What Otolaryngologists Need to Know about Biologics and Allergic Rhinitis

Will otolaryngologists someday use biologics to manage allergic rhinitis (AR)? Perhaps. Monoclonal antibodies have already expanded the list of available treatment options for patients with allergic asthma and chronic rhinosinusitis (CRS) with nasal polyps, offering relief and hope.

“Biologics have been game changing for patients with recalcitrant polyps and severe asthma,” said Sandra Lin, MD, professor and chair of the department of surgery division of otolaryngology–head and neck surgery at the University of Wisconsin–Madison. “But there are a lot of patients who have nasal polyps and asthma who don’t need these medications. When looking at new therapies, we need to be cognizant of how they compare to older treatments. How much do they add therapeutically, and who should we use them for?”

These questions are of particular importance as researchers and otolaryngologists consider the use of biologic agents to manage AR, a common, non-life-threatening condition.

Can Biologics Fulfill an Unmet Need?

Although there are dozens of available treatment options for AR, including immunotherapy and over-the-counter and prescription antihistamines and corticosteroids, many people with the condition still report reduced quality of life due to AR symptoms and treatment side effects. Successful management of symptoms with medication requires strict compliance with medication regimens and immunotherapy is time consuming, requires significant patient commitment, and includes a risk of potentially severe adverse reactions. As noted by the authors of a 2019 article published in Pediatric Investigation, “The use of biologics could overcome the limitations of other therapeutic modalities” (Pediatr Investig. 2019;3:165-172).

“Asthma, chronic rhinosinusitis, and allergic rhinitis all share a similar inflammatory immune profile,” said Amber Luong, MD, PhD, a professor of otorhinolaryngology with the McGovern Medical School at UTHealth Houston, so it’s reasonable to assume that biologics that effectively target elevated cytokines associated with allergic asthma and CRS may also decrease AR symptoms.

If we are going to prescribe something that is very expensive, we need to consider, how does it compare to other accepted therapies for allergic rhinitis. —Sandra Lin, MD

In fact, there’s a fair amount of evidence showing that biologic medications improve allergic rhinitis symptoms, said Christopher Brook, MD, assistant professor of otolaryngology– head and neck surgery at Harvard Medical School in Cambridge, Mass. “They suppress Th-2 inflammation, which is the driver for allergic rhinitis,” he added.

Omalizumab, a biologic that’s currently FDA approved to treat AR and CRS with polyps, is a monoclonal anti- IgE antibody that inhibits IgE binding and cross-linking. Mepolizumab (also FDA approved to treat allergic asthma and CRS with polyps) binds to IL-5 and decreases eosinophil levels. Reslizumab and benralizumab also both target IL-5 and are approved to treat allergic asthma. Dupilumab inhibits IL-4 and is FDA-approved to treat both allergic asthma and CRS with polyps (Otolaryngol Head Neck Surg. 2021;164(1suppl):S1-S21).

To date, no biologic medications have received FDA approval to treat AR; some of the research that led to the approval of biologics to manage allergic asthma and CRS with polyposis also reported improvements in AR symptoms, however.

Omalizumab, the first biologic approved to treat asthma, probably has the most robust evidence base to support its potential use as a treatment for allergic asthma. “Omalizumab studies have found that [the biologic] is helpful in reducing nasal symptoms and improving quality of life,” said Christine Franzese, MD, professor of otolaryngology at the University of Missouri in Columbia and a past president of the American Academy of Otolaryngic Allergy. “The dupilumab trials also looked at allergic rhinitis-associated symptoms and found improvement, as did studies of mepolizumab.”

However, she noted that there isn’t a lot of data to support using biologics to treat allergic rhinitis. “I don’t know if it’s enough to really justify their use,” Dr. Franzese said. “Patient-reported data and a few small studies show they help, but not a huge amount.”

The Role of Biologics: Comorbid AR, Asthma, CRS, and Atopic Dermatitis

Although no biologic medication has yet received FDA-approval to treat AR, biologics are worth consideration if a patient has AR and another inflammatory condition, such as asthma, CRS, or atopic dermatitis.

Evidence dating back to the early 2000s has found that omalizumab, which is generally safe and well tolerated in patients 12 years of age and older, and can improve asthma and AR symptoms and quality of life in people with both conditions (Allergy. 2004;59:709-717; Ann Allergy Asthma Immunol. 2003;91:160-167). Many patients with CRS and AR also experienced improved AR symptoms when treated with omalizumab (Otolaryngol Clin North Am. 2017;50:1135-1151).

“If you have someone who has really severe allergic rhinitis and can’t seem to get it under control, my suspicion is that they may have one or more of the other comorbid diseases that are often associated with it,” Dr. Luong said. “For that person, you may want to think about biologics not only to manage their allergic rhinitis but also their other comorbid disease.”

Biologics Plus Immunotherapy for AR

Immunotherapy can reduce AR symptoms and improve allergen tolerance in many patients who are unable to find relief with over the counter or prescription medication. But immunotherapy can also trigger serious adverse reactions, and some people do not experience a significant reduction in symptoms with immunotherapy treatment. Adjuvant administration of biologic medication may help. “There is some evidence that using a biologic in conjunction with immunotherapy can decrease the number of systemic reactions and also decrease symptoms overall,” Dr. Brook said.

One randomized controlled trial examined the efficacy of immunotherapy with or without concurrent omalizumab in adolescents with moderate to severe AR; the combination treatment led to significant improvements in symptom reduction and a decreased need for rescue medication (J Allergy Clin Immunol. 2002;109:274-280). Another study found that administering omalizumab with immunotherapy resulted in prolonged inhibition of allergen-IgE binding as compared with either treatment alone (J Allergy Clin Immunol. 2007;120:688-695). Additional research has also suggested that administering omalizumab prior to rush immunotherapy may decrease anaphylactic reactions (J Allergy Clin Immunol. 2006;117:134-140).

Omalizumab studies have found that [the biologic] is helpful in reducing nasal symptoms and improving quality of life. —Christine Franzese, MD

This can have profound impact on patient treatment outcomes. “Anaphylactic reactions can be deadly, so we’re talking about saving lives here,” said Mohamad Chaaban, MD, MSCR, MBA, associate professor of otolaryngology–head and neck surgery at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University in Cleveland, Ohio.

At least four trials have assessed the impact of combined biologic treatment and immunotherapy, and evidence to date suggests that the combination of omalizumab and immunotherapy is superior to immunotherapy alone, according to the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

Biologics for Cat and Birch Pollen Allergies

Researchers are currently studying various biologics to determine their effectiveness in managing symptoms resulting from exposure to specific allergens. Previous studies have shown that omalizumab treatment can decrease nasal ocular symptom scores (and decrease chest symptom scores and skin sensitivity) in cat-allergic people. Those treated with omalizumab tolerated a median of 50 minutes in a room containing cat allergen versus 22 minutes for the placebo group (J Allergy Clin Immunol. 2011;127:398-405).

A phase 2, randomized, double-blind study that examined the impact of an investigational antibody cocktail of two monoclonal IgG antibodies in cat-allergic patients with mild asthma found that antibody administration prevented early asthma reactions and increased the amount of cat allergen patients could tolerate. Phase 3 clinical trials are currently underway, according to Dr. Franzese. “We’re enrolling patients who are allergic to cats but live with their cat and don’t want to get rid of them,” she added. “They’re getting one injection every three months to treat their cat allergies.”

Scientists have also targeted birch pollen allergies. A phase 1, randomized, double-blind study of a Bet v 1-specific antibody cocktail found that administration of the cocktail significantly reduced total nasal symptom scores (relative to baseline) following birch nasal allergen challenge. Significant improvement was noted after just one week of treatment, and reduction in allergy symptoms persisted at least two months (J Allergy Clin Immunol. 2022;149:189-199). An ongoing clinical trial is assessing the safety and efficacy of low-dose IL-2 in birch pollen allergy; the estimated study completion date is March 2024.

The Cost of Biologics

Despite the promise of biologics, their high cost remains a significant hurdle, and one that otolaryngologists must consider as they decide whether to incorporate these drugs into the treatment of AR. “If we are going to prescribe something that is very expensive, we need to consider, how does it compare to other accepted therapies for allergic rhinitis,” Dr. Lin said. “New is great, but it’s not always cost-effective and may not have superior outcomes.”

Additional research is needed to help delineate which AR patients, under which circumstances, may most benefit from biologics. “We need to identify which subpopulation would benefit a lot in order to avoid a tremendous cost burden to the health system,” Dr. Chaaban added.

Research studies examining the cost-effectiveness of biologic treatment versus endoscopic sinus surgery for chronic rhinosinusitis, for instance, have found that surgery is a more cost-effective approach than treatment with dupilumab, regardless of the frequency of revision surgery (Laryngoscope. 2021;131:E26-E33). However, the $10,000 to $40,000 annual cost of biologic treatment may result in decreased annual health expenditures for patients with severe allergic asthma if such treatment decreases emergency room visits and intensive care admissions (Pediatr Investig. 2019;3:165- 172). It remains to be seen whether biologic treatment is a cost-effective approach to AR management.

The patent for omalizumab expired in 2018, and at least one omalizumab biosimilar has already demonstrated equivalent safety and efficacy in a phase 1 trial presented as a poster at this year’s American Academy of Allergy, Asthma, and Immunology’s annual meeting. The eventual availability of biosimilars may ease the cost burden of biologic treatment, increasing its utility in clinical practice.

Right now, it seems unlikely that biologics will be a first-line treatment for AR. Perhaps, as with chronic rhinosinusitis, biologic treatment primarily will be used to manage disease in patients who do not achieve satisfactory symptom relief with less expensive treatments. Early biologic treatment of AR symptoms may eventually help slow the atopic march and prevent the development of food allergies in some individuals. At present, otolaryngologists who have patients with difficult-to-control AR symptoms may want to dive more deeply into their patients’ dermatologic and pulmonary histories. Those who have a history of atopic dermatitis or asthma may benefit from biologic treatment.

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Jennifer Fink is a freelance medical writer based in Wisconsin.