Clinical data further demonstrates the efficacy of Pfizer's pregabalin (Lyrica) in the treatment of diabetic neuropathic pain

Approximately 9% of the US population suffer from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. This condition precipitates other serious pathologies such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide. Since chronic pain is notoriously difficult to treat using currently available therapeutics, the development of analgesics has represented a major pharmaceutical objective.

The origins of pain range from nociceptive (caused by tissue injury or inflammation) to neuropathic. Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments.

Neuropathic pain represents a problem associated with a wide variety of conditions including trauma, HIV infection, shingles, diabetes, immune disorders, and toxic neuropathies (for example following treatment with chemotherapeutics). The drug development community is starting to approach the various sub-types of neuropathic pain as separate etiologies in order to facilitate entry into this massive market and also in an attempt to improve therapeutic efficacy.

In the absence of specific treatments of neuropathic pain this market has been led by Pfizer's gabapentin (Neurontin). Gabapentin was originally approved by the FDA as an anti-convulsant for use in the treatment of epilepsy, and in 2003 it led the global anti-convulsant market with global sales across all indications of over $2.7 billion. This represented 19% growth compared to 2002 sales. It is however estimated that a significant proportion of gabapentin's sales are for neuropathic pain indications despite never receiving official approval for this indication in the US apart from postherpetic neuralgia. Diabetic neuropathic pain, a key symptom of diabetic neuropathy caused by chronic glycemia affects over 3.7 million patients in the US alone and represents one of the major off-label uses of gabapentin. This situation is about to change as result of two key events.

Firstly, Ivax recently received final approval of its abbreviated new drug application for gabapentin tablets from the FDA in April, 2004. Pfizer has attempted to prevent IVAX from selling gabapentin however legal appeals were blocked by US courts and IVAX went to market earlier this month. Secondly, in July, 2004, Pfizer won EU approval to market the follow-up to gabapentin, pregabalin (Lyrica) for the treatment of peripheral neuropathic pain and as an adjunctive therapy for partial seizures in patients with epilepsy. This drug is currently undergoing review by the FDA for the management of neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia, as adjunctive therapy for partial seizures, and for the treatment of generalized anxiety disorder (stop press...click here for Sept 2nd press release).

Like gabapentin, pregabalin, a 3-substituted analogue of gamma-amino butyric acid (GABA) binds to calcium channels and modulates calcium influx as well as influencing GABergic neurotransmission. This mode of action translates into anti-epileptic, analgesic and anxiolytic effects. Because it is more potent than gabapentin, pregabalin achieves efficacy at lower doses. This increases its therapeutic index with respect to gabapentin and should lead to fewer dose-related side effects.

Pregabalin is currently under review by the FDA for the management of neuropathic pain associated with diabetic neuropathic pain, shingles, as adjunctive therapy in the treatment of partial seizures, and for the treatment of generalized anxiety disorder in adults. US approval has however been severely delayed following safety concerns in animal models although the approval of pregabalin in the EU makes approval in the US all the more likely. In the meantime, the clinical experience gathered in Europe will help raise pregabalin profile and assist its uptake in the US. Likewise, data published in this month's edition of the journal Pain should also influence the FDA decision making process.

This randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) published by Rosenstock et al evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy. One hundred forty-six patients with a 1- to 5-year history of diabetic peripheral neuropathic pain were randomized to receive placebo or pregabalin 300 mg/day.

Compared to placebo, pregabalin produced significant improvements in the primary end-points, mean pain scores as well as sleep interference an effect of neuropathic pain that exacerbates the overall condition. In addition to altering these primary measures a number of secondary measures including other indices of pain, subjective assessment of treatment, and mood also improved. Pain relief and improved sleep began within 1 week and remained throughout the study. Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. The authors concluded that pregabalin is safe and effective in decreasing pain associated with diabetic neuropathic pain, and also improved mood, sleep disturbance, and quality of life.

These data as well as preliminary data from an open label study which demonstrated the durability of response over a 12-month period add to the escalating confidence in pregabalin and it is likely that Pfizer will enjoy first-to-market status (for diabetic neuropathic pain) with its expected launch during 2004. With the entrance of generic gabapentin to the market, the approval of pregabalin for indications such as diabetic peripheral neuropathic pain will allow Pfizer to differentiate its follow-up product from generic gabapentin and will be key to Pfizer protecting its pole position in the anticonvulsants market. Furthermore, with diabetes reaching epidemic proportions due to the increasing levels of obesity, and further indications expected, pregabalin has a major opportunity to provide Pfizer with equal or even higher revenues than its predecessor.

Entry date Friday, September 03, 2004

Adapted from Rosenstock et al, Pain. 2004 Aug;110(3):628-38.