Allergen Immunotherapy: Best Practices An Expert Interview With AAAAI

By Marrecca Fiore, Linda Cox, MD

Editor’s Note
Allergen-specific immunotherapy has been used to treat allergic rhinitis and asthma for more than a century. The long-term efficacy of this therapy, most often used for patients with allergic disease who do not respond adequately to medications or avoidance measures, has been reaffirmed in several recently published research papers.

Medscape interviewed Linda Cox, MD, President of the American Academy of Allergy, Asthma & Immunology (AAAAI) and author of several research papers examining allergen immunotherapy, to offer guidance to physicians on the use of this therapy. Dr. Cox, who coauthored AAAAI’s 2011 update to its allergen immunotherapy practice parameters,[1] also provides perspective on some of the recent findings in immunotherapy as well as thoughts on the more recent sublingual immunotherapy (SLIT).

Medscape: Allergen-specific immunotherapy (AIT) as a treatment for allergic rhinitis and asthma has been used for decades, but recently there has been an abundance of research reaffirming its efficacy in both the short and long term. If we can start with the basics, how does a physician determine which patients are good candidates for AIT?

Dr. Cox: If you’ve identified the patient as being allergic and they don’t have any preexisting medical condition that would make allergy immunotherapy truly unsafe, such as severe cardiac disease, any patient would, in theory, be a candidate for allergy immunotherapy. Let me explain that. Allergy immunotherapy is the only treatment that actually goes after the underlying cause and potentially leads as close to a cure as you can get when treating allergies. In other words, it’s the closest you can get to changing the way the immune system is responding to this particular allergen and shifting it towards a normal or a tolerant response.

All of the medications that we have available right now for allergies control the underlying symptoms of allergies, but when you stop those medications, the symptoms will come back. So, in theory, the majority of allergic patients might be good candidates.

However, in this country the only AIT approved by the US Food and Drug Administration (FDA) is subcutaneous immunotherapy (SCIT), and it does carry risks, meaning that it must be administered in a medical setting. I think that physicians in general will wait until the patient has severe-enough symptoms or long-term-enough symptoms — “long” meaning that they’ll experience symptoms over a couple of seasons — before they would [suggest immunotherapy]. But patients are going to have to commit some time to it, because they’ll have to go to a physician’s office weekly in the beginning and then monthly for the 3- to 5-year period that they’re on maintenance.

But there’s no hard and fast rule for when to recommend immunotherapy. I would recommend using these 3 criteria for determining whether a patient is a good candidate for immunotherapy. The patient:

• Has experienced 1 season of significant symptoms not controlled with medication. Symptoms may include asthma.

• Has experienced 2 bad allergy seasons. With 2 bad seasons the patient is experiencing a longer duration of symptoms, thus longer requirements for medication

• Has year-round allergens because this patient is requiring year-round medication.

Medscape: Is there a certain age group in which immunotherapy works better? Is it safe for both children and adults?

Dr. Cox: There has been a perception that it works better in children, but the studies haven’t really shown that — although there really haven’t been studies that do a side-by-side comparison of an adult vs a pediatric population.

The studies that use adults have shown results as favorable as in the pediatric population. There really isn’t an upper limit or a lower limit for allergy immunotherapy. It’s a matter of having the appropriate diagnosis and ensuring that the patient can cooperate with treatment. If they’re too young, for example a little 3-year-old, they might have a problem cooperating with treatment. The other concern is with injection immunotherapy; young children might not be able to verbalize when they’re having a reaction to the injection.

Medscape: Can you explain how SCIT is administered? What is the duration of treatment, and what are the latest findings in terms of short- and long-term efficacy?

Dr. Cox: SCIT has 2 phases. The first phase is called the buildup phase. It’s also known as up-dosing. That is when you’re increasing the amount of allergen in the injection. It’s generally given in weekly intervals.

There are a couple of different approaches. One is the conventional approach, whereby a single dose increase is given at each visit. The example of a schedule given in our practice parameters or guidelines is a 30-step dose increase. So, that would be 30 individual visits once or twice a week, or even 3 times a week. When the patient reaches the top dose, they transition out to the maintenance phase. Most maintenance injections are given at 4-week intervals, meaning a monthly maintenance. There are also more rapid buildup schedules. I do a fair amount of cluster; that’s where patients get 2-3 dose increases at each visit. The protocol I use, which is also in the practice guidelines, is an 8-visit protocol. Patients get 2 visits a week, so they’re up to the top dose by week 4. Then they transition out to the monthly maintenance.

There’s also a really rapid approach, called “rush,” where you get patients up to target dose within a couple days. That probably carries greater risk of having a reaction, unless you’re premedicating the patient. The recommended duration of maintenance, regardless of which buildup phase is used, is 3-5 years. The studies that have been done really cleanly and tightly, and which have followed treatment and placebo groups for years, have really been reassuring that the benefits of immunotherapy are sustained after discontinuation.

Medscape: You recently worked on a study[2] that found a significant reduction in healthcare costs for adults and children with allergic rhinitis who were treated with AIT. Can you talk about that research and its results?

Dr. Cox: It’s very exciting research in that it’s a retrospective claims analysis. We had access to the Florida Medicaid database, in a HIPAA-compliant manner, with all the codes for billing as well as the diagnosis codes for every part of an individual’s healthcare. The only thing you’re not capturing is the over-the-counter cost and indirect health cost, such as missed school and work.

This is our third publication about the work we did with this database. The first one compared a smaller group of children before and 6 months after immunotherapy.[3] We found a significant cost savings in the group when compared with costs before treatment. We went on to look at children over the long term, which was a 10-year study.[4] We found that there were significant reductions in healthcare costs when we took the population that received immunotherapy and then matched them to a group with the same diagnosis, same age at diagnosis, and comorbid allergy conditions but who did not receive immunotherapy.

Our latest study[2] was designed similarly to the previous studies, looking at both adults and children, but this time we looked at patients with newly diagnosed allergic rhinitis who received at least 18 months of care after diagnosis. Then we looked at the group that received allergy immunotherapy and matched them to a population on the basis of age of diagnosis, age of intervention, and illnesses such as asthma, conjunctivitis, and atopic dermatitis. We also matched them for something called the Charlson Comorbidity Index (CCI), which is a way of assessing disease burdens of all medical conditions to ensure that we weren’t looking only at the healthier people going on allergy immunotherapy.

What we found in the 18-month period after the diagnosis was a 42% reduction of healthcare costs in the pediatric population and a 30% reduction in healthcare costs in the adult population — significant savings in both populations. The costs that went down in the combined group included outpatient, inpatient, and pharmacy costs. My understanding from [study coauthor] Cheryl Hankin, PhD, who is a healthcare outcomes researcher, is that these are very significant savings.

We saw significant savings beginning at 3 months from treatment initiation. These significant savings continued to accrue through the 18-month follow-up. Some speculate that that’s not possible, that allergy immunotherapy has to be used for a long period of time to see benefits. What’s that all about? And then we saw the continued improvement through 18 months.

But the 3-month improvement could be due to a number of factors, including being under a specialist’s care. Also, studies that looked at the immunologic changes with immunotherapy have demonstrated that these changes can start happening early. So, clinical benefits would not be unexpected early on, particularly if you’re aggressively building up and patients are achieving target dose within a month.

Prescribing Subcutaneous vs Sublingual Immunotherapy (SCIT vs SLIT)
Medscape: Physicians in Europe have been using SLIT for some time now; however, this method of delivery for AIT hasn’t caught on in the United States. In fact, some US physicians remain skeptical about its effectiveness. That said, recent studies have found it to be an effective treatment for allergic rhinitis and comparable to SCIT in short- and long-term efficacy. Can you explain the differences between SCIT and SLIT? With time, do you think US doctors will become more receptive to SLIT?

Dr. Cox: I think that already has started to happen. A few years ago, Tucker and colleagues[5] did a survey of American College of Allergy, Asthma & Immunology (ACAAI) members and found that at that time, in 2007, about 5.9% prescribed SLIT. A follow-up was done with Sikora and colleagues[6] in 2011 and was just published. They found that 11.4% of members were now prescribing SLIT. That was a statistically significant comparison in terms of change.

Both surveys were done using the ACAAI membership database, so that’s comparing the same groups (for the most part) over a period of about 4 years. The main drawback in both surveys, the number-one reason why we aren’t prescribing it, is that there is no FDA-approved product for SLIT.

What that means is a few things. One is that you’re prescribing something off label, which we do a lot. That’s not necessarily a big deal. But having no FDA-approved product means that this is not a covered medical service. At least we know that Medicare and Medicaid wouldn’t cover it. Some private insurers might consider it. But they would have to use a code for unspecified services, which is a little more cumbersome than just using the usual codes electronically. So, this becomes a private pay treatment.

The other commonly cited reason for not using it was that we don’t know the effective dose for the US-licensed allergen extracts. Looking at the literature collectively, it’s really hard to tease out a one-size-fits-all dosing. With SCIT, it’s fairly consistent and within a fairly tight range of about 5-20 µg of the major allergen.

With SLIT, it’s all over the map. This could be because the drug manufacturers are measuring the potency with their own assays. And there may be variations with the performance of the potency assays. But there is a bit of variability, such that I wouldn’t know quite where to start in terms of dosing.

There have been a few US studies using our licensed products that give us a glimmer of what the dosing might be. But I’d like to see a little bit more — I think a lot of physicians would like to see a little bit more — solid information or more studies to show us what effective dosing would be. For instance, Greer Laboratories Inc. has been working with ragweed for a number of years. This year they came out with a study[7] that met primary outcome at a dose somewhere in the range of about 50 µg of the major ragweed allergen.

Whereas Merck[8] found with its new tablet that doses at 50 µg were actually at high risk for safety events, such that they decided not to explore a dose above 12 µg. So, with the solution from Greer at about 50 µg being well tolerated and achieving the desired outcome, and then the tablets coming in at about 12 µg, it’s kind of clear that you have to see the dosing study for each particular product before using it.

Medscape: Speaking of Merck’s tablet, in March the FDA accepted for review a Biologics License Application (BLA) from Merck for its investigational Timothy grass pollen AIT. This is in addition to Merck’s BLA for its investigational ragweed pollen AIT. What are your thoughts on administering immunotherapy in tablet form if they are approved? Might this be a game changer for the therapy going forward?

Dr. Cox: Regardless of whether there is approval, I think we’re still going to have people on SCIT because you’re only treating a small percentage of allergic patients subcutaneously — about 2%-5%. Cheryl Hankin and I saw that with the Florida Medicaid database study; in terms of the newly diagnosed allergic rhinitis patients, 2%-3% received immunotherapy.[2]

I think that where SLIT tablets will come in, and I’m kind of hoping they will, is treating those people who are just using allergy medications. Let’s say that you’re a patient having a mild season but still taking a couple of drugs for symptom control; if you heard that there was a tablet available and maybe all you had to do was take it for a few months before the season and during season, and within 3 years you’re done with medication, I think that would be palatable.

It’s this large population that we’re currently not giving any kind of disease-modifying treatment to that might be open to using these tablets and drops. So, I think it will be a game changer in that — and I’m being optimistic — we’ll be treating more and more of the allergic population with immunotherapy instead of only about 5%.

New Treatments in the Pipeline
Medscape: Why do you think such a low percentage of the population is using immunotherapy right now?

Dr. Cox: I think it’s because SCIT really is time-consuming. It’s hard to think about committing yourself to coming to a doctor’s office once or twice a week for a couple of months and then monthly for 3 or more years.

There are other barriers too. This is just an opinion, but I think there’s still a perception by some that it’s “voodoo medicine.” It’s not science-based. And I think we’ve been slow to educate the outside medical specialties about the science behind allergy immunotherapy. In terms of understanding the science, it’s really been in the past 2 decades that the understanding of the mechanisms has been taking place.

Immunotherapy was found to be effective after it was discovered in 1911. A few studies in the middle of the century showed that it was specific to the allergen. It was dependent on dose. And then there were another couple of decades when not much happened. But there has been a flurry of science — I’d say in the past 2 decades — looking at mechanisms and how to modify the allergen to make it safer and also more effective.

There are some exciting new products in pretty advanced clinical trials. For instance, there’s a cat peptide immunotherapy[9] in phase 3 clinical trials in the United States right now. And you know that phase 3 is sort of the end. Then, if you’re successful, you could potentially submit it to the FDA. Peptide immunotherapy chops up the allergen extract into small fragments that are recognized by the T cell — that’s the cell that gives you the good immunologic changes. But it’s not recognized by the B cell, which produces the IgE, which can cause the allergic reaction. So it seems to be a safer approach to achieving immunotherapy effectiveness.

So, there’s a lot of exciting stuff on the not-too-distant horizon. It may be that we have a menu of choices, not just sublingual. But there are short treatment courses. I guess the best way to describe them is to call them modified vaccines.

Medscape: What else do you see coming down the pipeline in terms of treatments?

Dr. Cox: Investigators also have been looking at different routes of treatment delivery. They’re exploring 2 different delivery methods that are kind of interesting. In one, injection is directly into the inguinal lymph node. One of those studies[10] used a modified cat extract as well and showed very promising clinical efficacy comparable to a 3-year treatment course of SCIT, but after only 3 injections. So, it’s quite possible that in the future, after 3 injections, patients might be done with their cat allergy.

There has also been some exploration of epicutaneous delivery, whereby the allergen is put on the skin as a patch and the patient would wear it for a period of time. So, there are some interesting approaches that are being explored. And, of course, sublingual tablets and drops offer the advantage of the patient being able to take it at home, which has tremendous convenience.

References

1. Cox L, Nelson H, Lockey R, Calabria C, et al. Allergen immunotherapy: A practice parameter third update. J Allergy Clin Immunol. 2011;127(suppl): S1-S55.

2. Hankin CS, Cox L, Bronstone A, Wang Z. Allergy immunotherapy: Reduced health care costs in adults and children with allergic rhinitis. J Allergy Clin Immunol. 2013;131:1084-1091. Abstract

3. Hankin CS, Cox L, Lang D, et al. Allergy immunotherapy among Medicaid-enrolled children with allergic rhinitis: patterns of care, resource use, and costs. J Allergy Clin Immunol. 2008;121:227-232. Abstract

4. Hankin CS, Cox L, Lang D, et al. Allergen immunotherapy and health care cost benefits for children with allergic rhinitis: a large-scale, retrospective, matched cohort study. Ann Allergy Asthma Immunol. 2010;104:79-85. Abstract

5. Tucker MH, Tankersley MS; ACAAI Immunotherapy and Diagnostics Committee. Perception and practice of sublingual immunotherapy among practicing allergists. Ann Allergy Asthma Immunol. 2008;101:419-425. Abstract

6. Sikora JM, Tankersley MS; ACAAI Immunotherapy and Diagnostics Committee. Perception and practice of sublingual immunotherapy among practicing allergists in the United States: a follow-up survey. Ann Allergy Asthma Immunol. 2013;110:194-197. Abstract

7. Greer Allergy Immunotherapy. GREER® investigational sublingual allergy immunotherapy liquid (SAIL)™ for short ragweed allergies data from phase III trial featured at allergy meeting. [Press release] February 24, 2013. http://www.greerlabs.com/files/2013-AAAAI-2_22_13.pdf Accessed April 29, 2013.

8. Merck. Merck announces FDA acceptance of biologics license application for investigational grass pollen allergy immunotherapy tablet. [Press release] March 27, 2013. http://www.mercknewsroom.com/press-release/research-and-development-news/merck-announces-fda-acceptance-biologics-license-applica Accessed April 26, 2013.

9. ClinicalTrials.gov. Phase III Cat-PAD study. February 2013. http://clinicaltrials.gov/show/NCT01620762 Accessed April 26, 2013.

10. Senti G, Crameri R, Kuster D, Johansen P, et al. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012;129:1290-1296. Abstract

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