Pfizer’s Pride-And-Joy Pain Drug Lyrica Slips In Two New Phase III Trials

One failed study tested Lyrica in a subset of difficult-to-treat patients in the approved indication of diabetic neuropathy, while another explored its use in neuropathic pain related to HIV.

Pfizer Inc.’s attempt to further elucidate the value of its blockbuster pain drug Lyrica (pregabalin) and to explore opportunities for new uses suffered dual setbacks with reports of two failed Phase III trials.

The drug, itself a follow-on to Pfizer’s now-generic Neurontin (gabapentin), is already a successful example of lifecycle management. It has four FDA-approved indications: partial onset seizures in adults with epilepsy, post-herpetic neuralgia, neuropathic pain associated with diabetic peripheral neuropathy, and fibromyalgia. In Europe, Lyrica is approved for neuropathic pain, epilepsy and generalized anxiety disorder.

The drug had almost $3.7 billion in sales for 2011, up 21% from 2010, making it the second best-selling drug in Pfizer’s portfolio after Lipitor (atorvastatin), which had $9.6 billion in sales for 2011 and lost exclusivity in the U.S. in November.

Feeling the sting of the Lipitor loss, among other factors, Pfizer recently announced that first-quarter revenues for 2012 were down 7% to $15.4 billion, but pointed to sales growth for Lyrica and other established products (Also see "Pfizer Downplays Risk Of Tofacitinib Panel Review As It Pushes Focus On Innovation" - Pink Sheet, 2 May, 2012.). First-quarter 2012 sales for Lyrica reached $955 million, up by 16% from the same period in 2011.

Much of the product’s continued growth has come from the addition of new indications – and Pfizer has continued to aggressively pursue new uses. But, the drug stumbled in two just-announced Phase III studies.

Based on input from an interim analysis by an external data monitoring committee, Pfizer has terminated the randomized, double-blind A00812244 study of Lyrica in patients with neuropathic pain associated with HIV neuropathy, the company announced May 4.

The study was set to randomize 416 patients to the drug or placebo, with an assessment planned at the mid-way enrollment point. The primary endpoint was improvement in pain, based on pain scores recorded in patient diaries. At the time of an interim analysis, when a total of 246 patients were enrolled, it was revealed that “improvements in neuropathic pain symptoms in this study were virtually identical between the Lyrica and placebo treatments,” Pfizer reported. There were no safety concerns in the DMC review, the company added.

Pfizer attributed the poor results to the “complexities of studying pain, particularly in a difficult-to-treat condition such as neuropathic pain associated with HIV neuropathy, for which there are no approved medications in the United States.”

NeurogesX Inc. has been targeting neuropathic pain in HIV with its Qutenza (capsaicin 8% patch). FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted against approval of the product in February, but opened the door for clearance in the future if the drug is studied successfully in a trial with a more appropriate design (Also see "Trial Design For NeurogesX’s Qutenza Pain Patch Should Exclude Opioids, Committee Suggests" - Pink Sheet, 13 Feb, 2012.).

Performance Disappoints In Tough To Treat

The second study reported by Pfizer – the Phase IIIb A0081242 trial – missed the mark in patients who had been inadequately treated for diabetic peripheral neuropathy. The protocol did not specify prior treatments, but other options in neuropathic pain include gabapentin (Pfizer’s Neurontin and generics) and Endo International PLC’s Lidoderm (lidocaine patch). Controlled-release, once-daily formulations of gabapentin are also available. Commenting on Lyrica sales in its annual report for 2011, Pfizer acknowledged that US revenues “continue to be affected by increased competition from generic versions of competitive medicines, as well as managed care pricing and formulary pressures.”

In the study, patients who had inadequate pain control while receiving medications were switched to Lyrica (150 mg or 300 mg/day) for a six-week, single blind, phase-in period. Those who achieved a minimum level of pain relief, defined as a 30% improvement, were then randomized to placebo or continued treatment with Lyrica for a 13-week, double-blind treatment phase. Out of 665 tested in the single-blind phase, 294 had at least a 30% improvement in pain control and were randomized for continued treatment with Lyrica or to placebo. Those in the Lyrica arm improved in terms of the primary endpoint of change in pain score relative to baseline, but there was no statistically significant difference compared to placebo.

Looking ahead, the drug could still expand in other indications and formulations. Lyrica is currently under review in the U.S. for central neuropathic pain due to spinal cord injury and a once-daily, controlled-release formulation of the drug is in Phase III, according to the company’s pipeline. For the FDA-approved indications, Lyrica is currently given in two or three divided doses daily.

Pfizer announced in December 2011 that the drug had positive results in a 12-month Phase III study of 700 patients with restless legs syndrome.

The clinicaltrials.gov website lists 14 open, industry-funded Phase III trials for pregabalin, with indications including frequent muscle cramp in patients with liver cirrhosis, partial onset seizures in children, fibromyalgia with comorbid depression and management of patients undergoing total hip replacement.

The drug is due to go off patent in December 2018 in the U.S. and July 2014 in Europe.