Interleukin 4 (IL-4) binds to its receptor.
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The possibility of utilizing biologic therapies for chronic rhinosinusitis (CRS), an inflammatory condition of the sinonasal mucosa, is a growing area of interest and research. This rise in interest is due in part to the success of biologics in treating other inflammatory conditions such as asthma and atopic dermatitis. A panel of experts gathered at the Triological Society Annual Meeting discussed the biologics that are being explored for CRS and nasal polyposis.
Jean Kim, MD, PhD, an associate professor of otolaryngology–head and neck surgery at Johns Hopkins University School of Medicine in Baltimore and panel moderator, said, “What makes antibodies so attractive is the specificity for the target. However, there are some previously reported uncommon nonspecific effects that may be detrimental, such as immunosuppression, cardiomyopathy, new cancer, and cytokine storm. Additionally, autoantibodies and allergy to the antibodies have also been reported.”
What is known about the biology of nasal polyps (NP) comes from understanding similarities with asthma, he said. In fact, he added, the rationale for NP drug development originates from studies of severe asthma. Both display similar patterns of Th2 (or type 2) inflammation. Their behavior is also similar, with both displaying a responsiveness to steroids. Thus, the targets that mediate Th2 inflammation are the biologic drug targets that are being developed for nasal polyposis, which include IgE, IL5, IL4, and IL13.
Dupilumab
Joseph K. Han, MD, director of the division of rhinology and endoscopic sinus and skull base surgery and medical director of the division of allergy at Eastern Virginia Medical School in Norfolk, and his colleagues recently completed a phase 3 trial on the use of dupilumab, which blocks IL-4 and IL-13, for nasal polyposis. This medication received priority review by the FDA, and full approval would make it the first biologic approved by the FDA to treat CRS with NP (CRSwNP), he said.
His study, which involved 276 patients, concluded that dupilumab is safe and effective for CRSwNP. Patients treated with this drug showed progress in as early as four weeks and experienced a reduction in the size of polyps, the severity of nasal congestion, and the need for surgery or steroids, said Dr. Han. These improvements continued through week 24, and the need for surgery in these patients was reduced by 73%.
The two primary outcomes, nasal congestion and NP, were both statistically significant, he added. Regarding congestion specifically, those who had medium to severe congestion at the outset of the study had zero to mild congestion by the end of the study.
I believe that these new biologics will have an extremely important role in the management of chronic sinusitis with and without NP, but this is a process and we must temper our exuberance. —Timothy L. Smith, MD, MPH
Another study endpoint was the sense of smell, which patients rated as more important than congestion. “In our study,” said Dr. Han, “patients whose sense of smell had disappeared were actually able to regain it, [which is] remarkable and vital to the quality of their lives.”
He thinks biologics will be effective for the management of nasal polyps but added that it’s unclear where within the range of available treatments they will fall.
Bias and Clinical Relevance
Timothy L. Smith, MD, MPH, vice chair of otolaryngology–head and neck surgery and professor of otolaryngology–head and neck surgery in the division of rhinology and sinus/skull base surgery at Oregon Health and Science University in Portland, said he has reservations about biologics.
First, he said, there is the risk of bias assessment. One systematic review looking at the potential for bias in biologics research found “encouraging” results, he said, but added that there there were indeed biases present and a high risk of bias for attrition and reporting, in particular (Rhinology. 2018;56:11–21).
“I sometimes question the clinical relevance of the outcomes in these studies,” Dr. Smith said. He referenced a 2017 randomized, double-blind, placebo-controlled trial that assessed the need for surgery; 105 patients received mepolizumab (n = 54) or placebo (n = 51) (J Allergy Clin Immunol. 2017;140:1024–1031). At the outset, 100% of patients needed surgery; by week 25 the mepolizumab group dropped to 70% and the control dropped to 90%. “That is not statistically significant until you do a post hoc analysis,” he added. “I think it is telling that after six months of expensive therapy, a full 70% [of participants] still needed sinus surgery.”
Regarding the visual analog scale (VAS) scores for NPs, the investigators did find a statistically significant improvement in nasal polyposis severity, but, asked Dr. Smith, “how important to the patient is being at 6.5 versus 5 after six months of expensive, systemic therapy?”
He added that one global issue is that nearly all studies involve some sort of relationship with a pharmaceutical company, with recent larger studies demonstrating multiple potential conflicts of interest.
“Looking back, it seems that we have been down this road before,” said Dr. Smith. “A study published in 2001 looking at montelukast resulted in tremendous hype about using it for NP (J Allergy Clin Immunol. 2001;108:466–467). But reflect on how it figures in our current practice … in my practice it is virtually irrelevant. I believe that these new biologics will have an extremely important role in the management of chronic sinusitis with and without NP, but this is a process and we must temper our exuberance.”
We need to be sensitive to cost, particularly as it relates to new drug development and how these costs factor into patient choices. —Erica R. Thaler, MD
Cost Effectiveness
Michael G. Stewart, MD, MPH, professor and chairman in the department of otolaryngology–head and neck surgery at Weill Medical College of Cornell University and otolaryngologist-in-chief at New York-Presbyterian Hospital/Weill Cornell Medical Center, addressed the issue of cost effectiveness (CE) assessment of biologics, which he said can be fairly complex.
“The concept of CE is cost divided by effectiveness,” he explained. “For example, if you start with something that costs $10,000 and it gives you 0.4 units of improvement in some outcome measure, that is $25,000 per unit of improvement. And if you have a $9,000 treatment that gives you 0.3 units, that would be $30,000 per unit of improvement, and that treatment is less costly but is also less cost effective.
He said it is important to remember that the cost is not just what is charged to the patient or their insurance; it is desirable to use cost rather than charges, but it also can be challenging to establish what the actual costs are. He added, “It can be equally difficult to assess exactly what is the effectiveness—is it an improved CT score, fewer admissions for asthma, a better quality of life, etc.?”
When measuring effectiveness, it is also important to assess duration of effect, said Dr. Stewart. Researchers typically used quality-adjusted life years (QALYs) to measure the value of health outcomes, and this is assessed by multiplying the utility of an outcome state with its duration in years. In the U.S., it is generally accepted that a level of acceptable cost effectiveness is approximately $50,000/QALY or less. “For example,” he added, “with cochlear implantation, cost effectiveness was calculated as $12,000 to $15,000/QALY. So, although it is an expensive one-time intervention, it is cost effective over the long term. Compare that to joint replacement ($20,000/QALY) and a coronary artery bypass graft in a 70-year old ($90,000/QALY).”
“Examining a 2019 Annals of Asthma, Allergy and Immunology study from Anderson and Stanley, we see that the calculated cost effectiveness of biologics for asthma is $325,000–$391,000/QALY (Ann Allergy Asthma Immunol. 2019;122:367–372); so, the drugs are not only expensive, they are not very cost effective when compared to other treatments. In addition, the incremental (or additional) cost effectiveness ratio of biologics versus long-term steroids in asthma is $174,000/QALY. The authors calculated that a 67% to 80% discount in drug price would be needed to reach an acceptable comparative level of cost effectiveness,” Dr. Stewart added.
Erica R. Thaler, MD, is professor and vice chair of otolaryngology–head and neck surgery at the University of Pennsylvania in Philadephia. Painting a clear picture of reality, Dr. Thaler said, “I am going to attempt to put some context around the issue of cost analysis so that you can understand what you’re suggesting to patients. We need to be sensitive to cost, particularly as it relates to new drug development and how these costs factor into patient choices. I will say that at least now we have more alternatives. When I graduated from residency in 1995, we were telling patients that their only options were surgery or Prednisone. And now, here we are 25 years later, and we are just beginning to have viable alternatives.”
The cost of bilateral endoscopic sinus surgery varies greatly by code, and the charges also differ by institution, with the institutional charges not including anesthesia or hospital fees, she said. “I think it is fair to say that you can double surgeons’ fees numbers if you think about this in an all-inclusive manner,” she added.
Regarding traditional medical therapy, Dr. Thaler noted that Prednisone is the “workhorse” when it comes to NP, largely because it is inexpensive. “Even topical steroids such as fluticasone aren’t overly economically burdensome. Lavage is relatively expensive, with a [prescription of] .25/mg/2ml daily costing $281/month. Montelukast is pricey, with 10 mg costing $248.22. Compared to biologics, however, these are all relatively inexpensive,” she said.
Putting your patients on a biologic will cost approximately $40,000 per year; insurance will cover some of this expense, but this will vary according to payer, she added. “The bottom line is that there is no set algorithm for patients with chronic sinusitis and nasal polyposis. The physician and patient, in partnership, need to figure out what is best for overall patient outcome. Cost-benefit should be first and foremost related to the medical care of the patient.”
Elizabeth Hofheinz is a freelance medical writer based in Louisiana.
Take-Home Points
- Biologics is a growing area of interest and research for CRS.
- There is a risk of bias assessment in studies, and some question the clinical relevance of study outcomes.
- Some uncommon potential effects have been reported; autoantibodies and allergy to the antibodies have also been reported.
- Biologics are costly and may not be cost-effective when compared with other treatments.
- There is no set algorithm for patients with chronic sinusitis and nasal polyposis.
Case Presentation: How Should We Use Biologics?
A 28-year-old female presents experiencing recurrent sinusitis. For her asthma, she has received inhaled steroids and the occasional rescue beta agonist. For her environmental allergies, she has been treated with SCIT immunotherapy. Both aspirin and NSAIDs cause an asthma flare. She has worsening nasal obstruction, loss of sense of smell, and has received intermittent intranasal steroids. There is increased dyspnea on exertion. She has bilateral nasal polyposis extending past the middle meatus. Her allergist has advised treatment with a biologic.
What are the panel’s recommendations?
Dr. Han: A biologic is probably not indicated at this time because there are other treatment options. You first give an antibiotic and steroids. If they fail, then you should discuss surgery. If the polyps recur quickly and she becomes steroid-dependent and fails aspirin desensitization, then consider biologics.
Dr. Smith: They are absolutely not indicated in this patient. I’m concerned that clinicians will treat all NP patients with these systemic, lifelong medications—that would be completely inappropriate and would in essence be overutilization.
Dr. Thaler: I agree. There is still a lot of work to be done with this patient. It would be absurd to start her on a biologic.
Dr. Stewart: Biologics are not indicated. Down the line this patient might be a candidate for a biologic, so when we have better data and if she is farther along in the process of trying and failing traditional therapy, maybe.
The patient underwent functional endoscopic sinus surgery with polypectomy. She was managed postoperatively with topical steroid irrigation. Her asthma improved, as well as her QOL. Six months later, she presented with recurrence of polyps and reduced olfaction.
Dr. Stewart: You could go back to remove the NP, but that is expensive. We have to ask, ‘Is the difference large enough to be worth it?’ At this time and in this patient, biologics might be indicated.
Dr. Thaler: There is more work to be done. These patients are not one phenotype. How many NPs, where are they located, is the asthma significantly exacerbated, can it be managed with periodic bursts of steroids? I would consult an allergist regarding aspirin desensitization.
Dr. Smith: I would do postop steroid irrigations and consider aspirin desensitization. The vast majority will do well with the things we’ve already discussed, and you would never have to contemplate an expensive, life-long, systemic therapy. Regarding olfaction, it is important to determine which cytokines were present at the time of surgery that might be impacting the olfactory cleft. If we just start randomly giving different biologics, then it’s not personalized medicine.
Dr. Han: Because this patient is likely to have elevated levels of IL-4 and eosinophils, the patient will benefit from anti IL4 and anti IL5 biologics.