Long-awaited FDA decisions on pain therapeutics

Approximately 9% of the US population suffers 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 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.

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 has long been 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. Although Pregabalin has been approved in the EU, safety concerns have severly delayed the FDA decision.

On Sept 2 however, Pfizer announced that US regulators had approved pregabalin if certain conditions are met.

Pfizer said the FDA had issued "approvable letters" indicating the drug, Lyrica, could be approved for partial seizures in adults, neuropathic pain caused by diabetes and pain following herpes infections, if the agency's conditions are met. The FDA however issued a "non-approvable letter" for use of the drug to treat generalized anxiety disorder, which makes approval for that indication less likely in the foreseeable future.

A company spokesman said he was not able to specify the FDA's conditions for approval or other details involving the agency review of pregabalin which Wall Street expects to become a blockbuster treatment if it wins final approval. "This is certainly not positive," said David Moskowitz, an analyst for Friedman, Billings, Ramsey, who added that his 2004 pregabalin revenue projection of $130 million was now at risk. "The fact that they got a non-approvable letter for generalized anxiety disorder is a negative since Lyrica was expected to get approved for all the off-label indications that Neurontin is being used for," Moskowitz said. SG Cowen analyst Steve Scala had estimated Lyrica would generate sales of $500 million in 2005, growing to $2 billion by 2008. But those numbers may now be revised downward. Other analysts including Sena Lund, at Cathay Financial were more upbeat commenting "At least it shows Pfizer is on track to get pregabalin out of the FDA and get it to market". Investors did not seem overly concerned by the apparent setback, moving Pfizer shares 1% higher on Thursday. Pfizer closed up 35 cents at $32.70 on the New York Stock Exchange. [More on this story]

A few days later on Sept. 7 Lilly announced that FDA has approved their neuropathic pain treatment, the antidepressant Cymbalta (duloxetine), judging it safe and effective for the management of diabetic peripheral neuropathic pain.

This announcement means that Lilly has beaten Pfizer to the post, with Cymbalta becoming the first FDA-approved treatment for pain caused by diabetic peripheral neuropathy. This approval came after a six-month priority review. This is the second time in a month that the FDA has judged Cymbalta, a balanced and potent serotonin and norepinephrine reuptake inhibitor, a safe and effective therapy for a major medical disorder. On Aug. 3, the agency approved Cymbalta as a treatment for major depression in adults. With the global antidepressant market valued at $16.6 billion in 2002, drugs for the treatment of depression have historically provided huge returns on investment. Several of the leading brands are expecting patent expiries over the next five years and the approval of Cymbalta for this indication means a predicted revenue of $2.1 billion by 2011. It's available immediately by prescription in pharmacies across the United States for the treatment of major depression or pain associated with diabetic peripheral neuropathy.

Lilly proved Cymbalta's safety and efficacy in the treatment of pain caused by diabetic peripheral neuropathy at doses of 60 and 120 mg per day in two randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in non-depressed adults who had the disorder for at least 6 months. Although both doses were safe and effective, 120 mg was not as well tolerated as 60 mg per day. In both studies, Cymbalta significantly reduced 24-hour average pain, compared with placebo. Improvements were noted as early as the first week of treatment and continued for the duration of the studies. In addition, Cymbalta showed rapid onset of action and sustained effect in reducing pain caused by diabetic neuropathy at both 60 mg per day and 120 mg per day, and was effective in relieving pain at night. Nighttime pain is especially troublesome to many patients with diabetic neuropathy, because it can interfere with sleep. [More on this story].