and unique mechanisms.

Lundbeck's takeover of the USA-based company Synaptic will also strengthen the company's research into depression. Synaptic currently has one antidepressant in phase I and a number of preclinical research projects.

Drugs for the treatment of depression have also proven effective for a number of anxiety disorders. As a result, Lundbeck has launched several clinical studies using escitalopram for anxiety disorders. Based on the outcome of these studies, Lundbeck expects to file an application for approval of the indication social anxiety disorder in 2003.

Prevalence
According to the WHO's latest report on depression, from 2001, an estimated 340 million people around the world suffer from the disease. It is estimated that, at any given time, 1.9% of all men and 3.2% of all women suffer from a depressive disorder for which they require treatment.

In the USA and Japan and the five major European markets (France, Germany, Italy, Spain, and the UK), an estimated 86 million people suffered from a depression disorder that required treatment in 2001.

Age (years)	Point prevalence (%)
All	Male 1.9
	Female 3.2

Diagnosis
Only about 35 million people, or close to 40% of those suffering from depression, in the seven major markets are diagnosed with depression, and only about two thirds of this group receive the correct treatment. The USA has the highest diagnosis rate, with about 55% of depression patients being correctly diagnosed. The diagnosis rate is 35-45% in Europe, and 15% in Japan.

The antidepressant market is dominated by the SSRIs. The SSRIs represent the latest generation of antidepressants and accounted for 88% of the US antidepressant market, and 82% of the European antidepressant market in 2001. The best known drugs in this group are Cipramil®/Celexa™ (citalopram) and Cipralex®/Lexapro™ (escitalopram) from Lundbeck, Seroxat® (paroxetine) from GlaxoSmithKline, Zoloft® (sertraline) from Pfizer and Prozac® (fluoxetine) from Eli Lilly. Eli Lilly's patent on Prozac® (fluoxetine) expired in the USA 2001. At that time, Prozac® was the best selling antidepressant in the USA. Since then, generic fluoxetine has been launched, taking over a large share of total fluoxetine sales.

Brand name	Active ingredient	Marketing corporation(s)	Sales 2001 worldwide (mUSD)	Growth in %
Seroxat®	paroxetine	GlaxoSmithKline	2848	18
Zoloft®	sertraline	Pfizer	2590	15
Prozac®	fluoxetine	Eli Lilly	2356	-18
Cipramil®/Celexa™	citalopram	Lundbeck/Forest	1632	48
Effexor®	venlafaxine	American Home	1609	38
Wellbutrin®	bupropion	GlaxoSmithKline	1143	40
Remeron®	mirtazapine	Akzo Nobel	584	48
Serzone®	nefazodone	Bristol-Myers Squibb	390	8
Fluoxetine Barr®	fluoxetine	Barr Labs	363	-

Anxiety and depression are often closely related, since nearly all patients with depression also suffer from anxiety, and many people with an anxiety disorder are also afflicted with depression. The SSRIs have proven to be effective in the treatment of anxiety, which makes it difficult to estimate the size of the anxiety market.

Anxiety can be divided into different indications, but the best known are generalised anxiety disorder, social anxiety disorder, panic disorder, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). In 2000, apart from patients who do not suffer from anxiety when suffering from depression, there were about 60 million people suffering from the five most common anxiety indications in the seven major pharmaceutical markets (France, Germany, Italy, Japan, Spain, the UK and the USA). Only a little more than one-fifth of these patients received the correct treatment. The lifetime risk of experiencing an anxiety disorder is 20% for men and 30% for women.

In 2000, the anxiety market amounted to USD 2.8 billion in the seven major pharmaceutical markets. In Japan, the anxiety market is expected to increase by more than 50% until 2010, partly because anxiety is not as recognised a disease in Japan as it is in the USA and Europe.

Cipralex® launch in Europe
Cipralex® was successfully launched in eight European countries in 2002. Unlike in the large homogenous American market, there are vast differences in the structure and dynamic of the European markets. In some countries, specialists play a crucial role in the speed with which new and improved medication is prescribed to patients. In countries such as the UK, general practitioners write more than 95% of all prescriptions. The presence or absence of manufacturers of generic citalopram, and intensive focus on health expenses related to drug consumption, also affect the degree to which patients are offered the possibility of receiving more effective and faster-working medication.

Country	Launch	Cipralex® % of total franchise (incl. generics)	Months after launch
Switzerland	March 2002	14.5%	+10
Sweden	April 2002	9.0%	+9
UK	June 2002	8.6%	+7
Denmark	August 2002	13.0%	+5
Latvia	August 2002	16.7%	+3
Estonia	September 2002	54.4%	+3
Austria	September 2002	21.4%	+4
Ireland	November 2002	8.6%	+2

Successful launch of Lexapro™ in the USA
The launch of Lexapro™ in the USA was highly successful: after 18 weeks on the market, Lexapro™'s market share of new prescriptions was 7.76%, making it one of the most successful drug launches ever in the USA.

Lundbeck now enjoys a fully developed marketing and sales organisation with subsidiary representation in more than 40 countries. In order to gain market access in countries in which an investment in Lundbeck's own infrastructure would currently be unfeasible, the company formed two important strategic alliances in 2002 – one with Janssen-Cilag International and one with Abbott Laboratories.

The alliance with Janssen-Cilag International concerns the right to market, sell and distribute Cipramil® (citalopram) and Lexapro™ (escitalopram) in China. Xian-Janssen Pharmaceutical Ltd will market and sell both products and provide regulatory support. Both Janssen-Cilag and Xian-Janssen are members of the Johnson & Johnson family of companies.

The combination of Xian-Janssen's expertise and infrastructure in China and Lundbeck's antidepressant brands, creates a strong foundation for the successful marketing of Cipramil® and Lexapro™ in China. Cipramil® and Lexapro^TM will be promoted by an extensive group of Xian-Janssen medical representatives in more than 200 cities and over 2,000 hospitals nationwide.

The alliance with Abbott Laboratories concerns the right to market, sell and distribute Lexapro™ (escitalopram) in all Latin American markets. As part of the agreement, Lexapro™ will be promoted by an extensive group of medical representatives, making the product the most widely promoted antidepressant in Latin America.

Cipralex® better than Cipramil®
At several international conferences, Lundbeck has presented the results of clinical studies, which show that Cipralex® offers patients early onset of symptom relief, good tolerability, and high efficacy.

At the 23rd Collegium Internationale Neuro-Psychopharmacologium (CINP) Congress in Montreal in June 2002, Lundbeck presented clinical results showing that Cipralex® (escitalopram) offered significantly greater efficacy than Cipramil® (citalopram).

An eight-week, placebo-controlled study with 468 patients has demonstrated that 20% more patients treated with escitalopram (10-20 mg/day) responded to the treatment, compared with patients treated with citalopram (20-40 mg/day) (p=0.021). Moreover, the rate of remission was approximately 25% higher for patients treated with escitalopram than for with patients treated with citalopram (p=0.036).

These findings are further supported by the findings of a six-month fixed-dose study of 357 patients with moderate to severe depression, in which escitalopram 10 mg/day was compared to citalopram 20 mg/day, presented at the 3rd International Forum on Mood and Anxiety Disorders in Monte Carlo in November 2002.

At the CINP Congress, Lundbeck also presented the results of a preclinical microdialysis study. Data from this study show that escitalopram, when administered subcutaneously (s.c.) in doses of 2.0 mg/kg, was more potent than an equivalent s.c. 4.0 mg/kg dose of citalopram (2.0 mg/kg S-enantiomer + 2.0 mg/kg R-enantiomer) in increasing brain serotonin levels (about 300% versus 200%, respectively). In contrast, the R-enantiomer of citalopram, when administered in s.c. doses of 2.0 mg/kg, did not increase brain serotonin levels.

The microdialysis findings can explain the clear clinical advantage of escitalopram over citalopram.

Cipralex® better than venlafaxine XR
The findings of a study presented at the 15th Congress of the European College of Neuropsychopharmacology in Barcelona in October show, among other things, that patients treated with Cipralex® achieved sustained response and sustained remission significantly faster than the venlafaxine XR-treated patients. In addition Cipralex® was better tolerated than venlafaxine XR with escitalopram-treated patients having significantly fewer discontinuation symptoms than the venlafaxine XR-treated patients.