The Food and Drug Administration on Tuesday did not approve Neffy, an epinephrine nasal spray from drugmaker ARS Pharmaceuticals, keeping the first needle-free option for Americans to treat severe allergic reactions off the market pending more trial data.
ARS had expected the FDA to approve Neffy for use in adults and children who weigh more than 30 kilograms, or around 66 pounds. The spray would have required a prescription, similar to EpiPens and other epinephrine injections that are currently used to treat anaphylaxis.
Epinephrine is crucial in an emergency to treat potentially life-threatening allergic reactions. The new spray, if eventually approved, would provide a welcome alternative for many families of children with severe allergies who’d rather avoid needles.
According to ARS, the FDA regulators decided Tuesday that more data was needed to evaluate the safety of repeated doses of the nasal spray before it could be approved. Some FDA advisers had suggested at a previous meeting in May that additional data would not need to be gathered in a trial after the drug was brought to market, so the drugmaker voiced disappointment over the Tuesday decision.
“We are very surprised by this action and the late requirement at this time to change the repeat-dose study from a post-marketing requirement, which we had previously aligned on with FDA, to a pre-approval requirement, particularly given the positive Advisory Committee vote,” said ARS Pharma co-founder, president and CEO Richard Lowenthal in a statement late Tuesday. “We are deeply disappointed that this action further delays the availability of neffy for the millions of people who are at risk of a potentially life-threatening severe allergic reaction. Patients and caregivers are waiting for neffy, and we aim to complete the newly requested trial as quickly as possible to meet the needs of patients.”
“Major barriers limit the rapid use of epinephrine in a community setting. Many patients fear needles and many are not comfortable with self-injection. There is also the impracticality of carrying the current available devices,” Lowenthal told a panel of the FDA’s outside advisers at the meeting in May to weigh the product.
Lowenthal told the committee that the company planned to provide the product in a “slim Neffy carrying case” that carries two sprayers each.
As many as 85% of patients who face severe allergies would be willing to carry epinephrine around with them daily if Neffy was an option, Lowenthal said their surveys suggested, up from around 55% with current options.
“If they don’t have it with them, it’s a moot point. They don’t deliver, they don’t have drug, they go to the hospital,” said Lowenthal in May.
The drugmaker says Neffy nasal spray works by delivering a dose of epinephrine to patients facing allergy attacks using two other technologies already used in other FDA-approved products. One is the substance dodecylmaltoside, licensed from drugmaker Neurelis, which it says “enhances drug absorption” through mucous membranes, which are cells that line the airways from the nose to the lungs. Neurelis has used this ingredient, branded as Intravail, in a spray of their own to treat epilepsy.
The other is a sprayer device sold by Aptar Pharma that is already used in a number of products. It’s the same type of sprayer used by the Narcan-brand nasal sprays of naloxone, which are used to treat drug overdoses and were recently greenlighted by the FDA for over-the-counter sales.
Despite the availability of some generic alternatives, some Americans continue to face steep price tags for annual purchases of the currently available epinephrine injection devices. Brand name EpiPen and its generic alternatives can cost some families more than $200 per year, which has led some states to explore caps on epinephrine prices.
More epinephrine nasal sprays are also in the pipeline. Drugmaker Bryn Pharma has touted promising results from its experimental epinephrine nasal spray Utuly, which they say could outperform current injectors.
Questions about effectiveness
The FDA’s request for more data was just the latest delay for ARS’ bid to bring the drug to market.
The company had previously said the FDA could decide on approval of Neffy by mid-2023. But ARS disclosed in June that the FDA had told the company it would need until September to decide on the approval. The extra time was needed to finish “labeling and post-marketing commitment discussions” raised after the FDA advisory committee meeting on Neffy, the company said.
A majority of the FDA’s Pulmonary-Allergy Drugs Advisory Committee ended up voting in May to back the product’s benefits outweighing its risks, after wrestling with a number of questions around whether the spray might be less effective than current injections.
“Following the strong endorsement of our clinical data for neffy at the May PADAC meeting, there was limited time to address any final questions and complete labeling,” Lowenthal had said in a release.
While epinephrine is widely accepted by experts as effective at treating severe allergic reactions, use of the chemical — purified adrenaline that dates back to the early 20th century — predates the existence of the FDA. That means epinephrine’s original use for treating anaphylaxis came about without clinical trials to directly prove that it works, as well as to better understand what measurements of the drug in the body are required for it to be effective.
The original EpiPen was approved in 1987 without clinical trials or detailed data on how the drug is absorbed or its effects on the body, the FDA says.
Clinical trials to prove that delivering epinephrine as a spray works as well as an injection would be difficult to run ethically, FDA officials acknowledged.
Instead, ARS Pharmaceuticals ran a variety of studies to generate so-called “surrogate” data aimed at figuring out whether its spray could likely be as effective as injections.
Those included dosing subjects exposed to seasonal allergens, as well as measuring concentrations of the drug in their body, which generated some conflicting data. Comparisons with measurements from epinephrine injections also led to varied results.
“I really want this product to work. I mean, we definitely benefit from a needle-less means of delivering epi. And I think the sponsor has done a nice job trying to find that balance. That said, I think we’re using weak surrogate data to assure ourselves,” Lewis Nelson, a member of the FDA committee, said at the May meeting.
Nelson echoed other committee members in praising the company and FDA’s approach to solving some of the substantial variabilities seen with other epinephrine injections. But he also said he thought more data would be needed in order to approve the drug.
“I really would hate to learn, without some better clinical data, that we recommend approval of a product on the basis of surrogate data that’s inconsistent and somewhat confusing and, ultimately because of that, patients are harmed,” he said at the meeting.