Getting Rid Of Allergies

Emily BurkeClinical Trials, FDA, The WEEKLY

Taking A Swing At Allergens

Watching a game at the ballpark and digging into a bag of peanuts is a source of entertainment for many Americans. For the 15 million who sufferer from peanut allergies, the idea of being taken out to the ballgame elicits concern—or even anxiety.

Food allergies—think tree nuts, milk, eggs, wheat, soy, fish, and shellfish—are on the rise. The mere dust particle of a freshly cracked peanut can be responsible for an unpredictable cascade of reactions, including death brought about by anaphylaxis.

This WEEKLY takes a swing at explaining how allergies develop, are currently treated, and what new products might change the way allergen desensitization therapy is delivered.

Something To Sneeze At

The host of symptoms dubbed “allergies” are the end result of the immune system responding to a normally harmless substance, as if it were a threat. An initial allergen exposure results in the production of a particular class of antibodies called IgE antibodies. Allergies develop if excessive amounts of IgE antibodies are produced.

IgE antibodies bind to a specialized type of white blood cell called a mast cell. When exposed to the allergen a second time, multiple allergen-IgE complexes bind to mast cells, triggering a release of histamines in an attempt to get rid of the allergen. Only some of the IgE antibodies need to recognize the allergen as harmful in order for the histamine release to occur.

Histamine binds to receptor proteins on the surface of blood vessels, which results in the modification of cadherin proteins. Cadherin proteins are intercellular proteins with the job of helping cells to stick together. Gaps then form between the cells that make up the blood vessels as a result of the modification, allowing fluid to escape. Histamines may also bind to receptors on certain types of nerve cells, resulting in smooth muscle contraction—and in some cases a sensation of itchiness. Antihistamines work by blocking the activation of the histamine receptor. Once a severe allergic reaction has occurred, however, it is too late for antihistamines to be effective.

Histamines are chemical messengers that trigger a whole spectrum of different symptoms ranging from annoying to deadly, including:

  • Increase in blood vessel permeability that allows fluid to escape, resulting in a runny nose and watery eyes.
  • Increase in smooth muscle contraction that leads to throat constriction and difficulty breathing.
  • Extreme tissue fluid release that causes a sudden drop in blood pressure, potentially bringing on a heart attack.
  • Difficulty breathing and swallowing, swelling, heart palpitations, and unconsciousness—occasionally causing death.

The latter symptoms are known as anaphylaxis. Anaphylaxis is treated with an injection of epinephrine—and the sooner, the better in cases where a life is on the line. Epinephrine helps to reverse histamine’s effects by stimulating the reformation of intact blood vessels, promoting the relaxation of smooth muscle cells, and stimulating the heart. People at risk for anaphylaxis need access to an epinephrine autoinjector—a spring-loaded syringe that makes the lifesaving injection readily available. The best known epinephrine autoinjector is Mylan’s (Canonsburg, PA) EpiPen. Other combination medical devices on the market include Amedra’s (Horsham, PA) Adrenaclick and Sanofi’s (Paris, France) Auvi-Q.

Revisiting the HYGIENE HYPOTHESIS

Epidemiologists have noticed an interesting trend as countries rise from developing to developed status: an improvement in sanitation and access to antibiotics means less pathogenic exposure and lower infection rate. As the infection rate drops, the incidence for different kinds of allergies shoots up.

Many scientists think early exposure to infection helps shift the immune response towards fighting pathogens while minimizing the production of IgE antibodies. Exposure to potential allergens (while the immune system is still developing) helps to desensitize the allergic response.

The Strategy Behind DESENSITIZATION THERAPY

The idea of allergy desensitization through controlled exposure has been around for decades. Desensitization is the principle behind allergy shots proven to be effective against pet dander, dust mites, and pollen. Desensitization therapy was once considered to be too risky for food allergies, but a number of new studies support the idea that gradual exposure to food allergens may also be beneficial.

With this strategy in mind, the Immune Tolerance Network (Seattle, WA) recently announced the results of a study that dialed the idea of desensitization back even further. Their hypothesis was that early exposure to potential allergens can actually prevent the development of allergies. Six hundred forty children between four and eleven months old (all of whom were considered to be at risk for developing allergies) were divided into two groups: peanut avoider or peanut consumer. The avoiders were given no peanut products until age five, while the consumers were given several snacks containing peanuts each week. Astonishingly, by the time the children reached age five, 17% of the avoiders had developed peanut allergy compared to only 3% of the peanut consumers.

Allergens By The Dose

The current allergen immunotherapy market includes the above mentioned allergy shots (which require monitoring by a physician) and drops or tablets dissolved under the tongue and swallowed (which can sometimes be taken at home). Allergen Research Corporation’s (San Mateo, CA) AR 101 is made of pharmaceutical grade peanut proteins and can be mixed with food as a means of delivery. Positive Phase II results prompted the FDA to award Fast Track designation—and the promise of AR 101 reeled in $80 million in funding earlier this month.

AR 101 Phase II studies report patients becoming desensitized to doses at least twenty times greater than the original allergy inducing dose—and in some cases, more than 100-fold greater. The goal is to reach a tolerance level that offers protection against accidental ingestion of peanuts, potentially avoiding a deadly reaction. As Allergen Research Corporation heads towards Phase III for peanuts, plans for clinical studies on immune system training for egg and milk allergies will begin later this year.

DBV Technologies (Bagneux, France) is also in the fight against allergies. They are currently conducting clinical trials on their Viaskin skin patch that delivers low doses of either peanut proteins, milk, or dust mite allergens. By delivering an allergen through the skin instead of the blood, the body will not react as severely, lessening the risk of anaphylaxis as a side effect. The Viaskin peanut patch—which is set to enter Phase III by year’s end—has been awarded Fast Track designation by the FDA. As allergen desensitization treatments continue to make their way through the drug pipeline, allergy sufferers remain hopeful for better and easier treatment options, and maybe even one day—a cure.