Ragweed allergy sublingual immunotherapy: an interview with Dr. Peter Creticos, Johns Hopkins University School of Medicine

Peter Creticos ARTICLE IMAGE

What is ragweed, where is it found and how many people are allergic to it?

Ragweed is a dominant seasonal allergen in North America (~26% of US and North American population is allergic to this noxious weed which pollinates from early August to early October).

The weed is most prominent east of the Rocky Mountains, which essentially serve as a natural land mass barrier. It is found in heaviest amounts in central Canada and the northern and central regions of the U.S.

It is found in moderate levels in the Eastern Agricultural belt of the U.S. and the mid-Atlantic region. It tapers-off the further south that you go.

Interestingly, due to air travel, you can find pockets in the western region of the U.S. Furthermore, air transportation hubs in certain parts of Europe during World War II may have been the basis for the entry of this weed to Europe.

It has gained a particular foothold in Eastern Europe where the climate is conducive to its growth.

What therapies are currently used to treat ragweed allergy?

The classic approach to treating allergic rhinitis in the U.S. has been pharmacotherapy with “controller” medications (e.g. nasal steroids) +/- addition of a leukotriene antagonist (for persistent unrelieved nasal edema and congestion) +/- use of an antihistamine (or antihistamine-decongestant combination) for “breakthrough” symptoms.

Allergen immunotherapy is typically considered when a patient, and his/her physician, find that medications have not effectively controlled symptoms, or when the patient finds it difficult to take the prescribed medications on a continuous basis (during the ragweed season), or when the patient experiences side effects that hinder his/her ability to use the medication regimen as directed.

Please can you give a brief introduction to sublingual immunotherapy? How does sublingual immunotherapy work and what has it been used to treat?

SLIT represents an alternate approach to injection immunotherapy in which the allergen is administered orally. Two approaches have gained favour as the most practical approaches – SLIT-tablet and SLIT-aqueous.

With SLIT-tablet, the allergen is administered as a dissolvable tablet which is placed under the tongue; typically, it dissolves over 30 -90 seconds and is taken-up by the rich vascular and lymphoid tissue in the sublingual region and processed in regional lymph nodes.

SLIT-aqueous is an analogous method in which a liquid extract of the allergen is “dropped” under the tongue, and after 1-2 minutes any residual is swallowed.

Only SCIT (subcutaneous immunotherapy) is approved in the U.S., with “off-label” use of SLIT being practiced by a segment of U.S. subspecialists. However, sublingual immunotherapy with grass has received regulatory approval in Europe, and, in addition, a 5-grass sublingual tablet was recently approved in Canada. Ongoing investigational studies with SLIT-tablet and SLIT-aqueous are underway in the U.S.

How does sublingual immunotherapy differ from antihistamines and allergy shots?

Allergen immunotherapy affords a method of treatment which is capable of “shutting-off” the allergic cascade through induction of “tolerance”, whereby the untoward allergic response is down-regulated through induction of “counter-regulatory” cells that suppress the allergic response. I like to use the term “clinical remission”, as an apt descriptor of what we are trying to accomplish with immunotherapy.

In contrast, nasal steroids are only capable of “controlling” symptomatology as long as they are used on a daily basis during/through the season. However, within 4-7 days of discontinuation of the nasal steroid preparation, symptoms will recrudesce.

Antihistamine agents are termed “relief” (or rescue) medications, as they are used to relieve “breakthrough” symptoms of sneezing, runny nose, and nasal itch. Likewise, decongestant tablets or sprays are used to relieve “breakthrough” nasal congestion.

How did your research into sublingual immunotherapy against ragweed allergy originate?

Interestingly, my group at Johns Hopkins performed some of the first work with oral immunotherapy in the late 1980s. In a series of three clinical trials over 3 ragweed seasons, we were able to demonstrate that oral IT (oral extract of ragweed which was swallowed and not held under the tongue) was a viable method of administering ragweed, and furthermore, through these dose-ranging studies, we were able to show both an immunologic response and demonstrable clinical benefit.

However, that initial work, although encouraging, did not continue due to funding problems. Hence, fast-forward to research efforts by other companies that aimed to evaluate other alternate approaches including the aforementioned SLIT-tablet and SLIT-aqueous regimens, as well as liposomal constructs and micro-encapsulated constructs for allergen administration.

During the past several years, I have provided consulting expertise to many of the companies involved in allergen immunotherapy studies. My focus has been on optimizing proper patient selection for clinical trials, developing more efficient methods for characterization of patients for clinical trials, and utilizing various provocation models for evaluation of allergic inflammatory mechanisms and for assessing therapeutic effect.

What did your research involve?

In this multinational clinical trial, we investigated the potential benefit of sublingual immunotherapy with a ragweed tablet vs placebo in ragweed-allergic adults with a history of seasonal symptoms of rhinitis +/- conjunctivitis.

To be enrolled in the study, patients had to demonstrate both positive skin test sensitivity to ragweed (Ambrosia artemisiifolia) and a positive blood test (IgE antibody) to the allergen.

A total of 784 consented research volunteers participated in the clinical trial. This was a randomized, double-blind, placebo-controlled pivotal trial of sublingual immunotherapy with a ragweed tablet, standardized based on its major allergen moiety [Ambrosia artemisiifolia major allergen 1 (Amb a 1 units)].

The clinical trial investigated the efficacy and safety of drug administered at three different doses (1.5 units; 6 units; 12 units) vs placebo [essentially, 1 unit Amb a 1 = 1 mcg of Amb a 1].

What did your research find?

In this pivotal multinational clinical trial, ragweed immunotherapy with a sublingual dissolvable tablet was shown to be well-tolerated and demonstrated meaningful clinical efficacy in subjects with ragweed-induced allergic rhinitis with/or without conjunctivitis.

The study established a dose-defining relationship for the therapeutic construct, wherein the 12 mcg dose demonstrated strong evidence of clinical efficacy vs placebo, both for the primary efficacy endpoint (TCS: Total Combined Score) * as well as all key secondary endpoints.

These results (findings) were superior to those demonstrated with the 6 mcg dose (albeit, which also showed efficacy in the primary endpoint and certain secondary endpoints vs placebo). The 1.5 Amb a 1 unit dose was not effective vs placebo. [Peak season TCS: 12 > 6 > 1.5 Amb a 1 unit dose: 24% ( p=.002) vs 19% (p=.01) vs 9% (p=.2;NS)].

Primary Findings: In this clinical study, the [12 Amb a 1] unit dose of ragweed was well-tolerated and effectively reduced symptoms and rescue medication use in subjects with ragweed-induced allergic rhinitis with/or without conjunctivitis.

* [Legend: the primary endpoint in this study was the total combined score (TCS), which was the sum of the AR/C (allergic rhinitis with or without conjunctivitis) daily symptom score (DSS) + the daily medication score (DMS) averaged over the peak ragweed season. [Hence, TCS = DSS+DMS].

Did any serious adverse events occur during the study?

This large-scale multinational study (n=784 patients) provided solid data that the sublingual treatment was well-tolerated over the full 1-year course of treatment, with mainly mild-to-moderate local (application-site reactions – that is, local oral adverse reactions such as oral itching, ear itching, oral tingling), but no documentation of serious local or systemic allergic reactions or anaphylaxis – adverse events which can be associated with injection immunotherapy.

How was this research funded?

This clinical trial was funded by Merck.

Do you think this oral tablet for ragweed allergy will win approval from the U.S. Food and Drug Administration (FDA)?

Investigational drugs must go through a series of Phase 1 (safety), Phase 2 (dose-ranging and mechanistic studies), and Phase 3 (pivotal clinical trials that aim to demonstrate safety and efficacy in large numbers of research volunteers).

The findings from these studies is presented to the appropriate regulatory body in a given country at the end of each phase in order to determine whether sufficient data has been presented to warrant continued investigation of the drug.

The study that we reported on in the JACI was a pivotal Phase 3 clinical trial. However, I would refer you to sponsoring company so that they might inform you of where they stand with their licensure application process with the FDA.

What impact do you think the pill will have on ragweed allergy treatment?

An alternate (oral) approach to immunotherapy for allergic respiratory disease would be a welcome addition to our armamentarium, as the current mode of treatment in the U.S. - that of subcutaneous injection immunotherapy - is saddled with a burdensome injection regimen that requires frequent office visits over a 4-5 year course of treatment. 

This study provides good safety data on the drug. It builds on the accumulated evidence for self-administration of the drug by the patient in the home setting. [This is in contrast to SCIT (subcutaneous immunotherapy) in which patients must go to the physician’s office for a treatment course that typically requires a “build-up” phase (with weekly injections over 4-6 months) followed by a maintenance phase (injections every 2-4 weeks over the subsequent 4-5 years)].

A sublingual treatment approach, in which the therapeutic agent is administered by the patient, would likely be appreciated by an allergic patient, as it would be seen as a more convenient method of treatment. However, the accumulated safety data will need to be thoroughly reviewed.

How do you think the future of ragweed allergy treatments will develop?

Clearly, our goal is to develop therapeutic agents that are safe and effective in the treatment of allergic disease. A clear step in research and development has been aimed at developing novel therapeutic agents capable of modifying the disease process with resultant disease remission (disease modification) and induction of immunologic tolerance with resultant long-lasting clinical benefit.

Where can readers find more information?

Literature resources include information from the AAAAI, the ACAAI, the EAACI, and the WAO.

About Dr. Peter Creticos

Peter Creticos BIG IMAGEDr. Creticos is an Associate Professor of Medicine at the Johns Hopkins School of Medicine with an appointment in the Division of Allergy & Clinical Immunology.

Peter Creticos, MD, is a recognized expert in the field of immunotherapy and was past chairman of the AAAAI Immunotherapy Committee, as well as Chairman of the Interest Section for Allergic and Respiratory Disease.  He is an associate professor of medicine in the Division of Allergy and Clinical Immunology at the Johns Hopkins University of Medicine.  He completed his fellowship in Allergy & Clinical Immunology at the Johns Hopkins School of Medicine under the tutelage of Philip S. Norman and Lawrence Lichtenstein, and joined the faculty in 1983.  He remained a member of the full-time faculty during this tenure and served as Clinical Director of the Division for the period 2000-2010.

In July 2010, he became a part-time member of the Division in order to set up a clinical research network in the mid-Atlantic region of the U.S., and in this capacity he is Director of Clinical Research for his own private entity, Creticos Research Group, LLC. He also consults to the pharmaceutical industry, foundations, and government entities, and is specifically focused on providing innovative solutions to clinical trial design. In addition, he serves as Clinical Director of Research for Allergy & Asthma Specialists of Greater Washington.

In addition to various pharmaceutical grants, Dr. Creticos currently holds investigator-initiated grants related to immunotherapeutics, and has a Federal grant on topics related to allergic diseases through the Johns Hopkins Evidence-based Practice Center and funded by AHRQ (Agency for Healthcare Research and Quality).

He continues to see patients in the clinical practice setting and has been consistently recognized by Best Doctors in America, the Asthma and Allergy Foundation of America - Maryland Chapter (1998 Physician of the Year), Top Doctors (Baltimore Magazine , 2007), Who’s Who in America & International , and various other organizations. In 1996, he was induction into the Collegium of International Allergology.

Dr. Creticos is widely sought after as a teacher and lecturer, both at the national and international level. His CV highlights that he has given Keynote and Plenary addresses at the American Academy of Allergy Asthma and Immunology (AAAAI), the American College of Allergy Asthma and Immunology (ACAAI), the Congress of the European Academy of Allergy and Clinical Immunology, the International Congress of Allergy Asthma and Immunology (ICAAI). Additionally, he is eagerly sought after to address allergy societies and academic institutions in both the national and international theater.

April Cashin-Garbutt

Written by

April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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  1. Andy Mattson Andy Mattson United States says:

    I was part of a Phase II trial by Greer on this kind of therapy, years ago.  I've definitely been less sensitive to ragweed in the seasons that followed the trial. I can't wait for this to eventually get approved.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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