Zecuity Redesign Got Migraine Patch Through FDA, But Burning Continued

FDA worries about burning and scarring with the battery-powered Zecuity patch prompted NuPathe to reconfigure the drug-device combo; our Drug Review Profile shows how FDA thought the problem was solved, but adverse reaction reports soon after launch led to marketing suspension.

FDA thought burning and scarring effects with NuPathe Inc.'s migraine therapy Zecuity could be addressed with a redesign that added technology to ensure proper placement of the patch, but persistent adverse events reported during the battery-powered transdermal system's short time on the market suggests that the agency's confidence that the problem had been fixed was misplaced.

FDA reviewers initially opposed approval of Zecuity, an iontophoretic transdermal system that delivered the venerable migraine drug sumatriptan (GlaxoSmithKline PLC's Imitrex and generics), in part because the patch caused burning and scarring in clinical trial subjects. At FDA's recommendation, the sponsor redesigned the product, and when the redesigned version was approved, the agency did not require a warning about those risks in labeling.

FDA approved Zecuity on Jan. 17, 2013, for the acute treatment of migraine with or without aura in adults, making it the only patch approved for the indication. NuPathe waited to commercialize the drug-device combination product until it could scale up manufacturing and find a domestic partner. (Also see "Allergan/MAP Planned Merger, Approval Of NuPathe’s Triptan Patch Change U.S. Landscape For Migraine Therapy" - Pink Sheet, 28 Jan, 2013.) Teva Pharmaceutical Industries Ltd. acquired NuPathe in 2014 and launched Zecuity in September 2015.

It was soon after Zecuity was launched that FDA learned that the modifications to the patch design were inadequate. FDA announced in June 2016 that "a large number of patients" had reported burns or scars from the patch, and Teva voluntarily suspended marketing of the product. (Also see "Teva Zecuity's Safety: Burns Go From Non-Issue In Label To Product Puller" - Pink Sheet, 13 Jun, 2016.)

In response to a Freedom of Information Act request, FDA provided a list of cases generated by the FDA Adverse Event Reporting System (FAERS). The list includes more than 600 reports of burns, including 23 reports of first- and second-degree burns. In addition, there were more than 140 separate reports of "sunburn."

Zecuity's Marginal Benefit-Risk Ratio

FDA's review team found Zecuity to be effective in relieving migraines, but they did not express much enthusiasm for the product and expected it would be used by a limited number of patients, review documents show.

"There is no definite evidence that this product addresses an unmet medical need," FDA Division of Neurology Products Deputy Director Eric Bastings, who served as the review team leader, said in a summary review of the application. "Patients with prominent nausea already have several non-oral alternatives, including a nasal spray, and a subcutaneous formulation for self-administration with an autoinjector, or with a needleless device."

"Overall, the benefits derived from Zecuity marginally outweigh its risks of causing numerous adverse events at the application site" – FDA clinical reviewer Nushin Todd

"Nevertheless, the product may offer benefit for patients who have prominent nausea or vomiting and who cannot tolerate or are unwilling to use the marketed formulations of sumatriptan," Bastings commented. "Arguably, that subgroup of patients represents a very small fraction of the migraine population, but also a very disabled subgroup," he added.

The transdermal route bypasses the gastrointestinal system, providing an alternative means of delivering sumatriptan to migraine patients who might not be able to tolerate oral medications. The iontophoretic technology allows the drug to transfer through the skin without needles.

Clinical reviewer Nushin Todd also gave the migraine patch a muted endorsement. "Overall, the benefits derived from Zecuity marginally outweigh its risks of causing numerous adverse events at the application site," he said.

More than half of the patients (57%) in two long-term safety studies sustained a treatment-emergent adverse event, Todd noted. The vast majority of AEs were related to application site conditions, most commonly pain and pruritis. He also pointed to the high rate (59%) of discontinuation in the studies, mostly due to withdrawal of consent and adverse events.

"Modifications made to the device portion of the product have mitigated the risks for potential severe burns and scarring that occurred in some patients in the clinical program," Todd concluded. "Local adverse events from use of the product, however, remain numerous."

Device Modifications

Zecuity is a disposable, single-use, co-packaged drug/device combination product that delivers 6.5 mg of sumatriptan over four hours. The drug portion consists of a reservoir card that has two reservoir pads, one containing sumatriptan and the other containing a salt solution. The device portion is an electrode patch containing positive and negatively charged electrodes connected to a programmed circuit. Patients remove the top foils protecting the drug reservoir and electrodes and apply the electrodes over the drug reservoir. The patch is applied to the upper arm or thigh and drug delivery is activated by pushing a button. After four hours, the system is automatically deactivated by the preprogrammed circuit.

FDA recommended that the product be redesigned after patients experienced burns and scarring in the clinical trial. NuPathe modified the patch to include a "pad detection system," which includes a pre-programmed microprocessor that conducts a series of diagnostic tests to verify pad placement, skin resistance and device functionality prior to drug delivery. If the pads are misaligned or missing, the system prevents pad activation.

Todd noted that 647 modified patches were tested in two clinical studies and reportedly were 100% effective in detecting misaligned or absent medication pads and preventing patch activation.

Safety, Usability Concerns Behind Extensive Complete Response Letter

While burning and scarring would cause the removal of Zecuity from the market, those adverse events were only one of many concerns about product design that FDA communicated to NuPathe. (Also see "NuPathe Must Patch Together New Zelrix Launch Timetable After "Complete Response" Letter" - Pink Sheet, 30 Aug, 2011.).

The complete response letter (CRL) the agency issued on Aug. 29, 2011, is notable for its length. The CRL cites nine concerns with clinical data, six concerns with microbiology – and 71 issues related to product quality.

FDA had already told NuPathe that the fundamental design of Zecuity was not acceptable in a May 2011 chemistry, manufacturing and controls (CMC) information letter.

The CMC letter previewed many of the issues cited by the CRL. "A lack of uniformity of drug formulation distribution, and issues with drug formulation containment, safe disposal procedures, and patient usability raise concerns about the safety and efficacy of the product," the information letter stated.

The agency said the amount of drug on the drug-containing pad was not evenly distributed and that variable amounts of the drug remained on the reservoir side after pad transfer. "This lack of uniformity may result in variable amounts of drug transferred from the packaging to the patient, which has potential safety and efficacy implications," the agency said.

FDA reviewers also cited the complicated assembly of the transdermal system, saying it could increase the chance for exposure to the drug formulation. They recommended that the sponsor conduct a comprehensive risk analysis identifying the use-related and medication error risks with the iontophoretic system.

NuPathe's response did not quell FDA's concerns. CMC reviewers followed up with a discipline review letter in July 2011 stating that the agency "remains unconvinced" that the lack of formulation containment, the drug formulation, and the large quantity of residual drug after use "do not pose a safety risk to the patient, health care provider, children, or pets."

FDA Skeptical Of NuPathe's Improper Application Explanation

FDA also cited inadequate chronic dermal toxicity testing and the risks of burning and skin discoloration. "We have serious concerns about the potential for your product to cause severe burns and permanent skin lesion," the complete response letter said.

The agency noted that the company's summary of clinical safety described several cases of patients who experienced permanent skin lesions, including one patient who had a consultation with a plastic surgeon to discuss cosmetic repair for the discoloration. FDA criticized the company's attribution of the lesions to "improper application."

FDA also noted that there were three adverse event reports of severe burns and two reports of moderate burns in long-term safety studies, and one report of "mild scar."

"In addition, we cannot rule out that your database includes additional cases of permanent skin lesions that were not described in your summary of clinical data," the agency said. "Unless you can provide evidence that cases of significant administration site adverse events (e.g., burn, scar, discoloration or abnormal pigmentation) in your database ultimately resolved, we believe that the risk of skin lesions (in particular with permanent sequelae) is not justified by the benefits of the product."

FDA said it was not able to estimate the exact incidence of adverse events because they were often reported by non-specific terms, such as "site reactions," or "adverse drug reactions." It directed the company to re-examine and recode the adverse events.

The agency also cited the high rate of discontinuation in long-term safety studies (55%) and noted that the most common reason the company gave for discontinuation was "withdrawal of consent." But FDA said the company did not include the reasons for withdrawal of consent in its database and pointed out that withdrawal is often due to an adverse event.

One Reviewer Opposed Approval

The sponsor resubmitted the Zecuity NDA in July 2012 with modifications that persuaded the review team to recommend approval – with one exception. Non-clinical pharmacology/toxicology reviewer Charles Thompson recommended a "not approvable" action, saying the sponsor's nine-month dermal toxicity study was inadequate and that the company had not provided sufficient information to warrant a waiver for a dermal carcinogenicity study.

Supervisory pharmacologist Lois Freed agreed with Thompson's conclusion that the sponsor had not provided sufficient nonclinical data to support approval of the NDA. However, in a Jan. 14, 2013, memo Freed said that since the clinical team had determined that Zecuity provided clinical benefit, particularly in migraine patients who cannot take sumatriptan orally, the nonclinical deficiencies could be addressed with post-marketing requirements.

Review team leader Bastings explained that the key question was whether Zecuity had a clinical benefit that would justify allowing the product to be marketed before the nonclinical studies were conducted.

Given the vast experience with other formulations of sumatriptan and the absence of a signal of carcinogenicity with the other routes of administration, he concluded that it was acceptable to have the sponsor conduct nonclinical studies as post-marketing requirements. The agency required an in vivo repeat-dose dermal-painting study of sumatriptan in an appropriate mouse model using various permeation enhancers and a dermal carcinogenicity study in mice.

As for the product's safety, Bastings said the sponsor provided adequate engineering evidence to support that the pad-detection system will operate as expected and the review team agreed it was sufficient to address the burn/scarring issue. However, he said that given the lack of clinical experience with the redesigned product, the sponsor would be required to report all postmarketing cases of burns and scarring as 15-day safety reports.

REMS Deemed Unnecessary

NuPathe itself had been cautious about the product's safety risks and proposed a Risk Evaluation and Mitigation Strategy, which included a Medication Guide and other elements. These other elements were redacted in FDA's July 2011 REMS review document.

The Division of Neurology Products had concluded that the product did not require a REMS to mitigate the well-known risks associated with sumatriptan, which were to be included in the proposed labeling, the Office of Surveillance and Epidemiology's Division of Risk Management noted.

The Division of Risk Management deferred comment on the proposed REMS since FDA was to issue a complete response letter. The CR letter said the agency did not believe a Medication Guide would be sufficient to mitigate the risks, as significant skin toxicity occurred in clinical trials despite patients being instructed how to use the product. But the agency said it had not yet determined if other REMS elements would be necessary.

FDA's approval letter does not mention a REMS. The agency's chief safety concern at the time of approval seemed to be the risk of cancer. FDA said it had determined that an analysis of spontaneous postmarketing adverse events would not be sufficient to identify an unexpected serious risk of the carcinogenic potential of Zecuity and required the two postmarketing studies in mice. The agency also required studies of Zecuity in adolescents with a history of migraine.

Labeling Identifies Allergic Dermatitis As Chief Skin Concern

The Zecuity NDA was filed under the 505(b)(2) pathway, allowing NuPathe to rely on FDA's prior findings of safety and efficacy for Imitrex tablets and subcutaneous injection. Only one pivotal efficacy study was required for approval, and it was a single-dose study, leaving the Zecuity dataset with less safety experience than a new molecular entity would need to provide. Controlled and uncontrolled data in the NDA came from a total of 796 patients treated with Zecuity.

The pivotal efficacy study randomized 530 subjects to a single dose of Zecuity or placebo; 454 subjects were included in the intent-to-treat population. The primary endpoint was absence of headache pain two hours after patch activation. The trial also included three key secondary endpoints looking at relief of other migraine symptoms: absence of photophobia, phonophobia and nausea two hours after activation.

The patch was superior to placebo across all endpoints. Forty of the 226 subjects (17.7%) in the Zecuity-treated group reported no headache at two hours compared with 21 of 228 (9.2%) subjects in the placebo-treated group. For the secondary endpoints, 116 of the patients in the Zecuity group (51.3%) v. 83 (36.4%) in the placebo group were free of photophobia at two hours after activation; 125 (55.3%) in the Zecuity group v. 89 (39%) in the placebo group were free of phonophobia; and 189 (83.6%) in the Zecuity group v. 144 (63.2%) in the placebo group were free of nausea.

The study looked for dermal effects of Zecuity, but burning and scarring are not among the effects described in approved labeling. The only dermatologic concern in the label's warnings and precautions section is allergic contact dermatitis, based on 4% ACD rate in open-label studies out to one year.

The label does advise users to remove the patch if they experience "a powerful burning sensation during use."

Labeling also does not address review team concerns about efficacy data in non-white patients. The label states that "analyses of the relationship between age, race, gender, or BMI and response showed no significant differences in response rates."

Bastings, however, observed that the efficacy results in non-white patients in the pivotal study appeared questionable. Subgroup analyses of the non-white population, which included 19% of the study population, "indicate that in non-white subjects, Zecuity was no better than placebo for the primary endpoint: 12.5% vs. 11.4%, p=0.87 (according to the sponsor analysis)," he said.

Additional analyses from the sponsor "do not provide a very convincing argument of efficacy in non-white patients," the team leader said, "with the caveat that the study was not powered to establish efficacy in that subgroup."

Will Teva Try Another Redesign?

Teva's 2014 acquisition of NuPathe for $144m was part of Teva's strategy to focus on pain and respiratory disease as its core therapeutic areas. Teva also said that the acquisition of the company, and specifically of Zecuity, would leverage Teva's commercial expertise in marketing complex products, such as its multiple sclerosis drug Copaxone (glatiramer). (Also see "Teva Wins Bidding For NuPathe And Its Migraine Patch, Topping Endo" - Pink Sheet, 21 Jan, 2014.)

The question now is whether Teva will redesign the product a second time and seek to return it to market. The company said it is working with FDA to explain and characterize the adverse reactions and determine the feasibility of bringing the product back to the market. It has not yet determined the root cause of the burning and scarring.

And FDA, having been burned by one redesign that did not solve the problem, may be more cautious in accepting further data on Zecuity safety.