The US Food and Drug Administration has requested more information before it will consider approving the first transdermal patch for migraine, according to NuPathe Inc., the company developing it.
The FDA acknowledged the efficacy of the iontophoretic patch for delivery of sumatriptan, but requested additional information, primarily about “chemistry, manufacturing and safety questions, which the company believes it has, or shortly will have,” NuPathe announced on Aug. 30.
The company said it may conduct additional phase I and/or non-clinical studies to address other questions. The FDA response means that the company will not launch its migraine patch in the first half of 2012, as previously announced. Neither the company nor the FDA would release more information about the specific concerns expressed in the response to the new drug application.
The patch, to be marketed under the name Zelrix, works by applying a nearly undetectable electrical current to drive ionized sumatriptan through the skin and into the bloodstream, which it would not otherwise do with a non-electrical transdermal patch.
Neurologists and others familiar with the patch, either because they have helped to develop it, participated in clinical trials, or served on the company's advisory board, said they still expect it to serve a significant niche of migraineurs.
“I don't think every patient needs the patch, but for people who aren't responding to oral medications or don't want to take an injection, I think it's going to be a good alternative,” said Alan M. Rapoport, MD, clinical professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles and president-elect of the International Headache Society.
While it does not work as fast as do injections of sumatriptan, the patch's effects may last longer in some patients and cause few of the side effects associated with triptan injection, Dr. Rapoport said.
“The fastest way to get relief from a migraine is with the injection,” he said. “It gives relief in about 70 percent of patients studied at one hour, 80 percent at two hours. But there are a lot of side effects. Most of the time they're acceptable side effects, but occasionally the side effects are so uncomfortable that patients won't take it again. Injections also have a fairly high recurrence rate in some patients.”
While the patch takes about two hours to reach maximum effectiveness, Dr. Rapoport said, “It causes virtually no or very few triptan-related adverse events. You're not going to get chest pain, nausea, vomiting, dizziness, and drowsiness. The patch stays on for four hours but the effect can last all day.”
Dr. Rapoport disclosed that he has served on advisory boards to the company, and has received honoraria from NuPathe, but has not participated in any clinical trials involving the patch nor has he been an employee of the company.
The side effects associated with injection of triptans are believed to be due to the rapid rise in blood levels of the drug, which is avoided by the slower absorption seen with the patch.
The patch likewise avoids the challenges of taking oral medications during a migraine, said Steven J. Siegel, MD, PhD, associate professor of psychiatry and director of translational neuroscience at the University of Pennsylvania.
“Oral absorption of any drug during a migraine is variable, because of gastroparesis and all the nausea and vomiting,” said Dr. Siegel, who was involved in the design and testing of an early iteration of the patch. “This is more reliable than the oral route in getting patients up to the desired blood level, but it's not the same instantaneous hit you'll get with an injection. It's more of a square wave than a spike and decay.”
The primary side effects reported in a phase 1 trial published in Headache in June of 2009 were skin reactions at the patch site, which were mild and resolved in most subjects with two to three days.
Results of a one-year, open-label safety trial involving 183 patients were announced by NuPathe in a news release in October of 2010, but have not yet been published in a peer-reviewed journal. According to the announcement, only three patients, or 1.6 percent, experienced triptan-related adverse events during the 12-month trial, while 25 patients, or 13.7 percent, withdrew from the trial due to adverse events, primarily due to application site reactions. Headache relief was achieved within two hours for 58 percent of migraines treated, and headache pain freedom in the same period for 24 percent, and freedom from nausea for 79 percent.
The only other peer-reviewed paper listed on PubMed describing clinical data on Zelrix was published by Mark W. Pierce, a scientist employed by NuPathe, in the April 2010 edition of the journal Neurotherapeutics. But according to a review by Dr. Rapoport and others published in November 2010 in CNS Drugs, “A large, randomized, double-blind, placebo-controlled, multicentre clinical trial showed statistically significant efficacy, good tolerability and virtually no triptan-related adverse events.”
Three nasal sprays are currently available on the market for treating migraine, but according to Stephen Silberstein, MD, professor of neurology at Jefferson University in Philadelphia, “One of the nasal sprays is terrible tasting, and most people don't want to use nasal sprays. Many people don't want to take an injection either. So having another delivery system is extremely important.”
Dr. Siegel, who has participated in clinical trials of Zelrix and served on the advisory board of NuPathe, said that several of the participants who used the patch during a trial “loved it. One or two complained of temporary irritation, but that was it.”
Joel Saper, MD, founder and director of the Michigan Head Pain and Neurological Institute, and clinical professor in neurology at Michigan State University in Lansing, also participated in a clinical trial of the NuPathe patch, and sat on an advisory board.
“We were blinded, so we didn't know who was getting the therapeutic patch or placebo patch,” he said. “But I don't recall anyone who was frightened or intimidated by it. A couple people had irritation of the skin from it, or didn't have any benefit.”
While the patch is designed to be kept on hand to be applied whenever a migraine begins, Dr. Saper said, “It's not as simple as opening up a Band-Aid. There are a couple of steps involved in taking it out of the packaging and putting it on your skin.”
He added, “I don't promote products. No drug for migraine is universally effective. But I think there will be a market for this drug in people who find it convenient, who don't want to take an injection, or who can't get better with oral medications.”