Anaphylaxis Management

To better understand the influence of extreme temperature on the potency of epinephrine, researchers collected stability data for 3 epinephrine products: neffy (epinephrine nasal spray; ARS Pharma); EpiPen (epinephrine prefilled autoinjector; Viatris); and Symjepi (epinephrine prefilled syringe; Adamis Pharma). 

These products were tested under extreme temperature conditions at 50°C (122°F) for 3 months and at 40°C (104°F) for 6 months. Room temperature stability testing at 25°C (77°F) was used as a reference point.

Findings showed that over 3 months at 50°C, epinephrine potencies were reduced by 56.6%, 41.6%, and 8.6% for Symjepi, EpiPen, and neffy, respectively. Over 6 months at 40°C/75% relative humidity, the change in assay results was -27.5%, -17.2%, and -13.9% for EpiPen, Symjepi, and neffy, respectively.

Based on these findings, the researchers concluded that “neffy (epinephrine nasal spray) was more stable than injection products and remained within shelf-life specifications for potency even after 3-months under extreme temperature conditions (50°C).”  

If approved by the Food and Drug Administration (FDA), neffy is anticipated to launch with an initial expiration period of 24 months, whereas the expiration period for epinephrine injectable products is 18 months.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

The Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to ARS Pharmaceuticals regarding the New Drug Application (NDA) for neffy^® (intranasal epinephrine) for the treatment of severe allergic reactions (Type 1), including anaphylaxis, for adults and children weighing at least 30kg.

The agency is requesting an additional pharmacokinetic (PK)/pharmacodynmic (PD) trial assessing repeat doses of neffy compared with repeat doses of epinephrine injection under allergen-induced allergic rhinitis conditions. In May 2023, the FDA’s Pulmonary-Allergy Drug Advisory Committee voted in support of the product, though concerns were raised over the lack of repeat dose studies under nasal allergen challenge conditions.

According to ARS, it was decided with the FDA that the repeat-dose study would be a postmarketing requirement, rather than being a necessary step for approval. “We are very surprised by this action and the late requirement at this time to change the repeat-dose study from a postmarketing requirement, which we had previously aligned on with FDA, to a pre-approval requirement, particularly given the positive Advisory Committee vote,” said Richard Lowenthal, Co-founder, President and CEO of ARS Pharma.

The NDA for neffy was supported by PK/PD data comparing the nasal spray formulation to epinephrine injection. Findings showed comparable epinephrine levels in the blood between the nasal and intramuscular formulations, including within the first 10 to 20 minutes after administration.

“…multiple Committee members highlighted the favorable profile of neffy in our completed single-dose nasal allergy challenge study and that any decline in exposure 20 minutes after dosing, after the expected response period, is of no concern,” added Lowenthal.

Given the new requirement, ARS expects to resubmit the NDA for neffy in the first half of 2024. The letter also requested testing for nitrosamine impurities as part of a new draft guidance issued by the FDA.

Resmetirom for Nonalcoholic Steatohepatitis (NASH) With Liver Fibrosis

PDUFA date: March 14, 2024

In patients with NASH, thyroid hormone beta activity in the liver is reduced, resulting in hepatic function impairment. Resmetirom is an oral thyroid hormone receptor (THR)-β selective agonist designed to target the underlying cause of NASH. The NDA submission included data from four phase 3 studies, including the pivotal MAESTRO-NASH trial (ClinicalTrials.gov Identifier: NCT03900429), which evaluated the efficacy and safety of resmetirom in more than 1000 patients with biopsy-proven NASH and fibrosis. Findings showed the trial met its dual primary endpoints: NASH resolution with at least a 2-point reduction in nonalcoholic fatty liver disease activity score (NAS) and with no worsening of fibrosis, or at least a 1-stage improvement in fibrosis with no worsening of NAS after 52 weeks of treatment.

Atidarsagene Autotemcel for Metachromatic Leukodystrophy

PDUFA date: March 18, 2024

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disease caused by a mutation in the arylsulfatase-A gene. This results in a buildup of sulfatides in the brain and other areas of the body. Atidarsagene autotemcel is a hematopoietic stem cell-based gene therapy that was evaluated in a clinical trial that included 39 pediatric patients with early-onset MLD. At the time of analysis, treatment with the one-time gene therapy resulted in a statistically significant and clinically meaningful improvement in severe motor impairment-free survival. If approved, atidarsagene autotemcel would be the first and only treatment for early-onset MLD in the US.

Sotatercept for Pulmonary Arterial Hypertension

PDUFA date: March 26, 2024

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening blood vessel disorder caused by hyperproliferation of cells in the arterial walls in the lung. The disease is characterized by the constriction of small pulmonary arteries and elevations in pulmonary arterial pressure. The BLA for sotatercept, a first-in-class activin receptor type IIA-Fc fusion protein, is supported by data from the double-blind, placebo-controlled phase 3 STELLAR trial. The study included 323 adult patients with PAH (WHO Group 1). Results showed a statistically significant and clinically meaningful improvement in 6-minute walk distance among patients treated with sotatercept compared with placebo.

Vadadustat for Anemia Due to Chronic Kidney Disease

PDUFA date: March 27, 2024

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor designed to mimic the physiologic effect of altitude on oxygen availability. This results in increased red blood cell production and improved oxygen delivery to tissues. The NDA submission included data from 36 clinical trials involving over 8000 patients. Findings from the INNO2VATE program, which included 2 open-label, active-controlled phase 3 trials, showed that vadadustat was noninferior to darbepoetin alfa in adult patients on dialysis with anemia due to CKD. Vadadustat was also found to be noninferior to a long-acting erythropoiesis-stimulating agent for the maintenance treatment of anemia due to CKD, in hemodialysis patients in the phase 3 FO₂CUS study.

Omalizumab for Reducing Allergic Reactions to Multiple Foods

PDUFA date: March 2024

Omalizumab, an anti-immunoglobulin E (IgE) antibody, is under review for the reduction of allergic reactions, including anaphylaxis, that may occur with accidental exposure to 1 or more foods in adults and pediatric patients aged 1 year and older with food allergy. The BLA is supported by data from the phase 3 OUtMATCH trial, which evaluated the safety and efficacy of omalizumab in patients 1 to 55 years of age who are allergic to peanuts and at least 2 other common foods. Findings showed that compared with placebo, omalizumab significantly increased the amount of peanut (primary endpoint), milk, egg, and cashew (key secondary endpoints) participants could consume without an allergic reaction.

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The Food and Drug Administration (FDA) has extended the review period of the New Drug Application (NDA) for neffy^® (intranasal (IN) epinephrine) for the treatment of severe allergic reactions (Type 1), including anaphylaxis, for adults and children weighing at least 30kg.

The new Prescription Drug User Fee Act (PDUFA) target date is September 19, 2023. The FDA extended the action date to allow additional time to complete its review. According to ARS Pharmaceuticals, no additional studies were requested by the Agency.

“FDA is working on labeling and post-marketing commitments as the final steps in the review process,” said Richard Lowenthal, co-founder, President and CEO, ARS Pharmaceuticals. “While the Agency extended the PDUFA timeline, we are hopeful that labeling discussions will be completed as soon as possible given the significant unmet need in the allergy community for a needle-free option that is easily carried and administered without anxiety or hesitation.”

In May 2023, the FDA’s Pulmonary-Allergy Drug Advisory Committee voted in support of the product though with some concerns.

The Food and Drug Administration’s (FDA) Pulmonary-Allergy Drug Advisory Committee voted 16:6 in favor for adults, and 17:5 in favor for children (<18 years of age and ≥30kg), that available data support a favorable benefit-risk assessment for neffy^® in the treatment of severe allergic reaction (Type 1), including anaphylaxis, for adults and children who weigh more than 30kg.

Neffy is an intranasal formulation of epinephrine. The application was supported by pharmacokinetic (PK)/pharmacodynamic (PD) data comparing the nasal spray formulation to epinephrine injection. Findings showed comparable epinephrine levels in the blood between the nasal and intramuscular formulations, including within the first 10 to 20 minutes after administration.

However, the panel noted that without a clinical efficacy trial, there were uncertainties with relying on PK/PD data given the severity of the indication. They specifically pointed to findings from a nasal allergen challenge study, which was designed to mimic nasal mucosa changes during anaphylaxis (eg, severe congestion, edema). Results showed a rapid increase in epinephrine PK with nasal administration compared with IM administration, followed by a rapid decline in epinephrine concentration 10 to 20 minutes postdose.

In the briefing document, the panel wrote that “the lack of epinephrine PK/PD sustainability under nasal allergen challenge conditions raises concerns for durability of effect, and the need for a repeat dose, in patients with anaphylaxis who experience nasal edema. Since repeat dose studies have not been performed under nasal allergen challenge conditions, and proposed labeling includes repeating a dose if symptoms persist, there is residual uncertainty in the PK/PD response following a repeat dose.”

While not bound to the committee’s recommendations, the FDA does take them into consideration when making final decisions on approval. If approved, neffy would be the first needle-free epinephrine product to treat severe allergic reaction. A decision is expected by mid-2023.

Commenting on the vote, Richard Lowenthal, Co-founder, President and CEO, ARS Pharmaceuticals, said, “We believe our clinical data from more than 600 individuals demonstrate neffy’s absorption-enhancing nasal spray technology is comparable to injectable products in delivering potentially lifesaving epinephrine, but with unique advantages of being small, needle-free and conveniently sized. We are committed to making it easier for patients and caregivers to carry and administer epinephrine without the anxiety and hesitation associated with using a needle-based device.”

Omalizumab, an anti-immunoglobulin E (IgE) antibody, is marketed under the brand name Xolair for the treatment of asthma, chronic rhinosinusitis with nasal polyps and chronic spontaneous urticaria. 

The BLA is supported by data from the phase 3, double-blind, placebo-controlled OUtMATCH trial (ClinicalTrials.gov Identifier: NCT03881696), which evaluated the safety and efficacy of omalizumab in patients 1 to 55 years of age who are allergic to peanuts and at least 2 other common foods. The multi-stage study is sponsored and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. In the first stage, patients were randomly assigned to receive omalizumab injections (either every 2 weeks or every 4 weeks) or placebo for 16 to 20 weeks. 

Data from the first 165 participants aged 1 to 17 years were examined at a pre-planned interim analysis by an independent data and safety monitoring board (DSMB). Findings showed that compared with placebo, omalizumab significantly increased the amount of peanut (primary endpoint), milk, egg, and cashew (key secondary endpoints) participants could consume without an allergic reaction. Based on these results, the DSMB recommended halting enrollment into the first stage of the trial.

“Despite the significant and growing health burden from food allergies, treatment advances have been limited,” said Levi Garraway, MD, PhD, Genentech’s chief medical officer and head of Global Product Development. “We are proud to partner with the National Institutes of Health and leading research institutions on this groundbreaking study. The FDA’s Priority Review designation acknowledges the unmet need for these patients, and we hope to make Xolair available to as many people as possible living with food allergies in the US.”

The FDA’s decision on the application is expected in the first quarter of 2024. If approved, omalizumab would be the first drug approved to reduce allergic reactions to multiple foods following accidental exposure.

Richard K. Gurgel, MD, from the University of Utah in Salt Lake City, and colleagues identified quality improvement opportunities and provided trustworthy, evidence-based recommendations for management of inhaled allergies with immunotherapy.

The guideline development group made a strong recommendation that the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. For patients with allergic rhinitis with or without allergic asthma whose symptoms are inadequately controlled with medical therapy, allergen avoidance, or both or for those who have a preference for immunomodulation, there is a recommendation for clinicians to offer or refer to a clinician who can offer immunotherapy. For patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine, clinicians should not initiate AIT. Signs and symptoms of asthma should be evaluated before initiating AIT, and signs and symptoms of uncontrolled asthma should be assessed before administering subsequent AIT. Clinicians should educate patients regarding the potential benefits of AIT. For patients experiencing symptomatic control from AIT, treatment should continue for a minimum of three years, with ongoing duration based on treatment response.

“We hope this CPG will be a valuable resource to optimize patient care and reduce unnecessary and costly variation in AIT management,” Gurgel said in a statement.

Several authors disclosed ties to industry.

Abstract/Full Text

To assess the risk for allergies in early childhood, study authors used the US network in the TriNetX platform to identify patients who were prescribed proton pump inhibitors (PPIs; n=56,492), histamine-2 receptor antagonists (H₂RAs; n=168,909), at least 1 antimicrobial (n=886,746), or at least 3 antimicrobials (n=216,009) during the first year of life from January 2015 to July 2021. 

The investigators examined 2-year outcomes, which included ICD-10 encounter diagnoses of food allergy (primary endpoint) and ICD-10 encounter diagnoses of anaphylaxis, atopic dermatitis, and allergic rhinitis (secondary endpoints). Patients with allergy-related encounter diagnoses prior to the prescriptions were excluded from the study.

Findings showed an increased risk for food allergies for patients exposed to PPIs, H2RAs, or antimicrobials during the first year of life. The highest risk of food allergy diagnosis was observed with PPI use (relative risk [RR], 6.41; 95% CI, 6.18-6.64). Antimicrobials were associated with a lower risk (antimicrobials ≥1: RR, 2.32; [95% CI, 2.27-2.37]; antimicrobials ≥3: RR, 2.93; [95% CI, 2.84-3.02]). Results were similar for the secondary outcomes (RR, 2.17 to 11.23; 95% [CI, 2.10-2.25 to 10.87-11.61]).

“We found that early exposure to acid-suppressive medications was associated with a 5-6 times higher risk of food allergy and anaphylaxis, with similar trends observed for antimicrobials,” said primary author Julia Tanzo while working with co-author Mohamad Chaaban, MD. “We hope that this association study will motivate future studies on the mechanisms underlying our findings and the role of potential confounding factors.”

Pneumonia treatment Xacduro now available; FDA denies approval of anaphylaxis treatment; flu vaccine efficacy results; flexible dosing for Talicia; change in therapeutic equivalence for certain tacrolimus capsules. 

First treatment approved to reduce allergic reactions in those with multiple food allergies; T-cell therapy given accelerated approval to treat unresectable or metastatic melanoma; vitamin D supplement recalled due to superpotency; cannabidiol may help resolve the symptoms of pericarditis; FDA warns against certain wearables that claim to measure blood glucose.

The table below is a review of notable updates that occurred in September 2023 for investigational products in development (not an inclusive list). Click on the status to view our full coverage.

Severe refractory anaphylaxis (SRA) is a rare IgE-mediated reaction characterized by persistent anaphylaxis despite treatment with at least 3 doses of epinephrine. To better understand this reaction, the study authors analyzed data from a pediatric food challenge cohort that included 91 pediatric patients, all of whom received at least 1 dose of intramuscular epinephrine for anaphylaxis. Among these patients, 7 experienced SRA to 6 different food triggers. 

Findings showed the SRA cohort was entirely male (median age, 13 years; interquartile range [IQR] 8.5-14) and all had allergic rhinitis. Asthma, atopic dermatitis and multiple food allergies were common comorbid conditions (86% for all); food triggers included tree nuts, sesame, peach, and cow’s milk. Two patients (29%) were also on dupilumab for severe atopic dermatitis.   

Using logistic regression models, a baseline diagnosis of asthma, moderate asthma severity, FEV₁ less than 80%, being on combination asthma therapy (inhaled corticosteroid plus a long-acting beta-agonist), and older age were found to be predictive of SRA. Moreover, skin symptoms, severe wheezing, and moderate to severe cardiovascular/neurologic symptoms during an oral food challenge (OFC) were found to be predictive of SRA.

Based on these findings, the authors concluded that “Providers must remain vigilant during an OFC and could consider obtaining spirometry in children with moderate-severe asthma prior to an OFC, especially if there are concerns for inadequate asthma control.” They also recommended immunologic profiling of the skin to help identify mechanisms contributing to severe anaphylaxis and that close attention be given to cardiovascular and neurologic status during OFC reactions. 

Edwin H. Kim, MD, from the University of North Carolina at Chapel Hill, and colleagues studied the safety and efficacy of SLIT for peanut allergy in 1- to 4-year-old children. The analysis included 50 participants randomly assigned to SLIT or placebo.

The researchers found that actively treated vs placebo participants had a significantly greater median cumulative tolerated dose (4443 vs 143mg), higher likelihood of passing the month 36 double-blind, placebo-controlled food challenge (60 vs 0%), and a higher likelihood of demonstrating remission (48 vs 0%). One- to 2-year-olds had the highest rate of desensitization and remission, followed by 2- to 3-year-olds and 3- to 4-year-olds. Longitudinal changes in peanut skin prick testing, peanut-specific immunoglobulin (Ig)G4, and peanut-specific IgG4/IgE ratio were seen in SLIT participants, but not in placebo participants. SLIT participants more commonly reported oropharyngeal itching, but skin, gastrointestinal, upper respiratory, lower respiratory, and multisystem adverse events were similar between groups.

“The desensitization levels we saw were higher than expected and on par with levels we normally would only expect with oral immunotherapy,” Kim said in a statement. “Just as important, rather than wearing off quickly, we were excited to see that over 60 percent stayed protected three months after stopping the treatment.”

Several authors disclosed ties to the pharmaceutical and biotechnology industries.

Abstract/Full Text