ARS Pharma continues epinephrine nasal spray studies while awaiting FDA approval
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Key takeaways:
- The FDA asked ARS Pharma for additional studies of neffy’s efficacy with comorbid allergic rhinitis.
- Results of these studies will be available soon, with a new application for approval to follow.
ARS Pharma continues to study the effectiveness and safety of its neffy epinephrine nasal spray as patients with allergies wait for an alternative to autoinjectors for anaphylaxis treatment.
“If you’re one of the 800,000 happy autoinjector users, keep it,” Richard Lowenthal, MS, MSEL, cofounder, president and CEO of the company, told Healio. “We’re worried about the 17 to 20 million people who don’t have any epinephrine product they are willing to use today.”
The approval process
In October 2022, the FDA accepted ARS Pharma’s new drug application (NDA) for a 2 mg dose of neffy, which was designed to treat type 1 allergic reactions in adults and children who weigh 30 kg or more.
Based on data from four primary registration studies, the FDA’s Pulmonary-Allergy Drug Advisory Committee recommended approval for both adult and pediatric use in May 2023.
“They were positive,” Lowenthal said.
But in September 2023, the FDA issued a complete response letter (CRL) asking ARS Pharma to assess the spray’s pharmacokinetic (PK) and pharmacodynamic effects under a nasal allergen challenge with induced allergic rhinitis conditions when dosed twice. ARS already completed a single dose study under nasal allergy challenge conditions that the FDA Advisory Committee felt was acceptable for approval.
Given that 10% of patients may require a second dose, Lowenthal explained, the FDA felt that assessing twice dosing with a 10-minute interval as would occur in an actual anaphylaxis emergency was important to optimize labeling and support final approval.
The FDA did not provide a clear explanation for why it wanted the additional studies at the time, Lowenthal said. A spokesperson for the FDA told Healio that the administration is generally unable to discuss existing or potential applications, including confidential commercial information.
Lowenthal also noted that the advisory committee did not feel any additional studies were necessary for approval, but ARS Pharma agreed with FDA to conduct a post-approval study of twice-dosing after a nasal allergen challenge.
“I’ve gotten complete response letters before, but I’ve never gotten one where I have no idea why or what’s going on or what the reason is,” Lowenthal said.
In fact, Lowenthal added, the advisory committee explicitly said that it did not have any concerns about results when dosing neffy with nasal allergen challenge induced rhinitis and its impact on neffy’s performance.
“Even the five members of the committee that voted against approval, none of them voted against approval for this reason,” he said. “They didn’t think it was an issue at the time.”
The studies leading up to ARS Pharma’s application included single dose nasal allergy challenges and studies with pollen-induced allergic rhinitis. FDA has not asked for such challenge studies with other emergency use nasal sprays such as naloxone hydrochloride (Narcan, Emergent BioSolutions) and, more recently, nalmefene hydrochloride (Opvee, Opiant Pharmaceuticals) both for opioid overdose, Lowenthal said.
“This study is a worst-case nasal condition challenge. It’s kind of the worst thing you could do to your nose and challenge it, and the advisory committee still felt it looked good,” Lowenthal said.
Epinephrine absorption was faster during these challenges, although the decrease in epinephrine levels was also more rapid, he continued.
While intramuscular (IM) injections reached maximum concentrations at approximately 45 minutes, Lowenthal said, neffy reached maximum concentration during nasal allergen challenge induced allergic rhinitis in 8 minutes.
“At about 20 minutes, we were the same epinephrine concentrations in plasma as IM injection, and then after that, we were a little below IM injection,” he said. “The FDA asked the advisory committee if there was any concern about the fact that plasma concentrations of epinephrine are not as high as IM after 20 minutes. The advisory committee said, ‘No, it either works very quickly in 10 minutes, or it doesn’t work and you give another dose.’”
Other ARS Pharma studies also showed that there was no negative impact on absorption of epinephrine or pharmacodynamic measures when patients had rhinitis, or significant congestion, from infectious disease such as colds and flu.
“In subjects with infectious rhinitis and significant congestion, there was no negative impact on PK or pharmacodynamic response,” Lowenthal said.
Additionally, Lowenthal said that rhinitis symptoms rarely develop as part of anaphylaxis.
“This is food allergy,” he said, adding that symptoms commonly include bronchial spasms, angioedema on the face and tongue, and gastrointestinal symptoms such as cramping and vomiting.
“But they don’t get rhinitis symptoms often,” he said. “It’s less than 4% based on literature reports.”
Despite these and other findings, Lowenthal said the FDA has not provided a complete explanation of why it wants this additional study, even though ARS Pharma has asked for one. The FDA did not share its reasoning in detail during an October 2023 type A meeting with the company either, Lowenthal continued.
ARS Pharma has appealed the FDA’s decision through its Formal Dispute procedure. The company is hopeful to get more clarity on the FDA’s specific concerns and confirm its pathway forward, Lowenthal said.
In the meanwhile, the requested study is underway. ARS Pharma will present findings from six other studies at the Academy of Allergy, Asthma & Immunology Annual Meeting, Feb. 23-26, in Washington, D.C.
Lowenthal also expects ARS Pharma to file a response to the FDA’s CRL sometime in the first half of this year.
Delays in approval
“We’re still on track to file,” Lowenthal said, adding that he was concerned about how these delays may impact patient care.
“They could take another 6 months to review after we respond to the CRL,” he said. “This would be a total delay of up to 12 months, and that just doesn’t make sense when the advisory committee was very clear that the results of our single dose nasal allergy challenge study were not a significant concern and additional studies would not be of value.”
Advocacy groups in the allergy community were disappointed with the lack of approval as well, Lowenthal added.
Snack Safely has a petition on Change.org with more than 39,000 signatures asking for rapid approval. Food Allergy Research & Education (FARE) submitted a white paper supporting neffy’s approval to the FDA as well, Lowenthal said.
“At FARE, we support the food allergy patient’s journey every step of the way,” Sung Poblete, PhD, RN, CEO of FARE, told Healio .
“We will always advocate for more innovation, science and research to bring the treatments so desperately needed to the over 33 million people suffering from the disease of life-threatening food allergies,” Poblete continued.
Also, Poblete said that FARE will continue to advocate for neffy and all innovations that support food allergy patients, such as needle-free epinephrine delivery devices, and that it supports the advisory committee’s recommendation for approval.
“We strongly believe that neffy should be given final approval by FDA,” Poblete said.
The benefits of an epinephrine nasal spray outweigh the risks for reduced absorption with rhinitis, Lowenthal continued.
“We do not believe that the Agency concern is significant relative to the unmet medical need and the fact that the reason people die from this disease is primarily because they don’t get any epinephrine at all,” he said. “If patients don’t have or carry their epinephrine product or are reluctant to dose, it results in worse outcomes. People that get epinephrine almost never die.”
Lowenthal indicated that between 90% and 95% of patients who should carry epinephrine do not for a variety of reasons, ranging from fear of the needle in the autoinjector to the costs of the device. A nasal spray would alleviate many of these barriers, he said.
“You’re not doing any good by waiting for this reason to approve,” he said. “We may actually be causing more harm to those who would otherwise get an alternative therapy, carry it and use it when needed.”
Even people who have autoinjectors wait to use them because they are afraid of the injection, Lowenthal said, and wind up going to the ED because of these delays in care.
“People are just not treating themselves properly with these autoinjectors,” he said.
Also, Lowenthal said he has been hearing from physicians who are concerned about the delays in approval.
“Some of our doctors, they’re being asked all the time by their patients. ‘When is this getting approved?’ They’re not worried at all about the happy autoinjector user,” he said. “They’re worried about all the people that are not protected.”
Despite these delays, Lowenthal said that he and ARS Pharma remain focused on patients who would benefit from neffy’s spray approach and ready for approval.
“We’re trying to get them something that will work and won’t cause pain,” he said.