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Clouded vision

Long confusion over defining fibromyalgia has meant slow development of drugs

A lone tree in a field surrounded by fogUp until 1492, the world was flat, and prior to 1990 fibromyalgia did not exist. Why? Because, until then, its reality had not been measured. There is no doubt now that the world is round, but how certain are we about the existence of fibromyalgia?

"Fibromyalgia" has troubled many of the world's population for centuries: it is a syndrome of idiosyncratic symptoms commonly involving pain, debilitating fatigue, sleep disturbances and a general reduction in quality of life. Collectively, these symptoms have been known as Gulf War Syndrome, "Yuppie Flu" and Chronic Fatigue Syndrome, among others. Diagnosis of the disorder has been controversial and usually assigned by default rather than fulfilling a discrete set of criteria. Management has been no more precise, as the symptoms often mimic rheumatic conditions without the accompanying abnormal laboratory parameters.

However, in 1990, the American College of Rheumatology officially "adopted" the disorder and proposed what has become the most widely accepted set of diagnostic criteria for the disease now known as fibromyalgia. It has been estimated that up to one third of patients seen by a rheumatologist will fulfil these criteria. They will typically fall into the 20- to 40-year age bracket and will be more commonly female. Interestingly, a definitive diagnosis of fibromyalgia using these criteria is still considered controversial, even by Frederick Wolfe, who initially defined the criteria. Nevertheless, their introduction in 1990 initiated a wave of positive research that has helped to unravel the complex mental/physical aetiology of fibromyalgia, which is reflected in the current pharmaceutical approach to its management.

Currently, there are six drugs under active phase II or III clinical investigation worldwide. The individual mechanisms of action vary, but the approach appears to be similar, in that all are directed at modulating centrally- and peripherally-acting neurotransmitters.

It appears that not only is the diagnosis of the disease fraught with controversy but so, too, is its management.

The pathway to approval has been difficult, with only a few drugs available for patients today. Indeed, there appears to be a "transatlantic" difference between the likelihood of approving drugs for use in fibromyalgia. This was echoed in a recent on-line forecast relating to the disease from Reuters. This report suggested that the US market offered the greatest potential for market growth in all current and future drugs indicated for use in fibromyalgia across the seven major markets. This is an important factor considering the prediction that the fibromyalgia market will double within the 10 years ending in 2018.

Looking at the drug development pipeline, it is obvious that the US leads the race in developing and marketing drugs for fibromyalgia.

This is illustrated by the recent milestones achieved for pregabalin, a member of the Pfizer Global Research and Development portfolio, and perhaps the most promising individual agent currently available.

Pregabalin capsules became the first US FDA-approved drug for the treatment of fibromyalgia in June 2007. Later, in May 2009, it was also launched in Canada for the treatment of pain associated with the disease. This was in contrast to the decision made earlier by the Committee on Medicinal Products for Human Use (CHMP) of the European Agency for the Evaluation of Medicinal Products (EMEA). In April 2009, they issued a negative opinion recommending non-approval of pregabalin oral capsules for the additional indication of fibromyalgia.

The CHMP concluded that the benefits of the agent in the treatment of fibromyalgia did not outweigh its risks, even though the adverse events data from phase III trials of the agent did not suggest evidence of any serious pregabalin-related adverse events.

Despite this negative response in Europe, a separate Japanese phase III trial was initiated in March 2009. This study is comparing pregabalin with placebo over 15 weeks in approximately 498 patients and the estimated completion date is September 2011.

 

Recently launched products

 

Generic name Trade name (company) Indication Country
Benzoyl peroxide Benzefoam (onset Therapeutics) Mild to moderate acne vulgaris US
Ibuprofen (IV preparation)  Caldolor
(Cumberland Pharmaceuticals)
Pain and fever  US
Levonorgestrel  Plan B One-step
(Teva Pharmaceuticals)
Emergency contraception  US
Morphine sulfate + naltrexone hydrochloride EMBEDA (King Pharmaceuticals) Moderate to severe chronic pain  US
Oxycodone hydrochloride OxiNorm powder 0.5% (Shionogi) Cancer pain  Japan
Trospium chloride Regurin XL
(Speciality European Pharma) 
Overactive bladder  UK
Ulipristal acetate ellaOne (HRA Pharma) Emergency contraception  France, Germany, UK
Vinorelbine  Sagent Pharmaceuticals) Advanced non-small cell lung cancer  US
Zolpidem Tartrate  EDLUAR (Meda) Insomnia US

 

Pregabalin is a calcium channel α-2-δ protein (CACNA2D1) ligand and a structural analogue of GABA. It modulates voltage-gated calcium channels in the CNS, and has the potential to treat a range of neurological, pain and psychiatric disorders and would seem fitting for the symptoms encountered in fibromyalgia.

A parallel path through the pipeline has been followed for duloxetine. It, too, has been more warmly received in the US than in the EU: in June 2008 it was approved by the US FDA and, as an orally active serotonin/norepinephrine re-uptake inhibitor (SNRI), is currently the only drug of its class to be available in the US market for managing fibromyalgia.

However, in October 2008, duloxetine was refused a change of marketing authorisation to include fibromyalgia by the CHMP of the EMEA.

A couple of agents further down the pipeline, under phase II investigation, have demonstrated how difficult it is to translate therapeutic efficacy in symptoms of one disease to those encountered in this notoriously difficult-to-treat fibromyalgia syndrome.

Rotigotine is a well-launched drug for Parkinson's disease and was under clinical investigation by Aderis Pharmaceuticals and Schwarz Pharma as a transdermal patch for fibromyalgia. However, it failed to achieve statistical significance for the reduction in pain (primary endpoint) associated with the disease.

The fate of Schwarz Pharma's lacosamide in fibromyalgia, however, remains to be seen. In October 2006, the company initiated a phase IIa trial of the agent and, although the trial was completed in February 2008, with promising initial results from this double-blind trial reported the same year, the information trail appears to end there. No further reports have been identified in relation to clinical investigation in this patient population, even though this selective sodium channel modulator has already been launched in the UK, Germany and the US as adjunctive therapy in patients with epilepsy.

Two other agents appear to be successfully surfing through the pipeline and data from each are scheduled to emerge in 2010.

AGN·203818 is under investigation in the US, where Allergan is conducting a two-part placebo-controlled study including 650 patients. In each study part, the drug is given twice daily at dosages of 6 to 120mg/day over four weeks (part one) or 40 to 320mg/day over 12 weeks (part two), with the reduction in daily pain scores as the primary endpoint for both.

AGN·203818 is an orally active, α-adrenoreceptor agonist that was discovered as part of a research programme between Allergan and ACADIA.

Development of droxidopa appears to be focused on co-adminstration with an already established drug – carbidopa. Droxidopa is an orally active synthetic precursor of norepinephrine (NE); it can penetrate the blood-brain barrier and provide both peripheral and central effects on circulating NE levels. The hypothesis is that carbidopa will limit the peripheral metabolism of droxidopa into NE before it crosses into the brain, thus promoting a greater central effect in those patients receiving combined therapy and allow lower doses of droxidopa to be used.

Chelsea Therapeutics has initiated a trial in the UK and intends to enrol approximately 120 patients with fibromyalgia to investigate the analgesic effects of droxidopa and carbidopa given alone and in combination over a nine-week period.

The current activity in the pipeline regarding drugs focused on managing fibromyalgia reflects not only the nebulous nature of the disease, but also the reluctance in recognising it as a separate disease state. If the forecast relating to the increasing worldwide prevalence of the disease comes to fruition, the EU may find it has missed the marketing boat.

The Author
Pipeline was written by Wendy McNeely of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Kuljeet Sohanpal on =44 (0)20 7981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com
To comment on this article, email pm@pmlive.com

23rd November 2009

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