Good afternoon and welcome to ARS Pharmaceuticals' 2024 Virtual Investor Event. Thank you for joining us. My name is Justin Chakma, and I'm ARS Pharmaceuticals' Chief Business Officer. We have a very exciting and robust agenda today. Our program will start with speaker presentations, followed by a question-and-answer session. This Q&A session will include both of our guest allergy speakers, along with the ARS management team. You may submit questions at any time using the text box below your webcast window. We will try our best to answer as many questions as we can before the conclusion of this event. If you have questions after the meeting concludes, please send them to ir@ars-pharma.com. As a reminder, matters covered in today's presentation, including the accompanying slides, include forward-looking statements. Such statements involve risks and uncertainties that may cause actual results to differ materially.
A discussion of these statements and risk factors is available on the Safe Harbor statement shown on slide two, as well as under the heading "Risk Factors" in our SEC filings. All forward-looking statements made are as of today's date, and we undertake no obligation to update such statements. Now, to begin the meeting, I'd like to turn the call over to Richard Lowenthal, ARS Pharma's President and Chief Executive Officer.
Thanks, Justin, and we appreciate all of you joining us today. Welcome to ARS Pharmaceuticals' first investor day event. Presenters from ARS Pharmaceuticals today will be myself and our Chief Commercial Officer, Eric Karas. We both have extensive experience developing and launching nasal spray products, including NARCAN, which achieved over 95% market share in a naloxone market that was previously injection-only. We also have two very distinguished allergists joining us today: Dr. Jonathan Spergel, Chief of Allergy at Children's Hospital of Philadelphia, and Dr. Thomas Casale, Chief of the Allergy Department at the University of South Florida. The focus of today's presentation is neffy, our needle-free epinephrine nasal spray for the treatment of severe Type I allergic reactions, including anaphylaxis. Type I allergic reactions are generally caused by exposure to an allergen and can be life-threatening if epinephrine is not administered in a timely fashion.
Today's treatments use a needle for the injection of epinephrine, which is often used incorrectly or well after significant hesitation, or worse yet, it's not used at all. Since our founding, our goal for neffy has been to alleviate the challenges of severe allergy patients and caregivers in their daily lives. Our goal has been to deliver epinephrine with comparable pharmacokinetics and pharmacodynamics to intramuscular injection, but to do so using a safe, low-dose nasal spray that is easy to use and eliminates the fear and hesitation of injecting with a needle. We are very pleased to say that in a comprehensive registration program, neffy has achieved these objectives.
Data across multiple clinical trials shows that neffy demonstrated comparable PK and PD profiles to approved injection products, including in a range of real-world scenarios such as self-administration, dosing in children, and in worst case, rare scenario of concurrent severe allergic rhinitis attack. We'll talk through our registration program, data package, new drug application, and FDA review process as part of today's presentation. To briefly summarize, we submitted a new drug application for neffy in late 2022 after extensive engagement with the FDA throughout its development. In May of 2023, FDA convened an advisory committee meeting, which conducted a thorough review of the neffy data and expressed overwhelming support for its approval, with no additional studies recommended. However, in late September of last year, we received a complete response letter from FDA requesting an additional study with neffy.
We have now completed that additional twice-dosing study of neffy under allergic rhinitis conditions, which provides further support of the potential of neffy in the treatment of severe Type I allergies. With completion of this study, we are preparing to submit our response to FDA's CRL by early second quarter of 2024 and anticipate a PDUFA action date and U.S. launch in the second half of 2024. If approved, we believe neffy's product profile as the first no-needle, no-injection solution has the potential to transform the treatment of Type I allergic reactions. In our assessment, this is a multi-billion dollar opportunity. The current auto injector market sees just over $1 billion in annual sales. However, as we will discuss a little later, only about 15% of diagnosed patients with severe allergy in the United States actually have a prescription for an epinephrine product due to their numerous limitations.
This means the opportunity for nasal spray epinephrine treatment to not only convert some of the injection market but also to expand the existing overall market is substantial. To execute the development and planned commercialization of neffy, we have built a deeply experienced team, many of whom have firsthand experience leading development and commercial efforts for approved nasal products such as NARCAN, VALTOCO, TOSYMRA, and most recently OPVEE. Our team also has extensive R&D, business, and regulatory expertise to support commercialization of neffy. With commercial launch and expansion plans in place for neffy, it is important that we are well capitalized. We have a strong balance sheet today, having ended the year with over $225 million in cash and securities, and with an expected operating runway of at least three years. These results position 2024 as a transformative year for neffy and severe allergy patients.
For today's presentation, I'll take a few minutes to go through the current treatment landscape and challenges associated with today's injection products, supporting the significant treatment opportunity we have with neffy. We're fortunate to have with us two of the nation's leading allergists, Dr. Jonathan Spergel from CHOP and Dr. Thomas Casale from the University of South Florida. Between these two physicians, they treat thousands of patients annually. Dr. Spergel will discuss the epidemiology and management of treatment of Type I allergies, including anaphylaxis, and why allergist advocacy groups and patients are demanding a needle-free epinephrine option. I will then review our registration data and the regulatory pathway agreed upon with FDA. Dr. Casale will then discuss the benefit-risk assessment of neffy, including its effectiveness, safety, and likelihood to be used by allergists.
Finally, Eric, our Chief Commercial Officer, will cover the market opportunity and focus on our commercialization strategy for neffy going forward. By way of background, today's epinephrine auto injectors can be painful and anxiety-inducing due to the needle injection, often resulting in the delay or failure to administer this life-threatening treatment at the onset of symptoms. This increases the risk for an allergic reaction to progressed anaphylaxis or other negative outcomes requiring emergency medical treatment and potentially hospitalization. Across the literature, extensive market research with patients, caregivers, and experts in the field, we know there are several critical issues with epinephrine injection devices.
As outlined in this slide, these issues result in a significant unmet medical need among 80%-90% of patients who have an active prescription but who do not carry or use epinephrine as indicated, as well as millions of more who are deterred from filling their prescriptions in the first place. neffy answers the allergies community call to solve many of these problems. neffy is small, similar in size to your earbud case, so that people can carry in their pocket discreetly at all times. neffy has no needle and therefore eliminates the fear that causes much of the hesitation to dose epinephrine. By removing the needle, neffy can be safer for both the patient and the caregiver. There is no risk of accidental injection into your hand or extremities, which can result in an ER visit.
There's also no risk in accidental injection into a blood vessel, which can cause some of the most serious adverse events with epinephrine. Nor is there risk of lacerations or painful injection into the bone of a small child, which can result in serious pain and also efficacy failures. neffy has been shown to be both easier to use and more consistent in dosing. In fact, in human factor validation studies, FDA requested that ARS evaluate the use of neffy in a group called passersby. This is somebody who has no knowledge of the disease or device and represents a person that would aid a patient in time of need. These passersby were able to read the directions without training and use neffy effectively 100% of the time. It's that simple.
Finally, the neffy device has been proven to be highly reliable in delivering an effective dose accurately, with less than one in 100,000 chance of being outside of the specifications for the dose delivered. Altogether, neffy offers peace of mind to patients, enabling them to administer epinephrine quickly, confidently, at symptoms onset. The potential for early administration at first signs of symptoms of an allergic reaction can lead to better clinical outcomes and improvements in daily living for patients and their caregivers. Ultimately, we intend to make neffy available to all patients living with allergic reactions worldwide. This will begin in the United States with an anticipated FDA approval of the 2 mg neffy dose in the second half of 2024.
We have also completed the required work for a 1 mg dose for children 15 kg-30 kg in body weight and expect to file supplemental NDA for this 1 mg neffy dose immediately following the anticipated FDA approval of the 2 mg dose later this year. Beyond the U.S., we have extensive global clinical and regulatory strategy. By mid-2024, we expect to receive a decision from the European Medicines Agency, and additional geographies are expected to follow shortly after, including marketing authorization application submissions in China, Japan, Canada, United Kingdom, and Australia, among other countries. neffy's utility isn't limited to Type I allergic reactions. We plan to expand neffy into other allergic indications.
At the recent American Academy of Allergy, Asthma, and Immunology meeting, we reported positive top-line data from our phase II in-clinic randomized controlled study with neffy as an acute treatment for exacerbations or flares in patients with chronic spontaneous urticaria. Based on a favorable result, we plan to initiate a randomized controlled phase 2b study in an outpatient urticaria setting with top-line data anticipated in the first half of 2025. This would be followed by a single phase III study in urticaria patients on antihistamine therapy who have frequent flare events as an alternative to managing these exacerbations and not progressing to other more expensive biologic treatments. We believe urticaria patients will use neffy more frequently, providing a potential significant growth opportunity for neffy in the future. Let me now invite Dr. Spergel to go through the epinephrine data and how patients are managed today.
Thank you, Rich, and good afternoon. My name is Dr. Jonathan Spergel, and I'm a professor of pediatrics and Chief of the Allergy program at the Children's Hospital of Philadelphia. My primary research focuses on the translational research in IgE-mediated and non-IgE-mediated food allergy, including novel clinical methods for desensitization and curing food allergy, as well as identifying predictive factors for severity of reaction. I'm delighted to be invited by ARS to discuss the pathobiology and the treatment of Type I allergic reactions and the importance of novel epinephrine delivery products to offer patient treatment options with the fewest side effects and the potential for increased quality of life. Type I allergic reactions are generally caused by exposure to a specific allergen such as food, venom, or drugs.
Type I reactions are typically rapid in onset, occurring within seconds to minutes following exposure, and in rare cases can be delayed up to four hours. Patient advocacy groups estimate that there are between 35 million-45 million people in the United States with a systemic Type I allergic reaction involving more than one organ system. Patients with these allergies experience a significant impact in the quality of life, as avoidance of the allergen is the primary treatment for food and medication allergy, and this often comes with anxiety, depression, and social isolation. Epinephrine is the first line of treatment for these severe Type I allergic reactions and is the only effective therapy to stop the progression of an allergic reaction to a more severe anaphylaxis event.
If a reaction is not treated with epinephrine in a timely manner, patients can experience a higher morbidity, hospitalization, biphasic reactions, and in rare cases, death. Nearly all the anaphylaxis cases are characterized by involvement of the skin or mucosal tissue. For example, angioedema is present in about 40%-45% of the time, extending into the tongue or larynx about 20%-25% of the time. Urticaria or hives are observed in about 50% of cases, as is difficulty breathing. Interestingly, many of the most severe cases just involve the respiratory and cardiovascular tracts.
The formal diagnosis guidelines state that anaphylaxis is highly likely when any of the following three criteria are fulfilled: First, if exposure to an allergen or trigger is unknown, anaphylaxis is likely to be occurring when a sudden onset of redness or swelling is observed and accompanied by either respiratory symptoms such as shortness of breath or wheezing, or a sudden reduction in blood pressure. The second is if exposure to an allergen is likely, the same criteria apply, except with the addition of sudden GI symptoms such as vomiting or abdominal pain, which are observed about 20% of the time. Third, if the exposure to the allergen is known, then reduced blood pressure alone is sufficient for diagnosis, since it is typically one of the hallmarks of severe anaphylaxis. On this slide, you can see the visible clinical manifestations of anaphylaxis.
On the left, we see angioedema symptoms that frequently occur, such as swelling of the face, lips, and tongue. Shown on the right are the lesions and erythema of the skin consistent with urticaria or hives that frequently occur. Since the symptoms of anaphylaxis are heterogeneous, making the diagnosis and real-time prediction of a reaction severity is challenging. Therefore, I recommend that my patients administer epinephrine as soon as anaphylaxis is recognized to prevent progression to more life-threatening symptoms. Epinephrine has been used for more than 100 years and has a well-known pharmacology and mechanism of action. Alpha and beta adrenergic receptors agonism by epinephrine reverses the Type I allergic reaction symptoms. The alpha-1 adrenergic receptor is primarily in the peripheral arteries and increases systolic blood pressure, causing vasoconstriction and decreases mucosal edema. The beta-1 receptor increases heart rate and decreases angioedema.
The beta-2 receptor is the most sensitive to epinephrine, activated at the lowest concentration. It relaxes bronchial smooth muscle to improve airflow and causes vasodilatation in the skeletal vasculature to improve blood flow. We also know that epinephrine can cause a decline in diastolic blood pressure. These three receptors have a dynamic response to epinephrine, which stops anaphylaxis reaction from progressing and reverses symptoms. The beneficial response to epinephrine treatment can be observed through the improvement in heart rate and blood pressure, which are the well-established pharmacodynamic markers that can predict efficacy in severe Type I allergic reactions. Turning to the next slide, literature on clinical outcomes with epinephrine support a single dose as effective in resolving a systemic Type I allergic reaction approximately 90% of the time. If the symptoms are not resolved after that initial injection, guidelines recommend administering a second dose.
That's why we recommend patients always carry two epinephrine devices. Generally, a second dose is needed when the event is more severe or if treatment is delayed. Based on analysis of 12 different published studies evaluating auto-injectors or intramuscular needle or syringe, the need for a second epinephrine dose when an effect was not observed in the first five-10 minutes was approximately 10%, regardless of the device used. This data supports clinical observation that there is no apparent difference in efficacy or time to effect between injection devices. Proper administration of epinephrine is the most critical factor that translates to better efficacy regardless of the device. Typically, patients know they're experiencing a reaction within minutes or even seconds of exposure to an antigen. The common symptoms include flushing, hives, bronchospasm, GI effects, angioedema, or hypertension.
Early epinephrine treatment after symptoms are detected almost always results in good clinical outcomes, regardless of the device used. However, even when patients are carrying their epinephrine product, they typically wait up to eight minutes to administer treatment when the event is warranted and clearly it justifies injection. This hesitation to dose is often due to the fear of the needle and the pain of the injection. This delay in treatment significantly increases the risk of abnormal vitals, the need for repeat doses of epinephrine, hospitalization, biphasic anaphylaxis, or progressing to a life-threatening reaction. The importance of a timely administration is well known, and the frequency of epinephrine treatment has increased over time with more education and increased availability of epinephrine products in the community setting.
However, studies have shown that upwards of 60% of patients diagnosed with anaphylaxis who visit emergency departments in the United States or Canada did not administer epinephrine pre-arrival, increasing the likelihood of a poor clinical outcome. There are four main reasons patients do not use epinephrine before arriving in the emergency room. First, after you prescribe epinephrine to our patients, insurance claims data indicates that more than 40% do not fill or refill the epinephrine prescriptions. Second, if the patients do fill the epinephrine prescription, 55%-60% do not consistently carry a single device, and up to 80% failing to carry the recommended two devices. Three, among those who have devices with them, 40% do not administer epinephrine at all. In fact, surveys indicate more than 50% of parents were afraid to administer an injection to their child.
Fourth, patients who carry and are willing to administer epinephrine have difficulty using the injection device correctly without training and may forget how to use the device over time. Today's injection device, while effective and known to have needle-related risks. Lacerations and bone injections are not uncommon. Based on the literature, I.V. bolus injections of epinephrine have a much higher rate of more serious adverse events compared to autoinjectors. That said, the current FDA labeling for autoinjections includes a needle-related warning as well. It's relatively common that people accidentally inject themselves in their hands or in fingers. There are approximately 3,500 such events reported in the United States each year. These are relatively serious events, especially when a caregiver or a patient self-injects a finger.
Not only is it a danger to the person who administered it, but the patient with the allergic reaction also ends up not receiving the necessary epinephrine treatment, and both people end up in the emergency room for care. Other issues with auto-injectors include pulling the device out too quickly, among other user errors, and other device malfunctions. The importance to the allergy community of removing barriers to prompt administration of epinephrine is reflected in the most recent 2023 American Academy of Allergy, Asthma, and Immunology or the AAAAI Anaphylaxis Treatment Guidelines. Historically, treatment guidelines recommend that patients activate EMS services or go to the emergency room following any administration of epinephrine. This requirement may deter patients and their families from giving epinephrine to avoid visits. The new guidelines allow for at-home monitoring after a single dose of epinephrine to assess if the reaction resolves or improves.
This is work done by my physician colleague, Dr. Casale, who's here today, and others evaluating outcomes of anaphylaxis in the ED during the COVID-19 pandemic. With these new guidelines, nine out of 10 patients will not have to visit the ED after an event. In conclusion, a needle-free epinephrine product like neffy can fill a great unmet medical need for patients and their caregivers. Epinephrine is a systemically active drug, and the route of administration does not impact efficacy. In fact, efficacy is the same across all approved epinephrine injection products, despite PK differences. The efficacy and the safety profile of epinephrine is well established, but delayed administration is the major factor in efficacy and leads to significant differences in clinical outcomes and mortality.
As a result, there is a significant unmet medical need for a product like neffy, one that is needle-free, easy to use, easy to carry, safe, and effective. Thank you again to Rich and the ARS team for having me here today. I'll turn the presentation back to Rich.
Thank you, Dr. Spergel. That was very informative and sets the stage for discussion of neffy clinical data supporting our anticipated approval. Continuing with our agenda, I'll provide an overview of the neffy product candidate and device, and then go through the clinical data generated across our registration program. neffy is a low-dose, saline-based epinephrine nasal spray that combines three well-established FDA-approved components. First, neffy includes the proven efficacy and safety of epinephrine, which has been used effectively in this indication for more than 100 years.
Second, the sprayer device we use is approved for seven innovator products in the United States, as well as many generic products. This is the same proven device that is easy to use without training and in stressful emergency situations, such as with NARCAN, VALTOCO, NAYZILAM, and OPVEE. Third, what makes the injection-like pharmacokinetics of neffy possible is an absorption-enhancing agent called dodecyl maltoside, also known by its trade name Intravail. Intravail is also well-established and used in three FDA-approved nasal spray products: TOSYMRA, VALTOCO, and OPVEE. By itself, Intravail administration in water-based formulations like neffy is not systemically absorbed intranasally. What makes intranasal systemic absorption of epinephrine possible without irritation, pain, or damage to the nasal mucosa is Intravail, which we have licensed exclusively for combined use with epinephrine.
Intravail is a generally recognized as safe GRAS food additive that is non-irritating and functions by loosening the tight junctions in the nasal mucosa. This allows for rapid absorption of epinephrine even at low dose, within the known therapeutic window of epinephrine. Doses of epinephrine higher than that used in neffy increase the risks of excess absorption intranasally and possible overdose, which can result in cardiovascular events that are life-threatening. Intravail also gives rise to our unique IP exclusivity position through at least 2038 without patent term extension. Our composition of matter patent protects the composition of epinephrine plus Intravail and other alkyl glycosides. Our method of treatment patent covers not just Intravail-like absorption enhancers but also low-dose water-based nasal sprays.
Not only does neffy deliver therapeutic levels of epinephrine safely at a low dose without pain or irritation, but neffy is also significantly smaller than autoinjector devices and convenient to carry. Currently, less than half of the patients carry one autoinjector device, and less than 20% carry the recommended two devices. Our goal is to ensure that patients will always carry neffy to ensure timely administration of epinephrine and to reduce the potential for progression to anaphylaxis. If approved, neffy will be made available with a carry case that holds two small devices along with directions for use. In addition, the quick reference guide inside the case will have a QR code that directs users to a brief training video for proper administration.
We designed the case with an attached clip to attach to your car keys or hook on the inside of a backpack or purse, or even the belt loop on a pair of pants. The easy-to-open zipper makes neffy easily accessible even for children when needed. Current FDA-approved epinephrine products include devices that can inject by both intramuscular and subcutaneous routes of administration. All of these products were approved with no clinical efficacy data, and most were approved without PK data. The first approved autoinjector was EpiPen in 1987. EpiPen was approved without efficacy, safety, or PK data, and its registration package was solely based on reference to the FDA-approved injection of epinephrine with a needle and syringe.
In practice, while all approved injection devices, including intramuscular and subcutaneous injections, have very different PK profiles, they have been used interchangeably and all work well, so long as they are administered properly and in a timely manner. Delayed treatment is the most significant factor that results in more serious clinical outcomes or biphasic reactions. On this slide, we summarize the PK data generated with approved epinephrine products. When analyzing the PK profiles of epinephrine products, we focus on Cmax and Tmax. Cmax refers to the highest concentration, while Tmax describes the time to reach that peak concentration. EpiPen tends to be the most variable product from study to study, with the potential for the highest Cmax and most rapid Tmax. Generally, intramuscular injection or IM injections give the lowest and slowest PK profile, with Tmax at approximately 45 minutes.
Other autoinjectors, such as SYMJEPI and AUVI-Q, fall within that range. Regardless of these significant PK differences on both Cmax and Tmax, all injection products work well and are used interchangeably. However, due to the variability of the PK, there wasn't just one product to compare neffy against. Conducting controlled randomized studies in patients with anaphylaxis is considered unethical. Therefore, our development program focused on demonstrating that neffy can deliver epinephrine effectively and safely, having a PK profile within the range of approved injection products. The approved injection products include both intramuscular and subcutaneous injection by needle and syringe or an autoinjector. Intramuscular and subcutaneous injection is the benchmark for efficacy at the lowest range of the pharmacokinetic profile and was the basis for approval of EpiPen. EpiPen's PK profile is at the highest end of the range of currently approved injection products and was our benchmark for safety.
Meaning, exposures to epinephrine higher than that seen with EpiPen poses additional risk to patients without clinical benefit. Having neffy's PK profile within the range of approved products is what we call bracketing, which is supported as the primary measure for use in registration by both FDA and the European Medicines Agency. This bracketing approach reflects FDA's repeated communications to us that the epinephrine therapeutic window is narrow, with both the bottom end for efficacy and the top end for safety. We also measure the PD responses, including blood pressure and heart rate that are activated by adrenergic receptors that reverse anaphylaxis symptoms, as Dr. Spergel presented earlier. A summary of our clinical trials is shown on slide 27. PD surrogates for efficacy were greater than or comparable to approved injection products.
There was a rapid and significant response on PD surrogates for efficacy, such as systolic blood pressure and heart rate, with responses observed even just one minute after dosing. As noted, PK was bracketed by approved injection products and was shown to be comparable across various real-world scenarios, as well as repeat dosing. Turning to safety, neffy was shown to be well tolerated. Well over 700 individuals have been treated with neffy in our clinical studies with doses ranging from 0.5 mgs to 2 mgs. Many of these received repeat doses in crossover studies, and twice dosing, they received two doses 10 minutes apart or 4 mgs total, as could be done in real life. Most adverse events were mild and comparable to injection products. In our clinical trials, there was no meaningful irritation or pain caused by neffy and no risk of absorbing epinephrine too rapidly.
With its needle-free administration, neffy offers safety advantages for both patients and caregivers by eliminating the risk of accidental self-injection into extremities like your hand or injection into a blood vessel or bone or lacerations. This figure on slide 28 aggregates neffy's single-dose PK results from our registration program compared to approved epinephrine products. In this figure, we see neffy in green has a PK profile between intramuscular epinephrine in orange, subcutaneous injection in purple, and EpiPen in blue. Interestingly, the PK parameters of neffy, Cmax, and Tmax are essentially identical to AUVI-Q, an approved branded autoinjector. Importantly, we notice similar results from either self-administration or neffy shown in the dash green line or caregiver administration of neffy shown in the solid green line. Whether you look at separate ARS studies or pre-specified integrated analysis, you can see that the neffy PK data are within the bracket of EpiPen studies.
This table summarizes the Cmax and Tmax obtained from all recent literature, ARS clinical trials, and other publicly reported studies with EpiPen. The table orders from highest to lowest Cmax across studies. The variability of neffy across our three primary studies is much less than EpiPen across both ARS and other publicly available studies. The reason for the variability of EpiPen is due to the technique in dosing. EpiPen can sometimes give an I.V. bolus-like PK profile that is high and fast when it hits a blood vessel, which could be dangerous, or a subQ-like PK profile that is lower and slower when it's injected into the fat instead of muscle. This bracketing is true for the Tmax of EpiPen as well. We also measure the PD responses, including blood pressure and heart rate, that are activated by adrenergic receptors that reverse anaphylaxis symptoms, as Dr. Spergel presented earlier.
Data on neffy's robust responses on PD surrogate markers for efficacy, such as heart rate and systolic blood pressure, are shown on this slide. Physicians have high interest in the PD data, which shows that responses are observed just one minute after dosing and comparable to or even greater than approved injection products, including EpiPen, which could be important in patients with significant hypotension. With these data in hand, the FDA Pulmonary -Allergy Drugs Advisory Committee, or PADAC, held a meeting in May of 2023 and voted in favor of neffy's approval, 17 - five for pediatrics and 16 - six for adults. During the PADAC, FDA particularly emphasized study results from our single-dose nasal allergen challenge study.
Nasal allergen challenge involves spraying purified antigen directly onto the nasal mucosa and administering neffy at peak NAC effect around 15 minutes after administration of the antigen, a worst-case experimental condition which we consider affects less than 0.5% of Type I allergic reaction patients. Under these unique circumstances with neffy, epinephrine is more rapidly absorbed but also declines more rapidly. Even so, epinephrine exposures with neffy were still greater than or similar to intramuscular injection. The FDA requested a comparator for this study through the first 20 minutes. This is important because the effect of epinephrine on the reversal of Type I allergic reactions is observed in approximately 10 minutes; otherwise, a second dose is given. That said, the question FDA had for the PADAC members was that after 20 minutes, would the reversal symptoms or durability be an issue?
Ultimately, all of the key anaphylaxis experts on the committee and all but one of the standing members of the PADAC voted in favor of approval without the need for additional clinical studies. When ARS met with FDA shortly after PADAC to discuss outstanding deficiencies, the agency requested ARS to complete the twice-dosing nasal allergen challenge as a post-marketing commitment. ARS agreed. Later, this post-marketing commitment was changed to a post-marketing requirement, which we also agreed. ARS was not aware of any deviations in the FDA's thinking until we received the complete response letter, or CRL, last September, which requested that ARS conduct this repeat-dose nasal allergen challenge study prior to approval. Following the CRL, we quickly initiated and have now successfully completed this repeat-dose nasal allergen challenge study and are preparing to respond to the FDA's CRL in April.
Epi18 was designed to address the FDA's outstanding questions regarding the about 0.5% subset of patients who require multiple doses of epinephrine and exhibit rhinitis symptoms when experiencing an allergic reaction to food or venoms. Epi18 is a randomized crossover study that enrolled 43 Type I allergy patients with a history of seasonal or pollen-induced allergic rhinitis. The trial compared neffy to intramuscular injection of epinephrine administered by needle and syringe as requested by FDA. The trial also compared how redosing neffy in the same or alternate nostrils may impact responses. After being administered purified antigen nasal spray, all patients received their first epinephrine dose within 15 minutes at the peak effect of this nasal reaction, followed by a second dose 10 minutes later as in real life. What are the key takeaways from this study?
First, as shown on this slide, the results demonstrate that PK exposures and PD response of repeat neffy under nasal allergen challenge, whether given in the same nostril or opposite nostrils, are comparable to or greater than that from intramuscular injection. Second, responses on PD surrogate markers for efficacy, such as systolic blood pressure and heart rate, correlate well with the PK exposures seen with neffy and were consistently higher for repeat doses of neffy compared to repeat doses of intramuscular injection. Third, dosing in the same nostril resulted in higher pharmacodynamic responses than injection at all time points measured, while dosing in the opposite nostril was higher than injection until 40-60 minutes time points, after which PD was indistinguishable from injection.
Similarly, pharmacokinetic exposures dosing in the same nostril were higher than injection at all time points measured, while PK exposures from dosing in the opposite nostrils were higher than injection for at least a period of expected clinical response to epinephrine. Finally, PD responses demonstrated that the epinephrine exposures achieved with repeat doses of neffy in the same or alternate nostrils fully activated the receptors involved in reversing anaphylaxis symptoms within a minute and addressed the FDA's concern from the Epi16 study. While FDA did not provide guidance on the pre-specified endpoints for this study, based on our further interactions after the CRL, we believe that these results will address FDA's concerns presented in the PADAC briefing package and post-CRL discussions, and the data are informative for labeling if a second dose of neffy is needed.
We also have completed human factor validation studies with labeling that instructs to dose in the same nostril twice, where 100% of untrained adults and children are able to read the instructions without training and follow the instructions effectively. Beyond the study we just discussed, the only outstanding request from FDA in the CRL was to complete nitrosamine testing to meet the updated guidance that was introduced in August 2023, a month before our original PDUFA date. We have now successfully completed that testing and have detected no nitrosamines in neffy with a limited detection well below the FDA thresholds for safety. With the completion of both of these items requested by FDA in their CRL, we are preparing to submit our response in April this year with an anticipated FDA approval and launch of neffy in the second half of 2024.
While the FDA PDUFA timeline is six months, we are hopeful that these compelling results will result in FDA approving neffy in an expedited fashion and before the six-month PDUFA period. The data package we have generated for neffy is the most extensive development program of any nasal spray approved in the United States. We believe the data package showcases the potential best-in-class attributes and performance of neffy in real-world scenarios, hopefully giving greater comfort to both prescribing physicians and patients using neffy. I will now turn to Dr. Casale to provide his perspective on how clinicians assess the data package we have generated for neffy and its appropriateness for their allergy patients.
Thank you, Rich. I'm delighted to join all of you in the ARS team for this important event. My name is Dr. Thomas Casale, and I'm a professor at the University of South Florida, where I am Chief of Clinical and translational research in the Division of Allergy and Immunology. I also sit on the Scientific Advisory Board of FARE, Food Allergy Research and Education, the largest food allergy nonprofit, and was previously their Chief Medical Advisor. My primary research focuses on the treatment and determination of the pathophysiologic mechanisms involved in allergic diseases. As my colleague, Dr. Spergel, outlined, there's a significant need for a needle-free option product like neffy. However, for any new medicine, there's always a risk-benefit assessment that must be made.
When I consider recommending a novel epinephrine delivery product to the thousands of allergy patients in our clinics at the University of South Florida, as a clinician, I need to know that the product works, that it is safe, and that patients will actually use it during an episode. To evaluate whether a delivery method will work, we rely principally on PK/PD surrogates for efficacy. We want to see that the PK/PD profile is not only in the range of approved epinephrine products but that it is highly consistent and reproducible across dosing conditions that may occur in the real world, including anaphylaxis symptoms during the event itself, pre-existing conditions, or any comorbidities.
In particular, clinicians want to see robust and rapid PD effects in systolic blood pressure and heart rate to demonstrate early and robust engagement of the receptors that reverse the anaphylaxis symptoms, which give us greater confidence that a product works. When comparing to the benchmarks set with epinephrine injection, we expect to see symptom improvement in the first 15 minutes, about 90% of the time. Once we get comfortable that the product works, the next question is whether it is safe to use. As we see with injections, there is risk of accidental lacerations and blood vessel injections. While needle-free products do not have needle-related risk, they may have other side effects to consider. What may not be obvious from adverse event tables is that epinephrine is known to have a narrow therapeutic window.
To reduce the risk of overdose, the dose of epinephrine in a new delivery vehicle should be as low as possible. As you heard from Dr. Spergel, the presentation of anaphylaxis symptoms is diverse and heterogeneous. New products that cause side effects that overlap with the symptoms occurring during anaphylaxis may confound our ability to monitor clinical response to epinephrine and effectively treat the disease. Now, even if the product is likely to work and has an acceptable side effect profile, the question clinicians need to consider when multiple treatment options are available is whether our patients will use the product, will they fill the prescription, carry the device, and use it when needed. Companies may state that a drug is well tolerated and safe, but specific side effects, even if mild, could impact patient preference and the willingness to use the product promptly.
We see this very clearly with the autoinjectors, which many patients do not fill, do not use, or do not use promptly despite demonstrating efficacy and having an acceptable side effect profile. As a clinician, I'm looking for an epinephrine delivery product with the fewest side effects of any severity that could act as a potential deterrent. In addition, to the extent possible, the product should be palatable, so no unpleasant taste or smell, and certainly no irritation or pain due to its formulation, all of which could deter use, especially if the patient has a negative first experience. Finally, the product should be easy to carry and easy to use, increasing the probability that the patient has epinephrine on hand to administer quickly when they have an allergic reaction. Let's apply this framework to critically evaluate the benefit-risk of neffy.
Turning first to the question of does neffy work, we've seen that systolic blood pressure and heart rate responses demonstrate engagement of the alpha-1 and beta-1 receptors involved in reversing anaphylaxis symptoms and that adequate epinephrine concentrations have been obtained to observe the PD activity. Beta-2 receptors that are involved in relaxation of the airways are the receptors epinephrine has the highest affinity to, and so activating alpha-1 and beta-1, as demonstrated by increases in systolic blood pressure and heart rate, provides evidence that the beta-2 receptor is also fully activated. In children, laryngeal and upper airway edema is the most common cause of fatal anaphylaxis, which is reversed by engagement of adrenergic receptors, especially alpha-1 receptors. Cardiovascular involvement, such as hypotension, is more common during the more severe reactions in adults as well as during reactions due to venom.
Therefore, increases in systolic blood pressure and heart rate are important to observe in order to provide reassurance that the epinephrine product will work during these severe anaphylaxis events. As previously shown, for both systolic blood pressure on the left and heart rate on the right, neffy exhibits an immediate effect as early as one minute. This is a highly reassuring result as systolic blood pressure and heart rate increases are surrogates for efficacy and clinically relevant outcomes that physicians expect when using epinephrine. Further, with repeat doses, neffy's PK profile is higher than repeated doses of intramuscular injection at all time points but comparable to repeat doses of EpiPen. This result is because a second dose of neffy is a consistent, proportional dose, whereas neither intramuscular injection nor EpiPen are dose proportional.
The second dose of intramuscular injection of EpiPen gives much less than twice the exposure of the first dose. This PK profile provides reassurance that during the 10% of events when anaphylaxis symptoms are more severe and a second dose is needed, a second dose of neffy should consistently achieve concentrations within the range of the approved injection products. Again, with both single and repeat dosing, the PD response is very robust with neffy, higher than intramuscular injection, and at least as good as EpiPen, thereby demonstrating that the adrenergic receptors necessary to reverse anaphylaxis symptoms are activated. While efficacy studies in anaphylaxis are not ethical nor practical, especially involving patients experiencing the most severe, potentially life-threatening reactions, efficacy of neffy has actually been evaluated in patients experiencing anaphylaxis symptoms of at least moderate severity, such as those that occur when allergists conduct an oral food challenge.
As presented at the American Academy of Allergy, Asthma, and Immunology meeting last month by Dr. Ebisawa, who is past president of the World Allergy Organization, 15 pediatric subjects were administered a single dose of neffy following presentation of anaphylaxis symptoms of at least moderate severity, grade 2 on a three-grade severity scale, following oral food challenge. While the study was a single-arm, open-label design, 100% of subjects responded. In other words, we had observable clinical improvement in the first 15 minutes following a single dose of neffy. It is even more encouraging that 100% of these patients experience complete resolution of the anaphylaxis symptoms following a single dose, with a 16-minute median time to complete resolution. Dr.
Motohiro Ebisawa reported that a single patient had a biphasic reaction almost three hours following complete resolution of their initial symptoms, which is known to occur at a similar frequency with epinephrine injection. This is one reason why a second dose of epinephrine is required approximately 10% of the time. Moving on, this slide shows the time course of decreasing severity and ultimately resolution of oral food challenge-induced anaphylaxis symptoms. We see clinical response in fewer than five minutes and complete resolution of anaphylaxis symptoms between 10 and 20 minutes, which is consistent with our clinical experience using the improved injection products. This efficacy profile of neffy in an anaphylaxis-induced oral food challenge is consistent with the clinical effects I observe when injecting epinephrine in the clinic, and confirms that epinephrine exposure is translating into clinical effects that are robust and rapid.
Randomized placebo-controlled efficacy data have also been generated for neffy in related IgE-mediated diseases, such as treatment refractory chronic urticaria. In this study, also presented at the AAAAI last month by Dr. Bernstein of the University of Cincinnati, 18 chronic urticaria patients on stable regimen of antihistamines or Xolair who still experience flares were treated with neffy. Patients visited the clinic when experiencing a flare and were randomized to receive either 2 mgs or 1 mg doses of neffy or placebo in a crossover fashion and then evaluated in the clinic for treatment response. Urticaria is one of the most frequent symptoms observed during anaphylaxis and one of the first to show visible improvement after dosing with epinephrine injection.
I'm particularly struck by the consistency of the PK/PD profile within minutes of dosing neffy and the statistically significant clinical improvements in urticaria symptoms in patients that do not respond to anti-IgE antibodies such as Xolair. In total, when you consider the robust PK/PD responses, the clinical efficacy data in oral food challenge-induced anaphylaxis and treatment refractory chronic urticaria, I'm highly confident that neffy will be effective even during severe anaphylaxis. Of course, we ideally want to ensure efficacy across all real-world scenarios, including any outlier conditions. One question that I'm asked by patients is whether rhinitis might negatively impact absorption of a nasal spray. Some may imagine that a runny nose would cause the drug to drip out or congestion would prevent absorption of the drug.
As Rich described earlier, the FDA requested ARS run a study that represents a rare, worst-case nasal insult when compared to normal, real-life rhinitis conditions. Purified antigen was sprayed directly into the nose of allergic rhinitis patients who experienced a severe allergic rhinitis attack with moderate to severe congestion and rhinorrhea and sneezing and itching. This was an artificial worst-case scenario to see the effect of concentrated antigen directly forced onto the nasal mucosa as opposed to a more likely real-world scenario of antigen circulating in the air and patients passively breathing it in. Within 15 minutes after the nasal allergen challenge, which does not allow the symptom severity to subside, neffy was dosed and epinephrine concentrations were measured. Counterintuitively, absorption of neffy was accelerated, leading to higher and faster concentrations in the first 15-20 minutes.
This time period is when we expect to see clinical improvement and if none is observed per guidelines, we give a second dose five-15 minutes later. We believe this may be due to the mucosal edema that occurs during an allergic rhinitis reaction that increases surface area and exposes blood vessels, which could enhance the absorption of neffy. When this data from the experiment was shown at the FDA Advisory Committee last year, committee members stated that they viewed the nasal allergen challenge data as encouraging and favorable because the concentrations were higher than normal in the first 15-20 minutes. Importantly, while the mean epinephrine concentrations rapidly increased during rhinitis and are enhanced with neffy administration, they are within the well-characterized range of concentrations observed with approved injection products with established safety bounds, minimizing overdose risk if too much epinephrine is absorbed too fast.
Mechanistically, epinephrine operates like an on/off switch. Once you give enough epinephrine and it stabilizes the mast cells and reverses the adverse consequences of mast cell mediated release, the reaction reverses and stops and if you don't see an improvement within 15 minutes, you dose a second time to resolve the reaction. Despite this mechanistic understanding of epinephrine, the FDA asked what the second dose of neffy under rhinitis would look like if clinical improvement is not observed in the first 10 minutes. Those results are on the right-hand side of this slide and show that repeat doses of neffy in the same nostril are higher than injection at all time points but still within the therapeutic window of concentrations, while repeat doses of neffy in the opposite nostril are higher than injection through the relevant period of expected clinical response.
In the first 10 minutes following the first dose, neffy exposures all three arms are higher than injection. More importantly, on this slide, irrespective of dosing in the same nostril or opposite nostril, the PD response is robust and rapid, with an increase observed even one minute after dosing and generally higher than injection. Again, the PD response is evident that the receptors involved in reversing anaphylaxis symptoms have been activated, so I personally do not have any concern about the efficacy of neffy whether dosing in the same or opposite nostrils. These data demonstrate that neffy's PK/PD profile is not negatively affected even in a worst-case artificial setting of induced severe allergic rhinitis. ARS also conducted a study in patients under real-life rhinitis conditions. In this study, patients had moderate to severe congestion and rhinitis due to naturally occurring viral upper respiratory tract infections.
The congestion and total nasal symptom score criteria were the same as the experimental nasal allergen challenge studies described earlier. Data show that when rhinitis is induced by real-world conditions, there is no meaningful impact on the exposures or pharmacodynamic response to neffy. In addition, nasal symptoms or rhinitis during anaphylaxis are relatively infrequent, especially compared to angioedema-related mucosal changes that are observed almost 50% of the time. In the literature, about 4% of U.S. anaphylaxis cases report rhinitis or nasal symptoms of note. Despite the infrequency, it's encouraging that we have positive data on neffy in these worst-case scenarios: moderate to severe rhinitis clinical studies for both single and repeat dosing if rhinitis accompanies a more severe reaction. In summary, do I believe neffy will work for patients? Simply stated, yes.
Given the PK/PD data, including both single and repeat doses in rare and most-case scenarios such as severe rhinitis and during self-administration, as well as the efficacy data in oral food challenge anaphylaxis and treatment refractory urticaria data, I'm incredibly confident that neffy will work for my patients. Having critically evaluated and concluded that neffy should work, we move on to whether neffy is safe and related question of whether patients will use the product. The story here is also simple. There are no needle-related risks with neffy and its side effect profile has been shown to be very benign, with mild nasal discomfort and mild headache infrequently reported. There's no stinging, burning, erythema, ulcers, and any other side effects that have been observed with other historic needle-free technologies. Many don't know that epinephrine is quite bitter-tasting, which may be especially problematic when treating children.
neffy has excellent palatability with no taste or smell, which removes yet another barrier to using the product. The adverse event profile for 2 mgs neffy can be seen in the first column of this table, which compares favorably to the autoinjectors, either EpiPen or AUVI-Q, shown on the right two columns. The adverse event profile of these injectable products shows rates of pain between 13%-24%, rates of anxiety between 7%-10%, and rates of injection site reactions or bleeding between 5%-10% of the time. What is not obvious from its adverse event tables and listings is that neffy has also achieved systemic exposures with a low dose of epinephrine. This is important because cardiac complications and even fatalities have been reported in the literature due to accidental overdosing with injection.
The dose range reported in the literature for accidental I.V. bolus epinephrine overdoses is above 4 mgs, so even if neffy's full 2-mg dose were 100% bioavailability, there would be no concern for overdose. This is reassuring as a clinician as it addresses any uncertainty around safety due to increased permeability and absorption that occurs during an allergic reaction or general population variability, anatomical variances or differences, or even the use of other substances or drugs that may alter the nasal mucosa. In addition, it's been reported that high doses can lead to swallowing the non-absorbed epinephrine, causing GI side effects such as vomiting and abdominal pain.
Not only can these side effects deter a patient from using their treatment promptly, but they are even more problematic from a clinical perspective since vomiting and abdominal pain are reported at a frequency of about 20% as a result of anaphylaxis and upwards of 40% in children who experience biphasic reactions one-48 hours later. Use of an epinephrine product that exhibits these GI side effects could confound monitoring of the clinical response, leading to unnecessary treatment and redosing, which in turn may lead to increased frequency or intensity of side effects and would still leave confusion regarding the resolution of the anaphylaxis event. As the data show, neffy has minimal to no such GI side effects. While overdosing with epinephrine is a well-known phenomenon, the PK/PD of an accidental I.V. bolus injection with EpiPen was published for the first time last year by Dr.
Ebisawa and colleagues. As shown in this graph, EpiPen's time to maximum concentration or Tmax is reached within two-five minutes, with a peak concentration about 900% higher than you would typically see with EpiPen when administered correctly. Accompanying this high concentration is a sharp, more than 100 mm Hg increase in blood pressure that could be dangerous in patients with preexisting cardiovascular conditions. neffy cannot inject into a blood vessel and lead to this type of I.V. bolus-like PK profile that is possible with autoinjectors. As Dr. Spergel explained, there are no known differences in efficacy between the various approved injection products. EpiPen has a 10-minute Tmax and the highest concentration at peak. AUVI-Q has a 20-minute Tmax and concentration lower than EpiPen at peak. An intramuscular injection of epinephrine via manual syringe has a 45-minute Tmax and the lowest concentration at peak.
All approved injection routes are observed to result in clincal response within five-10 minutes of injection in 90% of anaphylaxis events, irrespective of the apparent differences in Tmax and concentration Cmax. There is therefore no known clinical benefit from a product having a faster Tmax or higher concentration than intramuscular injection via manual syringe. In fact, as seen in this slide, there is significant evidence that higher or more rapid exposures than EpiPen have potential to increase the risk of the most serious adverse events with epinephrine. What is most important for efficacy is achieving sufficient early exposures. neffy's PK profile in the middle of the improved injection products combined with its low 2 mg dose is therefore ideal.
neffy has shown a faster Tmax than intramuscular injection to ensure efficacy but slower Tmax than EpiPen to ensure safety so that even if there is increased bioavailability of 2 mg neffy that leads to a higher concentration, the body has time for its compensatory mechanisms to epinephrine to activate so that sudden, dangerous changes in blood pressure are unlikely to occur. I do want to call out that vomiting and GI symptoms appear to occur at significantly higher rates in children, especially those with food allergies. Therefore, avoiding GI side effects that would overlap with anaphylaxis symptoms is an important consideration in evaluating the benefit-risk of a novel epinephrine delivery product. neffy, with its low dose of epinephrine in intranasal route of delivery, avoids the GI side effects that have been reported with other novel epinephrine delivery products.
Finally, let's look at the nasal sprayer device itself and whether patients can easily use it. Formal human factor studies have been conducted with neffy showing that 100% of both adults and children with training are able to use the device as well as 100% of adults with no training or experience. Ease of use is critical given that about half of the current epinephrine autoinjection users are children. This ease of use is not altogether surprising given that the same device is available over-the-counter for potential opioid overdose. This real-world reliability with millions of devices used in emergency situations where the risk of mortality is magnitudes higher without recalls is highly reassuring. The device is smaller than the epinephrine autoinjectors. Two devices in the blue case shown above are the same size as a single AUVI-Q and less than half the size of a single EpiPen.
We expect this will be well appreciated by our patients, particularly those who do not carry their devices due to lack of portability. Further, it holds great promise in increasing the probability that patients will carry two devices per guideline recommendations. In closing, critically assessing the risk-benefit demonstrates several important attributes. First, neffy has demonstrated it works. neffy has shown a rapid PK/PD effect within minutes that is supported by rapid resolution of anaphylaxis symptoms due to oral food challenge. neffy has shown a consistent and predictable dose-proportional repeat dose PK profile in the range of repeat doses of injection products. neffy has shown that severe rhinitis symptoms do not adversely alter the PK/PD results. Second, neffy is well tolerated. The side effect profile is benign with just mild nasal discomfort uncorrelated with pain, irritation, or mild headache after treatment.
There is no risk of injury due to needle and no risk of overdose. There are no side effects that confound clinical monitoring and treatment. Third, neffy is likely to be carried and used by patients. neffy is palatable with no taste or smell. There is no pain or irritation in delivery. neffy is small, the smallest device on the market, with two devices fitting easily in your pocket. neffy is easy to use, showing 100% of people can use the device without error. We believe the allergy community is eagerly awaiting new treatment options and neffy, if approved, is expected to meet such need. I greatly appreciate the efforts by the ARS team to advance this product candidate and their commitment to bringing forward a new option that I, like many of my treating colleagues, am excited to offer my patients once FDA approval.
Thank you, Dr. Casale. This has been a great session today and I am pleased to walk through our efforts at ARS to make sure that all patients who need neffy have access to neffy. My name is Eric Karas and I am the Chief Commercial Officer at ARS. It is exciting to be part of a team that is developing the first needle-free epinephrine treatment and to lead our commercial organization. Our team is comprised of dedicated and experienced professionals who are fully prepared to launch and deliver neffy to patients with severe allergic reactions. neffy presents a significant opportunity to change the treatment of Type I allergic reactions. With 40 million people in the U.S. alone suffering from this condition, the epinephrine market has experienced a compound annual growth rate of 6.5% since 2010.
The population is known to be responsive to promotion, yet there are limited direct-to-patient education and awareness campaigns. As we think about our commercial strategy, there are roughly 20 million patients who have been formally diagnosed and are managed by a physician, usually an allergist, of which approximately 3.2 million patients filled a prescription for epinephrine in 2023. More than 6 million patients today either do not fill their epinephrine prescription, do not use their current device at all, or use their device incorrectly. Dr. Spergel discussed the varying reasons patients do not fill their prescriptions and how they delay treatment with or misuse their autoinjector devices. The decision to avoid a known effective treatment is influenced by factors such as needle aversion, size, and portability of the injector.
We firmly believe many of these reasons can be addressed with a product like neffy, which is reliable, needle-free, easy to carry, easy to administer it. Ultimately, our goal with neffy is to bring forward a treatment solution that will help patients use their medication properly and in a timely manner. There is substantial opportunity to penetrate and significantly expand the epinephrine treatment market. The opportunity for neffy lies both in converting patients currently filling their prescription but dissatisfied and not carrying or timely using their auto-injector device, along with those diagnosed who are without treatment. We believe that neffy provides a best-in-class profile in terms of convenience, reliability, and speed of treatment for patients and caregivers. It is a simple place-and-press administration of medicine through a small, needle-free, easy-to-carry nasal spray device.
Based on our market research, neffy is positioned to be the solution that addresses current unmet needs in the severe allergic reaction market. Based on our research, a majority of patients that currently have an epinephrine prescription are likely to inquire about neffy. Around 90% of patients who did not fill their prescription stated that they would ask their physician about neffy. Further, of the patients that use over-the-counter medicines like Benadryl, which does not stop disease progression, including progression to anaphylaxis, more than 70% said they would use neffy first. And perhaps most importantly, approximately 80% of patients would opt for using neffy sooner than current needle injectors. The bottom line is that neffy's product profile clearly aligns with the needs of patients. It is also clear that neffy's attributes align with the needs of physicians.
HCPs give neffy a high rating and view the product candidate as a major advancement in treatment. Importantly, if a patient asks for neffy, our market research shows that 99% of physicians say they will prescribe it. Across specialties, when it comes to adoption, 2/3s of allergists and more than half of the general practitioners said they would start prescribing neffy as soon as possible upon FDA approval and launch. A majority of pediatricians expect to prescribe neffy within one year, with more than 40% noting they would prescribe neffy as soon as possible. The market research results for patients and caregivers are also very encouraging.
According to a survey of 100 patients and 100 caregivers who had actually injected epinephrine in the 12 months prior to the survey, both groups reported that they would use neffy much sooner after symptom onset in about half the time compared to their needle injector. The survey also found that 85% of patients and caregivers are likely to carry neffy with them compared to 55% that they currently carry at least one epinephrine device. Additional survey results show that patients and caregivers are highly motivated to discuss neffy with their healthcare provider, with 72% willing to schedule a special appointment just to do so. Given the contrasting statistics between needle injectors and neffy, we are optimistic about neffy's potential to improve patient readiness and care.
To put all of this in context, we want to share with you what we continue to hear from people in the severe allergic reaction community. The following is video speakers during the open public comment portion of the FDA advisory committee meeting held last May. The testimonials we heard in that meeting are the same as what we continue to hear today. Patients and caregivers are in desperate need for treatment that addresses the known challenges with current injection devices.
We saw in one survey of epinephrine autoinjector users that half of the adults and 30% of the children reported not having used epinephrine during at least one severe allergic reaction, in part because of fear of needles. And if you're afraid to use epinephrine first and fast, your risk of death increases. It's that simple.
She knew she needed EPI, but her first instinct is always to hide her reaction so she won't have to be stabbed again. It took the strength of my husband and I both to physically hold her down and inject her with EPI. The treatment is fear as much as anaphylaxis.
Though we carried this epinephrine everywhere we went, I subconsciously never imagined myself or anybody else having to administer what I believe to be a larger-than-life needle into my son's skin.
It's hard enough having to deal with food allergies, but knowing that if you have a reaction, my only option is to get a shot. It brings me fear.
This weekend, I actually had an allergic reaction, but I was very hesitant to give myself the EpiPen. And I kept trying to give it, and then I was like, "No, I don't need to," but, like, "I need to give it because it was life-saving." And if we can get this nasal epinephrine, it would be a lot better and a lot easier. I won't have to worry.
This new product will provide a first-line treatment option for anaphylaxis that is equivalent to an epinephrine autoinjector. And more importantly, it will be more effective because it's more likely to be carried and used at the onset of anaphylaxis.
In addition to these voices, we've heard from over 50,000 people advocating for and requesting access to neffy. It is clear that advocacy groups, parents, children, and healthcare professionals are waiting and excited about neffy. Let's transition to our commercial strategy, which is grounded in a comprehensive understanding of the patient and provider experience.
Personally, I have over 27 years of commercial experience. Prior to joining ARS two years ago, I was the general manager for North America at ADAPT Pharma and was responsible for commercializing NARCAN, a leading intranasal product. Both NARCAN and neffy use the exact same nasal sprayer device. NARCAN was also the first FDA-approved needle-free treatment for its indication of opiate overdose, and it achieved a 90% market share four years after launch. Like me, each member of our leadership team has more than 25 years of experience in the respective core functions. Together, we know how to bring a product to market and to grow the market over time. As a team, we have three main launch objectives: education, access, and activation. We are confident that neffy has a unique and convincing value proposition that will encourage people to use it.
We are committed to making neffy affordable for everyone, and we will offer patient assistance services for both patients and healthcare providers. Additionally, we have multi-channel plans ready to raise awareness about neffy and to educate and motivate patients and caregivers to specifically request it by name. If approved, we expect to launch neffy approximately eight-10 weeks once we have supply in place for distribution and the sales team is hired and trained. Our customer-facing team of 110 area managers and sales representatives will be calling on approximately 12,500 allergy specialists and high-volume treaters. In addition to targeting prescribers directly, we will have several educational and awareness initiatives planned to help drive adoption. We will also provide the neffy Experience Program, which includes a limited supply of courtesy packs of neffy for healthcare providers to utilize during their food challenge clinics.
We believe that this hands-on experience will help strengthen the trust and confidence healthcare providers have in neffy. Rapid payer coverage and patient access support are vital to our success. In the past year, we have developed a strategy to gain access to the market and have interacted with many payers to gather insights. We have received positive responses from payers during our clinical presentations, indicating that there is high interest in our product candidate. We will contract for unrestricted access and aim to achieve 80% commercial coverage within one year from launch. We plan to implement several programs. Patients with commercial insurance will be eligible for a copay savings program where most will only have a $25 copay. For those who are either uninsured or have a high-deductible health plan, we will offer a cash price of $199 for two doses of neffy.
In addition, patients who are underinsured or uninsured and meet certain criteria may be eligible to receive neffy at no cost through our patient assistance program. During the initial months of launch, the neffy Connect Program will assist in managing coverage by providing patients, caregivers, and healthcare providers with information regarding patient support programs and financial aid to help them navigate their treatment journey, including insurance requirements. We're excited about the neffy Connect Program as it embodies our mission of supporting patients and families in accessing epinephrine treatment. The third part of our commercial strategy is focused on creating awareness and encouraging patients and caregivers to specifically seek neffy as a treatment. Epinephrine can only be effective if it's readily available, if it's used at the first sign of symptoms, and if it's administered correctly.
We have a multi-channel consumer campaign ready to ensure that patients and caregivers are aware of neffy as a needle-free, easy-to-carry, easy-to-use treatment. We want to empower patients and caregivers who are at risk of severe allergic reactions to be well-prepared for any potential emergency. We have heard significant enthusiasm for neffy among patients and particularly parents of children who suffer from severe allergic reactions. It is critical that these individuals are aware of this treatment option and that they can request neffy by name from their healthcare provider. The use of nasal delivery as an alternative treatment has shown incredible results, and we're confident in our plans to successfully enter and expand the epinephrine market. For instance, VALTOCO and NAYZILAM collectively captured 75% of product share in the epilepsy market after launching during the peak of COVID.
Their market adoptions are good examples of higher demand for intranasal delivery treatments over other delivery modalities. As we consider the potential to convert and expand the market, we believe that neffy can achieve significant peak sales. This graph outlines the opportunities to expand the market to 14 million two-pack devices by 2034. The base epinephrine market is about 5 million two-packs annually, and there is a natural 0.6% year-over-year population growth. We expect some patients who never filled their prescriptions or avoided engaging with physicians due to needle-related or other reasons to engage their physician over a convenient needle-free treatment like neffy. We believe the diagnosed and treated population will grow further due to the impact of patient education from disease awareness and direct consumer marketing activities.
We also expect patients to use neffy more often than current epinephrine treatments due to the convenience and comfort with using a device like neffy. We believe patients are more likely to have their prescriptions on them during an allergic reaction and are more likely to administer neffy as opposed to going straight to the emergency room. Together, we believe the number of epinephrine two-pack devices sold in the U.S. has the potential to grow by approximately 9 million, if not more. I'm excited about what's ahead for us and for neffy. This product candidate is the first significant innovation in epinephrine delivery for over 35 years. We believe that neffy provides the attributes that patients, caregivers, and healthcare providers need and are looking for, and it is well-positioned to transform the care of people with severe allergic reactions. I'll now turn the call back over to Rich.
Thank you, Eric, and thank you to our audience for participating. We have an incredible opportunity ahead of us. As noted earlier, we are preparing our response to the FDA's CRL, and with the expected six-month review period, we are gearing up for anticipated approval and launch of neffy in the second half of 2024. We stand well-positioned to execute those efforts. We ended the year with a strong balance sheet of $228 million in cash and securities and no debt. This provides us an operating runway of an expected three years based on our current plans, which includes the launch and commercialization of neffy in the United States. We are wholly focused on launching and commercializing neffy in the United States and likely Canada. However, there is also significant opportunity for neffy to grow and expand the epinephrine market outside the United States.
Due to lack of almost any historic branded promotional or educational programs in the rest of the world, unlike the United States market, market adaptation rates are less than half of that in the U.S. overseas. We have already partnered in Japan and China and plan to partner in Europe and other regions, which will provide additional sources of value creation and cash flows to further strengthen our financial position. We have an exceptional team in place, and as you have heard, our U.S. commercial readiness efforts are well in hand. We are underway with our plans to help bring neffy to markets worldwide and to expand its utility into other allergy indications in the future. In closing, I'd like to thank our collaborators at FARE for their incredible support and enthusiasm for neffy. Thank you also to Dr. Spergel and Dr.
Casale for participating with us today and for sharing your perspectives. I'd also like to thank the physicians and medical teams who participated in our clinical trials and market research in an effort to advance neffy to an approval worldwide. Lastly, thanks to the patients who have been part of neffy's development program. Our number one goal since founding our company has been to bring patients a safe and effective, easy-to-carry, and easy-to-use epinephrine treatment as an alternative to current injection products. We are confident that neffy can be that treatment for patients and caregivers, especially the children and parents who have to deal with the daily stresses of managing their disease. This concludes our prepared remarks. We are now ready to take questions and answers for the rest of our event.
Great. So we'll now move on to the Q&A portion of the event. If you'd like to ask a question, please type it into the Q&A box shown in the bottom left of your screen. We'll start by taking questions from our analysts and then come to any additional audience questions. Could the operator please open the line for our first question from our analysts?
Thank you. And as a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question will come from analyst Tim Lugo from William Blair. Your line is open.
Thank you for the comprehensive presentation. I have a couple of questions on the marketing side and then maybe on the data. From a marketing perspective, given the kind of unfulfilled prescriptions and the response rates you're seeing from your survey data, it suggests that maybe you should eventually directly try and access patients through DTC. At what kind of point of the launch do you think DTC will be appropriate?
Yes. We would agree, Tim, and I'll let Eric go ahead and speak to that directly.
Thanks for the question, Tim. Absolutely. There's an opportunity here to educate and build awareness among patients and parents and caregivers. When we look at our strategy, we want to make sure that we secure access so it's easy for physicians to write the product and easy for patients to get it filled and affordability. We also want to make sure that we're driving adoption. So as we hit those key success factors, we'll be investing more into direct-to-consumer advertising.
But even at launch, there's several omnichannel social media, online, different things that we'll be doing to raise awareness, especially also working with our advocacy partners. They clearly see the benefits of neffy and the need in the marketplace and that we help fulfill that unmet need. So as time goes on, we're not only looking at branded kind of education and awareness, but also looking at unbranded and even considering PSA with one of the advocacy groups as well.
Okay. Thank you. And maybe on the pricing side, I think you suggested $199 for two doses. Is that a net price after discounts? And what is kind of the patient's out-of-pocket price going to look like versus the kind of economic value of that prescription?
Rich, I can take that one as well. So just to clarify, the $199 price is a cash price.
So if patients are in a high-deductible plan or for whatever reason they don't get coverage, they can pay cash $199 to access neffy. The way this is set up, this wouldn't be going through their insurance, so we wouldn't be paying any type of fees on that or rebates on that. At this point, we haven't shared anything specifically about our WAC. But as we look at the marketplace, and we've spent a lot of time on this talking with physicians, patients, and the payers, and most important, the advocacy groups, the most important thing that they're concerned about from an advocacy perspective is, what does the patient pay out of pocket? And as I went through in the presentation, we'll have a copay buy-down program to $25 for eligible commercial patients.
Then we'll also have a patient assistance program if a patient is in a situation where financially they can't afford the product. If they're eligible, they'll be able to access it potentially for free. So we spent a lot of time looking at this. And when we also spoke to payers in our market research and advisory boards, because they see the unmet need here, they see the complications with a needle injector product, they see the potential AEs, and they see all the value that neffy can provide in terms of an easier product, needle-free, easy to carry, the importance of a patient using at the first sign of symptoms, they really see the value of this product. And a modest premium to the other branded products in the marketplace, they feel, is appropriate.
Further, in addition to the clinical data, when we've gone through even information on our shelf life and temperature excursions, that provides even more value to the payers, and they're very encouraged by that profile for the product. So we're pretty confident, again, overall in our pricing and also making sure this is affordable and accessible for patients.
And Tim, just to add one point to that.
Thank you for that.
Tim, sorry. Just to add one point to that. Our $25 copay for most commercial-insured patients is actually lower than the generic price for the EpiPen generics. So they're averaging on filled prescriptions about $40 copay and even higher on abandoned prescriptions. And AUVI-Q is even a higher copay than that. So we actually will be very competitive from the patient perspective as far as the copay, even against the generic autoinjectors.
Thank you for that detail. On the development side, and this will be my last one, similar to how ARS had to run this kind of rare worst-case scenario and nasal insult study, do you think the FDA is going to require other companies in the space to run similar studies, even if maybe they're developing orally dosed products? And obviously, that would be kind of it wouldn't be a nasal insult. It would be some sort of other insult.
Yeah. We would expect that, actually. And in fact, as we pointed out during the presentation, the nasal route of administration is really the ideal route. I mean, it has the least potential for any kind of comorbidities with the allergic reaction to actually impact the absorption.
So rhinitis symptoms or any nasal symptoms, in fact, only occur in about 4% of the patients with a food allergy, as we showed in one of the slides. And these will be for some of you online that have asked in the chat line, these will be posted at our website after the presentation. But oral is a much more difficult route for this disease because about 50% of the patients are going to have angioedema, tongue swelling, lip swelling, other types of symptoms that affect oral. And about 20% have vomiting or other major GI symptoms. So oral route to us is not as ideal as nasal. And then other routes, we don't know about. There are other possible routes of administration, but we just don't know the effect of epinephrine, for instance, on the skin or other routes that could be used.
So we really believe that nasal is the ideal route of administration for an emergency use product like this.
All right. Thank you so much.
Thank you. One moment for our next question. Our next question will come from the line of Andreas Argyrides from Wedbush. Your line is open.
Hey, guys. And thanks for taking our questions. And also appreciate the thorough analysis here. It's been very helpful. Three questions for us. So you provided a lot of market research on the several segments of the autoinjector market. The current EpiPen and generic market is roughly $1 billion. So how are you thinking about penetrating the various segments of the epinephrine market and potentially growing it beyond the current autoinjectors and generics? I'll start there.
Yeah. I'll speak to that a little bit and then turn it over to Eric. I think where we see a huge gap in this indication, and we've been studying this for many years, and it's of any indication I've ever worked in, this probably has the largest educational gap with patients and caregivers and even doctors. So we work with allergists who are really very experienced and really well-published. And even allergists at AAAAI that we meet with are really the ones that are seeking education. But we know a lot of these patients are visiting general practitioners or others.
So we believe educational programs and really focusing on making sure people understand the use of epinephrine and working with the advocacy groups and the physician groups to really expand that, we believe that will bring a lot more people into the market who really need epinephrine and should have it but are not prescribed epinephrine and may even be prescribed things like Benadryl, which do not work to stop the reaction. So that's a big focus we're going to have in trying to expand this market beyond the auto-injector market. And of course, many of the auto-injector users are very unhappy with the auto-injector. So there'll be a large percentage of those that will switch because they're really not carrying or using the auto-injectors.
But focusing on patient education and also getting to the general practitioners and educating them on the proper use of epinephrine and supporting the advocacy groups and the medical community in doing that, I think, will go a long way to expand the market. Eric, do you want to go ahead and continue?
Yeah. To build on that, it's key in terms of the education. There's a great opportunity here to build awareness, not only with patients, caregivers, and parents, but as Rich said, with the medical community as well. There's a significant amount of work that we'll do around direct promotion, nonpersonal promotion, publications, CME, non-CME, speaker programs, a lot of awareness and education at conferences to really help not only understand the attributes of neffy but the appropriate patients.
When we look at the segments, first, the 3.2 million patients that have treatment right now, we know statistically from the research, 80%-90% of them are not compliant. They're not carrying the product. They're not using the product when they have symptoms. That's a major issue. In addition, there's another 3.3 million patients over the last couple of years that have had a prescription. Once it's expired, they haven't refilled the prescription. There's a group within that too that just hasn't filled the prescription, even though a doctor gave them a prescription. Combined, that's about 6 million patients. We see that as a prime opportunity to educate physicians. We see this in the research, as I mentioned in my comments. Patients that have treatment, they're very interested in our product. They're going to talk to their physician about it.
Patients that haven't filled or refilled their prescription, they're also very motivated to talk to their healthcare provider about this. And when you talk to them in market research and you ask them the reasons why, again, it comes down to needle, size, and portability. And obviously, we address all of those. In time, we'll be looking to expand even beyond that 6 million to the 13.5 million. But our education will be across the board in letting patients know that there's something that's easier, that's needle-free, that's easy to carry. And it's really important to be prepared in the event of an emergency. So as I mentioned to Tim and Tim's question, a significant amount of education, unbranded, branded.
We're very excited about potentially a PSA idea and then also partnering with advocacy to make sure that they're helping us, and they're very motivated by this, to build awareness and to educate patients as well.
Okay. Great. And for the team and Doctors Casale and Spergel, maybe we could start with just there was recent data for the repeat dose nasal study. And the repeat dose in the same nostril performed better than the contralateral nostril. Maybe you could talk a little bit about and maybe this is likely due to neffy's ability to reduce inflammatory response. Maybe you could just provide a little bit more clarity on why you believe that the same nostril works better than the contralateral. And then lastly, maybe some additional thoughts on the Urticaria data. This is for Doctors Casale and Spergel, on how the data has potentially provided evidence for neffy's efficacy. And how do you see neffy having the biggest impact in the urticaria market?
Thanks. Okay. So I'll start with the question about the rhinitis study and then go ahead and turn it over to Doctor Casale and Doctor Spergel to speak a little bit about the urticaria data. So the result in our study is actually quite expected. In fact, it was really anticipated by FDA too. But it answers one question they had with us about the potential for twice dosing with rhinitis. So as you might recall and we presented, twice dosing with neffy under normal conditions, normal nasal conditions, which is, again, the vast majority of the cases when you have a food allergy reaction, was very, very dose proportional, well behaved.
So we get a single dose, and then a twice dose was literally 200% double the single dose. So that was not a concern for FDA. They were questioning whether that second dose would be absorbed well and better because epinephrine is very well known to reverse the effects of rhinitis, and it's very rapid at doing that. If you look at our data, the second dose, even when we dose contralaterally in the opposite nostrils, is actually better than the first dose. But in the same side, you're really affecting the rhinitis. You're reversing the rhinitis very rapidly. So the second dose is even better absorbed and really almost the same as under normal conditions. So we really kind of anticipated that.
But FDA did want to confirm that because they had some reason in the background to believe that there may be a negative effect and that twice in one nostril may actually be poorly absorbed. But this proves that that's not the case, that there's no other effects going on like vasoconstriction or other things that some people may have been worried about. And this is really showing what we anticipated and, in fact, many at FDA anticipated, which is that the first dose is actually more or less curing the rhinitis. And the second dose looks just like a normal condition dosing. And that gives us great assurance that there'll be no issue with efficacy with neffy, even under this worst type of situation. Now, maybe I could let Dr. Casale speak to urticaria data since he presented some of that.
And then Doctor Spergel can add to that if he has any comments.
Thanks, Rich. I agree with everything you said about the nasal challenge model. And I think just decreasing congestion and stopping mucus production is a big plus for using the same nostril, maybe why we get better absorption. For the urticaria study, we did that for a couple of reasons. The first is that even though we have great PK/PD data, I think clinicians want to have some assurance, does this preparation work in a disease that we might want to treat or in a manifestation of a disease like food allergy? So we know that people with food allergies, when they have an allergic reaction, often have urticaria.
The fact that by using epinephrine intranasally, those urticarial lesions were markedly improved in a very rapid time course is reassuring that the drug, in fact, reaches target organs that we are concerned with as clinicians. It has a rapid onset of action, and it relieves symptoms evaluated by both patients and clinicians. So I think this is a type of study that is, as I said, very reassuring but also points to the need of another potential way one could use epinephrine. If you have acute urticaria and you have to get some relief, or if you have chronic urticaria and you want to get some relief, using an epinephrine product such as this will give you temporary relief. It's not going to cure your disease, but it will give you relief that lasts for hours. And oftentimes, that could make a big difference in people's lives.
I'm just going to add one thought. When patients have acute reactions, many patients are too nervous to use their epinephrine device. So they treat with antihistamines. Now, knowing that they can use this device and really resolve their urticaria. They may be much more willing to treat with an epinephrine device, which is going to be the correct treatment for not only their urticaria but for their anaphylaxis. So I actually think it's going to be encouraging to families like, "Hey, this medicine is going to treat your urticaria. You'll get better," whether your urticaria is acute, preceding anaphylaxis, or it's just random urticaria. I think that's going to be a major benefit. And the other comments I agree completely with our last two speakers.
Okay. Great. Thanks for taking our questions.
Okay. Thank you. One moment for our next question. And our next question comes from Roanna Ruiz from Leerink Partners. Your line is open.
Great. Afternoon, everyone. So a couple from me. First is, if neffy is approved, I was curious, how long might it take to add neffy into medical guidelines for Type I allergy? And to what degree do you think these guideline additions might be a tailwind for neffy use and prescribing, particularly with primary care physicians in general?
Okay. So just to start out with that question, so I think we're already proactively working. There's different types of guidelines, different types of issues we're working on. For example, there is a lot of also local legislation that we're already proactively working on and have actually been successful already in some states in making sure that legislation is not specific to autoinjectors and talks to any FDA-approved epinephrine product. With regards to the guidelines from the medical communities, I'll refer to Doctor Spergel first and then Casale on what they think the time frame of updating those guidelines are and whether really there's much impact at all on the use of neffy given the guidelines that are out there today. Doctor Spergel, do you want to do you want to start?
Sure. So it's going to be an interesting question. It depends on how fast this gets approved. The guidelines, since the new guidelines recommend not going to the they're being revised. The anaphylaxis plan is being revised right now. So if it can get and that probably will take, excuse me, several months because those things move slowly. So it is entirely possible they can be added into this current update if things move, depending on the FDA. So it could be very quickly.
I think it's not going to be a major obstacle. I am not a writer of the guidelines, but many people who've written the guidelines have written articles talking about the need of other devices. So I think there's a general consensus among the guideline people that they will accept this pretty quickly. But it really depends on timing. But if experts out there and I think there's a general consensus, as you can see in the previous slides, that everyone is excited about it, I think there's going to be a very rapid uptake in its use. So I'll pass it on to Tom if you have other thoughts.
Yeah. Thanks, Jonathan. I think one of the reasons that the new guidelines have been updated to state that you don't necessarily need to activate EMS when you have an acute allergic reaction from food or venom or whatever is because when we looked at the information out there, it turns out that a lot of people hesitated to use epinephrine because they didn't want to activate EMS. They were embarrassed that an ambulance might come, etc. So they didn't bother using epinephrine, period. Now that that barrier is overcome with the revision, I think people will be more eager to get the appropriate treatment more rapidly by either treating a loved one or treating themselves. And having a needle-free option, I think, will definitely accelerate that. And there are also many paramedics that are eager for this type of option because they're used to using NARCAN in overdoses.
This would be another way that they could render emergency treatment. We, as a specialty in allergy and immunology, have been pushing for better educational programs, especially in regards to emergency medical responders as well as emergency rooms because oftentimes we see there's a reluctance to use epinephrine, which is, as Jonathan said, the absolute first-line treatment. So showing an intranasal needle-free product that's safe and effective will hopefully help us as educators move the needle even quicker towards the uptake.
Yep. And so, Eric, just to tie this up, so if other routes of administration, neffy nasal, is not yet included in the guidance, do you see that as much of an impact on the marketing?
I don't. I mean, from a payer perspective first in the retail space, there's strong interest in this product for all the reasons that we talked about.
So part two of our strategy, once we are approved, is to move forward and push for formulary reviews for the P&T committees. So they're not going to look at any guidelines to say that restricting this product. They understand the challenges in the marketplace. They understand the compliance issues, and they really see our value proposition. So this is not an issue. I think Rich, as you spoke, on a state level with school legislation, that is something that we're working closely with advocacy on. Wisconsin has updated their law about six months ago to make sure the language is broad, not just needle injectors. And then a bill was just introduced about two weeks ago in California. It has bipartisan support. And the bill right now, the way it's written, is it has a broad language around epinephrine. It's not specific to epinephrine needle devices.
So I don't see this being an issue.
Okay. So, Roanna, hopefully that answers your question.
Yep. Super helpful. And just wanted to follow up on the Japan study as well with the oral food challenge-induced anaphylaxis symptoms. I was just curious, how well can physicians extrapolate that data to help them understand neffy's performance in more severe situations like grade 3 anaphylaxis, particularly in the U.S.?
Yeah. I'll let Dr. Casale speak to that. But one thing I'll point out is that ideally, when patients experience symptoms, they're supposed to be treating themselves really at the first signs of symptoms, right, so that you're going to treat yourself early. So that study really represents kind of the real-world way that neffy should be used. And we expect it to be used. And again, a lot of the people are delaying treatment because of fear of the needle, or they're just not carrying their device. So if we can improve on those areas, we think people will treat themselves sooner, and it will be more reflective of what real life is. But Doctor Casale, you can speak to the more severe anaphylaxis and any concerns in that area.
Yeah. I think the biggest thing that we've learned over the years is that there are a couple of factors that tie into the severity, the ultimate severity of a reaction, as well as the potential for a mortality. And that is delay in epinephrine use. So having a needle-free option that's readily available, I think, will abrogate a lot of these more severe reactions.
Doing a study like Professor Ebisawa did, where you're doing oral food challenges to things that people are allergic to until they get a grade 2 or grade 3 reaction, and then reversing that rapidly with the intranasal epinephrine in all 15 instances, I think, is extremely reassuring for all of us who want to try this option for our patients and also in clinic when we do food challenges or when we do allergy shots or other things that, unfortunately, may provoke an acute allergic reaction. So I'm very encouraged by the results. And I think this is a positive step forward for the product itself.
Yeah. And then one other point just to make is that, again, our whole strategy was to design neffy to be within the range of injection products, which are all known to be very effective, even in more severe anaphylaxis.
Our PD responses in blood pressure, heart rate are actually as good or better than EpiPen and better than IM, as you've seen in our data. So that should give real reassurance. Then finally, we talked about the urticaria data, but that's really demonstrating mast cell stabilization. And that's really critical in a severe reaction, that you immediately stabilize mast cells, maybe the most important function of epinephrine, in order to stop the reaction from progressing and allows the patient to recover quickly. So we really don't believe there's any concern about the severity of the anaphylaxis, that it should be as good as injection products. And certainly, we know those are effective.
But also, we've demonstrated in multiple ways that it should behave at least as good, if not better, and especially that urticaria adds that aspect of that data to the whole story where we can see mast cell stabilization almost immediately after administration.
Yep. Got it. Thanks.
Thank you. And I'm not showing any further questions over the phone line. I'll turn it back to our speakers for any other questions.
Okay. Thank you. So we'll move on to the questions from the audience members now. We did several questions around neffy's shelf life and temperature stability. Rich, if you wanted to answer that.
Yeah. So we anticipate, based on our interactions with the FDA, that the initial approval will be with a 24-month expiry. That's longer than the current autoinjectors, which are 18 months.
In addition, we've done stability for three months at 50 degrees Celsius, 122 degrees Fahrenheit. We did that to replicate car temperature in the summer. For three months, neffy met specifications at that temperature, so much better. We published that at AAAAI recently, where autoinjectors fail very quickly at that temperature. As far as high temperature, there will be a statement in the labeling that says excursions are permitted up to that temperature, 122 degrees Fahrenheit, for short periods. We don't want it stored at that temperature, of course. But if it does heat up to that temperature, the device is still fine. The product is fine. In addition, a lot of the autoinjectors can't be frozen. In fact, I think all of them can't be frozen. If they freeze, you could have a failed injection, so the device may not work properly.
neffy can be frozen. Again, we're not recommending you freeze it. It's inadvertent. So if you leave it in your car in the winter and it freezes, it doesn't freeze that easily, but it freezes maybe about 5 degrees Fahrenheit. But if it accidentally freezes, you could just thaw it out, and it's fine. And there'll be labeling to speak to that as well, that if inadvertently frozen and thawed for 20 minutes before use, of course, the device won't function when it's frozen, but once it's thawed, it should not affect the device at all.
Great. Thanks, Rich. Then we had a couple of questions I think that are probably directed to our two guests, allergists. Someone's asking what types of patients would be appropriate or not appropriate for neffy.
So this one is obviously, there's a weight at the current dose, the 2 mg dose. So it's basically anyone who doesn't have some rare facial abnormalities would be an ideal patient. I can't think of anyone who would not be a good patient for it, to be honest. Patients ask. I often have patients ask me, "Is there any device coming on the market?" Because patients know. And I said yes. They're like, and I describe it similar to the device from NARCAN, and they're all very excited. So I can't see anyone I would not prescribe it or give them the option. Obviously, patients can have a choice of which device because I think efficacy and safety will be anything the same, if not better.
I agree. I think the only exceptions, as Jonathan pointed out, is if we have patients that have some sort of obstructive nasal disease like severe nasal polyps or a very severe deviated nasal septum. We would have to evaluate those patients a little bit more closely. But otherwise, this would be a wonderful option for the vast majority of patients.
Great. And then we had another question about there's multiple needle-free delivery options in development, right, including nasal sprays and sublingual. Kind of if there's any commentary from ARS on those other approaches and how neffy compares.
Yeah. We don't want to speak directly to other potentially competitive products and their data, but we could speak to the benefits of neffy directly, which I think could address that question. So as we said, the nasal route, we believe, is the ideal route of administration. Very few side effects of anaphylaxis, of food allergy reactions, would impact the absorption. And as you saw, that would entail a 4% or so of the population that could have nasal symptoms, rhinitis-type symptoms.
That's why FDA asked us to challenge that condition, and we showed that data today. In addition, we're using epinephrine. We're not using a prodrug or other types of modifications of the epinephrine molecule to be able to get absorption. So when you use a prodrug, you also have other potential risks involved and potentially even safety risks because the drug being absorbed initially is not really the target drug that it then forms in the blood. The nasal spray device, as we said, is well proven. It's very rapid to administer. You just place, press, fire. You don't have to hold it. You don't have to hold it like an autoinjector in place, and you don't have to hold it in your mouth.
So it's really very simple and easy to deal with a child that may be panicking from an allergic reaction to basically just place, press, push, and you're done. And just like has been well proven in emergency medicine with NARCAN and now with OPVEE and even with VALTOCO and NAYZILAM in seizures, it's really one of the most ideal ways to administer medication in those kind of situations. The device is also super reliable, so it's been very well proven. It's almost foolproof. We've tested to less than one in 100,000 chance of a failure. And it's never been known to fail or been recalled off the market. No product has been recalled off the market with this sprayer device. Also, we showed the PD response is very important. That shows receptor binding response that you want to see with epinephrine. So you need to see that PD response.
We get very good response, as you saw, really within one minute, you see pharmacodynamic response after administration. The low dose, we believe, is important. There's many reasons why. One, obviously, we don't want to give too much epinephrine. We want to stay within the therapeutic range that is known to be safe and effective. And with any other route of administration, the higher you go up in dose and the lower the bioavailability, the more risk there is of some sort of condition allowing more nasal absorption or more buccal absorption. And you could get an excess absorption, and that could be toxic. So we tend to want and we strive very hard to keep the dose as low as possible for that reason, to avoid any risk of overdose. In addition, epinephrine orally is irritating to the GI and can cause people to vomit.
It's one of the known side effects of epinephrine, even through injection. But the more you give by either oral or intranasal, the more likely you are to see GI effects and vomiting. And given our low dose, we don't see that type of problem. We see very infrequent nausea and vomiting well below 2%. So that's important because one of the major side effects of an anaphylactic reaction are GI symptoms and vomiting. And if you're confused about whether the vomiting and GI symptoms that the patient's experiencing are caused from either the anaphylactic reaction itself or the drug, it really confounds the use of the product and may lead to additional doses being given that were really not needed and, again, risk of overdose. Again, we've kept our PK within the range of injection products, either with one or two doses.
Even with two doses, normal condition, we're still almost the same as EpiPen, two EpiPens. So that ensures safety as well. No pain or irritation with our product. Easily portable. And we have pediatric data. So we've now published at AAAAI our full 80-dose, 80-patient pediatric study. Dr. Spergel was one of the investigators in that study, so he can actually speak to how well the children tolerate it. And the PK in the children is really very, very good. We see great absorption, even down to four-year-olds. So we have data all the way down to four-year-olds. And again, we'll be getting approval with the 30-kg and above children and adults for 2 mg, and we'll immediately follow with the 1 mg dose, which FDA we have the study finished.
FDA asked us to hold it till they approve because they want to approve as quickly as possible once we get the rhinitis, the twice-dosing rhinitis data. So they've told us not to send anything other than that so they can finish the NDA review very quickly and then file the supplement immediately after approval with the 15-30-kg children and the 1 mg dose to get approval there. So that's also a huge advantage given that about 50% of the population here is children.
Rich, can I add a couple of more things to consider?
Sure.
Is that when you have a patient that has an anaphylactic event, the lips and tongue can be swollen, so that can affect the absorption of any other type of epinephrine product that might be administered through that route. The second thing is the advantage another advantage of intranasal is that it is probably the easiest way to administer a drug in an uncooperative or unconscious patient. That, I think, is a major advantage because it's very easy to administer to someone.
I'll just add. I mean, parents, and we do lots and lots of food challenges. Holding a kid down for a shot when they're screaming is a challenge. Sticking in the nose, families were so much happier that way. It's such an easier way. They're like, "Oh, it's just quick, quick, done." It was, I would say, universally accepted. It is just people much happier that way than a needle and the kid that you have to hold down for two-five seconds. It's a much quicker, easier way to give a dose, as Dr. Casale said.
Okay. Great. So I think the next question is also probably with Dr. Spergel and Dr. Casale, which is, can you think of how or when you'd suggest the option of neffy to your patients? Would you wait till they ask for it, or would you present it as an option?
I can go first. I mean, we're not going to call up all of our patients saying, "Hey, there's a new device." But when they come in for their follow-up for the thing, it's like, "There is a new" we always give patients devices. There's, "Here's the epinephrine devices that exist. What is your choice?" Well, I mean, we do that now. We show them the AUVI-Q, the EpiPen, the generic. "Which one would you like?" Now we'll show them neffy. "Which one would you like?" And we'll give them a choice. We'll say, "They all work. Which one would you like?" And that's the way we plan on doing it in our offices.
Yeah, I agree. I don't think we're going to go out and solicit individuals to switch. Rather, I believe that when people come in for their epinephrine autoinjector renewal, we'll present them the opportunity to consider using an intranasal or any other product as an alternative. But as what often happens in medicine, especially if you do DTC type of advertising, patients will also come into us and ask for the opportunity to use it. And again, if a person is completely comfortable with an injection product and they've used it and they've done well with it, we don't see a reason to switch. I think that they're all going to be effective clinically. So it's going to be patient preference, which I know is really going to favor anything but a needle in most patients.
Okay. Great. Yep. So we had another question about whether there'd be an opportunity to access non-retail segments, government, police, defense.
Yeah, absolutely. I think that is not only government, even military use, but also use in airplanes. Even FDA, just to make one comment around this, FDA did ask us in our human factor validation studies to also test our instructions for use and the use of our device in a population of people called passerby. So at first, that was a little bit unusual. You don't normally take somebody off the street who doesn't know anything about the disease, anything about the product, the device, and say, "Here's a scenario. You're in a restaurant. Somebody's having a reaction. Read these instructions and do it." Everybody was able to do it correctly and dose neffy properly. That is really setting up for the potential for neffy to be even in public places such as restaurants or other areas.
But certainly, we think there's a large application for use in various different places, including police, fire rescue, who currently don't usually inject. They would have to call an emergency medical unit. But as we know with NARCAN, same scenario. Every police car in the country has NARCAN in it now. We can envision that most police cars or maybe every police car, every fire rescue car or fire rescue unit will have neffy in it eventually as well because it's just that easy to administer, and there's no risk of self-injection. So that opens up the door to those kind of other uses. I don't know, Eric, do you want to add anything to that, or?
Yeah, a couple of thoughts. I mean, there's so many similarities to neffy with our experience, Rich and my experience with NARCAN nasal spray. And when you think about this product, we refer to NARCAN as a community-use product. It was a very easy, intuitive product to use. As everyone has said, it's place and press, and you're able to administer medication. So there is opportunity outside of the retail setting, as Rich said. We have know-how around some of the specialty distributors with airlines. Even think about colleges. If you ask a parent when they worry the most, it's when the kid goes off to college, and are they going to be carrying their epinephrine with them? We believe, obviously, our products are going to be easy to carry. But that's something that should be available at colleges. It should be in dorms. It should be at restaurants, hotels.
You think about sporting events. So there is opportunity outside of the retail setting to educate. And when we've talked to the EMS, a couple of folks already, they see the value of this product as well. They're very excited about it. So it's something that we, in time, will look to build out and to educate and penetrate that market even more.
Great. Thanks, Eric. So Rich, we got a clarifying question about the repeat dose neffy study, which is the exposures are higher than IM, right, for repeat doses of neffy within that. Is that a concern that it's higher than IM?
Right. No, no, it's not a concern at all. If you remember from our other data, EpiPen is actually higher than neffy under normal conditions. And in that rhinitis study, FDA wanted us to use IM needle and syringe because they're not worried about too much neffy. They're worried about making sure there's enough. But we did include two doses of neffy under normal conditions, which we know is about the same as two doses of EpiPen. And that's showing that even under rhinitis conditions, twice in one nostril, we were slightly less on the Cmax than two doses under normal conditions. So that's still within that bracket of safety and efficacy. So it's still within that range of what you'd expect from an autoinjector with the upper end of that range being EpiPen. So we just didn't include EpiPen. Again, five arms, having people be treated five times.
These are the same people in a crossover study and drawing blood from them five times. That's about the limit of what you can really do in a clinical trial. So we had to choose, and FDA was not interested in seeing EpiPen data again in that study. They would just wanted IM, so we did not include the EpiPen as the upper bracket for that study. But the two doses of neffy under normal conditions confirm that it's not going to be higher than what we've seen in other studies and higher than EpiPen.
Great. Thanks, Rich. So I think we're almost up on time. So this may be one of the last questions, which is, how do you think neffy is going to overcome a product like EpiPen that's been out for, as you said, over 30 years, and it's a household name?
Yeah, I mean, I'll start out, and then Eric may want to speak to that, and maybe even Dr. Spergel and Dr. Casale. EpiPen's been out for a long time, and it's a good product. It was, for a long time, the only product that you can use outside of a hospital where somebody could self-inject. So it's done an amazing job of benefiting people for many years. But as you've heard, people are not really happy with EpiPens. They don't like carrying them. You've heard about temperature issues, so they're not that convenient, and they're really scared of the needle. I mean, it's surprising how much they are afraid of that needle, and it's a very deep injection. It's not a subQ injection. It's a very deep intramuscular injection with that device. So it's painful.
I think we know through our market research that there's probably about 60%-80% of people that are so dissatisfied with those autoinjectors that they're going to switch very quickly within the first year or two. There'll be some people that tolerate the autoinjector and may or may not switch right away or may have both. Again, there's also a lot of people that refuse to get the autoinjectors in general, and they want to get something different. Once they see that there's an alternative on the market, we believe that they'll come back into the market. Eric, I don't know if you want to add to that.
Yeah, to build on that, I'll share. Over the last three-six months, Rich and I have attended a handful of advocacy meetings where they have hundreds of families attend. And when we talk to parents and caregivers and even children, you hear the same message. "I dread the moment I have to inject my child or inject myself," or the anxiety that they have. So thinking about a product like ours, when they look at the attributes of it, this is something that is going to fill that unmet need. It's going to be a solution to all the challenges that we've talked about on this call.
It's interesting when we've done our market research around kind of creative concepts around education and awareness, we really ask parents, "What is the motivating factor?" What they say to us is that neffy is going to provide them peace of mind. And when we talk to patients and we ask them, "What's going to drive you in terms of going and getting this product?" And it's about freedom. It's about being able to go out on the weekend, carrying something. It's convenient. It's not invasive. So we're pretty excited about this opportunity. Of course, there's going to be education and awareness and things that we need to do from a payer perspective and adoption and education. But we clearly know from all of our interactions, the market research, that the market wants a product like this.
Great. Any closing remarks from Dr. Spergel or Dr. Casale? I think that was our last question that we had time for.
Well,
from a clinical perspective, I think oh, I'm sorry, Jonathan. I think we're all excited about getting a needle-free option because that has been the single most factor in patients delaying the use of epinephrine is fear of the needle. And having a needle-free option is very good. And also, since the guidelines, as Jonathan mentioned, has changed that you don't have to activate EMS if you use epinephrine, that will also provide another impetus to use this and to use it quickly, which I think should hopefully avoid a lot of emergency department visits, hospitalizations, and hopefully the few deaths that we have from food allergy and other causes. Jonathan, I'll let you wrap it up.
Yeah, so I'll just wrap it up from a personal side. It's like my son, who's a college student, has food allergies and has significant food anaphylaxis. I have asked him, "What would you do?" It's like, "Oh my God, this would be so much easier to carry around. This is going to be I can't wait till it's out." So from a perspective of one patient and one parent, we're anxiously waiting the device because it's going to be so much easier and will give me, as they were saying, that peace of mind that now my son, who will carry it around with him instead of carrying the larger devices. So there's a lot of excitement in the field from a provider, parent, patient standpoint.
Okay. Thank you, Dr. Casale and Dr. Spergel. I think this has been a great discussion and conclusion to our event. Again, thank you both for joining us, and thanks for everyone for taking the time out of your busy schedules to dial in. We look forward to keeping you posted on our progress and neffy's progress. If you have any further questions that we didn't get to, again, please feel free to reach out to ir@ars-pharma.com. Operator, you may now end the stream. Thank you.
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