IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, affects patients of all sexes, but men account for a disproportionate share of diagnosed cases in many populations. Despite decades of observation, researchers have not identified why IgAN demonstrates this consistent male predominance.

Studies have reported higher rates of IgAN among men, particularly in Western cohorts, although the magnitude of this difference varies across geographic regions. Differences in screening practices, kidney biopsy patterns, and genetic background may contribute to these variations.

Why Does IgA Nephropathy Affect More Men? With Ramy Hanna, MD

For Ramy Hanna, MD, associate professor in the Division of Nephrology, Hypertension and Kidney Transplantation at UC Irvine School of Medicine and director of the Center for Rare Kidney Diseases and Glomerulonephritis at UC Irvine Health, the question represents one of the many remaining opportunities to better understand IgAN biology.

“Whenever there’s a disparity by gender, you have to think of two things: genetics and environment,” Hanna said in an interview with 

IgAN shows a consistent male predominance in many populations, although rates vary by geography.

Researchers have not identified the mechanism responsible for this sex disparity.

Potential explanations include genetic differences, hormonal signaling, epigenetic regulation, and immune responses.

The IgA-producing mucosal immune system may be an important area for future research.

Genetic testing may be appropriate for selected patients with suspected inherited kidney disease.

Why Is IgA Nephropathy More Common in Men?

The reason for IgAN’s male predominance remains unknown, but Hanna said potential explanations may involve differences in genetics, hormonal signaling, and environmental influences.

One possibility involves differences in sex chromosome biology. Hanna noted that women have 2 X chromosomes, whereas men have 1 X chromosome and 1 Y chromosome, creating fundamental biological differences between sexes.

However, he emphasized that this concept has not been established as a specific explanation for IgAN. Instead, it represents one possible framework for understanding how genetic differences may influence disease susceptibility.

Beyond chromosomes, Hanna pointed to the potential role of hormones and epigenetic changes, biological processes that influence whether genes are turned on or off, as additional factors that may contribute to differences between men and women.

How Could Sex Differences Influence IgA Nephropathy Biology?

Hanna said the immune system may be central to understanding why IgAN affects men more frequently.

IgAN is driven by abnormal immune activity involving IgA production and immune responses at mucosal surfaces, including tissues such as the tonsils and Peyer patches. Because immune pathways can respond differently to hormonal signals, Hanna suggested that sex-based differences in immune regulation could influence disease development.

“Something about genetics, epigenetics, or hormonal androgen levels may affect the IgA-producing Peyer patches and mucosal surfaces differently,” Hanna said.

Still, he cautioned that these mechanisms remain hypotheses and have not been proven to explain the observed sex disparity.

“I could be wrong, but this would be a great NIH question,” Hanna said, emphasizing the need for additional research into the molecular basis of sex differences in IgAN.

What Research Is Needed to Understand Sex Differences in IgAN?

According to Hanna, answering why men are more likely to develop IgAN will require translational research that combines genetics, immunology, and experimental models.

He said the question will likely require collaboration among investigators across the United States, Europe, and Asia, where IgAN represents a significant clinical burden.

As new therapies continue to expand treatment options for IgAN, understanding why certain patients develop disease may become increasingly important for identifying risk factors and improving individualized care.

Should Patients With IgA Nephropathy Consider Genetic Testing?

Although the reason behind IgAN’s male predominance remains unresolved, Hanna emphasized the broader role of genetics in kidney disease.

“Keep in mind that approximately 20% of kidney disease has a genetic basis,” Hanna said. “We have genetic testing available, and IgAN is no exception.”

Familial forms of IgAN have been described, although they represent a small proportion of cases. Hanna said clinicians should consider genetic evaluation in selected patients, particularly those with a strong family history of kidney disease or features suggesting an inherited condition.

Editor’s Note: Hanna reports relevant disclosures with Alexion Pharmaceuticals, Novartis, AstraZeneca, and others. 

Stamellou E, Seikrit C, Tang SCW, et al. IgA nephropathy. 

 2023;9(1):67. doi:10.1038/s41572-023-00476-9.

Lee M, Suzuki H, Nihei Y, Matsuzaki K, Suzuki Y. Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis. 

 2023;16(suppl 2):ii1-ii8. doi:10.1093/ckj/sfad199.

Videos

IgA nephropathy shows a male predominance, but researchers have not identified why. Ramy Hanna, MD explores possible biological explanations.


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Why Does IgA Nephropathy Affect More Men? With Ramy Hanna, MD 

Chelsie Derman is an associate editor for 

who covers allergy and  psychiatry. She joined MJH Life Sciences in September 2023 after graduating from The College of New Jersey with a bachelor’s degree in journalism and professional writing. In her free time, she enjoys creative writing and reading.

David Golden, MD, clinical associate professor of medicine at Johns Hopkins University School of Medicine.

Marcus Shaker, MD, a professor of pediatrics and medicine at the Dartmouth Geisel School of Medicine

Screenshot 2025-11-06 at 10.12.42 AM.png

Jacqueline Ross, MD, a physician at Allergy Partners of New Jersey.

Featured: David Golden, MD (top), Marcus Shaker, MD (bottom left), and Jacqueline Ross, MD (bottom right)

A patient who’s terrified of needles now has a legitimate needle-free option for treating 

: epinephrine nasal spray (neffy), approved on August 9, 2024.

However, if this patient were to ask whether the guidelines favor epinephrine nasal spray, the honest answer is not quite yet. 

When people ask, “Do I recommend Neffy?” Golden knows they are really asking the following:

“Guidelines don't happen overnight,” David B.K. Golden, MD, associate professor of medicine at Johns Hopkins and co-chair of the 2023 practice parameter update in anaphylaxis, told

. “First of all, they take 1 to 3 years to develop. When something new comes on the market, there's not going to be a guideline for it, and that guideline may not happen for years."

About 3 years ago, in December 2023, an updated anaphylaxis practice parameter was published in the Annals of Allergy, Asthma, & Immunology.

 This update focused on 7 key areas: diagnosis, infants and toddlers, community settings, epinephrine autoinjectors, beta-blockers and ACE inhibitors, mast cell disorders, and perioperative anaphylaxis.

At this time, epinephrine autoinjectors were strongly recommended for high-risk patients. The update advised clinicians to deliver an epinephrine autoinjector at the first sign of expected anaphylaxis, not preemptively before symptoms arrive. Clinicians could choose between Adrenaclick, Auvi-Q, EpiPen, EpiPen Jr, Twinject, Adrenalin, and Symjepi.

Epinephrine Nasal Spray Outperforms in Patient Preference, Efficacy Data

With the approval of epinephrine nasal spray, clinicians gained another treatment option: 1 delivered without a needle. A randomized crossover study presented at the 2026 American Academy of Allergy, Asthma, & Immunology (AAAAI) annual meeting in Philadelphia, found that 88% of 90 participants preferred the intranasal device over injectable epinephrine.

Patients preferred the intranasal spray for its needle-free design, ease of use, portability, and the sense that bystanders could administer it more easily in an emergency. Nearly all participants (98%–100%) rated its size, weight, and temperature flexibility favorably.

Epinephrine nasal spray also works just as quickly as any other epinephrine, taking about 5 minutes to take effect.

 A large real-world analysis showed that epinephrine nasal spray performed as effectively as epinephrine injections with success rates of 89.9% and 88.9%, respectively.

“Pharmacokinetic studies have been done, and these are the studies that look at epinephrine drug levels. Epinephrine drug levels are very similar whether epinephrine is delivered by the nasal route or by the intramuscular route,” Marcus Shaker, MD, from Dartmouth Health, told 

Neffy's pharmacokinetic profile fell within the range of the approved injectable products, with a mean peak plasma concentration of 481 pg/mL, which is higher than manual intramuscular epinephrine injection (339 pg/mL) but lower than EpiPen (753 pg/mL). Both single and double doses of epinephrine nasal spray produced greater pharmacodynamic effects than either EpiPen or manual injection.

Still, epinephrine only helps if it's actually used. In 2023, only 3.2 million of the 20 million patients treated for severe reactions filled an auto-injector prescription, and about half consistently carried one.

“We know that there have been many reports of incorrect use of auto injectors, often leading to significant injuries,” Golden said. “Every product has potential usability and reliability questions.”

Fill rates for neffy aren't yet available, but ARS Pharmaceuticals reported > 5000 prescriptions written as of May 2025, about 8 months after approval.

2025 Delphi Consensus on Anaphylaxis Treatment

Although the official anaphylaxis practice parameters have not been updated since the approval of epinephrine nasal spray, and may not be for some time, informal recommendations have started to emerge. In December 2025, a Delphi panel of 34 experts developed consensus recommendations for treating acute allergic reactions.

“The number 1 question that I get when patients leave our emergency departments, when we prescribe them an autoinjector, is: When should I administer epinephrine? What symptoms should I administer epinephrine for?” first author Timothy E. Dribin, MD, from the division of emergency medicine at Cincinnati Children’s Hospital Medical Center, told 

“It's a very complicated answer because there's no consensus on what symptoms warrant epinephrine and what symptoms do not warrant epinephrine.”

The panel reached consensus recommending epinephrine in 21 of 24 scenarios, with strongest agreement for reactions involving multiple organ systems or isolated severe respiratory or cardiovascular symptoms.

 Mild isolated cutaneous or GI symptoms did not warrant it, and moderate mucocutaneous symptoms alone lacked consensus. The recommendations did not mention epinephrine nasal spray, nor did they recommend any epinephrine form over another.

“Epinephrine is no different for these different forms,” Golden pointed out. “The only recommendation that's strong for epinephrine is that it should be used as the first and most important treatment for anaphylaxis... From there on, it's all conditional recommendations.”

To earn a strong recommendation, Golden said double-blind, placebo-controlled, randomized trials would need to show clear superiority of 1 treatment over the other. However, that isn’t possible in anaphylaxis research.

“There's never been any proof that epinephrine works,” Golden said. “You can't really do a controlled trial of epinephrine because you can't tell someone [with] anaphylaxis: ‘Well, we're going to give you placebo, and compare it to someone else who gets epinephrine.’ That would not be a good thing to do. Conditional recommendations are recommendations that have good evidence to support them, but not the best evidence, and it leaves some room for question[s] about what every doctor wants to prescribe.”

Golden also offered advice on what not to do: prescribe antihistamines for anaphylaxis and wait to see if it improves. Jacqueline Ross, MD, a physician at Allergy Partners of New Jersey, emphasized this too in an interview with 

 She said allergists still need to re-educate patients on the 2023 parameter update, which states epinephrine should be the first-line treatment.

“Antihistamines are not only not first-line in anaphylaxis or allergic reactions, [but] they aren't really a part of the standard therapy at this time,” Ross said. “We need to be identifying anaphylaxis early and administering this life-saving device.”

Epinephrine Nasal Spray and Cold or Respiratory Infection Questions

Golden estimated that it will be 3 to 5 years before a formal anaphylaxis update. In the time before anaphylaxis receives updated practice parameters, clinicians may have questions about newer epinephrine options.

“Patients have wondered, ‘Hey, I have a cold or an upper respiratory tract infection, will the nasal epinephrine work just as well?’ Oppenheimer and colleagues did a study in 2024, which also provided really good reassurance around this question,” Shaker said. The study showed that having an upper respiratory tract infection did not have a significant impact on the way epinephrine nasal spray works.

Golden’s 3 Epinephrine Questions: “Will It Work? Can I Trust It? Is It Dangerous?”

“When doctors ask me, ‘Do I recommend?’ ‘What should I prescribe?’ what they're really [asking] is: Will it work? Can I trust it? Is it dangerous? I always address those questions with patients and with doctors:

 Yes, it's FDA-approved, and everything we know about it is that it's going to work the same as any other epinephrine.

 No, epinephrine is not a dangerous drug. The only thing that's dangerous is not using it when you should.”

Smith T. FDA Approves Epinephrine Nasal Spray for Emergency Treatment of Allergic Reactions. HCPLive. Published August 9, 2024. Accessed July 23, 2026. 

https://www.hcplive.com/view/fda-approves-epinephrine-nasal-spray-for-emergency-treatment-of-allergic-reactions

Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: A 2023 practice parameter update. 

Epinephrine (injection route). Mayo Clinic. Accessed July 23, 2026. 

https://www.mayoclinic.org/drugs-supplements/epinephrine-injection-route/description/drg-20072429

Mack D. Epinephrine Nasal Spray Shows Strong Patient Preference, With Douglas Mack, MD. HCPLive. Published March 12, 2026. Accessed July 23, 2026. 

https://www.hcplive.com/view/epinephrine-nasal-spray-shows-strong-patient-preference-douglas-mack-md

Smith T. Thomas B. Casale, MD: Discussing New Findings on Neffy for Urticaria Flares. HCPLive. Published February 26, 2024. Accessed July 23, 2026. 

https://www.hcplive.com/view/thomas-casale-md-discussing-new-findings-neffy-for-urticaria-flares

Clayton J. How Long Does It Take for an EpiPen to Work? Pharmacist-Backed Answers to 7 EpiPen FAQs. Goodrx. Published October 8, 2024. 

https://www.goodrx.com/epinephrine-epipen/how-long-does-it-take-for-an-epipen-to-work?srsltid=AfmBOoqOP8_jxjrW-kpl1koiW5IjfwFllvKV8SUfdS4E56OFMYeHrQa4

Casale T. Epinephrine Nasal Spray Shows Comparable Efficacy to Injection, With Thomas Casale, MD. HCPLive. Published September 15, 2025. Accessed July 23, 2026. 

https://www.hcplive.com/view/epinephrine-nasal-spray-shows-comparable-efficacy-to-injection-with-thomas-casale-md

Casale TB, Ellis AK, Nowak-Wegrzyn A, Kaliner M, Lowenthal R, Tanimoto S. Pharmacokinetics/pharmacodynamics of epinephrine after single and repeat administration of neffy, EpiPen, and manual intramuscular injection. 

ARS Pharmaceuticals Reports First Quarter 2025 Financial Results and Highlights Progress in U.S. Commercial Launch of neffy® (epinephrine nasal spray). ARS Pharma. Published May 14, 2025. Accessed July 23, 2026. 

https://ir.ars-pharma.com/news-releases/news-release-details/ars-pharmaceuticals-reports-first-quarter-2025-financial-results

Dribin T. International Consensus on Epinephrine Use, With Timothy E. Dribin, MD. HCPLive. Published February 25, 2026. Accessed July 23, 2026. 

https://www.hcplive.com/view/international-consensus-epinephrine-use-timothy-e-dribin-md

Oppenheimer J, Casale TB, Camargo CA Jr, et al. "Upper respiratory tract infections have minimal impact on neffy's pharmacokinetics or pharmacodynamics." 

https://www.jaci-inpractice.org/article/S2213-2198(24)00263-0/fulltext

Articles

Epinephrine nasal spray (neffy) offers a needle-free option for emergency treatment of anaphylaxis, but formal practice parameters typically lag new approvals by years. Current anaphylaxis guidance continues to emphasize prompt epinephrine as first-line therapy, historically via autoinjectors, and discourages delaying treatment with antihistamines. Emerging data show strong patient preference for intranasal delivery, rapid onset, comparable real-world effectiveness to injection, and pharmacokinetic/pharmacodynamic profiles within or exceeding approved injectable ranges. Underuse and carrying nonadherence remain major gaps.

Allergists explain what's settled about epinephrine nasal spray, what's not, and how to counsel patients before anaphylaxis guidelines catch up.

Allergy

Allergy condition center page is a comprehensive resource for clinical news and insights on allergic and inflammatory diseases. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for food and seasonal allergies, as well as allergic asthma and related conditions.

Anaphylaxis

The HCPLive anaphylaxis page is a comprehensive resource for clinical news and insights on acute allergic reactions. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for preventing anaphylaxis, and more.

Epinephrine Nasal Spray Is Here. Updated Anaphylaxis Guidelines Aren't.

Victoria Johnson joined MJH Life Sciences in 2020 and has written for NeurologyLive, CGTLive, and is now an assistant managing editor for HCPLive and RheumatologyLive. She doesn’t have enough time for her numerous hobbies. You can reach her at vjohnson@mjhlifesciences.com.

Biologic therapy has fundamentally transformed the management of severe 

, with 7 approved agents now spanning 4 mechanistic targets — anti-IgE (omalizumab), anti-IL-4/IL-13 (dupilumab), anti-IL-5 and anti-IL-5 receptor (mepolizumab, benralizumab, reslizumab, and depemokimab), and anti-TSLP (tezepelumab) — and long-term extension studies demonstrating durable exacerbation reductions of 45% to 70% over 3 to 4 years.¹ 

The December 2025 FDA approval of depemokimab (Exdensur; GSK), the first biologic in any class dosed every 6 months, introduced a novel adherence and access paradigm built on SWIFT-1 and SWIFT-2 data showing 58% and 48% annualized exacerbation reductions, respectively.² The chronic obstructive pulmonary disease (COPD) biologic landscape has expanded similarly: dupilumab was formally incorporated into GOLD 2025 at a blood eosinophil threshold of 300 cells/µL or greater in patients with chronic bronchitis on maximal triple inhaled therapy, supported by BOREAS and NOTUS demonstrating 30% to 34% exacerbation reductions and a distinctive FEV1 improvement of 62 to 83 mL — a signal not replicated with IL-5 antagonism.³,⁴ 

Mepolizumab subsequently received COPD approval and was incorporated into GOLD 2026, with the MATINEE trial providing the pivotal data establishing its 18% to 21% exacerbation reduction benefit and broadening the eosinophil threshold to 150 cells/µL.⁵ Despite this expanding evidence base, real-world biologic prescribing in asthma and COPD remains heavily constrained by insurance formulary decisions, documentation burden, and access gaps — challenges that fall disproportionately on advanced practice providers who in many settings are the sole or primary pulmonary clinicians managing these patients.

 convened a panel of advanced practice providers from across the United States for a virtual roundtable on biologic therapy in asthma and COPD. The forum was moderated by Melissa Dolbec, NP, a nurse practitioner at the Oregon Clinic in Portland with a focus on pulmonary hypertension and a background in general pulmonology, and included peers representing academic medical centers, multi-specialty community groups, rural solo practices, and hospital medicine across Oregon, Iowa, Tennessee, Idaho, Minnesota, California, Louisiana, and Ohio, providing a granular view of how biologic therapy is accessed, administered, and navigated across heterogeneous payer environments. The discussion was structured around four interactive polling questions and open exchange, spanning OCS burden thresholds for biologic escalation, agent selection rationale, mucus plugging data, and the distinct practical landscape of COPD biologics.

How Are APPs Navigating Formulary Barriers?

The panel's most consistent and candid finding was that insurance formulary, not clinical pharmacology, determines which biologic patients receive in most real-world practice settings. A polling question on biologic selection drivers returned biomarkers as the top-cited factor (53.8%) and clinical phenotype second (46%), but open discussion immediately shifted to the practical reality: as 1 panelist put it, "the person at the insurance company who failed organic chemistry chooses it for me." 

Panelists described selecting agents based on what is most likely to be approved, using comorbidities (nasal polyps, atopic dermatitis, eosinophilic esophagitis) to pursue alternative indications when asthma approval fails, and delegating the selection process entirely to embedded pharmacists via medication therapy management (MTM) consults — a workflow Sara Kraus, NP, described as allowing her to simply refer patients for pharmacist review and receive a managed approval outcome without direct involvement in the prior authorization process. A standout operational innovation emerged when Kraus described the Epic-integrated Evidently AI tool, which allows natural-language search of entire patient records for eosinophil counts, prednisone prescriptions, and clinical history — dramatically accelerating the tracking of cumulative OCS exposure from external providers such as urgent care and primary care settings, where most panelists reported receiving no notification when steroids are prescribed. 

Dolbec relayed a related insight from an MSL interaction: biologic manufacturers maintain dedicated formulary advocacy teams that will challenge insurance companies on coverage decisions — a resource most panelists were unaware they could activate. The forum reinforced that the biologic escalation conversation should begin with the first OCS burst, well before GINA's step 5 phenotyping recommendation: as Stephanie Arceneaux, NP, noted, "If we're waiting that long to phenotype them and endotype them, and it's almost too late, how many pulse doses of steroids have they received?" — a statement consistent with retrospective data suggesting measurable long-term morbidity with as few as 3 lifetime OCS bursts. 

Depemokimab's Q6-month, office-administered dosing was identified as particularly appealing for needle-phobic patients, college students home on academic breaks, and non-adherent patients in whom guaranteed administration eliminates uncertainty about self-injection compliance. Brian Bizik, PA, offered an important mechanistic clarification that had direct clinical implications: adverse reaction duration with biologics is governed by host depletion dynamics — the reservoir of available histamine, leukotrienes, and other mediators — not by the drug's half-life; an adverse event with a 6-month drug does not last 6 months any more than a Q4-week drug's adverse events last 4 weeks.²

How to Manage Patient Expectations With COPD Biologics?

The COPD discussion surfaced a consistent theme: biologic therapy in COPD is clinically meaningful but subjectively difficult for patients to perceive, and expectation management is as important as agent selection. Dupilumab emerged as the near-universal first-choice agent across the panel, driven by faster insurance approval timelines, greater prescriber familiarity, and consistent outcomes data — while mepolizumab was positioned as a practical alternative when insurance approves it preferentially at lower eosinophil thresholds. 

The BOREAS and NOTUS FEV1 improvement signal of 62 to 83 mL — absent from mepolizumab's COPD trial program — was identified as a meaningful differentiating feature for panelists who discuss functional outcomes with patients, though several noted that the core clinical argument for COPD biologics is exacerbation prevention, not symptom relief.³ As Bizik framed it: "Exacerbations are not like with asthma — they're life-changing, life-altering, lung volume losing events that they never come back from. So they're one-way streets, nobody comes back from an exacerbation like they were before." 

An underappreciated clinical observation raised during the discussion was comorbidity unmasking: as biologic therapy effectively suppresses inflammatory exacerbations in COPD, previously occult conditions — left heart disease, pulmonary hypertension, and severe deconditioning — may emerge as the residual source of dyspnea. Ensifentrine (Ohtuvayre; Verona/Merck) access was described as consistently poor across the panel, with patient assistance programs reportedly exhausted and prior authorization success through the designated specialty pharmacy declining — a practical barrier to a therapeutic option that several panelists saw as valuable for patients not meeting biologic eosinophil thresholds. 

The panel identified 4 high-priority unmet needs: validated biologic de-escalation protocols in both asthma and COPD; patient-centered quality of life data capturing personally meaningful functional goals rather than validated questionnaire scores alone; real-world effectiveness evidence for COPD biologics and ensifentrine to support patient motivation and payer conversations; and renewed investment in pulmonary rehabilitation, which multiple panelists characterized as dramatically underutilized relative to its evidence base and for which NP and PA prescribing authority remains legislatively incomplete in some states.

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2025. Accessed July 2026. https://ginasthma.org

Jackson DJ, Wechsler ME, Menzies-Gow A, et al; SWIFT-1 and SWIFT-2 Investigators. Twice-yearly depemokimab in severe asthma with an eosinophilic phenotype. 

 2024;391(24):2337–2349. doi:10.1056/NEJMoa2406673

Bhatt SP, Rabe KF, Hanania NA, et al; BOREAS Investigators. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. 

 2023;389(3):205–214. doi:10.1056/NEJMoa2303951

Bhatt SP, Rabe KF, Hanania NA, et al; NOTUS Study Investigators. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. 

 2024;390(24):2274–2283. doi:10.1056/NEJMoa2401304

Sciurba FC, Criner GJ, Christenson SA, et al; MATINEE Investigators. Mepolizumab to prevent exacerbations of COPD with an eosinophilic phenotype. 

 2025;392(17):1710–1720. doi:10.1056/NEJMoa2413181

Biologic therapy now spans seven agents across four targets in severe asthma, with long-term data supporting sustained 45%–70% exacerbation reductions. Depemokimab’s FDA approval introduced twice-yearly, office-administered dosing with ~48%–58% annualized exacerbation reductions. In COPD, dupilumab entered GOLD 2025 for chronic bronchitis on maximal triple therapy at eosinophils ≥300/µL, showing 30%–34% exacerbation reductions and modest FEV1 gains; mepolizumab followed in GOLD 2026 down to ≥150/µL. Real-world access remains payer-driven, intensifying APP administrative burden.

APPs discuss insurance barriers, dupilumab as the default COPD biologic, depemokimab adherence advantages, and why pulmonary rehab remains critically underused.

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Dupilumab, Depemokimab, and COPD: What APPs See in Practice

The biologic landscape for obstructive airway disease has expanded markedly over the past decade, with 7 agents now approved for 

 across 4 mechanistic targets — anti-IgE (omalizumab), anti-IL-4/IL-13 (dupilumab), anti-IL-5 and anti-IL-5 receptor (mepolizumab, benralizumab, reslizumab, and depemokimab), and anti-TSLP (tezepelumab) — and 2 agents approved for eosinophilic COPD, with clinical trial evidence supporting exacerbation reductions of 18% to 70% across the approved indications.¹

 In asthma, long-term extension data now demonstrate durable efficacy: the TRAVERSE study showed annualized exacerbation rates remaining low through week 96 of dupilumab treatment, with 75% to 90% reduction in oral corticosteroid (OCS) exposure in OCS-dependent patients who originally received placebo in VENTURE, while COLUMBA confirmed a 56% exacerbation reduction over a mean 3.5 years of mepolizumab treatment.²,³ The December 2025 approval of depemokimab (Exdensur; GSK) — the first biologic in any class dosed every 6 months — marked the latest expansion of the asthma armamentarium, with SWIFT-1 and SWIFT-2 demonstrating 58% and 48% annualized exacerbation reductions, respectively.⁴ In chronic obstructive pulmonary disease (COPD), dupilumab's BOREAS and NOTUS trials demonstrated 30% to 34% exacerbation reductions — alongside a distinctive FEV1 improvement of 62 to 83 mL not observed with mepolizumab — while the METREX, METREO, and MATINEE program placed mepolizumab in the GOLD guidelines at a blood eosinophil threshold of 150 cells/µL, lower than dupilumab's 300 cells/µL payer-enforced threshold.⁵,⁶

 convened a panel of pulmonologists from Pennsylvania, Georgia, and Florida for a virtual roundtable discussion on biologics in asthma and COPD. The forum was moderated by Frank Sciurba, MD, a pulmonologist with extensive COPD research expertise at University of Pittsburgh, and included peers from Jefferson Health, multi-physician private groups, a solo office-based independent practice, and a long-standing academic community practice in central Pennsylvania, as well as practices in Atlanta and Miami. The discussion spanned OCS burden thresholds for biologic escalation in asthma, biologic selection rationale, mucus plugging as an emerging endpoint, and the distinct clinical and practical landscape of COPD biologics.

MOA, Samples, Insurance, and the Mepolizumab Tachyphylaxis Signal

The panel converged on a finding that will be familiar to practicing pulmonologists: biologic selection in asthma is as often determined by what a patient can access and what samples a practice has available as by any pharmacologic reasoning. A polling question on the most important treatment driver returned nearly equal weight across biomarkers, access and logistics, and clinical phenotype — with Sciurba noting that at $80,000 per year out of pocket, any drug is "dead in the water" regardless of biomarker profile. 

Within the clinical data, one panelist positioned tezepelumab and dupilumab as preferred first choices based on their broader upstream mechanism — tezepelumab targeting TSLP at the epithelium to suppress both innate and adaptive TH2 responses, and dupilumab blocking IL-4/IL-13 signaling with direct epithelial effects — compared with agents acting further downstream on IL-5 or its receptor. One panelist offered a counterpoint grounded in practical reality: initial biologic selection in her practice is driven primarily by which drug she has samples for, enabling same-visit initiation that reduces time-off-work burden and builds patient buy-in. 

Outcomes across agents were described as broadly transformative in asthma: A panelist described the nasal polyp/aspirin-exacerbated respiratory disease/asthma overlap population as "extremely well" responders, and John Solick, MD, reported a patient who remained asymptomatic off omalizumab after 10 years on the drug — an anecdote consistent with published evidence supporting omalizumab disease modification.⁷ A clinically significant and novel observation emerged from Richard Friedenheim, MD, who described apparent mepolizumab tachyphylaxis in approximately 5 to 6 patients across his 12-member practice, with efficacy loss occurring at roughly 18 months prompting switches to benralizumab with improved outcomes. 

Sciurba contextualized this as possibly reflecting immunogenic responses — mepolizumab turning antigenic over time and inducing an abrogating immune response, a phenomenon with published mechanistic support for this drug class — and noted that whether benralizumab shares this property is not yet established.⁸ The mechanistic distinction carries additional implications for COPD: benralizumab's complete eosinophil depletion via IL-5 receptor antagonism — as opposed to mepolizumab's anti-ligand approach, which leaves low-level eosinophils intact — has been associated with benralizumab's failure in 3 pivotal COPD trials, a paper Sciurba described as currently in peer review. His hypothesis is that complete eosinophil depletion may interact unfavorably with the neutrophilic TH1-dominant environment of COPD, potentially triggering a rebound TH1 effect and abrogating possible eosinophil contributions to viral containment — dynamics less consequential in TH2-dominant asthma.

COPD Biologics: Payer Thresholds Are Driving Agent Selection More Than Trial Data

The COPD discussion surfaced a consistent theme across practices: prescribing decisions are predominantly shaped by payer-enforced eosinophil thresholds rather than clinical preference. Mepolizumab's accessibility at blood eosinophil counts of 150 cells/µL makes it the default agent for many patients in the 150 to 300 range, despite Sciurba highlighting that the forest plot for this subgroup without a historical count above 300 shows only approximately 8% exacerbation reduction — not impressive by any clinical standard, but still the only approved option available.⁶ 

The panel noted that dupilumab's FEV1 improvement of 62 to 83 mL — expanding to 120 to 140 mL in patients with FeNO above 20 ppb — remains a meaningful differentiating feature absent from the mepolizumab trial program, and 1 that may be relevant to shared decision-making in patients who care about functional decline.⁵ An unpublished subgroup observation flagged by Sciurba described eosinophil variability — specifically patients with counts well above 300 at some timepoints but below at others — as among the best dupilumab COPD responders, suggesting that reactive eosinophilic response, rather than a persistently elevated threshold, may be the true pharmacologic target. 

Real-world COPD outcomes were described with considerably more reserve than asthma: one panelist reported no good experience, with patients perceiving no difference, and another stated she does not have “high hopes for biologic COPD right now," reflecting a subjective success rate described by multiple panelists as substantially lower than in asthma. Sciurba challenged the outcome metrics being applied — noting that exacerbation reduction is the validated endpoint, not symptom improvement or lung function, and that patients who had 2 exacerbations instead of 3 will never know the counterfactual — but acknowledged the practical challenge of maintaining adherence in oxygen-dependent patients who feel no different. 

The panel identified head-to-head asthma biologic trials, combination biologic therapy, prospective biologic holiday studies, and validated predictive biomarkers for COPD response as the most urgent research priorities — with Sciurba quoted the late Jeff Drazen: companies would "rather have X% of the market than 0% of the market if they lose a head-to-head," a structural barrier to the comparative evidence clinicians need most.

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2025. https://ginasthma.org

Wechsler ME, Menzies-Gow A, Brightling CE, et al. Evaluation of dupilumab's long-term safety and efficacy in patients with moderate-to-severe asthma: the TRAVERSE open-label extension study. 

 2022;10(1):11–25. doi:10.1016/S2213-2600(21)00322-2

Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial [COLUMBA follow-up data]. 

 2012;380(9842):651–659; Khatri S, Moore W, Gibson PG, et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. 

 2019;143(5):1742–1751. doi:10.1016/j.jaci.2018.09.033

 2023;389(3):205–214. doi:10.1056/NEJMoa2303951; Bhatt SP, Rabe KF, Hanania NA, et al; NOTUS Study Investigators. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. 

Pavord ID, Chanez P, Criner GJ, et al; METREX and METREO Investigators. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. 

 2017;377(17):1613–1629. doi:10.1056/NEJMoa1708208

Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. 

 2017;140(1):162–169. doi:10.1016/j.jaci.2016.08.053

Castro M, Papi A, Porsbjerg C, et al. Effect of dupilumab on exhaled nitric oxide, mucus plugs, and functional respiratory imaging in patients with type 2 asthma (VESTIGE): a randomised, double-blind, placebo-controlled, phase 4 trial. 

 2025;13(3):208–220. doi:10.1016/S2213-2600(24)00362-X

Biologic therapy for obstructive airway disease now spans multiple targets in asthma and eosinophilic COPD, with exacerbation reductions varying widely by indication and phenotype. Extension studies support durable asthma control with dupilumab and mepolizumab, and depemokimab introduces twice-yearly dosing with robust exacerbation reduction. Real-world prescribing is frequently dictated by access, samples, and payer rules rather than biomarkers alone. A possible mepolizumab tachyphylaxis signal was raised. In COPD, payer eosinophil thresholds drive agent selection despite modest perceived benefit; dupilumab shows differentiated FEV1 gains.

Pulmonologists weigh in on biologic selection, mepolizumab tachyphylaxis, COPD payer barriers, and why asthma outcomes far outpace COPD in real-world practice.

Asthma

The HCPLive asthma page is a comprehensive resource for clinical news and insights on asthmatic disease. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for allergic and severe asthma, and more.

Biologics in Asthma and COPD: Real-World Gaps, Outcomes, and Unmet Needs

Ryan Livingston joined the MJH Life Sciences team in March of 2025, shortly after graduating from TCNJ with a bachelor’s degree in English. He enjoys creative writing, reading, and scuba diving. He can be reached at rlivingston@mjhlifesciences.com.

Kenneth Custer, PhD | Image Credit: Eli Lilly

Eli Lilly announced positive topline results from 2 phase 3 trials of retatrutide in adults with 

 and major cardiometabolic comorbidities on July 23, 2026. The investigational once-weekly agent met the primary weight-loss endpoint at 80 weeks in TRIUMPH-2 and TRIUMPH-3, according to the company.

Drug: Retatrutide, GIP/GLP-1/glucagon agonist

Status: FDA submission planned for Q1 2027

“Across five positive Phase 3 studies, retatrutide has shown powerful efficacy, and we believe it could be an important future tool in the management of cardiometabolic health,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a statement. “With the positive results from TRIUMPH-2 and TRIUMPH-3, we now have the clinical data package to support global submissions for retatrutide as a potential treatment for obesity, knee osteoarthritis pain, and obstructive sleep apnea.”

What the TRIUMPH-2 and TRIUMPH-3 Trials Showed

 and obesity or overweight. Participants were randomly assigned 1:1:1:1 to retatrutide 4 mg, 9 mg, or 12 mg or placebo. Mean baseline body weight was 106.4 kg, mean body mass index was 38.2, and mean glycated hemoglobin (HbA1c) was 7.7%. Treatment began at 2 mg once weekly, followed by dose escalation every 4 weeks.

At week 80, mean weight changes under the efficacy estimand were -12.7%, -19.1%, and -20.8% with the 4 mg, 9 mg, and 12 mg doses, respectively, compared with -4.0% with placebo. Mean HbA1c changes were -1.4, -1.6, and -1.5 percentage points, respectively, versus -0.2 points with placebo.

TRIUMPH-3 randomly assigned 1949 adults with a body mass index of at least 35 and established cardiovascular disease to retatrutide 9 mg, retatrutide 12 mg, or placebo in a 1:1:2 ratio. T2D was permitted. At week 80, mean weight decreased by 21.6% and 22.6% with retatrutide 9 mg and 12 mg, respectively, compared with 3.2% with placebo.

Cardiovascular Analyses and Safety Findings With Retatrutide

In the prespecified in-study analysis of TRIUMPH-3, 44 MACE-5 events occurred in the pooled retatrutide groups and 52 occurred with placebo, yielding a hazard ratio of 0.82 (95% CI, 0.55-1.22). MACE-5 included all-cause death, myocardial infarction, stroke, heart failure events, or coronary revascularization.

For MACE-3, encompassing cardiovascular death, myocardial infarction, or stroke, 27 events occurred with retatrutide and 23 with placebo. The hazard ratio was 1.12 (95% CI, 0.64-1.96). Both confidence intervals crossed 1, leaving cardiovascular effects unresolved. Lilly also reported reductions in triglycerides, non–high-density lipoprotein cholesterol, systolic blood pressure, waist circumference, and high-sensitivity C-reactive protein with the 12-mg dose.

Gastrointestinal events predominated in both trials. Diarrhea, nausea, constipation, decreased appetite, and vomiting were common in TRIUMPH-2. In TRIUMPH-3, diarrhea occurred in 30.1%, 24.4%, and 8.7% of participants receiving 9 mg, 12 mg, and placebo, respectively. Adverse-event discontinuation reached 13.5% with 12 mg in TRIUMPH-3 versus 4.8% with placebo.

Retatrutide Mechanism and Planned FDA Submission

Retatrutide is a single-molecule agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. Lilly is studying the agent across obesity-related conditions, including obstructive sleep apnea, knee osteoarthritis pain, cardiovascular and renal outcomes, and metabolic dysfunction–associated steatotic liver disease.

The company plans to submit a Biologics License Application (BLA) to the 

 in the first quarter of 2027 after completing its chemistry, manufacturing, and controls package.

Eli Lilly reported topline Phase 3 data showing once-weekly retatrutide achieved substantial 80-week weight loss in adults with obesity plus type 2 diabetes (TRIUMPH-2) or established cardiovascular disease (TRIUMPH-3). In TRIUMPH-2, weight reductions ranged from 12.7% to 20.8% with concurrent HbA1c declines of 1.4–1.6 points; TRIUMPH-3 showed 21.6%–22.6% weight loss. Gastrointestinal adverse events were most frequent, with higher discontinuations at 12 mg. Cardiovascular event analyses were inconclusive.

Retatrutide met 80-week weight-loss endpoints in TRIUMPH-2 and TRIUMPH-3, prompting a planned FDA submission in Q1 2027.

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