Biologics represent a breakthrough in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). But with high non-response rates and other unresolved issues, researchers are exploring how best to put these therapies to work, panelists said in a session at the Triological Society Combined Sections Meeting.
“The magnitude of this condition [CRSwNP] is significant,” said Erin Wright, MDCM, MEd, professor of surgery at the University of Alberta, where he specializes in rhinology.” It’s also common. About 12% of adults have CRS, and 4% of the general population has nasal polyps (J Allergy Clin Immunol. 2017;140:1024–1031.e14). CRS is associated with repeat surgeries, late-onset asthma, and increased use of oral corticosteroids.
In type 2 nasal polyposis, a host factor starts a cycle of cytokine production, leading to tissue swelling and inflammation, and expansion of type 2 inflammatory cells, such as interleukin (IL) 4, IL-13, and IL-5, followed by tissue remodeling within the polyp and further expansion of the inflammatory cells, according to Dr. Wright.
“This process will start to really drive itself, becoming a self-fulfilling cycle,” he said.
Targets for biologics include immunoglobulin E (IgE), IL-5, and IL-4/13. IL-4, he said, makes for a good target because of its production of IgE, class-switching in local tissues, barrier disruption, and remodeling that allows polyps to form.
Another target for biologics, IL-5, enhances eosinophil tracking to tissues and activation in the bone marrow, he said.
The array of options for biologic therapy has amazed even him, he said.
“When I was an undergrad doing my degree in immunology in the late ’80s and when I was a research fellow as a resident in the late ’90s, we were trying to understand the mechanisms of how CRS, how allergic rhinitis, came to be,” said Dr. Wright. A string of interleukins was discovered during that period. “Never did I think that we’d have the tools to be able to directly address [CRS]. Lo and behold, here we are 20-odd years later, and we can do that. So we’re living in a golden age for rhinology, with novel therapies to help manage the worst of the worst polyposis.”
Biologic Options
The parade of biologics for CRSwNP began in 2019 with the approval of dupilumab as an add-on therapy to nasal corticosteroids, which had been shown to be effective in comparison with placebo in nasal polyp scores and nasal congestion, said Jean Kim, MD, PhD, associate professor of otolaryngology–head and neck surgery at Johns Hopkins in Baltimore.
“However, when you take the drug [away], the polyps return, so basically it’s a drug that does not modify the outcome of the disease, yet is able to control the polyp size,” she said.
The next year, anti-IgE mepolizumab was approved, with similar benefits seen in clinical trials, but, as with dupilumab, symptoms return when it is discontinued.
Mepolizumab, an anti-IL-5 therapy, was approved after being found to improve nasal polyp score and nasal obstruction as measured by the visual analog scale.
“They’re certainly a good alternative to systemic steroids in controlling the immune-mediated disease,” Dr. Kim said. “However, the cons are they do not modify disease, and they’re similar—they’re great when they’re on, but when they’re off, disease comes back.”
Biologics don’t work for about half of patients (Lancet Respir Med. 2021;9:1141–1153). “There’s no telling whether [a patient is] going to be on the responder side [or] the non-responder side,” said Dr. Kim. “And that’s where we need more information on how we can match maybe some of these biologics with the endotype of the patient.”
An analysis found that functional endoscopic sinus surgery (FESS) was more cost-effective than dupilumab for CRSwNP—at any frequency of revision surgery and at any yearly cost of dupilumab that was considered, noted Dr. Kim (Laryngoscope. 2021;131:E26–E33).
How to use biologics in combination with surgery hasn’t been determined.
“We really still have very little in the way of a real evidence-based algorithm on treating these patients with biologics in combination with surgery, before surgery, after surgery, in place of surgery,” she said. “We really still don’t know.”
In a consensus statement, the European Forum for Research and Education (EUFOREA) recommends biologic use in patients who have had previous FESS if three of five of the following apply: 1) evidence of type 2 inflammation; 2) a need for systemic corticosteroids in the past two years; 3) a significant impairment in quality of life; 4) a significant loss of smell; and 5) a diagnosis of comorbid asthma. For those who have not had previous FESS, four of those should apply (Allergy. 2019;74:2312–2319).
Dr. Kim said interest is growing in anti-thymic stromal lymphopoietin (TSLP), which is in a phase 3 trial for uncontrolled severe asthma. The main outcome is for asthma control, but clinically meaningful improvement in sino-nasal quality of life (SNOT-22) scores—10 points greater than placebo—has been noted.
Research is also moving forward on TSLP specifically for the treatment of nasal polyps.
Dr. Kim pointed out that mometasone, an implantable corticosteroid designed to deliver medication directly to the mucosa, is in a phase 2 trial (Int Forum Allergy Rhinol. 2022;12:147–159).
Case Discussion
A case discussion illustrated some of the patient management considerations for otolaryngologists: A 32-year-old woman with recurrent sinusitis with nasal polyps is refractory to maximal medical management but has not had nasal and sinus surgery. She doesn’t have asthma and has normal allergy testing, and a computed tomography (CT) scan shows inflammation.
Dr. Kim said she would check serology with regard to eosinophilia.
Dr. Wright said he would check IgE levels and try to find out exactly how much systemic corticosteroids she has had.
Dr. Kim said the patient would need to realize there would be a wait before they would know whether they’re responding to a biologic; in the studies, responses were seen only after four to six months (Lancet Respir Med. 2021;9:1141–1153; Lancet. 2019;394:1638-1650). “So you’re going to have to advise the patient,” she said, that they may not have an immediate response.” The likelihood is you’re going to need four to six months of treatment to see if there’s a response.
Ahmad Sedaghat, MD, PhD, professor of otolaryngology–head and neck surgery at the University of Cincinnati College of Medicine in Ohio, said he would want to know the burden of disease “beyond just the objective”—not just a CT scan, but how the person is feeling—to make sure it’s a severe burden.
Dr. Sedaghat would want to know what the “maximal medical management” was in this case because “maybe there’s more that we could have done.”
There may be another comorbidity involved that hadn’t been considered, Dr. Sedaghat added.
Looking to the Future
Important questions remain when it comes to the future use of biologics in CRS patients, Dr. Sedaghat said. For one, might CRS patients without polyps benefit? Some studies have suggested they might (Int Forum Allergy Rhinol. 2021;11:1152–1161; Allergy Asthma Proc. 2021;42:417–424).
Also, what about special populations, such as pregnant women? With direct studies unavailable, researchers are turning to registries to try to answer this question, adding cases to their datasets one by one, Dr. Sedaghat said.
New biologics under development include a long-lasting IL-5 inhibitor, depemokimab, administered every six months—kind of a long-lasting mepolizumab—which has shown early promising results.
New monoclonal antibodies targeting IL-4 are also under development, and a “promising new avenue” is TSLP blockade; at least five registered trials are looking at this approach, said Dr. Sedaghat.
There are also monoclonal antibodies directed at biofilms being studied.
“I have a number of patients [for whom] biofilms play a predominant role in terms of their disease,” Dr. Sedaghat said.
Researchers and clinicians are still trying to determine the order in which biologics and surgery should be tried, with different guidelines setting forth different recommendations.
Biomarkers are being sought to try to match certain patients with certain biologics.
“We have to ask…who do we give these biologics to?” Dr. Sedaghat said. “There’s even a question of whether we should be giving them to patients with moderate disease. I think we have to think about some of these questions. And we are.”
Thomas R. Collins is a freelance medical writer based in Florida.