Randomized Controlled Trial of a Ragweed Allergy Immunotherapy Tablet in North American and European Adults

MedicalResearch.com eInterview with
Author Peter S. Creticos, M.D. (corresponding author)

Dr. Creticos’ Comments:

This paper reports the first successful randomized, double-blind, pivotal trial of sublingual immunotherapy with a ragweed tablet. The relevance of this lies in the recognition that ragweed is the dominant seasonal allergen in North America (~26% of US population is allergic to this noxious weed which pollinates from early August to early October). An alternate (sublingual) 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.

Furthermore, this large-scale multinational study (n=784 patients) demonstrated 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 adverse events or anaphylaxis – adverse events which can be associated with injection immunotherapy.

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.

The study established a dose-defining relationship for the therapeutic construct, wherein the 12 Amb a 1 unit dose (~12 mcg) demonstrated meaningful evidence of clinical efficacy vs placebo, both for the primary efficacy endpoint (TCS) 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)].

The primary findings from this clinical trial demonstrate that sublingual immunotherapy with a dissolvable ragweed tablet may provide an effective and well-tolerated treatment option for patients with ragweed-induced allergic rhinitis/conjunctivitis.

This study also provides strong 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)].

Previous published work in Europe and North America has also shown the safety and efficacy of a Timothy grass sublingual tablet for treatment of grass-allergic individuals (Merck + ALK partnership). Furthermore, a 5-grass sublingual tablet (Stallergenes) has completed clinical trials in the U.S.  Both the Timothy grass tablet and the 5-grass tablet have received approval in Europe, and the latter tablet was recently approved in Canada. Hopefully, the data from the grass and ragweed clinical trials will lead the path towards licensure in the U.S. in the near future.

Future research in this area should be aimed at evaluating other relevant aeroallergens (such as dust mites and animals, which are important perennial allergens for many allergic patients in N. America), assessing the optimal duration of therapy, and developing additional efficacy and safety data in asthmatics and polysensitized patients.

Citation:

Randomized Controlled Trial of a Ragweed Allergy Immunotherapy Tablet in North American and European Adults

Peter S. Creticos, MD, Jennifer Maloney, MD, David I. Bernstein, MD, Thomas Casale, MD, Amarjot Kaur, PhD, Robert Fisher, MD, Nancy Liu, PhD, Kevin Murphy, MD, Kristof Nekam, MD, and Hendrik Nolte, MD, PhD [J Allergy Clin Immunol 2013;131:1342-9].

Press Release:

TUESDAY, MAY 7, 2013

STUDY DEMONSTRATES THAT ONCE-A-DAY PILL OFFERS RELIEF FROM RAGWEED ALLERGY SYMPTOMS

An international team of researchers, led by physician-scientists at Johns Hopkins, reports that a once-daily tablet containing a high dose of a key ragweed pollen protein effectively blocks the runny noses, sneezes, nasal congestion and itchy eyes experienced by  ragweed allergy sufferers.

Tests showed that treatment with the pill, which contains the protein Ambrosia artemisiifolia major allergen 1, and is placed under the tongue to be absorbed, also reduced the need for anti-allergy drugs to get relief. More than 80 million Americans are allergic to ragweed.

The study is believed to be the first and largest, multicenter, double-blind, randomized controlled trial of its kind to investigate the use of sublingual immunotherapy against ragweed allergy. Begun in April 2010, it was funded by the drug’s manufacturer, Merck of Whitehouse Station, N.J.

Results of the trial, described this week in the Journal of Allergy and Clinical Immunology, showed that overall symptoms and need for such allergy medications as antihistamines and nasal steroids fell by 27 percent in people who took a pill containing 12 units of the allergen. During peak ragweed season, the roughly two-week period between August and October when pollen counts are highest, symptoms and medication use dropped 24 percent.

Researchers say that if the pill wins approval from the U.S. Food and Drug Administration, it could serve as a more convenient, less painful option than weekly or monthly allergy shots. The pill also presents fewer potential side effects than allergen injections.

“Our results show this oral tablet for ragweed allergy is highly effective and well-tolerated, and offers considerable relief from what many allergy sufferers consider the most agonizing part of the year,” says allergist and lead study investigator Peter Creticos, M.D.

Some 784 men and women from the United States, Canada, Hungary, Russia and the Ukraine volunteered to take part in the year-long study, in which participants were randomly assigned to take either a high-, medium-, or low-dose tablet, or placebo. Neither researchers nor study participants were aware of which dose of the pill or placebo they were taking. Patients kept track of their symptoms and medication use through detailed and daily diaries, which were later scored by researchers for analysis.

“Physicians treating ragweed allergy sufferers may soon have an alternative to the current approach to managing ragweed allergy, which usually involves weekly or monthly visits to the doctor’s office for allergy shots and carries the risk of swelling and pain at the injection site, plus risk of anaphylactic shock,” says Creticos, an associate professor at the Johns Hopkins University School of Medicine.

Creticos says that no serious adverse events occurred during the study. The only side effects observed were mild throat irritation, itchy tongue and swollen lips.

Creticos says his team has also begun studies of other non-injectible forms of immunotherapy, including ragweed allergy drops, and treatment applications where the allergen is lightly pricked or inserted into the middle layers of the skin.

Other researchers involved in the study are Jennifer Maloney, M.D., Amarjot Kaur, Ph.D., Nancy Lui, Ph.D., and Hendrik Nolte, M.D., Ph.D., at Merck; David Bernstein, M.D., at the Bernstein Clinical Research Center and University of Cincinnati College of Medicine, in Ohio; Thomas Casale, M.D., at Creighton University in Omaha, Neb.; Robert Fisher, M.D., at Allergy Research and Care in Milwaukee, Wis.; Kevin Murphy at Boys Town National Research Hospital in Omaha, Neb.; and Kristof Nekam, M.D., at Hospital of the Hospitaller, Brothers of St. John of God, in Budapest, Hungary. During the conduct of the study, Creticos was a paid member of a Merck scientific advisory board.

 

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