- Category: Mitochondrial & Neuropathy
- Published on Tuesday, 14 February 2012 00:00
- Written by Liz Highleyman
An advisory committee of the U.S. Food and Drug Administration (FDA) last week unanimously voted against approval of a capsaicin patch for relief of HIV-related neuropathy pain, due to insufficient evidence of its effectiveness.
An advisory committee of the U.S. Food and Drug Administration (FDA) last week unanimously voted against approval of a capsaicin patch for relief of HIV-associated peripheral neuropathy pain, due to insufficient evidence of its effectiveness.
Peripheral neuropathy, or nerve damage, is characterized by pain, burning, or tingling in the extremities, primarily the feet. It is common among people with HIV, especially those who took older antiretroviral drugs including didanosine (ddI; Videx) or stavudine (d4T; Zerit). Current management strategies -- including opiate drugs, SSRI antidepressants, anticonvulsants, and medical cannabis -- are only partially effective and can have undesired side effects.
Capsaicin, derived from hot peppers, interrupts pains signaling and perception. An 8% capsaicin patch, marketed as Qutenza by San Mateo-based NeurogesX, is FDA-approved for management of post-herpetic or shingles pain. At the hearing on February 9, the FDA's Anesthetic and Analgesic Drug Products Advisory Committee considered whether the patch should also be approved for HIV-related neuropathy.
This multinational, double-blind trial included 494 adult participants with painful HIV-associated distal sensory polyneuropathy. Most (about 90%) were men and the average age was approximately 50 years. They had well-controlled HIV, with a mean CD4 T-cell count of 400-500 cells/mm3. Average duration of neuropathy pain was 5-6 years. Those taking other medications for neuropathy pain had to be on stable doses for at least 3 weeks before and throughout the study.
Participants were randomly assigned to use either the 8% capsaicin patch (known as NGX-4010) or a .04% strength patch as an "active control," after applying an anesthetic cream. The low-dose patch was used instead of a completely inactive patch because the patch itself can cause pain or irritation at the application site that could have given away the patients' blinded assignments.
Participants used their assigned patch on both feet for either 30 or 60 minutes (the other Phase 3 trial also tested a 90-minute application). They reported pain levels during the prior 24 hours using the standardized Numeric Pain Rating Scale. The primary endpoint was the mean percent change from baseline through week 12.
- Overall, painreduction did not differ significantly between the 8% patch group and the active control group (-29.5% vs -24.5%, respectively; P = 0.097).
- Paid reduction was greater in the 60-minute versus 30-minute control group (-30.0% vs -19.1%), suggesting the active control patch had some effect, and interfering with some planned comparisons.
- Reported pain reduction was greater in the 30-minute 8% patch group compared with the 30-minute control group, but the difference did not reach statistical significance (-26.2% vs -19.1%, respectively; P = 0.103).
- Pain reduction in the 60-minute 8% patch group and control group was similar (-32.8% vs -30.0%, respectively; P = 0.488).
- Significantly more participants in the overall and 30-minute 8% patch groups reported improvement on the patient global impression of change scale compared with their corresponding control groups (67% vs 55%; P = 0.011 and 65% vs 45%; P = 0.006).
- Treatment was safe and generally well tolerated.
- The most common adverse event was transient mild-to-moderate pain and erythema (redness) at the patch application site.
- Severe application site reactions were more common in the 8% capsaicin group compared with the control group (19% vs 2%, respectively), and among 60-minute compared with 30-minute 8% patch recipients (24% vs 14%, respectively).
Based on these findings, the study authors concluded, "Although the primary endpoint analyses were not significant, trends toward pain improvement were observed after a single 30-minute NGX-4010 treatment."
"Interpretation of the study was complicated by the use of concomitant medications with real or potential analgesic benefit and by the skin irritation and strong placebo effects caused by the application of long duration placebo patches," they elaborated in their discussion. "Given these results, its unique mode of action and efficacy in other neuropathic pain syndromes and further evaluation of NGX-4010 as a nonnarcotic treatment modality to address HIV-associated peripheral neuropathy should be considered."
FDA Committee Decision
The FDA advisory committee signaled its hesitancy in an advance briefing document released February 7. "It would not be in the best interest of these patients for us to approve a product for which substantial evidence of efficacy has not been demonstrated, or one for which the benefits do not clearly outweigh the risks," it stated.
As described in a companion article by patient advocate Matt Sharp, who participated in the advisory committee, the panel was restricted in the type of evidence it could consider.
Even though some of the study data were promising, the trial did not meet its primary endpoint -- that is, it did not show what it initially set out to demonstrate. Key outcome differences between the groups did not reach statistical significance, meaning they could have been due to chance. Finally, the fact that all patients used at least a very low dose of capsaicin, and some used additional pain medications, may have minimized or masked the true treatment effect.
The full FDA is not required to abide by the advisory committee's recommendation, it usually does so. According to a press release issued by NeurogesX, the agency's decision under Priority Review status is expected by March 7, 2012. Physicians currently may prescribe Qutenza off-label as they see fit, but insurance companies often do not pay for unapproved indications.
"We will continue to work closely with the FDA to address the Advisory Committee's comments as the agency finalizes its review of our supplemental new drug application," said Ronald Martell, CEO and President of NeurogesX. "We remain confident that Qutenza has the potential to address significant, unmet medical needs and to improve the quality of life for patients with HIV-peripheral neuropathy."
Investigator affiliations: Department of Neurology, Washington University School of Medicine, St. Louis, MO; Department of Neurology, Mount Sinai School of Medicine, New York, NY; AIDS Research Alliance, Los Angeles, CA; Chelsea and Westminster Hospital, London, UK; Departments of Neurology and HIV Medicine St Vincent's Hospital and St Vincent's Centre for Applied Medical Research Sydney, NSW, Australia; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada; NeurogesX, Inc, San Mateo, CA.
DB Clifford, DM Simpson, S Brown. A Randomized, Double-Blind, Controlled Study of NGX-4010, a Capsaicin 8% Dermal Patch, for the Treatment of Painful HIV-Associated Distal Sensory Polyneuropathy. Journal of Acquired Immune Deficiency Syndromes 59(2):126-133. February 1, 2012.
NeurogesX. NeurogesX Provides Update on Qutenza (Capsaicin) 8% Patch for New Indication to Treat HIV-PN Following FDA Advisory Committee Review. Press release. February 9, 2012.
Qutenza Full Prescribing Information. http://www.qutenza.com.