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Symptom Overview
- Current Treatments - Drugs in Development

 

 

BIOTECHNOLOGY / PHARMACEUTICALS

TABLE OF CONTENTS

1. FIBROMYALGIA SYNDROME (FMS)                                                       
    STATISTICS                                                                                  
    SYMPTOMS AND ASSOCIATED SYNDROMES

2. TREATING FMS: OVERVIEW

3. TARGETING FMS: COMPETITIVE LANDSCAPE

4. APPENDIX: FMS MEDICATION TREATMENTS

ANTIDEPRESSANTS
SEROTONIN SPECIFIC REUPTAKE INHIBITORS (SSRIS)
PAXIL® - GLAXOSMITHKLINE
ZOLOFT® - PFIZER
CELEXA® - FOREST LABORATORIES
TRICYCLIC ANTIDEPRESSANTS (TCAS)
ELAVIL® - ASTRAZENECA
TOFRANIL® - MALLINCKRODT PHARMACEUTICALS
SINEQUAN® - PFIZER
SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)
EFFEXOR® - WYETH
CYMBALTA® - ELI LILLY
NOREPINEPHRINE SEROTONIN REUPTAKE INHIBITORS (NSRIS)
MILNACIPRAN – CYPRESS BIOSCIENCE

5. OTHER TREATMENTS FOR SYMPTOMS OF FMS PAIN

ULTRAM® - JOHNSON & JOHNSON
VICODIN® - ABBOTT LABORATORIES
NEURONTIN® - PFIZER
PREGABALIN - PFIZER
CYCLOBENZAPRINE – PFIZER
ZANAFLEX - ELAN
CELEBREX – PHARMACIA, PFIZER
KLONOPIN® - ROCHE
XANAX® - PHARMACIA
AMBIEN® - SANOFI-SYNTHELABO
MIRAPEX® - PHARMACIA

DISCLOSURES

1. FIBROMYALGIA SYNDROME (FMS)

Fibromyalgia Syndrome (FMS)-"fibro" meaning fibrous tissues, "my" meaning muscles, and "algia" meaning pain- is achronic disorder characterized by generalized pain, fatigue, and tenderness. The pain and tender points occur in themuscles, tendons and ligaments, particularly in those that support the neck, spine, shoulders and hips. Whilstsymptoms associated with FMS fluctuate from person to person, most sufferers complain of "aching all over".

Othersymptoms include diarrhea, constipation, morning exhaustion, insomnia, morning stiffness, chronic headaches, skin and chemical sensitivities, restless legs, twitching muscles, urinary frequency or urgency, facial or jaw pain, cognitive or memory impairment, weakness and muscle pain after exertion, dysmenorrhea, numbness and tingling sensations, dizziness or lightheadedness, swollen feeling in extremities, dry mouth, and chest pain/shortness of breath.

FMS primarily occurs in women, but children, the elderly, and men are also affected. Researchers don’t agree on whatcauses fibromyalgia (genetic predisposition, injury or trauma affecting the central nervous system, an event triggering adormant abnormality or virus, etc.) and the ultimate cause of FMS still remains unknown.

Diagnosis of the syndromeappears somehow difficult since many of its symptoms mimic those of other chronic conditions such as chronic fatiguesyndrome, myofascial pain syndrome, headaches, irritable bowel syndrome, Gulf War syndrome, etc. There is nosingle approved treatment for FMS and current therapy approaches focus on palliating symptoms.

STATISTICS

FMS is the most frequent cause of chronic, widespread pain and is estimated to affect 2% to 4% of the population.

In 2002, 5.7 million people are expected to be diagnosed with FMS in the U.S, or 2% of the total population. Of the 5.7 million patients suffering from FMS, an estimated 38%, or 2.1 millions will be actively seeking treatment. FMS is second only to osteoarthritis as the most common diagnosis made in rheumatology practice and is diagnosed four times more frequently in women that in men. FMS is most often diagnosed in the primary care setting, with almost half of FMS-related office visits to internal medicine and family practice providers. Rheumatologists are the leading specialty group treating FMS patients; 16% of office visits made by FMS patients are to this group of physicians. The remainder of office visits are to a variety of tertiary care providers, including pain centers, physical medicine specialists, and psychiatrists.

SYMPTOMS AND ASSOCIATED SYNDROMES

The fibromyalgia syndrome is considered one of the so-called "unexplained clinical conditions" 6 or "functional somatic syndromes, characterized more by symptoms, suffering, and disability than by consistent tissue abnormality." Functional Somatic Syndromes (FSS) are a group of chronic pain syndromes that present both physical complaints, such as pain, and psychiatric symptoms, such as depressed mood. In Functional Somatic Syndromes, the physical symptoms are often exacerbated by stress, and may be the first signs of any psychological distress. In fact, according to a study published in the American Journal of Psychiatry, 80% of patients experiencing depressed mood originally seek medical care for somatic, or physical complaints. Of all such complaints, pain has been reported to be most reliable in predicting risk for affective or mood disorders.

Pain is the defining symptom of FMS and patients typically suffer from both allodynia (perceiving pain even from a nonpainful stimulus such as light touch) and hyperalgesia (augmentation of pain processing in which a painful stimulus is magnified and perceived with higher intensity than it would be by a normal subject).

Below are the most common symptoms shown in patients with FMS, as well as its frequency at the time of diagnosis:


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1 Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995; 38:19-28.
2 Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. Aspects of fibromyalgia in the general population: sex, pain threshold, and fibromyalgia symptoms. J Rheumatol. 1995; 22:151-156.
3 Jacobsen S, Bredkjaer SR. The prevalence of fibromyalgia and widespread chronic muscoloeskeletal pain in the general population. Scand J Rheumatol. 1992; 21:261-263.
4 Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromylagia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990; 33:160-172.
5 1998 National Ambulatory Medical Care Survey. Princeton, NJ: Covance, Inc.; 1998.
6 Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med. 2001; 134(9 Pt 2):868-881
7 Barsky AJ, Borus JF. Functional somatic syndromes. Ann Intern Med. 1999;130:910-921.
8 Kranzler JD, Gendreau JF, Rao SG. Psychopharmacology Bulletin. Vol 36. No 1. 2002

Pain - Pain is the defining symptom of FMS and required for an official diagnosis. According to the wpe4.jpg (3313 bytes)American College of Rheumatology diagnostic guidelines, fibromyalgia is characterized by widespread pain of three months duration or more and tenderness in at least 11 of 18 specific anatomical locations referred to as "tender points". A tender point is a pressure point that, when pressed, feels sore. There are 18 defined tender, or pressure, points on various parts of the body - from the elbows down to the knees (see picture on the left). Typically, FMS pain severity varies day-to-day and from person-to-person. Described as deep muscular aching, burning, throbbing, shooting and stabbing, it can range from mild discomfort to intense, disabling whole-body pain. Unlike pain commonly associated with arthritis, the pain associated with FMS can move from one body part to another, and it must occur both above and below the waist, on both sides of the body. Quite often, the pain and stiffness are worse in the morning, hurting more in muscle groups that are used repetitively.

Fatigue - This symptom can also be mild in some patients and yet incapacitating in others. The fatigue has been described as "brain fatigue" in which patients feel totally drained of energy, they have difficulty concentrating, and they feel like they have a chronic case of the ‘flu’.

Sleep disorders - Most fibromyalgia patients have an associated sleep disorder called the alpha-delta -EEG anomaly, in which patients can fall asleep without much trouble, but their deep level sleep is constantly interrupted by bursts of awake-like brain activity. It should be noted that most patients diagnosed with chronic fatigue syndrome have the same alpha-EEG sleep pattern and some fibromyalgia-diagnosed patients have been found to have other sleep disorders, such as sleep myoclonus or PLMS (nighttime jerking of the arms and legs), restless leg syndrome and bruxism (teeth grinding).

Irritable Bowel Syndrome - An estimated 40% to 70% of FMS patients show gastrointestinal symptoms including constipation, diarrhea, frequent abdominal pain, abdominal gas and nausea.

Chronic headaches - Recurrent migraine or tension-type headaches are seen in roughly half of fibromyalgia patients.

Temporomandibular Joint Dysfunction Syndrome (TMJD)- TMJD produces mild to severe face and head pain in one quarter of FMS patients. However, a 1997 report indicated that as many as 90% of fibromyalgia patients may have jaw and facial tenderness that could produce, at least intermittently, symptoms of TMJD. Most of the problems associated with this condition are thought to be related to the muscles and ligaments surrounding the joint and not necessarily the joint itself, as with true TMJD.

Chemical and Sensory Sensitivity - It is estimated that about half of FMS patients show increased sensitivity to chemicals such as fragrances, household cleaners, odors, noise, bright lights, medications, foods, etc, and experience allergic-like reactions (itching, rash, nasal congestion, runny nose, sinus pain) but without the measurable immune responses characteristic of allergies.

Other Common Symptoms – Other symptoms commonly associated with FMS include: dysmenorrhea (painful menstrual periods); cognitive disorders (feeling "spacey", difficulty remembering simple nouns or people's names, etc), chest pain; genito-urinary problems (irritable bladder, painful vulvar region and/or pain during sexual intercourse), paresthesia (numbness, tingling, prickly feeling or burning), problems with equilibrium (dizziness, impaired coordination), dry eyes and mouth, and changes in eye prescription. Changes in weather, cold or drafty environments, hormonal fluctuations (premenstrual and menopausal states), stress, depression, anxiety and over-exertion can all contribute to symptom flare-ups.

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TREATING FMS: OVERVIEW

There is currently no single drug therapy available that addresses all symptoms of FMS. Current drug treatments are tailored specifically for the patient and address the more troubling FMS symptoms. Treating pain, the defining symptom of FMS, is the center cornerstone of effective FMS therapy. However, fibromyalgia conforms to the characteristics of "functional somatic syndromes" and, as such, psychosocial elements have to be considered.

There are several general categories of drugs that are used by physicians to treat FMS patients. Medicines that boost the body’s level of serotonin (5-HT) and norepinephrine (NE) - neurotransmitters that modulate sleep and pain, among other things - are commonly prescribed, including Serotonin Specific Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), and Norepinephrine Serotonin Reuptake Inhibitors (NSRIs).

Serotonin Specific Reuptake Inhibitors (SSRIs) (e.g., Prozac®, Paxil®, Zoloft®, and Celexa®) have an almost pure 5-HT effect and have shown antidepressant activity and questionable efficacy in pain. Commonly prescribed SSRIs Prozac® and Celexa®, for example, have NE:5-HT relative activity of 1:55 and 1:3300 respectively, with an obvious preference for serotonin. These drugs target psychiatric symptoms (depression, anxiety) versus chronic pain states. Whilst serotonin (5-HT) was the first neurotransmitter hypothesized to be involved in FMS9, clinical data suggests that both noradrenergic (NE) and serotonergic (5-HT) activity can be antinociceptive (break the pain) in chronic pain states, and that the combination of NE and 5-HT is synergistic 10and may be optimal for FMS treatment. It also appears that 5-HT may play a secondary role to NE for an analgesic effect in chronic pain11. Thus an antidepressant with combined NE and 5-HT activity would have more analgesic activity than those with NE alone, which in turn would have more analgesic activity than those with only 5-HT activity12.

Tricyclic Antidepressants (TCAs) (e.g., Elavil®, Tofranil® and Sinequan®) TCAs, with dual reuptake activity (Elavil® has a 1.6:1 NE:5-HT balance) and preference for NE, have been proven efficacious in treating chronic pain with significant efficacy shown in multiple chronic pain conditions, including fibromyalgia. Unfortunately toxicity and negative anticholinergic and antihistaminergic side effects limit their use. While new antidepressants have displaced tricyclic antidepressants (TCAs) for most psychiatric indications, TCAs remain in clinical use in chronic pain states, where they have consistently demonstrated superior efficacy to serotonin specific reuptake inhibitors (SSRIs), Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and non-opiate pain medications.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) (e.g. Effexor®, and newly approved, yet not marketed, Cymbalta®) with dual NE/5-HT reuptake inhibitors but preference for 5-HT, show good antidepressant activity but have only shown moderate efficacy in FMS based on limited empirical and pilot results. Effexor® has a 1:30 NE:5-HT balance, Cymbalta® has a 1:8 NE:5-HT balance. These drugs have some NE but still mostly 5-HT effect and are thus currently positioned in the market as anti-depressants focused on the psychiatric symptoms (depression, anxiety). Note, SNRIs have even less favorable balance of the NE analgesic component than TCAs but have a more favorable balance of NE:5HT than SSRIs when examining effects on chronic pain states associated with FMS. Whilst data on duloxetine for FMS has not been released yet, registration of Cymbalta® for chronic pain indications is not expected, although trials in the area are anticipated in order to support its market position as an anti-depressant that can also address some of the somatic symptoms of depression, including pain. This means that Cymbalta® will primarily be prescribed to treat depression, though it is anticipated that it will also be considered off-label for FMS in the future.

The first of a new class of agents known as NSRI's, or Norepinephrine Serotonin Reuptake Inhibitors, is called milnacipran, a chemically novel, dual acting reuptake inhibitor in development. Distinguished from the SNRIs by its preference for norepinephrine (NE) reuptake inhibition over serotonin (5-HT) at a 3:1 ratio, milnacipran is expected to work better for FMS and chronic pain states. While mimicking the NE preference seen with TCAs, first-line treatment for many chronic pain states and the agents shown to best palliate the pain associated with FMS, milnacipran lacks the side effects of TCAs, which limits their use, whilst potentially providing relief to other symptoms associated with FMSsuch as fatigue and depression.

9 Moldofsky H. Sleep and musculoskeletal pain. Am J Med. 1986; 81(3A):85-89.
10 Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum.1996;39:1852-1859.11 Atkinson JH, Slater MA, Wahlgren DR, et al. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Pain. 1999; 83:137-145.12 Max MB. Antidepressants as Analgesics. Progress in Pain Research and Management; 1994:229-246; Fishbain D, et al. Pain Med. 2000; 1(2):310-316.

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3. TARGETING FMS: COMPETITIVE LANDSCAPE

Due to the therapeutic need for a drug to better treat the chronic pain and associated symptoms of the Fibromyalgia syndrome, the outlook and market potential of an FDA-approved therapy for the treatment of FMS in the U.S. is promising. A parallel scenario could be drawn from the similar case that took place 14 years ago, when Eli Lilly & Company launched Prozac® (fluoxetine). At the time when Prozac was launched, the anti-depressant market was dominated by tricyclic antidepressants. Prozac®, a SSRI, was considered to have a better side effect profile than other TCAs, which are known for their severe side effects. From January through April 1988, Prozac® was promoted exclusively to psychiatrists. In May 1988, Eli Lilly began Prozac® sales to primary care physicians. By September 1988, Prozac® became the top selling branded anti-depressant, which eventually established a multi-billion dollar franchise. Due to Prozac®’s unique composition in the market at the time, prescription numbers grew very quickly and achieved a total of $2.5 million. Total prescriptions grew to 6.1 million for the second year and 10.3 million for year three. Prescriptions fell to 9.7 million in the 4th year due to adverse publicity, and 9.6 million the following year when

Zoloft® was launched. The compound’s annual growth rate over the five years was 40.6%. The first SSRI class competition to Prozac® appeared in January 1992, four years later, when Pfizer launched Zoloft® (sertraline). Another major competitor appeared in January 1993, when GlaxoSmithKline’s division introduced Paxil® (paroxetine) at a 12.6% discount to Prozac® pricing. Then in 1994, Prozac® was approved for obsessive-compulsive disorder treatment.

We believe that a safe drug that is efficacious in treating chronic pain as well as other symptoms associated with FMS could follow a similar growth profile as Prozac®. Compounds with the possibility of targeting the FMS market, either off-label or by carrying the FMS indication label, include: pregabalin by Pfizer; Effexor® by Wyeth; Cymbalta® by Eli Lilly; and milnacipran by Cypress Bioscience.

PREGABALIN: Pregabalin is a more potent version and the intended successor of Neurontin® (gabapentin). Both agents were developed by Pfizer Inc. (NYSE: PFE). Neurontin® became the first oral medication approved in the U.S. for postherpetic neuralgia (pain in the area affected by herpes zoster) and it is also approved in more than 50 countries for the adjunctive treatment of epilepsy and for a range of neuropathic pain conditions. Neurontin® is the number one anti-epileptic drug worldwide with 2001 sales of $1.8 billion. Pregabalin, currently in Phase III clinical trials, is being developed for the treatment of epilepsy, neuropathy, and anxiety disorders. Pfizer plans to file pregabalin for approval for neuropathic pain, epilepsy add-on therapy, and generalized anxiety disorder in 2003. Subsequent filings could be pursued in the future, including social anxiety, panic disorder, fibromyalgia, and epilepsy monotherapy.

In October 2002, at the annual meeting of the American College of Rheumatology, Pfizer presented data on a clinical trial on pregabalin for the treatment of FMS. Pregabalin achieved statistical significance on the primary endpoint of global pain (29 percent of pregabalin-treated patients reported at least a 50 percent reduction in pain, compared with 13 percent of patients who received placebo) and significantly improved sleep quality and fatigue.

Whilst it is expected that pregabalin will enter the market with an anticonvulsant and anti-anxiety label, it could become the first on the market with a "fibromyalgia" label, expected towards the end of 2004.

On the other hand, Effexor® (venlafaxine), Cymbalta® (duloxetine) and milnacipran, compete more closely in that all three are dual reuptake inhibitors.

EFFEXOR®: Effexor® (venlafaxine), developed by Wyeth (NYSE: WYE), is a SNRI approved to treat depression and generalized anxiety disorder (GAD). Effexor® has become the fastest growing therapy option in the US antidepressant market and it is the first antidepressant drug in the market to target both serotonin and norepinephrine. Effexor® has been demonstrated to work in FMS in a small trial, but only at very high doses, and in a group of patients with relatively mild disease. Effexor® is already on the market, and an FMS label is not expected to be pursued since the patent life remaining on the drug is only a few years.

CYMBALTA®: Cymbalta® (duloxetine) is a SNRI being developed by Eli Lilly & Co. (NYSE:LLY) to treat depression. Like Effexor®, Cymbalta® enhances the levels of both norepinephrine (NE) and serotonin (5-HT). The balance of Cymbalta®’s NE to 5-HT is 1:10. Whilst Lilly’s data on duloxetine for FMS has not been released yet, Lilly has stated that they do not intend to pursue registration of Cymbalta® for chronic pain indications, but will continue to do trials in the area to support their market position as an anti-depressant that can also address some of the somatic symptoms ofdepression, including pain. This means that Cymbalta® will primarily be prescribed to treat depression, though it is anticipated that it will also be considered off-label for FMS in the future.

MILNACIPRAN: Milnacipran, being developed by Cypress Bioscience, Inc. (NASDAQ SC: CYPB), shares pharmacological profile with TCAs, considered the most effective drugs for treatment of FMS, while appearing to lack the side effects associated with the latter. Unlike Effexor® (venlafaxine) and Cymbalta® (duloxetine), milnacipran is the only dual reuptake inhibitor with more NE than 5-HT activity and it is therefore considered part of a new class of agents known as NSRIs (Norepinephrine Serotonin Reuptake Inhibitors). Milnacipran’s balance of norepinephrine (NE) to serotonin (5-HT) of 3:1, similar to Elavil® (amitriptyline, a tricyclic that has demonstrated efficacy in FMS) which is 1.6:1, as compared to Effexor®, which is 1:30, or Cymbalta®, which is 1:10. In addition, because of milnacipran’s effect on 5-HT, it should also be effective in treating other symptoms such as fatigue, sleep disturbances and depressed mood, which are associated to FMS, as well as other functional somatic syndromes

Milnacipran is currently being evaluated as a potential treatment for FMS in a Phase II clinical trial. Positive preliminary data from the Phase II study was released on December 10, 2002. Of the 95 patients that had completed the trial as of the date of this analysis, 87% of all milnacipran-treated patients reported overall improvement, compared to 33% in the placebo group.

Further, 36% of milnacipran treated patients reported at least a 50% reduction in pain intensity, compared to 9% of patients who received placebo, and milnacipran significantly improved fatigue and depressed mood.

Filing of the NDA for milnacipran for the treatment of FMS is expected in mid to late 2005 and market launch as early as mid 2006. In the long run, Cypress intends to expand the clinical evaluation of milnacipran to other functional somatic syndromes, including Non-cardiac Chest pain, Tension Headaches, some types of Lower Back Pain, Irritable Bowel Syndrome, and Interstitial Cystitis.

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APPENDIX: FMS MEDICATION TREATMENTS

As for many other chronic pain states, antidepressants are the most common form of therapy for patients with FMS. In addition to antidepressants, other drugs commonly prescribed for their analgesic effect in FMS include NSAIDs, antiepileptic drugs, antispasticity agents, muscle relaxants and to some degree opiates. Other compounds such as sedatives and/or hypnotics, although shown to be not effective in treating pain are often used in treating associated symptoms in FMS.

ANTIDEPRESSANTS

Antidepressants are the most common form of therapy for patients with FMS. The majority of antidepressants produce their antinociceptive effect (blockage of pain) by increasing the levels of serotonin (5-HT) and/or norepinephrine (NE),neurotransmitters playing a central role in descending pain-modulation. 5-HT and/or NE levels are increased by either inhibiting the reuptake of the neurotransmitter (thus increasing the concentration of the compound in the synaptic cleft and therefore increasing the neurotransmitter mediated response) or by interfering with the breakdown of the neurotransmitter after its release into the synaptic cleft. One of the differences between the various antidepressant categories is their different preference and activity on the uptake of NE and/or 5-HT. Although the optimal combination of 5-HT and NE modulation is not well defined for FMS or any other chronic pain state, it is perceived as a key component for therapeutic success. Below is a table comparing the relative activity of different antidepressant categories and compounds and their efficacy in FMS.


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SSRIs, with almost pure 5-HT effect and little to no effect on NE show high antidepressant activity and questionableefficacy in pain.

TCAs, with dual reuptake activity and preference for NE, have been proven efficacious in treating chronic pain withsignificant efficacy shown in multiple chronic pain conditions, including fibromyalgia. Unfortunately toxicity andnegative side effects limit their use.

SNRIs, with dual NE/5-HT reuptake inhibitors but preference for 5-HT show good antidepressant activity but only moderate efficacy in pain.

Serotonin Specific Reuptake Inhibitors (SSRIs)
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SSRIs are compounds that specifically inhibit serotonin (5-HT) reuptake. This contrasts with TCAs that nonselectivelyinhibit the uptake of NE and 5-HT, and block muscarinic, histaminic and adrenergic receptors. As a result, SSRIscause less adverse effects than TCAs. Because of SSRIs’ high specificity in blocking serotonin uptake, SSRIs result inhigh antidepressant efficacy and are used to treat FMS when fatigue and mood problems are a major symptom.

However, their lack of NE reuptake effect result in SSRIs not being effective for FMS chronic pain related symptoms.The most common adverse reactions to the SSRIs are gastrointestinal (especially nausea) and neuropsychiatric(particularly headache and tremor).

The major SSRIs compounds include: fluoxetine (Prozac®); paroxetine (Paxil®); sertraline (Zoloft®); and citalopram(Celexa®).

According to Therapeutic Categories Outlook 2002, Paxil® by GlaxoSmithKline (NYSE:GSK), Zoloft® by Pfizer(NYSE: PFE), Prozac® by Eli Lilly & Co (NYSE: LLY), Celexa® by Forest Laboratories (NYSE: FRX), and Effexor®by Wyeth (NYSE: WYE) are the leading anti-depressant drugs in 2002, in terms of revenue, with an estimated revenueof $2.6 billion, $2.4 billion, $1.9 billion, $1.5 billion, and $1.1 billion respectively. GlaxoSmithKline’s Wellbutrin®, AkzoNobel’s (NASDAQ: AKZOY) Remeron®, and Pfizer’s Serzone® follow as other considerable players in the market.

PROZAC®: Eli Lilly’s (NYSE:LLY) Prozac® was the first SSRI to be approved for use in the United States. This medication helps patients with depression by increasing the availability of serotonin in the brain. Prozac® was initiallyapproved for treatment of depression in Belgium in 1986 and in the United States in 1987. Since then, it has beenapproved and marketed in more than 90 countries and used by more than 40 million people worldwide. The Companyhas lost its patent protection, which has resulted in cheaper generics crowding out its once dominating market share.

The safety and effectiveness of Prozac® have been thoroughly studied in clinical trials with more than 11,000 patients.There have been more than 3,500 publications on Prozac® in medical/scientific journals.

Depression is not fully understood, but a growing amount of evidence supports the view that people with depressionhave an imbalance of the brain's neurotransmitters, the chemicals that allow nerve cells in the brain to communicate with each other. Many scientists believe that an imbalance in serotonin, one of these neurotransmitters, may be an important factor in the development and severity of depression. Many scientists believe that Prozac® works by blocking the action of the serotonin uptake pump. When serotonin is released from the "sending" nerve cell, an uptake pump reabsorbs some of it. By blocking the serotonin uptake pump, Prozac® increases the amount of active serotonin that can be delivered to the "receiving" nerve cell. This may help message transmission return to normal. Thus Prozac® may help to correct this imbalance by increasing the brain's own supply of serotonin. While Prozac® cannot be said to "cure" depression, it does help to control the symptoms of depression, allowing many people with depression to feel better and return to normal functioning.

Lilly currently has a once a week dosage form of Prozac®. It is indicated for the continuation treatment of depression in depressed patients stabilized on 20mg Prozac® daily, and is expected to provide depression patients with a simpler option for long-term treatment.

PAXIL®: GlaxoSmithKline’s (NYSE:GSK) Paxil® (paroxetine) is a potent and selective SSRI. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors. This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects. Paxil®, which was introduced to the U.S. market in December of 1992, has been on the market for more than 8 years, achieving worldwide sales of $2.7 billion in 2001, $1.8 billion of which was in the U.S. In April 2002, Glaxo released Paxil CR® a new controlled-release formulation, reformulated using SkyePharmas’ Geomatrix ™ oral drug delivery technology. Over the last year, Paxil® has been riddled with controversy surrounding the potential for serious side effects caused by withdrawal and dependence, which has spawned a number of civil actions against the company – in the UK, USand Canada.

ZOLOFT®: Pfizer’s (NYSE:PFE) Zoloft® (sertraline hydrochloride) is a SSRI that since its approval more than a decade ago, is available in 96 countries. Sertraline HCl is indicated for depression, posttraumatic stress disorder (PTSD), panic disorder (with or without agoraphobia), and obsessive-compulsive disorder (OCD). It has been shown to be safe for long-term use in the treatment of pediatric OCD when used as prescribed. Sertraline HCl is the first and only FDAapproved therapy for the long-term treatment of PTSD.

The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline HCl blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline HCl is a potent and selective inhibitor of neuronal serotonin reuptake but only has very weak effects on norepinephrine and neuronal reuptake.

CELEXA®: SSRI antidepressant Celexa® (citalopram), introduced by Forest Laboratories (NYSE:FRX) in 1998, is still the fastest growing SSRI in the market. Given the recent FDA warning letter to Forest concerning promotional materials for Celexa®, we expect Forest Labs to make a big push for its newest SSRI, Lexapro® (escitalopram oxalate) a single-isomer of Celexa®, recently approved by the FDA August 15, 2002. The recommended dose of Lexapro® is 10 mg daily, which was comparable in a clinical trial to the higher titrated dose of Celexa® at 40 mg daily.

In addition, Lexapro® has longer U.S. patent protection.

Tricyclic Antidepressants (TCAs)

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TCAs have been prescribed since 1950’s to treat depression. They are the oldest antidepressants being used today. Opposite to SSRIs, which preferentially block the reuptake of serotonin (5-HT), TCAs have a norepinephrine (NE) reuptake inhibition preference. Studies have demonstrated that TCAs, particularly those that preferentially block the reuptake of norepinephrine, have superior efficacy to SSRIs in chronic pain states. Therefore, TCAs are the preferred choice for patients with chronic pain, and second choice to SSRIs for patients with major depression with panic disorder, postnatal disorders and patients with psychotic depression. TCAs, unlike many other pain related medicines, which work after a couple of doses, do not work immediately. After one starts using TCAs, it usually takes at least 5 days before a patient feels the effects.

Although TCAs have been proven to be more effective in treating pain, a major symptom of FMS, they tend to have more unpleasant side effects than SSRIs or SNRIs. TCAs, when given in high doses, have been reported to produce arrhythmias, sinus tachycardia and prolongation of the conduction time. Other side effects range from general dry mouth, dizziness, sedation, weight gain, constipation, urinary retention, blurred vision, and nausea to serious cardiovascular side effects such as arrhythmias, which can be fatal. In addition, SSRIs have been found to be far safer than TCAs in overdose.

ELAVIL®: Elavil® (amitriptyline HCI), developed by AstraZeneca (NYSE: AZN) and manufactured by Merck (NYSE:MRK), is a tricylic antidepressant with sedative effects. This medication also carries the names Amitril, Endep, Enovil, Etrafon and Limbitrol. Canada markets it as Apo-Amitriptyline, Levate and Triavil. Elavil® contains NE: 5-HT balance of 3:1, preferentially blocking the reuptake of norepinephrine over serotonin. It is very often prescribed for neuropathic pain – where nerves themselves have been attacked – and is one of the most prescribed antidepressants to treat FMS today.

TOFRANIL®: Mallinckrodt Pharmaceuticals, a Tyco International Ltd. company (NYSE: TYC), purchased from Novartis (NYSE: NVS) four tricyclic antidepressants -- Tofranil® (imipramine HCl, USP) and Tofranil-PM® (imipramine pamoate), Anafranil® (clomipramine HCl), and Pamelor® (nortriptyline HCl, USP). Tofranil® (imipramine) is the prototypic TCA which boosts levels of the nerve impulse transmitters serotonin and norepinephrine.

It is utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. That is, it takes approximately 5 days for the analgesic (pain relieving) properties of this drug to take affect - so a patient takes their prescribed dosage and waits to see if it will help. If a patient is taking the medicine for depression and non-pain problems it usually takes 2-4 weeks to notice the full effect of this medication. Since this drug has painrelieving properties, in addition to depression, the drug is most commonly prescribed to relieve pain from diabetic neuropathy, postherpetic neuralgias, cancer pain, migraine headaches, bed-wetting and sleeplessness.

SINEQUAN®: Pfizer’s (NYSE: PFE) Sinequan® (doxepin hydrochloride) also known as Adapin, Zonalon and Triadapin is a tertiary tricyclic, used in many types of depression. It is effective in treating patients whose depression and/or anxiety is psychological, associated with alcoholism, or a result of another disease (cancer, for example) or psychotic depressive disorders (severe mental illness). It is often used to combat chronic pain in arthritis, diabetes, herpes, migraines, cancer, etc., including FMS.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

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SNRIs are compounds showing dual activity on serotonin and noradrenaline reuptake with lower norepinephrine(NE):serotonin(5-HT) ratio. Studies suggested that SNRIs have higher efficacy than SSRIs in treating depression and chronic pain. Venlafaxine (Effexor®) from Wyeth (NYSE: WYE) and duloxetine (Cymbalta®) from Eli Lilly & Co (NYSE:LLY) are the two notable SNRIs for the treatment of depression. Wyeth’s Effexor® is already on   the market, while Eli Lilly & Co’s high profile Cymbalta® has recently received the approvable letter from the FDA (September 16th, 2002) and will be expected in the market soon.

EFFEXOR®: Effexor® (venlafaxine HCl), a SNRI approved to treat depression and generalized anxiety disorder (GAD), has become the fastest growing therapy option in the US antidepressant market according to IMS National Prescription Audit (NPA) data. It is the first non-tricyclic antidepressant drug in the market to target both serotonin and norepinephrine. The balance of NE:5-HT for Effexor® is 1:30. Effexor® is thought to work by a dual mechanism of action increasing the levels of serotonin and norepinephrine by inhibiting their reuptake and weakly inhibiting dopamine reuptake. Like SSRIs, studies suggest that Effexor® had no significant affinity for muscarinic, histaminergic, or adrenergic receptors. The adverse effects of Effexor® include nausea and dizziness and tend to decrease after 2 to 3 weeks of therapy, suggesting that physiologic adaptation occurs.

The efficacy and safety profiles of Effexor® make it an important first-line therapy for the treatment of depression. In pooled analysis, Effexor® was more effective than certain SSRIs in helping patients achieve remission, or virtual elimination, of their depression symptoms. Data from eight comparable randomized, double blind studies of major depressive disorders were pooled to compare remission rates during treatment with venlafaxine (n=851), SSRIs (fluoxetine, paroxetine, fluvoxamine; n=748) or placebo (four studies; n=446). The results showed that the remission rates were significantly higher with venlafaxine than with an SSRI, with remission rates of 45%, 35%, and 25% for venlafaxine, SSRIs, and placebo respectively.

CYMBALTA®: Cymbalta® (duloxetine) is a SNRI being developed by Eli Lilly & Co. (NYSE:LLY) to treat depression. Following the success of Prozac®, a SSRI, there are high expectations for Lilly’s new SNRI depression entrant. While the most commonly used antidepressants, such as Prozac® only affect serotonin, Cymbalta® enhances the levels of both serotonin (5-HT) and norepinephrine (NE). The balance of Cymbalta®’s NE to 5-HT is 1:10. Lilly submitted its marketing application for Cymbalta® in November 2001, only months after Prozac®'s U.S. marketing exclusivity ended.

Eli Lilly & Co. has received an approvable letter from the FDA for Cymbalta® to treat depression. Approval is contingent upon labeling discussions and resolution of Lilly’s outstanding manufacturing issues. The Company submitted its New Drug Application (NDA) for Cymbalta® in November 2001 with data from five placebo-controlled depression studies and a one-year open label safety study. Thus far, more than 3,000 patients have taken Cymbalta® in clinical trials. Clinical results suggest Cymbalta® 60 mg once daily relieves symptoms of depression, such as low mood, anxiety and physical symptoms like aches and pains, as measured by a commonly used depression rating scale – Hamilton Depression Rating Scale. Patients who took Cymbalta® were up to three times more likely to have complete remission of their symptoms as patients on placebo. Currently, launch of the drug is being held up by the FDA because of manufacturing concerns, which are expected to be resolved sometime in 2003.

Whilst Lilly’s data on duloxetine for FMS has not been released yet, Lilly has stated that they do not intend to pursue registration of Cymbalta® for chronic pain indications, but will continue to do trials in the area to support their market position as an anti-depressant that can also address some of the somatic symptoms of depression, including pain. This means that Cymbalta® will primarily be prescribed to treat depression, though it is anticipated that it will also be considered off-label for FMS in the future.

Norepinephrine Serotonin Reuptake Inhibitors (NSRIs)

 

NSRIs (norepinephrine serotonin reuptake inhibitors) are distinguished from other SNRIs by their preference for norepinephrine (NE) reuptake inhibition over serotonin (5-HT). This profile most closely mimics that seen with certain TCAs such as amitriptyline. While new antidepressants have displaced TCAs for most psychiatric indications, TCAs remain in clinical use in chronic pain states, where they have consistently demonstrated superior efficacy to SSRIs,

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and non-opiate pain medications. Importantly, whilst mimicking the NE preference seen with TCAs, Cypress Bioscience’s (NASDAQ:CYPB) milnacipran, the lead compound under development in this new NSRI category, lacks the other receptor interactions that underlie the side effects of TCAs, and limit their use.

MILNACIPRAN: Milnacipran, the first of this new class of agents known as NSRIs, shares a pharmacological profile with TCAs, considered the most effective drugs for treatment of FMS, while appearing to lack the side effects associated with the latter. Milnacipran’s balance of norepinephrine (NE) to serotonin (5-HT) of 3:1, similar to Elavil® (amitriptyline, a tricyclic that has demonstrated efficacy in FMS) which is 1.6:1, as compared to Effexor®, which is 1:30, or Cymbalta®, which is 1:10. In addition, because of milnacipran’s effect on 5-HT, it should also be effective in treating other symptoms such as fatigue, sleep disturbances and depression, which are associated with FMS, as well as other functional somatic syndromes.

Milnacipran is currently being evaluated as a potential treatment for FMS in a Phase II clinical trial. Positive preliminary data on a Phase II clinical trial was released on December 10, 2002, showing that 87% of all milnacipran-treated patients, as of the date of the analysis reported overall improvement, compared to 33% in the placebo group. Further, 36% of milnacipran treated patients reported at least a 50% reduction in pain intensity, compared to 9% of patients who received placebo, and milnacipran significantly improved fatigue and depressed mood. Filing of the NDA for milnacipran for the treatment of FMS is expected in mid to late 2005 and market launch as early as mid 2006. In the long run, Cypress intends to expand the clinical evaluation of milnacipran to other functional somatic syndromes, including Non-cardiac Chest pain, Tension Headaches, some types of Lower Back Pain, Irritable Bowel Syndrome, and Interstitial Cystitis.

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OTHER TREATMENTS FOR SYMPTOMS OF FMS:

There are other drugs that are prescribed to treat certain symptoms of FMS, such as pain or insomnia. Below is a selection of the most commonly prescribed compounds to treat such symptoms of FMS.

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ULTRAM®: JOHNSON & JOHNSON (NYSE: JNJ) Ultram® (tramadol HCl) is a centrally acting synthetic opioid analgesic. Indicated for the management of moderate to moderately severe chronic pain, Ultram® was approved in March 1995. Analgesia in humans begins approximately within one hour after administration and reaches peak levels in approximately two to three hours. While the mode of action of Ultram® is not completely understood, laboratory studies suggest that at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to µ- opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Although different from other opioid analgesics, such as codeine or morphine, Ultram® administration may produce a constellation of symptoms apart from analgesia (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. Tramadol has been prescribed in more than 21 million patients in the United States and 55 million patients worldwide. Ultram® sales reached $650 million in 2001.

VICODIN®: ABBOTT LABORATORIES (NYSE: ABT) Vicodin® combines hydrocodone, a narcotic (semi-synthetic opiate) pain medication (analgesic), and acetaminophen (a non-narcotic analgesic) for the relief of moderate to moderately severe pain. As other narcotic pain relievers, Vicodin®’s role in fibromyalgia is to temporarily relieve an exacerbation of FMS pain. Hydrocodone acts on the central nervous system and smooth muscle tissue, slowing the central nervous system. It is not clear exactly how acetaminophen works to ease pain. Vicodin® was approved by the FDA in 1982.

Other names for this drug combination include: Vicodin ES, Vicodin HP, hydrocodone apap 5/500, Anexsia, Co-Gesic, Hydrocet, Lorcet, Lortab, Maxidone, Norco, Stagesic, Ugesic, Vendone, Vanacet, Zydone.

NEURONTIN®: Discovered and developed by Warner-Lambert, which merged with Pfizer Inc. (NYSE: PFE) in 2000, Neurontin® (gabapentin) was first approved by the FDA in 1993 as an add-on treatment for partial epileptic seizures (the type in which symptoms are limited). In May 2002, Neurontin® became the first oral medication approved in the U.S. for postherpetic neuralgia (pain in the area affected by herpes zoster). Neurontin also is approved in more than 50 countries for the adjunctive treatment of epilepsy and for a range of neuropathic pain conditions.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not interact with GABA receptors, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin’s mechanism of action in the human brain is not definitively known, but it is thought to act by blocking certain ion channels in nerve cells. Neurontin® is the number one anti-epileptic drug worldwide. In 2001, sales increased by 31% to $1.8 billion. Pfizer has been accused of aggressively marketing the medication for more than a dozen medical conditions for which it is not approved. In July 2001, the FDA released a warning letter to Pfizer objecting to the Company's promotional materials for the drug.

PREGABALIN: Pfizer Inc. (NYSE:PFE) Pregabalin is a derivative of gabapentin (Neurontin®). The product is in Phase III clinical trials, including for the treatment of epilepsy, neuropathy, and anxiety disorders. Pfizer plans to file pregabalin for approval for neuropathic pain, epilepsy add-on therapy, and generalized anxiety disorder in 2003.

Subsequent filings could be pursued in the future, including social anxiety, panic disorder, fibromyalgia, and epilepsy monotherapy. Pregabalin has the potential to become an important billion-dollar brand for Pfizer. Pfizer has been developing pregabalin as a successor to its anticonvulsant medicine Neurontin. In October 2002, at the annual meeting of the American College of Rheumatology, Pfizer presented data on a clinical trial on pregabalin for the treatment of FMS. Pregabalin achieved statistical significance on the primary endpoint of global pain (29% of pregabalin-treated patients reported at least a 50 percent reduction in pain, compared with 13% of patients who received placebo) and significantly improved sleep quality and fatigue.

Whilst it is expected that Pregabalin enter the market with an anticonvulsant and anti-anxiety label, it could become the first compound to market with a "fibromyalgia" label, expected towards the end of 2004 and it is expected, as Neurontin® is, to be used as an adjunct therapy and not as monotherapy.

CYCLOBENZAPRINE (FLEXERIL®): Cyclobenzaprine is a muscle relaxant which shares structural and pharmacological similarities with TCAs. Cyclobenzaprine is prescribed to relieve muscle spasms resulting from injuries such as sprains, strains, or pulls. Combined with rest and physical therapy, cyclobenzaprine provides relief of muscular stiffness and pain. Cyclobenzaprine is not useful for pain that is not caused by sprains or strained muscles, though it is sometimes prescribed for the treatment of chronic muscle pain associated with fibromyalgia. ALZA Corporation (NYSE: AZA) acquired the rights for Flexeril® from Merck in February 2001 and will be producing a long acting version of the drug.

Flexeril® was first introduced in the US in 1977 and is currently a generic product. With over 30 million prescriptions written on an annual basis in the US, cyclobenzaprine has been the most commonly prescribed therapeutic agent for the treatment of muscle spasms.

On October 28, 2002, Vela Pharmaceuticals Inc., a privately held pharmaceutical company announced the successful completion of its Phase II study of very-low dosage cyclobenzaprine on subjects suffering from fibromyalgia syndrome and poor sleep. In this study, subjects received either very-low dosage cyclobenzaprine (1--4 mg, taken as a single dose before bedtime), or placebo for eight weeks. Results indicate that, compared to placebo, very-low dosage cyclobenzaprine dramatically reduced musculoskeletal pain and fatigue, and improved sleep. No serious adverseevents were reported throughout the study.

ZANAFLEX®: Elan Corporation, plc (NYSE: ELN) Zanaflex® (tizanidine) is an agent indicated for the management of increased muscle tone associated with spasticity, a condition affecting the central nervous system ("CNS") causing muscle stiffness and rigidity. Spasticity can occur as a result of many CNS disorders, particularly multiple sclerosis and spinal cord injury. Tizanidine, as an alpha-2 agonist combines sedation with analgesia and is thought to be useful in the treatment of numerous chronic pain syndromes, including FMS. Alpha-2 agonists are unique because of their muscle relaxation properties and because they are non-addictive. Approved in December 1996, brand sales of

Zanaflex(R) tablets were approximately $150 million for the year-ended December 2001. Generic equivalents of Zanaflex(R) brand tablets are marketed by Alpharma Inc.,Teva Pharmaceutical Industries Limited, Eon Labs, and Par Pharmaceuticals, Inc.

CELEBREX®. Pharmacia (NYSE: PHA) and Pfizer Inc. (NYSE: PFE) Celebrex® (celecoxib) is the first of a new type of nonsteroidal anti-inflammatory drugs (NSAIDs) which preferentially inhibit the COX-2 versus COX-1 enzymes, thereby carrying a much lower risk of gastrointestinal side effects. Other NSAIDs, such aspirin, ibuprofen and naproxen, are nonspecific and inhibit both COX-1 and COX-2 enzymes. As a result, they have the desired effect of treating pain and inflammation but also may damage the stomach lining and lead to ulcers. Celebrex® was approved by the FDA in December 1998 for the relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis, and in October 2001 for the management of acute pain and primary dysmenorrhea (menstrual pain) in adults. Celebrex® is number one selling prescription arthritis brand worldwide and achieved sales of $3 billion in 2001.

INSOMNIA

Typical drugs prescribed as sleep aid to treat insomnia associated to FMS include benzodiazepines, the most widely prescribed compounds in the treatment of Generalized Anxiety Disorder (GAD). GAD, a psychiatric disorder with some symptoms similar to those of FMS, is characterized by chronic and excessive worry and tension as well as physical symptoms such as poor sleep, fatigue, and restlessness. Other compounds often prescribed to treat insomnia associated to FMS include non-benzodiazepine hypnotics, antihistamines, and antidyskinetics. Below is a selection of the most commonly prescribed compounds for insomnia associated with FMS:

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KLONOPIN®: Roche (PNK: RHHBY.PK ) Klonopin® (clonazepam) is a benzodiazepine primarily used in the treatment of seizure and anxiety disorders. This drug may also be used to treat movement disorders, Restless Leg Syndrome, relieve trigeminal neuralgia, atypical, akinetic, myoclonic, or absence seizures, etc. The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of GABA. Clonazepam was approved by the FDA in 1975 and it is also one of the top 200 drugs prescribed in the United States.

XANAX®: PHARMACIA (NYSE:PHA) Xanax® (alprazolam) is a benzodiazepine indicated for the treatment of Generalized Anxiety Disorder, as well as the management of panic disorder with or without agoraphobia. Alprazolam is commonly prescribed for the management of the anxiety and insomnia typical of FMS. Alprazolam is often preferable to other benzodiazepines, such as chlordiazepoxide, clorazepate, and prazepam, because alprazolam has a relatively shorter half-life and does not have active metabolites that can lead to accumulation, particularly in the elderly. Alprazolam was approved by the FDA in 1981 and became available as a generic in 1993.

AMBIEN®: SANOFI-SYNTHELABO, Ambien® (zolpidem tartrate) is a non-benzodiazepine hypnotic from a newer group of drugs called imidazopyridines. Launched in France in 1988 under the tradename Stilnox®, and in the US in 1993, where it is marketed by Lorex, a joint-venture between Sanofi and Pharmacia Corp., Ambien is used primarily for shortterm treatment of insomnia in adults with a selective hypnotic action lasting for six to seven hours. Though chemically different from benzodiazepines, Ambien acts as an agonist binding with high and low affinity to BZ1 and BZ2 benzodiazepine receptor subtypes, respectively. In contrast to benzodiazepines, Ambien® has the advantages of having almost no adverse effects such as daytime loss of memory and attention as well as a minimal risk of dependency. In 2001, Ambien®/Stilnox® generated €215 million in revenue, expected to reach €1.9 billion in 2005.

MIRAPEX®. Pharmacia (NYSE: PHA) Mirapex® (pramapexole) is a dopamine agonist indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease. Mirapex® is commonly used off label for the treatment of Restless Leg Syndrome (RLS). RLS, and its cousin, periodic limb movements during sleep (PLMS) occur in roughly 50% of FMS patients. Mirapex® 2001 sales totaled $148 million.

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DISCLOSURES

RATINGS: Griffin Securities, Inc. has no investment ratings on any of the companies mentioned in this report except from Cypress Bioscience, Inc. rated BUY.

MARKET MAKING: Griffin Securities, Inc. does not maintain a market in the shares of any of the companies mentioned in thisreport.

The information herein was obtained from various sources; we do not guarantee its accuracy or completeness. ADDITIONAL

INFORMATION AVAILABLE UPON REQUEST. No part of this material may be (i) copied, photocopied, or duplicated in any form

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© Griffin Securities, Inc. 2002. All rights reserved.

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