Allergy Immunotherapy is the Real G.O.A.T.

Over 17.6 million American adults (about 7.5%) experience allergic rhinitis (also called hay fever or seasonal allergies). Many different substances (called allergens) can trigger allergic rhinitis, such as tree or grass pollen, and each person has their own set of problematic allergens.

The constant annoying symptoms of seasonal allergies can really be a nuisance to sufferers. Fortunately, there are lots of OTCs in your local pharmacy: decongestants reduce your stuffiness temporarily but shouldn’t be used long-term (Sudafed, Claritin-D, Afrin), antihistamines block histamine, a symptom-causing chemical released after you’re exposed to an antigen (Benadryl, Claritin, Zyrtec), nasal steroids suppress allergy-induced inflammation in the nose (Flonase, Nasacort, Nasonex), and saline nasal rinses clear out mucus and allergens.

Unfortunately, those drugs all provide temporary relief by addressing the symptoms and immune system overreaction but don’t address the underlying issue: allergen oversensitivity. Allergen-specific immunotherapy (ASIT), such as allergy shots, can treat the underlying sensitivity and provide relief long-term. In fact, allergy shots reduce allergy symptoms in about 85% of people with allergic rhinitis.

Despite its proven success as a treatment, ASIT is underused. This is due to various unmet needs, such as high out-of-pocket costs due to a lack of insurance coverage and the long-term, often inconvenient nature of the therapy. In this report, we will discuss what ASIT is, FDA-approved drugs, what drugs are in the pipeline, and the outlook of the ASIT field. Although we will focus on the U.S., we will also compare the U.S. to the other major markets (Europe and Japan).

The World Health Organization (WHO) estimates that 10-30% of people globally have allergic rhinitis. Grass and tree pollen are among the most common allergy triggers. Top grass pollen allergens in North America include ryegrass, Bermuda grass, Timothy grass, and Kentucky bluegrass. Trees in the birch, cedar, and oak families produce particularly allergenic pollen. For example, Japanese cedar pollen is the most common culprit for seasonal allergic rhinitis in Japan, affecting over one-quarter (26.5%) of Japan’s population. The number of Japanese affected by cedar pollen allergy has been on the rise, prompting Japanese cedar pollen allergy to be considered a “national affliction.”

Each season represents the peak time for various allergens: late winter into early spring is peak tree pollen allergy season followed by late spring into summer being the primary grass pollen allergy season.

Allergen-Specific Immunotherapy (ASIT)

Allergen-specific immunotherapy is a treatment in which a patient is repeatedly exposed to tiny amounts of an allergen in gradually increasing doses to provoke an immunological response. This ultimately results in increased tolerance to the allergen and reduced allergy symptoms. There are two main types of ASIT: well-known allergy shots and newer allergy tablets/drops.

Allergy shots, formally called subcutaneous immunotherapy (SCIT), inject allergens under the skin of the arm using a needle. According to the American College of Allergy, Asthma, and Immunotherapy (ACAAI), allergy shots are the “most commonly used and most effective form of allergy immunotherapy” – they have been around for more than 100 years.

Injections are given in two phases: the first involving injections a few times each week for about six months with increasing allergen doses, and the second maintenance phase involving injections once or twice a month. Treatment typically lasts 3-5 years but may last longer depending on the type and severity of the allergy.

Allergy shots can provide protection from multiple allergens at once and can last a long time after therapy ends; they may even be able to prevent new allergies and asthma from developing! However, the dosing schedule can be burdensome and expensive because you must return to your allergist so often.

Side effects such as injection site irritation and allergy symptoms (sneezing, congestion, hives) may occur – this isn’t surprising since you’re exposing yourself to a known allergen. There is also a small risk of a severe allergic reaction called anaphylaxis, so allergy shots are given in an allergist’s office.

Allergy tablets or drops, formally called sublingual immunotherapy (SLIT), involve placing a tablet or liquid containing the allergen under the tongue to dissolve. These have been shown to be just as effective as allergy shots at controlling allergy symptoms and providing long-term protection after treatment stops. However, each tablet only provides protection against one type of allergen. SLIT drops, like allergy shots, can contain multiple allergens, but they are only available off-label in the U.S.

Tablets or drops are taken a few times per week (as frequently as daily) for at least three years, if not long-term. Although some people experience long-term relief after three years of treatment, many will have their symptoms return after a few years and will need to go back on treatment. Only SLIT tablets are FDA-approved so far.

Mild side effects, such as an itchy mouth or stomach discomfort, may occur, but tablets have a better overall safety profile compared to shots. This allows the tablets to be given at home (after the first dose is given in a medical setting). However, there is still a small risk for anaphylaxis, so it is recommended that patients are prescribed an at-home epinephrine auto-injector, like an EpiPen, to be used in case of a severe allergic reaction.

FDA-Approved ASIT Products for Grass and Tree Pollen Allergies

Because allergy shots have been around for so long, there are standardized FDA-approved bulk allergen extracts for nine different types of grasses made by six manufacturers (ALK-Abello, Inc., Allergy Laboratories, Allermed Laboratories, Antigen Laboratories, Greer Laboratories, Jubilant HollisterStier). There are no standardized FDA-approved tree allergen extracts, but non-standardized allergen extracts are licensed for distribution in the U.S. from the same six manufacturers. Allergens are considered standardized when they are compared to a U.S. reference standard for its potency.

Rose Joachim, Ph.D., a Senior Healthcare Analyst at GlobalData, told BioSpace, “Only the most prevalent allergens are standardized. Although it would be optimal to have standardized extracts for all allergens, this would neither be feasible nor economical. Non-standardized allergen extracts are still useful in ASIT, but may show some inter-batch variability that allergists need to work around.”

SCIT formulation in the U.S. is quite different than it is in Europe. In the US, the injections are formulated directly by allergists in their offices using FDA-approved allergen extracts purchased in bulk. In Europe, pre-formulated SCIT products are purchased from manufacturers and used as-is. Companies like Allergy Therapeutics are beginning to try to introduce these pre-formulated products into the U.S. market. In Japan, unstandardized bulk grass pollen allergens and standardized bulk Japanese Cedar pollen allergens are available, however, SCIT is not very commonly used in that country.

“In the U.S., allergists create patient-specific ASIT formulations that can include one to over 15 allergens at concentrations that are matched to the patient’s level of sensitivity,” Joachim explained. “The ability to tailor therapy directly to the needs of a particular patient is a huge benefit. However, the specific efficacy and safety of these combinations have not been studied directly in clinical trials.”

There are four FDA-approved SLIT tablets for allergic rhinitis, two of which are for grass pollen: Oralair (Stallergenes Greer), which contains extracts from 5 different grass pollens and Grastek [Grazax in Europe] (Merck/ALK-Abello), which contains Timothy grass pollen. (The other two approved SLIT tablets are for short ragweed pollen, Ragwitek [Ragwizax in Europe] (ALK-Abello) and dust mite allergen, Odactra [Acarizax in Europe, Miticure in Japan] (Merck/ALK-Abello).) Cedarcure (ALK-Abello/Torii Pharmaceutical) is the only formally approved SLIT tablet for tree pollen allergy but is only marketed in Japan for the treatment of Japanese cedar pollen allergy.

Because SLIT tablets are newer, long-term safety and efficacy are not fully understood yet. No SLIT drops are approved currently in the U.S., but they still may be prescribed by some doctors for off-label use.

“Although SLIT has been around a much shorter time than SCIT, it has been experiencing a big uptake in Europe and Japan,” Joachim said. “Patients in these regions like the ease of use as well as the improved safety. While SLIT tablets have been very successful in Japan and Europe, their uptake in the U.S. has been far less than anticipated. This is mainly due to poor insurance coverage as well as a continued focus on the use of multi-allergen SCIT.

Interestingly, the heavily ingrained culture of in-house ASIT formulation has even led to an increased usage of off-label SLIT drops that are formulated in a similar manner to SCIT treatments.”

Source: Originally published Feb 27, 2020 by C. W. Burke

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