The new AAAAI podcast is about Palforzia–surprise surprise. It was recorded just three days after the introduction. Like all these podcasts the host is our friend Dr. David Stukus. Appropriately the interviewee is Dr. Andrew Bird from Dallas who contributed a piece to this website five years ago called Food Allergy Testing in the Coming Age of Prescription Immunotherapy. Dr. Bird wrote at the time, “The response from the medical community must be to ensure that patients are appropriately diagnosed and diagnostic methods are used intentionally in patients with a history supporting a role of immediate reactivity following food ingestion.” Five years later, that remains a key concern as this first-ever drug enters the market and is clearly explained, as are such issues as cost, dosing, maintenance, overall efficacy for certain patients, reactions, goals of treatment, and why patients choose to discontinue treatment. There’s also forthright discussion of the pros and cons of offering the treatment for allergists and shared decision making in choosing to start the treatment or not.
BRISBANE, Calif.–(BUSINESS WIRE)–Aimmune Therapeutics, Inc. (Nasdaq: AIMT), a biopharmaceutical company developing and commercializing treatments for potentially life-threatening food allergies, today announced that the U.S. Food and Drug Administration (FDA) approved PALFORZIA™ [Peanut (Arachis hypogaea) Allergen Powder-dnfp]. PALFORZIA is the first approved treatment for patients with peanut allergy. It is an oral immunotherapy indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. PALFORZIA is approved for use in patients with a confirmed diagnosis of peanut allergy. Initial dose escalation may be administered to patients aged 4 through 17 years. Up-dosing and maintenance may be continued in patients 4 years of age and older. PALFORZIA is to be used in conjunction with a peanut-avoidant diet. PALFORZIA is not indicated for the emergency treatment of allergic reactions, including anaphylaxis.
“This is a defining moment for the peanut allergy community and for Aimmune Therapeutics, and we are excited to bring the first FDA-approved treatment for peanut allergy to patients and their families,” said Jayson Dallas, M.D., President and CEO of Aimmune Therapeutics. “Our commercial field team is ready to begin engaging with allergists to help them prepare to safely incorporate PALFORZIA into their practices and, with approval in hand, our payer team can also immediately begin work to secure formulary access to PALFORZIA. We view this approval as just the beginning for Aimmune, and it underscores our continued commitment to bringing innovative treatments to people with potentially life-threatening food allergies.”
“Not only is PALFORZIA the first approved therapy for peanut allergy, but it is the first approved therapy for any food allergy,” said Daniel Adelman, M.D., Chief Medical Officer of Aimmune Therapeutics. “We truly appreciate the efforts of the peanut allergy community who contributed to the development of PALFORZIA – including the more than 1,200 patients and their families who participated in our clinical trials, the study investigators and their staff, the advocacy community, and our dedicated employees – all of whom have helped us develop and deliver this first-of-its kind therapy.”
Peanut allergy is one of the most common food allergies in the world, affecting more than 1.6 million children and teens in the United States alone.i,ii It can be a chronic and life-long condition, and reactions to peanut can range from mild to potentially life-threatening,iii with one in five peanut-allergic patients visiting emergency rooms each year due to accidental exposures.iv
“Peanut allergy is more common now than ever before and has become a serious public health concern. The food allergy community has been eagerly awaiting an FDA-approved treatment that can help mitigate allergic reactions to peanut and, as allergists, we want nothing more than to have a treatment option to offer our patients that has demonstrated both the safety and efficacy to truly impact the lives of patients who live with peanut allergy,” said Christina Ciaccio, M.D., Associate Professor of Pediatrics and Medicine and Chief of Allergy/Immunology and Pediatric Pulmonary Medicine at the University of Chicago Medical Center and Biological Sciences. “With today’s approval of PALFORZIA, we can – for the first time – offer children and teens with peanut allergy a proven medicine that employs an established therapeutic approach.”
PALFORZIA is a complex biologic drug used with a structured dosing approach that builds on a century of oral immunotherapy (OIT) research.v With OIT, the specific allergenic proteins are ingested initially in very small quantities, followed by incrementally increasing amounts, resulting in the ability to mitigate allergic reactions to the allergen over time. PALFORZIA is a rigorously developed, pharmaceutical-grade OIT for peanut allergy with a well-defined allergen profile to assure that every dose, whether 0.5 mg (equivalent to 1/600th of a peanut) or 300 mg, has been prepared and analyzed for consistency.
The Biologics License Application (BLA) for PALFORZIA included efficacy and safety data from seven clinical studies, including the pivotal Phase 3 PALISADE and RAMSES clinical trials. In addition, data from the Phase 2 ARC001 study and the ARC002 open-label follow-on study were included, as well as data from ARC004, ARC008 and ARC011, which are ongoing studies.
PALFORZIA is available only through a Risk Evaluation and Mitigation Strategy (REMS). Requirements of the REMS include: the prescribing physician and patient must be enrolled in the REMS prior to initiation of treatment; the initial dose escalation and the first dose of each up-dosing level must be administered in a certified healthcare setting; epinephrine must always be immediately available to patients; and pharmacies/distributors must be certified with the REMS and dispense PALFORZIA only to certified healthcare settings or to patients who are enrolled in the REMS. Consistent with approved immunotherapies indicated to treat allergic conditions, the Prescribing Information for PALFORZIA contains a boxed warning.
Aimmune will provide resources to patients and families who, upon consultation with their physician, wish to seek treatment with PALFORZIA. These resources will include educational materials, a dedicated call center, a co-pay program for eligible patients, and a Patient Assistance Program to provide PALFORZIA at no cost to eligible patients.
“Peanut allergy carries an overwhelming psychosocial burden that impacts patients and their families daily – peanuts are everywhere, and the threat of a severe reaction related to an accidental peanut exposure dominates families’ daily lives,” said Lisa Gable, Chief Executive Officer, Food Allergy Research and Education (FARE). “The risk of accidental exposure is real, and we, as a community, have long awaited an option beyond avoiding peanuts alone. As one of the organizations that originally highlighted the need for an FDA-approved oral treatment approach to food allergy back in 2011, we are thrilled with today’s FDA approval of PALFORZIA as it fills a long-standing need in the treatment of peanut allergy.”
Aimmune Therapeutics was founded directly in response to a united call to action by leading stakeholders in food allergy. At an advocacy-sponsored research retreat in 2011 aimed at reaching consensus on the direction of food allergy treatment research, a group of parents of children with severe food allergies, patient advocacy organizations, leading clinical and academic physicians, representatives from government, and members of the pharmaceutical industry recognized the need for a structured approach to OIT and approved treatments. This meeting eventually led to the formation of Aimmune Therapeutics to specifically address that need.
By Dr. Paul Ehrlich
With the age of prescription therapy for food allergies rapidly approaching, it’s not too early to start figuring out what patients will prefer among the options presented. Allergists and their patients have confronted similar dilemmas before, although simple preference doesn’t solve the problem. For example, we have been offering shots for a hundred years, and no one is terribly fond of them. To many, sublingual immunotherapy (SLIT) sounds like a dream, but experience teaches us that in the real world patients don’t like them in nearly equal measure. Taking a medicine every day is burdensome, and many patients don’t like the way the medicine feels and tastes in their mouths.
Thus, it was fascinating to read about Dr. Matthew Greenhawt’s presentation to the ACAAI meeting in Houston about patient and caregiver feelings concerning two modes of therapy that are rapidly nearing availability—Palforzia oral immunotherapy (OIT) and the Viaskin “peanut patch,” also called epicutaneous immunotherapy or EPIT. A total of 200 children aged 7-11 and 206 caregivers were surveyed with questionnaires replete with emoticons to express their feelings in addition to straight answers. Compliments to Matt and his team for their imagination in assaying patient emotions as part of the package.
Unsurprisingly their greatest concerns were over the prospect of medical emergency, but they were also deeply disturbed by things like touching, tasting, and smelling peanuts. Questioned about the prospective treatments, many rejected the oral approach. Many more were drawn to the idea of the patch.
Looking at the numbers, I began to think about my own experience over many years. The two key senses—taste and smell—have figured heavily in the lives of many patients whom I first met as children, and treated on into adulthood, and in many cases treated their own children. While there was no such thing as active treatment all those years, some of them did manage to outgrow their allergies, including to peanut. I would test them for IgE and do skin prick testing and urge them to try their allergens or do an office food challenge. But for some, the chance to eat the allergen just wasn’t enough to overcome that sensory aversion, although some do arrive at some remarkable strategies over time. The key is to associate food with the pleasure it is meant to give rather than regard it as medicine.
It’s early days for food immunotherapy, but it’s not so early that we can’t start figuring in the dimension of time. Longitudinal data for some of the earliest studies show that many subjects drop out. Medication fatigue is a real thing with all chronic disease management. It’s likely to factor heavily as OIT, the patch, and other non-curative treatments hit your allergist’s office. Those early aversions and fears at the front end have their analogues on the back end.
But maybe that’s not a bad thing. In a recent talk, one of the pioneers of private practice OIT observed that patients he had treated as little kids would come to him as they reached adolescence and inform him they were quitting. He was okay with that. He had helped them deal with their allergies long enough to come of age and could make their own decisions. They could negotiate the risks for themselves. I liked hearing this.
With a range of treatment options on the horizon, the allergist’s responsibility remains the same. To understand patient and caregiver needs and fears, to provide treatment when appropriate while explaining all the risks and offering lots of encouragement, and be just as considerate and well-reasoned when rejecting a treatment. One thing is sure: all those fears and aversions covered in Matt’s study are going to be a constant. We may have seen it all before, but it’s always new to the patient.
Several years ago, Dr. Paul Ehrlich explained why he wouldn’t be taking up any of the new food allergy treatments that were coming into the medical marketplace. He wasn’t against it in principle so much as he wasn’t prepared to offer the kind of attention required when therapy consists of daily doses of the offending foods. He described such a practice in this way: If you are going to use this kind of therapy, the kind of practice you should go to, [is] one where current practitioners are either pioneers or who have worked directly with the pioneers.” We found one. Nikhila Deo Schroeder, M.D., who also holds a Masters in Engineering from MIT, started her own practice in Charlotte, North Carolina called Allergenuity Health whose aim is to safely teach and retrain the immune systems of allergic patients via a method called Sublingual Immunotherapy (SLIT) – the system of placing antigen under the tongue (via liquid or “drops”). After her Allergy & Immunology fellowship training at the University of Virginia, Dr. Schroeder worked for several years at Allergy Associates of La Crosse with Dr. Mary Morris, the standard bearer for the work done by her father Dr. David Morris, who attended a Sublingual Immunotherapy conference in the 1960’s and recognized the significant potential for this type of treatment in his mold allergic patients. Dr. Schroeder’s experience in La Crosse treating over 1000 patients with food and/or environmental allergies using Sublingual Immunotherapy gave her an in depth look at how the immune system responds to this type of allergen introduction and ideas for its further therapeutic potential. – Henry Ehrlich
AAC: Thank you, Dr. Schroeder, for taking time with our readers. First I’m intrigued by your background in engineering. What made you leave for medicine?
Nikhila: Thank you so much for the invitation to talk with you and your readers, Henry! I’m so happy to be here. I have always had a love for math, logic, and problem solving. Paired with my creative side, engineering was a very appealing career choice because it allowed me to use my skills to invent solutions for people. But being a doctor felt even more natural. My mom often shares the memory that when I was a really young girl, anytime someone was sick on our block, I would take them a can of chicken noodle soup from our pantry and keep them company. That’s just who I was and what I wanted to do from a young age onward. So in the end, I decided to go for both engineering and medicine and see what I could do with them together.
AAC: Does engineering inform the way you think about your allergy practice and your approach to patients?
Nikhila: Absolutely. My time studying engineering really cultivated my critical thinking skills and I apply that to my practice and my care of patients. Nearly every homework assignment or project at MIT was a complex problem that needed to be solved, and memorization or looking something up in our textbooks or on the internet was not going to cut it. Believe me, my friends and I tried. Though sometimes it was overwhelming, I’m so glad I pursued engineering first because it really taught me how to actively think and more importantly, to not be scared of doing so. Problems often have more than one solution, and that is a beautiful and extremely useful concept to remember in health. One solution may be the best overall for one person and a different solution may be best overall for another person with the same underlying issue. Being able to navigate, think, create, and adjust solutions to the individual person can help patients in ways that following a predetermined or standard solution simply can’t, so I’ve kept that idea central to my practice of medicine. Now that my husband and I have opened our own allergy clinic, we have incorporated these philosophies into not only our medical care but also into our overall health care process. Our clinic, Allergenuity Health, is in almost no way standard, and our approaches to everything from the care we provide to our business policies and price transparency are all designed to provide options and solutions to patients. It takes a lot of work, but it is worth it.
AAC: When you were doing your allergy training, was there much discussion of OIT and SLIT? What prompted you to pursue SLIT over OIT?
Nikhila: OIT and SLIT were essentially theoretical treatment possibilities during my fellowship training. They were an occasional topic of a research presentation or a Journal Club discussion. This makes sense to a large extent, since fellowship programs are designed to train budding allergists in the main diagnosis and treatment methods of the field, not necessarily in highly sub-specialized areas of the field. However, when I saw how much allergy patients and families were suffering and how inadequate the traditional therapies were in so many instances, I was motivated to look for or create something better and to further sub-specialize. I became very interested in immunologic signaling and how we could use that to help people with allergies. As I learned more about various types of immunotherapy, SLIT made a lot of sense to me. It actually made more sense overall than any other form of immunotherapy. It is scientific, uses a natural route of tolerance-training literally handed to us by our bodies, has been proven effective, and is safer than any other form of immunotherapy. Why weren’t we talking more about this? I still don’t know.
The safety aspect was the kicker for me that solidified my in-depth pursuit of SLIT. I had listened intently as so many patients and families shared their incredible stories, their worries, and their goals with me over the years. Safety, both in daily life and in treatment options, was overwhelmingly their main goal. What they desired most (other than a complete cure of course) was a treatment option that provided them with a safe way to build allergen protection, reduce chronic symptoms, and minimize the likelihood of anaphylaxis if they accidentally encountered their allergen(s). For example peanut-allergic patients and families made it more than clear that being able to eat peanut butter was not their goal, especially if they had to undergo a risky procedure to get to that point and then sustain a lifelong, daily risk to maintain it. And I completely saw their point. OIT’s risk of anaphylaxis for patients was and is still far too great for most specific patient situations, in my opinion. Some reports suggest that the average risk of anaphylaxis from OIT treatment may even be higher than the average natural risk of anaphylaxis in a food allergic patient. Though epinephrine is a life-saving medicine in anaphylaxis, it is not effective to rescue 100% of individuals from anaphylactic reactions even when used early and appropriately, so I take risk of anaphylaxis from a treatment extremely seriously. Given that SLIT can achieve many very useful and potentially life-saving results in a very safe way, without this substantial risk of anaphylaxis from the treatment itself, I knew that I personally would not be satisfied without seeing first-hand what SLIT could offer all of these patients looking for such an option.
AAC: So what did you find that Sublingual Immunotherapy (SLIT) could offer patients?
Nikhila: Essentially everything patients desire. SLIT checks off nearly all the boxes of an ideal allergen immunotherapy treatment.
- It is non-invasive. No shots, no pain.
- It can be used to treat environmental allergens and food allergens, and more than one allergen at once if needed.
- It can be used even in severely allergic patients.
- It is easy for patients and families to do.
- It is high reward for low risk, helping patients build substantial levels of protection without a significant risk of anaphylaxis from the treatment method itself.
- Its most common side effect is a temporarily itchy mouth.
- It can be done at any age, including as early as infancy.
- Depending on the method of SLIT, it does not require any significant exercise limitations, rest periods, or lifestyle restrictions. And missing an occasional dose when “life happens”, even during the buildup phase has no detrimental effects on the overall level of protection you have developed.
- It is non-intrusive. There is no need to find ways to get your child to eat something they may not like the taste of or that is anxiety-provoking.
- It saves families a lot of time and money in the long run – much less ER and other doctors’ visits, less testing, less medications.
- It can be done with infrequent appointments – nowhere near weekly or monthly like other forms of immunotherapy.
- It can dramatically improve a patient’s (and their family’s) quality of life with significant symptom relief and substantial allergen protection over time.
- Some patients can come off the treatment and have sustained results for some time. For those who have better relief and protection on the treatment than off or for whom it may be too risky to gamble with discontinuing, it is extremely easy to continue long-term.
- It is easy to travel with when needed, and treatment can be done and maintained long-distance if you’re on a trip, away at college, or move to a different state during the course of your treatment.
- It involves forming a simple habit just like brushing your teeth, but even easier.
Liquid antigen SLIT treatment is done by literally just holding a sweet-tasting liquid droplet – a very specially formulated one – in your mouth a few times each day. Like any form of allergen immunotherapy, achieving substantial, true immunologic change does take time and a commitment. But I have not currently come across anything better than SLIT to help most patients and families safely build towards their goals and improve their quality of life.
AAC: Is there anything that SLIT doesn’t offer patients that OIT does?
Nikhila: Yes, there is one main limitation of food SLIT compared to OIT. SLIT will not be able to give a patient or family real-time information on their exact level of developed tolerance or desensitization. For patients on food SLIT, the allergen amount a patient can tolerate if ingested is typically much higher than the SLIT dose being administered, but we don’t have an easy way to know exactly what that amount is at any given timepoint in the process (without doing an oral challenge) since the treatment does not involve someone actually ingesting the food like OIT does. With OIT, since you are ingesting a particular dose of an allergen each day, you know that if the next day you were accidentally to ingest up to that same amount of the allergen before you took your daily dose, you would probably be ok (unless you were exercising, hot, stressed, or ill at the time, so it is still not a guarantee). Though I wish this limitation didn’t exist, SLIT is not alone in this. It’s similar to allergy shots in which we cannot answer this question in real-time either. However, in the case of allergy shots and environmental SLIT, patients are naturally and repeatedly exposed to many of their environmental allergens, so they physically see their results at those times since those are essentially allergen challenges. With food SLIT, since you’re also avoiding the food at the time (at least initially), we can’t really use that method either unless you have an accidental exposure.
Here is what we do know though, which helps support patients through this limitation with SLIT:
- Studies that have challenged patients after even short SLIT courses have demonstrated substantial protection, with improvements in tolerance from their pre-treatment level of over 100-fold. The longer the time on SLIT treatment, the further this increases.
- Short-term studies have shown that successfully consumed doses in challenges have ranged from 250-2,500 or more times the SLIT treatment dose at the time. So we can make some educated estimates. (And again, the longer the time on SLIT treatment, the further this can increase.)
- Anecdotal experience with accidental exposures repeatedly shows significant protection gained already within the first year and even more in the subsequent years, and we get more than enough evidence of the power of SLIT to protect against allergen exposures from what we see with environmental allergy symptom relief to frequent natural allergen challenges.
- There are clues of the protective immunologic changes that we can see in test results as well (though we have a long way to go as a field in terms of getting access to much needed better tests in this area).
AAC: SLIT and OIT are often compared as if they approach “desensitization” via the same mechanisms. Is that true?
Nikhila: SLIT and OIT can be used similarly or very differently. That’s where a lot of confusion comes from, even by physicians. Not all procedures offered under the same name do the same thing. And one version of SLIT is certainly not the same as another version of SLIT, so it is important that patients research and interview providing physicians. The underlying knowledge of immunologic mechanisms, immunotherapy design skill, type of protocol, and experience of the providing physician can make a huge difference. This is probably similar with OIT, since both SLIT and OIT are sub-specialized treatments. I’d be happy to help explain the basics of these comparisons here.
AAC: So how can SLIT and OIT be used similarly to achieve desensitization?
Nikhila: Classic desensitization by OIT or SLIT is similar to what we offer in the hospital to desensitize penicillin-allergic patients if they really need penicillin treatment for a particular infection. The process involves introducing a particular allergen into the body in a fairly quick, increasing, step-wise manner. This essentially plays a trick on the immune system, which is why results are so quick and can be so high. But along with this type of result comes significant risk. There are two main parts to how this type of desensitization trick is achieved, which would take quite a bit of time to explain fully. But the basics of it are, one of the things that introducing allergen in small, increasing, repetitive ways can do is use up the system’s allergic mediators bit by bit by activating allergy cells in chunks until all the mediators have been released. This is of course not without risk of the patient developing some type of symptom along the way, and symptoms do commonly occur in classic desensitization procedures as allergy cells are activated. The hope is to stay under the threshold of anaphylaxis, but that unfortunately is not always the case because there is no way to know what that threshold is. The other thing that increasing, repetitive introduction of allergen can do is slowly flood the system with so much allergen that it gets a chance to bind in many more places than usual, including plugging up both binding sites on IgE antibodies, effectively blocking IgE antibodies from cross-linking with each other which is a main signal needed for activating allergy cells. So, both of these types of actions can occur as a person gets desensitized, rendering their allergy mediators either all used up or their IgE antibodies all blocked up, or striking some sort of balance in between. Regardless of exactly what occurs, once the short-term desensitization trick is achieved, the immune system is in a balanced state of “temporary tolerance” in which it still very much wants to react when it sees that allergen – it does not think the allergen is any less harmful than it did before – but it is just much more difficult for it to be able to do so. In order to keep the body in this type of desensitized state, a persistent and high amount of that allergen needs to remain in the system, at least for quite a long time if not indefinitely. It has been well-proven that in the short term, if the high allergen load is stopped, the patient’s immune system has a very good chance to replenish its allergic mediators to substantial amounts, and all the allergen plugging up the IgE antibodies gets a chance to be released such that these IgE antibodies can cross-link again. And when those things happen, allergic reactions to allergen exposures can again occur. For patients receiving drug desensitization to penicillin in the hospital, once the procedure is stopped, we make it a point to emphasize to them that they are still very allergic to penicillin and they should not take it again on their own for anything else even though they just took it for treatment at high doses.
Classic desensitization is an incredibly cool trick, but it is kind of like cheating on a test. The immune system appears to know how to handle an allergen, but in the short run it didn’t actually learn much about how to properly handle that allergen, and that can come back to haunt it. That’s not to say this type of desensitization is not without its uses, or that there aren’t potentially additional beneficial long-term effects if desensitization is carefully maintained (but our understanding of this is in its infancy since we do not maintain drug desensitization long term). What is very important is to understand this type of desensitization for what it is – a quick, high-dose, temporary fix that comes with risk, is high maintenance, and can fairly easily come undone. Since the main component of this desensitization is merely being able to get an allergen into the system repeatedly and at higher and higher doses, either OIT or SLIT can be used effectively for this purpose. OIT can more easily reach higher doses because you are using the actual food so you can consume as high of a dose as a person needs to institute this trick, but that comes with the disadvantages for some people in terms of not liking the taste of the food, as well as the risks of allergen ingestion and entrapment in the stomach. If a reaction begins after an OIT dose, it is not easy to remove the allergen from the body and minimize the reaction. SLIT can also reach substantially high doses because you need much less allergen (1000 times less or possibly even less) presented via the sublingual route to achieve similar results to the gastic route, but there are some limits to how much allergen can be physically held in the sublingual space as well as the expense of FDA-regulated, purified liquid antigens. However, if a reaction begins to occur with a SLIT dose, the antigen can be spit out and the mouth can be rinsed out to try to disrupt any further allergen capture, so risks and reactions can be better managed. The take-away here is that substantial desensitization of this type can and has been achieved with both SLIT and OIT methods. OIT can reach higher doses (if needed) more easily, but the safety with the SLIT route is overall better and the taste factor is a non-issue with SLIT since the allergen is in a purified liquid form.
AAC: And how can SLIT be used differently than OIT and other forms of immunotherapy?
Nikhila: This is the crux of why I personally find SLIT to be superior as an overall immunotherapy option and as the best place for most patients to at least start if not also finish. Sublingual Immunotherapy (SLIT) has the unique ability of exposing the immune system to its allergens via special highly tolerogenic (tolerance-promoting) immune messenger cells found only in the mouth. These cells are called oral Langerhans cells, and they are very efficient at capturing substances present in the mouth and then sending calming signals to the rest of the immune system via specific tolerance-promoting natural chemicals (cytokines such as IL-10 and TGF-b) and important T and B cell influences. In fact, this appears to be a main part of their job – to help the immune system learn to tolerate the exposures seen regularly and non-threateningly in the mouth. This has been supported in basic science studies, but it makes common sense too. Our vital substances all come through the mouth – water, food, air – and we need to overall be able to tolerate them in order to survive. These cells help teach the rest of our immune system what to tolerate. We can use them to help teach our immune system that “allergens” are harmless too.
Though the sublingual route can be used to attempt to achieve the classic type of desensitization I described before, it can also be used in a different way to try to retrain the immune system to think properly about allergens. This form of SLIT often includes many of a person’s allergens (not just one) and uses a lower and slower approach to allergen introduction. By purposefully giving low doses of allergen, especially at first, the allergen is mostly picked up by the special tolerogenic messenger cells I mentioned before (oral Langerhans cells), engaging those tolerance promoting mediators. Very little of the allergen in the treatment reaches the mast cells (allergy cells) in the mouth or elsewhere in the body, so very few allergic mediators are released and therefore symptoms are minimal and risk of anaphylaxis is essentially only theoretical when SLIT is done this way. (For example, I have not seen anything close to anaphylaxis from the SLIT treatment I have done in over 1000 patients now.) This type of SLIT method allows a skilled allergist to very safely direct the immunologic signals being generated in favor of tolerance-promotion rather than allergic pathway activation, thereby retraining the system towards realizing that all of these substances it thinks are dangerous allergens are truly harmless at baseline, and that activating allergy pathways is not a productive response. It is akin to giving the immune system a tutor to help it understand a concept that it had gotten confused about before. In the short term, fostering these calming signals can reduce inflammation and decrease the reactive cytokines released via allergic pathways. This lessens both symptoms of chronic allergic disease and a person’s immediate reactivity to their allergens. In the long-term, creating a persistent environment of these calming signals causes many favorable effects: a shift in the entire immune system away from desiring to produce IgE and towards producing other antibodies, downregulation of IgE receptors so any IgE produced becomes less able to cause detrimental actions anyway, and a change in the overall composition of immune cells away from those involved in creating and perpetuating allergic pathways and towards those found in tolerant, non-allergic individuals.
I have seen such good things come from this type of SLIT approach without significant inconvenience to families or safety risk to patients. And that makes this type of SLIT treatment extremely valuable and unique compared to all other forms of immunotherapy.
AAC: SLIT has been criticized for a lower reported efficacy than OIT. Can you help our readers navigate this comparison?
Nikhila: Of course. The efficacy comparison has been so oversimplified so frequently that it has led to a lot of perpetuated misinformation and confusion. But this is understandable because these topics are so complex that quick summaries by default miss and skew crucial points. I won’t even be able to get into the half of it here either without going on for hours, so I’m happy to talk more about it with anyone interested. The main thing it is really important for patients and families to know is that both OIT and SLIT are effective options to choose from. Risks of reaction to exposures generally improve by substantial levels with either method. SLIT does not only max out at “bite-proof” for everyone, and this has been clearly proven in peanut SLIT studies with many participants being able to eat anywhere from 1-20 peanuts after a relatively short SLIT course. It has also been shown in a milk SLIT study with participants being able to tolerate 1/8th-1 full cup of milk. And I have seen a wide range of incredible results in private practice as well to further confirm the potential with SLIT. Think about it – to be able to safely improve a peanut-allergic patient’s tolerance to even just 1 peanut, let alone potentially much more. That is what the vast majority of patients in the real-world want, so why isn’t SLIT being promoted more as an available, sub-specialized option? It doesn’t make much sense that it is not, except that the definition of efficacy has unfortunately strayed from what many patients truly desire to what type of high-dose result can be academically achieved.
The commonly used marker of “efficacy” in discussion is “high-dose tolerance as quickly as possible.” If that is the entire definition of efficacy, with no regard to safety or other factors, then a classic desensitization procedure via either OIT or SLIT would be the best route, with an advantage to OIT since the dose can easily be increased however high is needed to achieve the desired result for an individual. However, if we take into account what is desired by a particular family in their real-life in terms of what level of protection is effective for them – balanced with other factors like the risks of achieving that protection in a certain time-frame and the required maintenance to keep it up indefinitely – then “efficacy” takes on a whole different definition. Most patients are not looking to be able to fully eat a previously anaphylactic food. Many don’t even like the taste. They just want to be able to live their life as “normally” as possible with as much protection from accidental exposures, as minimal interference in their life, and as low of a safety risk from the treatment itself as possible. For these people, SLIT is the most effective option. And even for those who do want to be able to eat full servings of a previously anaphylactic food someday, SLIT may get them there, so it still is a great option to consider starting with given its other several benefits. If needed, OIT can be done afterwards with a more safe and smooth course thanks to the beneficial foundation laid by the initial SLIT course. So it’s also important to not think these treatments are mutually exclusive – the solution for a particular individual may involve both. In the end, overall efficacy of all of these treatments actually comes down to a family’s personal factors, and the simple, isolated comparison of “tolerated dose in a short time-frame” can really mislead a family trying to understand all of their options.
AAC: Who manufactures your drops at your clinic Allergenuity Health? Can they be combined to reduce the daily dosing burden or is each allergen treated separately? If so how many allergies can you treat simultaneously?
Nikhila: We formulate our own SLIT drops at Allergenuity Health, based off of my formulas and my direct, personalized management of the SLIT procedure course all along the way. We use FDA regulated antigens that come from the 3 major world-wide antigen companies who collect the allergen material and purify it into a liquid suspension. I absolutely treat multiple allergens at one time if possible for a patient, which greatly reduces patient burden and time to protection as well as has many other synergistic health benefits. We keep environmental and food allergens separate for logistic reasons, and in our typical dosage range I can fit up to 20 allergens in each bottle. That allows me to treat up to 20 environmental allergens and 20 food allergens with my most common method, and I have found that for most patients that is more than enough. Additional allergens or more concentrated high doses can be made available if needed, as I am always open to optimizing the treatment structure to each patient, so we get creative if need be to make a plan best suited to each patient.
AAC: Do you have any exclusion criteria for new patients such as uncontrolled asthma, EoE, or a history of frequent severe reactions?
Nikhila: This is a great question and the answer is – no! In fact, one of the wonderful features of the kind of SLIT I do is that I can actually use it to help all of these patients who are so often excluded from immunomodulatory treatments for safety reasons (which I’ve always found ironic since these are the patients who could benefit from immunotherapy the most). I use additional precautions in these patients to make sure that we really ease into allergen introduction to their body, but the beauty of this treatment method is that tolerance-generating mediators are released by the immune cells we are engaging with allergen, not allergic mediators. So, the allergen we’re introducing via the sublingual route is not significantly activating their allergic disease, but rather helping healing mediators be released. It’s pretty incredible that allergen particles can be both the problem and the solution, depending on the signal they send. But it makes sense because “allergens” are truly harmless themselves. SLIT has finally given me a fantastic and safe way to truly help all patients from mild to severe allergic disease so that no one is left out without an immunomodulatory option.
AAC: A few years ago we published an article about a Netherlands study that showed patient compliance with SLIT, which is better established in Europe than it is here, was lower than allergy shots. Last week I saw a presentation by a major figure in the field who showed similar data. She said the most important figure in getting good compliance is the doctor’s secretary who can call to remind patients. What is your experience with patient compliance? Also, she said that she doesn’t insist on SLIT patients carrying epinephrine. Where do you stand on that?
Nikhila: My experience with patient compliance with SLIT in private practice has been very good. I think that is because we make it a point to make sure that SLIT treatment is a good overall fit for the family before we start, and we make time up front to answer a family’s questions so that they understand how, when, and most importantly why they should properly take their doses. Additionally, we discuss what is and is not feasible for a family, and I take those factors as well as their medical situation into account as I formulate a personalized plan for them. As we go along, I tweak the plan as needed so that we can keep any symptoms from the allergen exposure in the treatment as minimal as possible. When the treatment is easy, families understand what they need to do and why, and the dosing doesn’t cause too many adverse effects, compliance is generally good. Families do have to take some responsibility for dosing properly on their own since the treatment is largely home-based unlike allergy shots, but most families we work with are motivated and we do our part as well to best set them up for success without too much inconvenience or stress. We certainly don’t have a secretary that calls and reminds patients to take their doses, and thankfully we have not found that to be needed at all. From what I have come across, compliance is lower when high doses are jumped into early on which leads to adverse effects and when proper education has not been allowed to take place. This often happens when treatments become standardized and patients are pushed through quickly. Thankfully, I have left that part of our health care system and am able to approach SLIT treatment in a completely different way for my patients.
My policy on epinephrine for SLIT patients is different for each patient. In an ideal world, I think every person, known to be allergic or not, should have epinephrine rescue readily accessible. Anyone can have a surprise allergic reaction at any time, not just those who have had one before. So I am always happy to prescribe it. For SLIT patients, for those who have epinephrine auto-injectors prescribed for their allergic conditions, I recommend that they bring them to their up-dose appointments. (They should anyway, because they should have them with them all the time.) However, for those on SLIT with no history or testing suggestive of severe allergic reaction risk, we discuss risks and the need for epinephrine and weigh all the factors. I will happily prescribe it, but that is not always what works best for a patient. It is my job to educate them and help them make the best decision for them. Carrying epinephrine in its current form certainly affects many aspects of a person’s lifestyle and routine, and it can be very expensive. So prescribing it just for it to sit in a drawer or never be picked up is also not useful if the patient’s risk for anaphylaxis is extremely low and they are not concerned. Since the method of SLIT that I do is overall so safe and nothing close to anaphylaxis from proper dosing has ever been an issue, I agree that from what I’ve seen, mandatory epinephrine carrying for certain types of SLIT treatment does not appear to be warranted and it should be discussed on a case by case basis.
AAC: Your website is quite detailed and clearly tilted in the interests of patients, including the creation of community. How did you arrive at this approach?
Nikhila: It’s just what we want to do. My husband and I see community and building strong relationships as the foundation of all good things in life, and we have both always been very service and community oriented. None of us do better alone than we do together with great and supportive people at our sides, and everyone’s health benefits from “TLC”. We were so tired of the often cold, competitive, and lonely nature of the standard, insurance-managed health care system in this country, both from the patient and physician perspectives. So when we decided to open our own clinic, we made sure to structure it based on our own values. Our patients become like family to us. We know our patients’ names, and their parents’ names if they are a child. We know about their favorite animal or toy if they’re a child or their hobby if they’re an adult. We give our young patients “superhero support” and “bottle buddies” to let them know that they are strong themselves but they are also not alone. We connect them to one another, and we have plans to do specific types of Allergenuity Health community events as we continue to grow. Knowing you are a part of a caring community can sometimes make all the difference, and we want our patients to never feel alone because once they’ve joined us, they never are.
AAC: Do you have any thoughts for your fellow allergists who are on the fence about offering new therapies or are firmly opposed?
Nikhila: My personal approach has always been simple – to make sure to keep an open mind about new or additional treatment possibilities that appear to make some scientific and common sense, and that has served me very well with my patients. But it has also not been easy to do so in this insurance-driven healthcare culture that so strongly restricts all of us to mass standardization and protocolization of healthcare and away from critical thinking, innovation, and personalization of care. So I completely understand why not all of my colleagues may embrace the same approach that I have. I guess I would encourage my colleagues to try hard to keep an open mind about reasonable therapies even if they are not interested in or willing to offer them, and to not dismiss a therapy or procedure based on summarized data without first trying to gain a better understanding of it. Though there are as many if not more terrible, unfounded therapies being pushed out there as there are great, underutilized therapies, if one or more of our allergist colleagues really stands behind a treatment, I would hope it would at least beg the question from fellow colleagues of “I wonder why?” and a subsequent “Let me reach out to my colleague and find out more.” The more we are open to listening to and learning from one another about things we have not thought deeply about or experienced ourselves, the better we can learn from our collective experiences and come together to help allergy patients. We don’t need to all offer the same highly specialized treatments, and in fact that would probably not be feasible because there are reasons that these treatments are highly specialized. But if we learn which of our colleagues is skilled at which treatment, and if we make an effort to understand what each treatment can offer patients, we can guide our patients to the best options for them whether or not we offer them, and that is what we are all here to do as the experts in our field.
AAC: Do you have final any thoughts for patients pondering their treatment options?
Nikhila: Choosing a treatment option is a very personal decision and there is no right or wrong. No single type of treatment is going to be the right choice for everyone, and thankfully there are several effective options available for patients and families to choose from (though some may require travel, as we have only been open a couple months and are honored to already be working with patients from 11 different states). SLIT offers significant benefits to the majority of allergic patients in a safe, easy, and convenient way, which is why I have chosen to specialize in comprehensive SLIT treatments and help make them more available to patients. But I also completely respect all the other treatments available and discuss them with patients regularly, including the option of avoidance, as each option has specific merits that may be a better fit for certain families.
In that light, I’ll share some final guidance here for families that may be trying to choose between starting with SLIT or OIT (or SLIT or allergy shots). Since each of these treatments has been proven effective to a substantial degree, it often really just comes down to thinking about your top priority/goal/concern and which treatment suits that best to start with:
- If you are concerned about a treatment’s risk of anaphylaxis, SLIT would be the better route for you.
- If your primary priority is being able to eat an allergenic food in large amounts as quickly as possible, OIT would be the better route for you.
- If you don’t like shots, SLIT would be the better route for you.
- If you have multiple allergens or some type of chronic allergic condition (eczema, asthma, seasonal allergies, etc), multi-allergen SLIT would be more helpful for you overall. SLIT would be a good initial foundation to calm down your immune system in general first if you are planning to later pursue OIT for one allergen in specific.
- If you need to know in real-time exactly what minimum amount of the allergen can likely be tolerated, OIT would be the better route for you.
- If your allergic child is very young, SLIT would be the better (and possibly only) safe immunotherapy option for you at this time.
- If your child doesn’t like the taste of the allergenic food, or if you cannot keep up with or don’t want to deal with the exercise, rest period, and other restrictions, SLIT would be the better option for you.
Thank you so much for the opportunity to speak with you and your readers.
Dr. Nikhila Schroeder is board certified in both Allergy & Immunology (adult and pediatric) and Pediatrics. She was born and raised in Wisconsin. She attended college in Cambridge, Massachusetts at the Massachusetts Institute of Technology where she obtained both Bachelor’s (2004) and Master’s of Engineering (2005) degrees in electrical engineering and computer science with concentrations in music biomedical engineering and music. She went on to medical school in Madison, Wisconsin and earned her Doctor of Medicine degree from the University of Wisconsin School of Medicine and Public Health in 2009. She then completed her Pediatrics Residency training program (2012) and Allergy/Immunology Fellowship training program (2014) both at the University of Virginia. From 2014-2017, she treated nearly 1000 patients with sublingual immunotherapy from all over the country. In 2018, Dr. Schroeder and her husband James Schroder decided to move their family to Charlotte, North Carolina and open Allergenuity Health Associates together in their vision, as a direct care comprehensive sublingual immunotherapy treatment center, to bring high-quality, scientific, comprehensive sublingual immunotherapy treatment regimens and a health care model that supports a strong patient-doctor relationship (including patients having direct access to their allergist) to the region. For more information go to http://allergenuityhealth.com/
Patient photo by permission of families, granted to Allergenuity
By Wayne Shreffler MD, Paul Hesterberg MD, Yamini Virkud MD MPH, Perdita Permaul MD, Michael Pistiner* MD
We have received several recent inquiries about the follow up study on Dr. Mimi Tang’s peanut oral immunotherapy with probiotics trial (PPOIT), first published in 2014 (https://tinyurl.com/y83eg5an). This seems like a good opportunity to review with all of you, our patient community, where we think things stand regarding interventions for people with food allergies.
The first attempts to apply immunotherapy for the treatment of allergy are as old as the application of vaccinations to infectious disease, reaching back more than a century. As applied to allergy, immunotherapy refers to an intervention, for those with established allergy, designed to induce a new immune response to the targeted allergen that protects from subsequent reactions. At this point, there have been dozens of studies of immunotherapy to treat food allergy, most by giving initially tiny and gradually increasing doses of the allergen every day for many months. Most have been small single-center trials, including two here at MGH, but the field has slowly matured to the point that there are now two multi-center industry-sponsored phase 3 clinical trials of immunotherapy for peanut allergy as well as a multi-center phase 2 trial for milk allergy. FDA approval appears to be likely for these treatments of peanut allergy as soon as 2018. In parallel to the progress in clinical trials, though despite current recommendations by professional societies and the NIH, more and more practitioners, including allergists, are offering oral immunotherapy in clinical practice.
There is more than one way to think about success in the context of immunotherapy treatment. Most patients and parents are less interested in being able to eat the food they are allergic to ad lib (remission) as they are in reducing the risk of a serious accidental reaction (protection) — though that can vary depending upon the food allergen (e.g., milk versus peanut). What the numerous studies have shown is that most individuals can tolerate the therapy, but will only achieve short lived protection. For these patients (roughly 75 percent), they must regularly eat the allergen (the usual recommendation is daily) to maintain protection. It is more challenging to study remission, as it is difficult to define in a time-limited study. Even protection that lasts over a few weeks or months of post treatment avoidance — the longest typically looked at in a research design — might eventually wane. Research shows that only about one quarter to one third of patients will achieve the desired outcome of a more durable benefit.
The PPOIT Study
In Dr. Tang’s study, 56 patients who had been evenly divided between receiving either placebo or a combination of peanut OIT with probiotics were contacted about 4 years after completing the initial trial. The goal was to see how many were still eating peanut. Of the original 56, 48 individuals participated in this follow up, and of those, 16 of the 24 who received active treatment were eating peanut. Only 1 of the 24 who received placebo treatment was eating peanut. To get a sense of how stable their tolerance is (protection versus remission), the 16 individuals eating peanut were invited to once again strictly avoid peanut for 8 weeks and then undergo a food challenge test. Of the 12 who agreed, 7 could fully tolerate peanut after the 8 weeks of avoidance. Research is voluntary, of course, and people can have all sorts of reasons for not participating. However, the most rigorous and appropriate way to evaluate the results of a clinical trial is a sort of worst-case scenario called intention-to-treat analysis (https://tinyurl.com/jqtxzo9). Because a very important reason people may not participate is that they did not do well, this analysis assumes that when the data are missing, the treatment failed. By this conservative approach to analysis, the results of the PPOIT study are essentially the same as we have seen from other OIT studies generally: 16 out of 28 participants (~60%) achieved protection and 7 of 28 (25%) achieved remission. Even if we assumed the most generous assessment, that 16 out of 24 (66%) achieve at least temporary protection, this is hardly what we would consider a ‘cure’, despite numerous headlines (e.g., https://tinyurl.com/ycgbfp3t).
Another way to evaluate the efficacy of this trial is to ask whether allergic reactions were prevented. In PPOIT, the results were that for over the more than 4-year follow-up period, 4 patients treated with PPOIT experienced 11 reactions and 6 patients treated with placebo experienced 9 reactions.
Importantly, this study did not include a treatment arm of peanut oral immunotherapy alone, without the addition of probiotics, which unfortunately leaves us unable to say whether the additional probiotics had any impact on outcomes.
Most of my colleagues from around the country and I believe that oral immunotherapy is and will be helpful for many individuals, but we also worry that through the lens of sharing stories on social media and by way of often over-exuberant news media, this therapy enjoys an undeserved shine. There are many reasons for us to want to treat OIT as more than it is. We each have a natural bias toward positive stories, and there is much over diagnosis of food allergy —and subsequent “curing”—among people who are not truly allergic. Those of us who see patients with allergies also worry that many people overestimate the risk and burden of managing food allergies by avoidance, while at the same time underestimating the risk and burden of receiving oral immunotherapy treatment. It is inherently difficult to make a choice that feels passive and wait for more definitive answers when we want to be pro-active. An active treatment like immunotherapy satisfies that desire.
Immunotherapy at MGH
Since the Food Allergy Center was established at MGH in 2010, we have supported the current recommendations regarding immunotherapy. Specifically, that more research was needed before immunotherapy should be regarded as a justifiable option for use in every day clinical practice. Now, in 2017, the paradigm is shifting, the use of immunotherapy is supported by more evidence and we believe that outpatient practice is a more justifiable option for patient management. Despite the reservations articulated above, and as more studies have demonstrated at least limited efficacy, we recognize that patients and their families can, should and are weighing the benefits and risks of OIT and deciding for themselves.
Though we anticipate FDA-approved options for the treatment of peanut in the next 1-2 years, we acknowledge that it will take many more years for approval of each major allergen treatment and that many patients have multiple allergies. Furthermore, the willingness on the part of many insurers to now cover this service has lowered financial barriers for our patients and families. Given our extensive experience in conducting oral immunotherapy trials since 2010, we believe that the FAC@MGH is in a strong position to offer this therapy safely, supported by rigorous pretreatment diagnosis and appropriate education about the benefits risks and burdens associated with this treatment modality.
If you would like to join that discussion to offer your perspective, we invite you to do so by emailing us at firstname.lastname@example.org. Please follow us here for updates on our plans to offer immunotherapy and educational programs around it in the coming months.
* Note: Dr. Pistiner has previously published on this site.
By Henry Ehrlich
For more than a hundred years, allergists have been trying to cure patients by exposing them to small amounts of their allergens and escalating the doses to allow them to tolerate the offending substance. This process has been approached using injections (sub-cutaneous immunotherapy, or SCIT), ingestion (oral immunotherapy—aka OIT), under the tongue (sub-lingual immunotherapy, or SLIT), and more recently, in the form of a patch worn on the skin (epicutaneous immunotherapy—EPIT).
Now a new horse is entering the race—Oral Mucosal Immunotherapy (OMIT), which, like SLIT, has an evocative word as an acronym. One version of OMIT, for respiratory allergies, goes by the brand name Allerdent, suggesting how this new product is introduced to the body in a familiar way—in the form of toothpaste. It is the brainchild of William R. Reisacher, MD, FACS, FAAOA Associate Professor, Department of Otolaryngology–Head and Neck Surgery, Weill Cornell Medical College/New York-Presbyterian Hospital. The idea is a happy juncture of physiology and human behavior.
It is also very timely because allergists are facing new rules that may make their meat-and-potatoes offering of allergy shots more expensive to the practice and to patients, and early case studies testing the efficacy of OMIT for allergic rhinitis, described in an article by Reisacher and two co-authors, are very encouraging.1 They cite a 2013 World Allergy Organization position paper touting the potential of the mucosal tissue of the oral vestibule and gingiva for enhancing immunotherapy based on the density of oral Langerhans cells (oLC). In my quick and inevitably superficial scan of the literature. I saw these cells described as the “masters of tolerance”2 and as the “sentinels” of the mucosa. They “alter… the immune system not only to pathogen entry but also of tolerance to self antigen and commensal microbes. Oral mucosal Langerhans cells are capable of engaging and internalizing a wide variety of pathogens.”3
Most of the articles I looked at discuss these cells in conjunction with SLIT. However, Reisacher et al suggest that the high density in cheek and gums compared to the low density under the tongue “might explain the suggested decrease in efficacy when multiple antigens are placed in a SLIT vial.”
As for the behavioral part of the equation, almost all of us brush our teeth, including our small children. Compliance being a problem with all the new allergy therapies, including SLIT, OIT, and Chinese herbal medicine, suggests that combining the task of dosing with something you have to do anyway would be an advantage. I learned about this a long time ago when I worked for a bank at the dawn of the automated teller machine. They learned that customers who liked using a teller wouldn’t be coerced into using an ATM. It was only when ATMs started showing up in convenience stores, gas stations, and supermarkets that people realized they could eliminate special trips to the bank and save time. The long-term compliance issues with SLIT and SCIT are well studied, and as Larry has written, completion rates are abysmal.
Allovate Therapeutics, a New York City-based start-up company, is developing Allerdent, a platform for respiratory allergies. A second New York company, Intrommune Therapeutics, is developing OMIT for food allergies. OMIT is only one of Dr. Reisacher’s many ideas. Another one under development is a novel diagnostic that works by sampling epithelial cells from the mouth and nasal turbinates. Immunovent is developing this test, which goes by the name LAMB-Dx.
I was introduced to the company by Danya Glabau, who came on as as Director of Medical Affairs in June 2015 while writing a doctoral thesis on the patient experience of food allergies and food allergy activism. After being in close contact throughout her research, she invited me to meet two of her new colleagues over lunch, Erick Berglund, Allovate’s Chief Executive Officer, and PhD in biochemistry, who has extensive background in research, and Michael Nelson, Chief Financial Officer, who is also a lawyer. (Full disclosure: they paid for the meal.)
Being unfamiliar with the development of a new technology at this stage and the building of a new company, I decided to reach out to them and ask a couple of questions geared to their specific roles in the new company. I hope at some point to follow up with Dr. Reisacher.
Thanks, gentlemen, for taking some time with our readers.
AAC: You mentioned over lunch that Allovate is a “virtual” company, which I inferred means not integrated vertically or horizontally, so you must collaborate with others to do a lot of the work. Can you describe what you meant in a bit of detail, how you choose your collaborators, and the kinds of tasks that they do?
Erick: As a start-up company in a city with very high real estate expenses, we’ve built a lean, smart, flexible core team who work together daily in our Harlem office. They cover the essentials of running the company. We also work with a number of allergy researchers and experts in areas like the law, accounting, and manufacturing. They help us plan and carry out longer-term projects. Ultimately, the benefits of being in the vibrant, rapidly expanding biotech community in New York – the networking, the proximity to smart people in the city’s multiple medical schools – outweighs the challenge of finding the right office space.
AAC: Can you describe the funding and regulatory challenges that lie ahead?
Michael: Biotechnology has always been a high risk, high reward field. It has paid off in many high-need areas, like cancer immunotherapy. Allergy immunotherapy is just getting started as a major part of the biotechnology sector. At Allovate, our early study data and the robust knowledge that scientists already have about allergy immunotherapy makes Allerdent less risky than many new technologies out there.
With respiratory allergies, one big challenge is that doctors in different parts of the world have treated allergies in different ways. Another is that different allergies are prevalent in different regions. Safety regulations for respiratory allergies have substantial regional variations. One big consideration for Allovate is to make sure that Allerdent changes the paradigm for allergy treatment while respecting some of the “facts of life” of treating allergies in different regions and countries of the world.
The situation is a little bit different with food allergies. Treating food allergies is very delicate because of the risk of anaphylaxis. Regulators, doctors, and patients all expect – and deserve – a high level of safety. Companies that do research in the area put many layers of safeguards in place to protect current and future users, from optimizing the dose, to making sure the length, number, and size of studies tell the company and the FDA everything there is to know about a new treatment, to planning extensive physician education on how to safely use the product.
AAC: The cases in Dr. Reisacher’s article in the International Journal of Pharmaceutical Compounding are about allergic rhinitis, and Allerdent seems to be very effective. However, many of our readers are also food allergy parents, and they are interested in the prospects for that. Can you describe any of the special challenges for moving into food?
Erick: Allovate is licensing the OMIT technology to Intrommune Therapeutics, a separate company, to develop the OMIT platform for FDA-approved food allergy treatments. As food allergy parents know, food allergies are a complicated disease that needs to be managed very carefully. Intrommune has assembled a team of staff and advisors with deep clinical research experience with food allergy. They will be developing several safe and effective products for food allergies.
The safety piece is really important, since food allergy is a complicated condition that can be very serious and disproportionately affects children. Intrommune is designing the best studies possible to ensure not only that the technology works, but that it works without causing additional stress due to side effects, something that has been seen in research on other food allergy immunotherapy technologies. The company’s current plan is to start clinical trials in late 2016 in the US and to have OMIT FDA approved and widely available for food allergies starting in 2020.
AAC: Two new forms of food allergy immunotherapy, Viaskin™ and ARA101™, seem to be moving very rapidly. I can understand that the regulators are anxious to green-light new therapies since there is no conventional treatment and the therapeutic agents are familiar. Do you sense that this is a favorable environment to pursue the OMIT platform?
Michael: There is a huge unmet need for treatments for food allergies – 15 million people in the US alone could benefit from safe, effective new options. We get feedback all the time from researchers and food allergy parents about the clear potential they see for OMIT to make a difference in the lives of millions.
There are a number of other companies developing new treatments in the food allergy space, and everyone is working hard to get to the day when food allergies become a treatable condition. Recently completed research has helped to clarify some best practices for studies in the field. Everyone is hoping this will smooth the way to making new, FDA-approved treatments widely available.
The need is there, the interest is there, and the science is now coming along as well. We’re excited that Intrommune Therapeutics is developing our OMIT technology for the treatment of food allergy. We hope to see OMIT become a big player in this area.
1 William Reisacher, MD, FACS, FAAOA, Shara Rudner, RPh, FIACP, FACA, Viktoriya Kotik International Journal of Pharmaceutical Compounding
Vol. 18 No. 4 | July | August | 2014
2 Langerhans Cells and Their Role in Oral Mucosal Diseases
Juhi Upadhyay, Ram B Upadhyay, Pankaj Agrawal, Shweta Jaitley, and Rhitu Shekhar
N Am J Med Sci. 2013 Sep; 5(9): 505–514.
3 Immune mechanisms of sublingual immunotherapy: Are oral Langerhans cells the masters of tolerance? Mark Larché Journal of Allergy and Clinical Immunology September 2010 Volume 126, Issue 3, Pages 646–647
By Henry Ehrlich
The outline for the next big step in the search for a cure for food allergy traveled from New York to Palo Alto in a purse. I know because I saw it Tuesday when I joined Dr. Xiu-Min Li and Dr. Kari Nadeau at a restaurant near Mount Sinai at Madison Avenue and 98th St. You’ve heard about Abraham Lincoln writing the Gettysburg Address on the back of an envelope? The doctors outlined the structure for a major study of oral immunotherapy for food allergies (OIT) on a paper napkin. As witness to this conversation (fly on the wall wouldn’t be fair to the restaurant) I had a glimpse of how science is conducted. Far from being a highly technical or detached process, this was a lively conversation between women who clearly like one another and want to bring their intellectual and institutional resources to bear on behalf of people they care deeply about: food allergic people of all ages, particularly children. “Chemistry” in this case describes far more than just what is measured back in the lab.
Kari, you will recall, achieved mainstream prominence recently in the New York Times Magazine for her OIT research at Stanford. Among the studies she has conducted are “rush” OIT, using anti-IgE drug omalizumab (Xolair) to reduce allergic reactions and allowing higher allergen dosing to expedite desensitization, and using Xolair to allow desensitization to multiple allergens.
Xiu-Min, who works with Dr. Hugh Sampson and the rest of the Jaffe Food Allergy Institute All Stars at Mount Sinai, is pioneering the use of traditional Chinese medicine (TCM) to treat allergic diseases including food allergies and asthma. Her Food Allergy Herbal Formula-2 (FAHF-2) has reversed anaphylactic peanut-allergy in mice and is now in advanced human trials. Dr. Li’s treatment differs from immunotherapy in that it modulates the immune system instead of in effect over-stimulating the production of allergen-specific IgE to the point of exhaustion, allowing non-allergic IgG antibodies to take up all the space on mast cells and basophils.
The crux of the project they discussed Tuesday is to test FAHF-2 as an alternative to Xolair for rush OIT and for multi-allergy OIT. This would be a tremendous advance because Xolair, while promising for these purposes, has some big drawbacks. It is really expensive, is administered only by injection (sometimes producing serious reactions), and can be very painful. It is currently used mainly for severe asthma and lately has attracted attention for helping with otherwise-untreatable chronic urticaria. By contrast, FAHF-2 in its latest highly refined version can be taken as six pills a day and is proven safe.
Both ends of this collaboration have institutional capabilities that can be shared. For example, Stanford has three staff members who specialize in the packaging of therapeutic doses of allergens for use in the trials. Mount Sinai has the connections in China for ensuring uniform, high-quality FAHF-2. Dr. Nadeau also mentioned that a great byproduct of the Times story is that she has received a huge volume of mail from patients asking for treatment, which comprises the basis of a larger research population than ever before, and which will be shared with collaborators at medical centers around the country.
After lunch we went back to the Annenberg Pavilion where Kari was to give a talk. On the way, we chatted about the plight of patients and their families. One thing she said really stood out. After observing that OIT is nothing new conceptually, having been tried a century ago, and should be more advanced, she said, “Science never got ahead of patients’ needs.”
The talk itself was noteworthy for several reasons. On a very superficial level, as one slide after another went up on the screen, with the authors of different studies listed under the data, as often as not three or four of them were actually sitting in the room. This was a high-powered audience.
More important was the description of variables from all European and U.S. OIT studies thus far published that make desensitization to food so hard to achieve: up to 98% of participants in OIT studies overall will have allergic reactions during the course of the study, and up to 10% of these reactions occur during home dosing. Up to 4% of these reactions are severe and need epinephrine intramuscular injection. Up to 20% of subjects tested with abdominal complaints had positive results for eosinophils in the esophagus. Dr. Nadeau said investigators around the country and Europe aren’t sure whether the appearance of eosinophils during OIT represents a phase parallel to the spike in IgE that accompanies regular dosing, is a new disease induced by the treatment for another, or whether it is there all the time and is “unmasked” by the close attention patients are paying to their health during study. An estimated 20% drop out rate due to non-compliance or untoward side effects has been reported in U.S. and european OIT studies. One thing is sure: no single treatment is going to work for every patient.
All in all, not a bad way to spend a few hours.
By Kari Nadeau, MD, PhD, FAAAAI
I don’t have to tell readers of this website about the heartbreak and anxiety of food allergies. The Lucile Packard Children’s Hospital at Stanford houses the Stanford Alliance for Food Allergy Research (SAFAR) the only research center on the West Coast conducting oral immunotherapy (OIT) trials, often in concert with other centers east of the Rockies. We are the focal point for the hopes of thousands of children and families for relief from this evolutionary mistake, this maladaptation, in which the body’s own immune system turns against us. My colleagues and I take these hopes very seriously.
The demographics of food allergy ought to alarm anyone concerned with the health of future generations. Food allergies are emerging in alarming numbers of children under three. While many of their elders might continue to dismiss them as marginal “nuisance” diseases that can only be managed, not cured, children’s food allergies, like other chronic illnesses, have life-long behavioral and learning consequences as well as physical ones. When the clock starts ticking at age three, the cost in quality of life can be high.
The SAFAR network of physicians and scientists is working across multiple disciplines to achieve what we all hope for most: a cure. Our current research is promising! The families who turn to us for treatment of food allergies and related disorders every year offer the unique opportunity for research and clinical studies that could lead to new insights and the development of novel therapies. We are carrying out clinical food immunotolerance studies, including oral immunotherapy for milk and peanut allergies and research in eosinophilic esophagitis, a commonly associated inflammatory disorder of the esophagus.
We are also the only center in the country to offer clinical research studies to patients with multiple food allergies. For example, in the spring of 2009, we conducted a study using a course of treatment I developed in immunotolerance, where individuals with severe food allergies consume minute doses of the allergens, and then gradually increase the dosage as they build tolerance. This study included 21 children between the ages of 6 and 13.
Today, every one of the study participants is desensitized to the allergens—that means that they can eat the foods that in the past were considered life threatening. More recently, we have been pursuing treatment courses in immunotolerance that are aimed at making immunotherapy accessible to more children.
Studying Root Causes
However, while the expansion of immunotherapy to food allergens is an almost miraculous prospect, we also need to look at how this maladaptation comes about. If immune disorders such as allergies are responses to changes in the way our bodies interact with the environment in the gut, the lungs, sinuses, and skin, it is critical that we understand the mechanisms involved. It makes greater public health and financial sense to treat the root causes in addition to treating the disease. While OIT may look like magic to families that already have food-allergic children, it still requires years of commitment and money.
That is why I would like to discuss another area of research* I have been involved with in which we have already uncovered a cause-and-effect relationship between an environmental trigger–ambient air pollution (AAP)–and an allergic disease—asthma. Asthma is the most frequent chronic disease in children.
You may be familiar with the term epigenetics. This involves not the characteristics encoded in the DNA but rather the “expression” of those genes, i.e. when and how they reproduce themselves in different cells throughout the body. A process called DNA methylation decreases expression and function of genes, most pertinently for our purposes, a gene called Foxp3, which is key to the work of so-called Regulatory T (Treg) cells. These “peace-keeping” cells prevent excessive immune responses. Children lacking Foxp3 have greater incidence of severe allergies, asthma, gastrointestinal disease and type-1 diabetes than those with normal Foxp3. Because AAP exposure can induce epigenetic changes we hypothesized that Treg-cell function would be impaired by high levels of air pollution, amplifying the inflammatory response.
Children with and without asthma from Fresno, California, which has high levels of black carbon air pollutants, were compared with those from Stanford, California, which has much cleaner air. We used peripheral blood Treg cells in functional and epigenetic studies. Asthma severity was assessed by a score derived from criteria in the Global Initiative for Asthma. Foxp3 was measured in respect to genetic expression, Treg-cells function and asthma-symptom score.
We found that increased exposure to AAP is associated with hypermethylation—suppression–of Foxp3. The gene was there but, as predicted, it wasn’t working fully because of the chemical assault by pollutants. In all 3 measurements, Foxp3 expression was lowest for the Fresno-asthmatic group, next lowest for Fresno non-asthmatics, higher for Stanford subjects with asthma, and highest for the Stanford group without.
In other words, air pollution alters genetic function so that the immune systems of non-asthmatic children begin to mimic those of asthmatic children, and already-asthmatic children get worse. If, as has already been proven in other research, these epigenetic changes can be inherited by the next generation, it would account for the increasing severity of allergic disease from one generation to the next that we have seen in the past few decades. We have found that if one parent has an allergy of any kind, their child may have a 65% chance of developing an allergy. If both parents have allergies, the likelihood can climb to as high as 85%.
The science is moving as fast as our funding will allow. This relationship between a form of pollution and an impaired immune system leads us to think that other environmental links can be found. We may well find that food additives, antibiotics, climate change, and the rest of the usual suspects are indeed contributing to the epidemic. Actually doing something about it will require an extraordinary cooperative effort. Finding cures for both effects and causes is becoming increasingly urgent.
Dr. Nadeau is Associate Professor, Stanford Medical School and Lucile Packard Children’s Hospital Division of Immunology and Allergy. Director of Basic Science and Clinical Research of SAFAR (Stanford Alliance of Food Allergy Research). Chief Investigator for all food allergy studies at Stanford.
*Ambient air pollution impairs regulatory T-cell function in asthma
Journal of Allergy and Clinical Immunology. 2010 Oct;126(4):845-852.e10. Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J, Tager I.
By Kathy Franklin
Sally Noone, RN, MSN, is one of the most respected professionals in the field of food allergy. She has worked in allergy research for 21 years, at Johns Hopkins and at Mount Sinai, and has co-authored 20 publications, including “Dietary baked milk accelerates the resolution of cow’s milk allergy in children,” “Clinical safety of Food Allergy Herbal Formula-2 (FAHF-2),” “Development and validation of educational materials for food allergy” and “Dietary baked egg accelerates resolution of egg allergy in children,” published this month in the Journal of Allergy and Clinical Immunology. The recipient of numerous awards, Sally was recently honored with the American Academy of Allergy, Asthma and Immunology’s Allied Professionals Recognition Award, and with her third Mount Sinai Medical Center Employee Recognition Service Award. Sally was kind enough to take some time out of her very busy schedule to speak with me about her work, her career, and the latest research news.
From Patients to Paperwork: Running a Clinical Trial
Sally Noone has served since 2005 as Clinical Research Manager at the Jaffe Food Allergy Institute. She is currently the Clinical Research Coordinator on two studies, Milk Oral Immunotherapy (OIT) plus Xolair® (omalizumab, anti-IgE) and Food Protein-Induced Enterocolitis Syndrome (FPIES).
What is a Clinical Research Coordinator? The CRC is the primary patient contact for a research study. She answers questions about the research from anyone interested in learning more, including parents, prospective volunteers, allergists, pediatricians, and even inquiring bloggers; she screens patients who wish to participate, seeing whether they qualify for a study; and she gives them all the information they need to decide whether a study is right for them. Sally encourages the patient to generate a list of research-related questions to ask their own physician, to help them better evaluate the potential risks and rewards of the treatment. Should someone decide to volunteer for the research, the CRC walks them through all the consent forms, and handles all scheduling. (As you can see, this job involves a lot of paperwork and a lot of phone calls!) When the patient begins a trial, the CRC is in charge, along with the study doctor, and spends a great deal of time with the patient, administering the treatment and monitoring their progress. Each visit generates a lot more paperwork. The CRC also keeps in contact with the patient between visits. She must keep track of all “adverse events” — everything from a cold to a rash to a sprained ankle must be recorded, monitored, and reported.
The Clinical Research Coordinator also is responsible for the annual submission to the IRB, the Institutional Review Board, which regulates and monitors all human research, ensuring that each study is safe, scientifically sound, and meets all ethical standards. The IRB requires that the doctors and nurses running the study are highly qualified, and ensures the risks to patients are minimized and the potential benefits are maximized. Every change in a study protocol, large or small, requires approval from the IRB. For example, reimbursement for transportation and free parking for study participants for Milk OIT has been added. They will cover local Metro North or Long Island Rail Road train costs, or transportation to and from a local airport. (Yes, people fly in from other cities to be part of this groundbreaking research, although airfare is not reimbursed.) Since that was not part of the original proposal, covering those costs required new IRB approval (and new paperwork for the CRC) before it could be instituted.
In addition to her own two studies, Sally supervises all of the other CRCs at the Jaffe Food Allergy Institute, who are working on other ongoing allergy studies. The CRCs work very closely together, and each of them is qualified to work on any study, so if Sally has too many visits scheduled on the same day, another CRC can see one of her patients that day. They all share responsibilities for all the studies. If a CRC knows she will be away the next time the patient is scheduled, she will introduce the patient to the person who will be covering them.
Sally has always shared her time and knowledge with her colleagues and the community; she is a tireless advocate and educator. She recently gave three workshops/symposia at the annual AAAAI meeting, on GI Allergies, on Food Challenges, and on Patient Recruitment and Retention. This generosity and dedication has drawn high praise from professionals. Our contributor Anne F. Russell BSN, RN, AE-C Faculty, Spring Arbor University Department of Nursing says: “Sally has a wealth of food allergy clinical, educational and research experience. She has generously shared her abundant clinical expertise with me, and many others. She is not only a trailblazer in the field of food allergy science but also in the Profession of Nursing.”
Educating School Nurses
Sally also presents to school nurses at FAAN Conferences. “More than anything, school nurses need support. They know what to do medically in an emergency, but they need a lot of reassurance that they know what they know. It’s a tremendous responsibility, and they feel that responsibility. Sometimes they feel a lack of support, and feel that they have to rely on the families for their food allergy information.” Sally recommends three new web-based teaching initiatives as an important source of support for school nurses. FAAN & FAI have collaborated on a free, interactive online course available at http://allergyready.com. There is also a training module at http://www.allergyhome.org/schools. CoFAR, the Consortium of Food Allergy research, provides information online in their Food Allergy Education Program, at https://web.emmes.com/study/cofar/EducationProgram.htm. While the CoFAR teaching tools are primarily for parents, Sally recommends the site to school nurses as a good way for them to see what parents are learning.
A common complaint among school nurses is that parents of food-allergic students are obsessively concerned about their children’s health and safety. Nurse Sally makes a special point of explaining to them that these parents are not “hyper.” “For the most part, school nurses don’t see a serious allergic reaction. The ‘hyper’ mother has seen her child have a serious reaction. This isn’t ‘hyper’ anything, it’s appropriate behavior and it’s necessary.”
This concern for the feelings of parents is widely recognized by those who work with her. Mary Jane Marchisotto, Executive Director of the Food Allergy Initiative says, “Sally has been a source of compassion and information about food allergies for thousands of families. She also plays a key role in educating health professionals and recruiting patients for important clinical trials. For all of us at FAI, it is a privilege to work with her and learn from her.”
While food allergy education and awareness have “gotten better,” Sally is still regularly invited to speak at schools, particularly at the beginning of the school year. She’s happy to oblige, but her busy schedule only allows her to speak in the evenings or late afternoons; other MSSM staff also will speak on food allergy at local schools whenever possible.
From Research to Therapies
Sally is excited by the current progress in research. “For the first time, we are starting to work on therapies. It seems to be within striking distance, that there might be something to offer other than strict avoidance. For example, the baked milk and baked egg studies have been amazing for people, many of whom can now safely eat milk and eggs.” [For those not familiar with these studies, researchers have found a way to introduce small amounts of well-baked milk or egg to highly-milk and egg-allergic patients, gradually increasing the doses – under strict medical supervision – until the patient is eating the foods, even unbaked, with no allergic reactions. Sally calls it “amazing”; several participants I have spoken with call it “life-changing.”]
What’s been the biggest surprise in conducting research? “I thought the shots [in the Milk Allergy Research with Xolair] would be the biggest turn-off for my patients, especially the younger ones. But after the first shot, it just wasn’t that big a deal to the kids. I have 7- and 8-year-old patients who don’t make any fuss about shots. I thought that would be a much bigger deal with the kids than it is.”
Another pleasant surprise for Sally is that “parents are our best recruiters and resources. Many parents have spontaneously offered to talk to other parents, explaining how the research experience was for them, sharing mealtime strategies, tips on how their children successfully managed to take their daily doses at sleep-away camp, and generally offering to be useful to other families participating in the study. That has been a huge positive.”
Does Sally have any allergies of her own?
“I don’t have any food allergies. I always thought I had a nickel allergy, because I can’t wear jewelry without getting a rash, but recently was tested by a dermatologist, and it turns out I’m allergic to gold, not nickel.” Her other allergy, ironic for an allergy researcher, is to hydrocortisone.
If there were more hours in the day, how would Sally use them? “See more patients, and make more phone calls to patients.”
Hugh A Sampson, MD
Mount Sinai School of Medicine; Jaffe Food Allergy Institute
Food allergy has become a major health problem in westernized countries, now affecting approximately 3.5% of the U.S. population, or about 12 million Americans, and is the leading single cause of anaphylaxis treated in U.S. emergency departments. The standard of care for dealing with food allergies has been to educate patients and their families how to avoid allergenic foods and to recognize and treat allergic reactions if they have an accidental ingestion. In the past 5 years, there has been a growing interest in oral immunotherapy (OIT) for treating food allergy, a practice that was first reported in The Lancet over 100 years ago in an article called “A case of egg poisoning” [Lancet 1908; 1:716]. Considerably more recently, several small clinical trials of OIT for milk, egg and peanut allergies have yielded some promising results, and some practicing allergists have even begun using OIT to treat food-allergic patients.
I certainly can’t fault the desire of patients and patients’ parents to seek relief from the difficulty of managing a severe food allergy (and who pay for these treatments out of pocket). However, I wish to caution that widespread adoption of any OIT methods is premature, and may lead to crushing the hopes of patients, and worse.
Three carefully conducted scientific reviews* of trials have raised serious questions about OIT’s effectiveness, safety and long-term benefits, with the most recent concluding that “the overall low quality of evidence leaves important uncertainty about anticipated effects of immunotherapy due to very serious imprecision of the estimates of effects and the likelihood of publication bias for some of the critical outcomes.” In other words, we can’t judge on the basis of these trials whether it’s really working or not, or whether some researchers are getting the results they want instead of what the data really shows.
Our understanding of the underlying immunologic changes brought about by OIT is very limited and published reports provide inconsistent results. OIT appears to induce “desensitization,” or a clinical state in which the quantity of food required to trigger an allergic reaction is raised while on therapy, in most patients. “Tolerance,” or the long-term loss of allergic reactivity following the discontinuation of therapy, i.e. “a cure,” has been reported in some OIT trials, but most of these trials lack the appropriate controls. Different treatments follow different protocols, creating apples-and-oranges comparisons. In some cases, we can’t distinguish whether improvements with milk are the result of the therapy or whether a child is merely outgrowing the problem, as happens with milk allergies about 80% of the time. In fact, the only OIT trial to date stringently controlling for the natural development of tolerance in food-allergic children failed to find a difference in outcome between treated and control subjects.
In spite of the reservations my colleagues and I have, there are many instances of what we might call “retail OIT” being offered by some practicing allergists. The history of medicine is replete with examples of how premature adoption of new techniques can go wrong. Drugs and technologies that showed “no harm” in trials have often proven to be problematic as they made their way into wider use. We are nowhere near that regulatory threshold with OIT.
Furthermore, administering an experimental therapy creates management problems. Even in a research setting, patients must endure much of the discomfort and reactions that make food allergies a problem to begin with, necessitating a good deal of after-hours support and encouragement; do OIT doctors provide that? And while I trust my fellow allergists to treat emergencies, proliferation of unproven therapies creates more and more probability of mishaps. How long before a patient who believes himself “cured” suffers because he has ignored elementary precautions?
At this time, oral immunotherapy should be considered a promising experimental treatment for food allergy, but proper well-controlled trials are needed to demonstrate that it is safe and effective before the FDA will approve it for general use by practicing allergists.
* [(1)Brozek JL, Terracciano L, Hsu J, Kreis J, Compalati E, Santesso N et al. Oral immunotherapy for IgE-mediated cow’s milk allergy: a systematic review and meta-analysis. Clin Exp Allergy 2012; 42(3):363-74;
(2) Sheikh A, Nurmatov U, Venderbosch I, Bischoff E. Oral immunotherapy for the treatment of peanut allergy: systematic review of six case series studies. Prim Care Respir J 2012; 21(1):41-9; and
(3) Fisher HR, Du TG, Lack G. Specific oral tolerance induction in food allergic children: is oral desensitisation more effective than allergen avoidance?: a meta-analysis of published RCTs. Arch Dis Child 2011; 96(3):259-64]
Dr. Sampson is the Kurt Hirschhorn Professor of Pediatrics and the Dean for Translational Biomedical Research at the Mount Sinai School of Medicine in New York, and the Director of the Jaffe Food Allergy Institute at the Mount Sinai Medical Center. Dr. Sampson’s research interests and publications have focused on food-allergic disorders including the immunopathogenic role of food hypersensitivity in atopic dermatitis and anaphylaxis, characterization of food allergens, and immunotherapeutic strategies for treating food allergies. His research has been funded continuously by a number of grants from the National Institutes of Health and private foundations. Dr. Sampson is the principal investigator of the NIH-sponsored Consortium on Food Allergy Research and an AADCRC program project conducting a number of clinical trials investigating novel therapies for the treatment of food allergy and investigating basic immunologic mechanisms. He has published over 350 articles and 60 book chapters on food-allergic disorders and co-edited four books, and was elected to membership in the Institute of Medicine of the National Academies in 2003 for his research on food allergies. Dr. Sampson is past chairman of the Section on Allergy & Immunology of the American Academy of Pediatrics and past president of the American Academy of Allergy, Asthma and Immunology.