FDA advisors recommended that the agency approve an intranasal epinephrine product for type I allergic reactions, including anaphylaxis, despite concerns about the lack of clinical efficacy data.
On Thursday, members of the agency's Pulmonary-Allergy Drugs Advisory Committee largely agreed that the benefit-risk assessment for the product, ARS-1 or neffy, was favorable as an emergency treatment of allergic reactions and anaphylaxis for both adults and kids weighing 30 kg (~66 lb) or more, with votes of 16-6 and 17-5, respectively.
The panel concluded that the surrogate endpoint data presented by manufacturer ARS Pharmaceuticals were sufficient to support the efficacy of the novel noninjectable epinephrine.
"It's been 36 years since EpiPen and EpiPen Jr's initial approval, with no access to other alternative treatment routes," noted Michael Nelson, MD, PhD, of the University of Virginia School of Medicine in Charlottesville, who voted in support of the product for kids and adults.
"It is my hope that this application and the conversation around it will serve as a reset, breaking down barriers to access and use that we heard about today, and some we didn't hear about -- particularly disparities of care rooted in social determinants of health," he continued. "Whether the drug is approved or not, I think there's a real opportunity here to reset the playing field for all, and I hope that the entire medical and regulatory community will take full advantage of it."
While allergen avoidance is often used to prevent type I allergic reactions, in the event of a reaction, epinephrine remains the first-line emergency treatment. Nevertheless, there are certain barriers to use, including a fear of needles or issues surrounding correct administration that can delay or prevent crucial treatment. If approved, the nasal spray under consideration would be the first needle-free form of epinephrine.
However, clinical efficacy trials were not included in the development of ARS-1, with the sponsor citing feasibility and ethical concerns due to the potentially dangerous, time-sensitive nature of anaphylaxis.
"We spend our lives doing clinical trials of the disease of interest and here we're not studying the disease of interest, we're studying multiple surrogates, be it PK [pharmacokinetic] or PD [pharmacodynamic]," said Leonard Bacharier, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, during discussions. "We understand why we can't study it in the setting of acute anaphylaxis, for all the appropriate reasons."
"I guess my real question is, What more can we reasonably, legitimately, expect?" said Bacharier, who ultimately voted in support of the product for kids and adults. "And if that turned out exactly the way we wanted, would we have that much greater confidence than where we sit now?"
The advisory committee did express concern regarding the data, noting that a lower concentration of epinephrine was seen in the 10 minutes immediately after administering a single-dose of the intranasal product in healthy patients, as well as potential risks for diminished PK/PD sustainability as the result of nasal congestion from anaphylaxis.
A number of panelists suggested that if approved, postmarketing trials should be conducted.
"I would like to see postmarketing studies on the effectiveness and safety out in the real world, but I think that the benefit-risk was sufficient," said Jennifer Schwartzott, MS, the committee's patient representative, who voted in support of the nasal spray.
"This is a life-or-death unmet need. I believe that there was more risk in not approving it than of harm coming from the drug," said Schwartzott. "This gives the patients a choice."
But other committee members questioned that unmet need, and took issue with trials being conducted in healthy individuals.
"We have a good treatment now in the [epinephrine injection] EpiPen, and I think to iterate on that, to get a better treatment, the bar is high," said panelist Lewis Nelson, MD, MBA, of Rutgers New Jersey Medical School in Newark, who voted against recommending ARS-1 for approval.
"Although I do see some benefits to this alternative route of administration, I think there are some potential limitations in terms of some risk and utility," Nelson said. "But the single biggest issue that I still struggle with is that even if you believe the PK/PD data to be spot-on, we're still studying them in the wrong disease or the wrong population. I just don't know that we can apply healthy people data to people with anaphylaxis."
A lack of precedent surrounding approval of any form of nasal epinephrine raised concerns to FDA reviewers. The EpiPen had not been required to submit PK/PD data for approval decades prior, and other injectable versions of epinephrine had been approved using the previously established efficacy of epinephrine products atop chemistry and manufacturing data, and human factors data.
During the committee meeting, ARS Pharmaceuticals presented PK/PD data that compared the intranasal epinephrine product to existing, approved forms of epinephrine injection. PK data for one dose of ARS-1 was found to be within the determined brackets when compared with single doses of Adrenalin 0.3 mg or EpiPen 0.3 mg after the first 10 minutes of administration.
ARS Pharmaceuticals also noted that the sprayer used on the intranasal epinephrine product is the same form currently used in FDA approved nasal spray products including naloxone (Narcan) and diazepam (Valtoco).
While the FDA is not required to follow the recommendations of its advisory committees, it typically does.