Oct. 27, 2021 — When Heather Sapp’s 11-year-old daughter was diagnosed with allergies to eggs, peanuts, and tree nuts a decade ago, food allergy treatments were scarce. The family looked into a research study of oral immunotherapy (OIT), a process that helps patients raise their allergen threshold by eating some of the culprit food each day, but she did not qualify for the trial.
Today, oral immunotherapy is more available — there’s an FDA-approved product for peanut allergy (Palforzia), and some 15,000 patients have been treated by a small but growing number of doctors offering home-grown oral immunotherapy with commercial food products.
But oral immunotherapy can be unnerving.
“Her whole life, essentially, she’s been avoiding these foods,” Sapp says of her daughter, now a preteen who cannot stomach the thought of having to eat her allergens daily for treatment. “It’s a psychological thing.”
The treatment is also time-consuming, requiring rest periods after each day’s dose and in-office visits to raise the dose every few weeks. Plus, it raises a patient’s risk for allergic reactions.
While browsing Facebook 5 or 6 years ago, Sapp, who lives in Phoenix, AZ, learned about something called sublingual immunotherapy (SLIT), a slower treatment approach that seemed simpler and less stressful.
Rather than going through the digestive tract, this treatment delivers allergens in much smaller amounts through drops placed under the tongue. There, the food proteins seep into immune cells that induce tolerance, which can dampen the body’s response to the allergens if the drops are taken daily for several years.
Sublingual immunotherapy is “very simple to do,” says Edwin Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina School of Medicine, who led two recent trials in peanut-allergic children. “It’s a bunch of drops you put under your tongue, you hold it for a couple minutes, and then you’re done for the day.”
In Kim’s 2019 study of children with peanut allergies ages 1-11, the treatment offered a level of protection on par with Palforzia, the FDA-approved peanut allergy drug, while causing considerably fewer adverse events. And at the 2021 annual meeting of the American Academy of Allergy, Asthma and Immunology in February, his team reported that the treatment produced stronger, more durable benefits in toddlers.
To guard against reactions from cross-contamination or accidental exposures, Kim says, sublingual immunotherapy “is pushing pretty close to what (low-dose oral immunotherapy) is able to provide but seemingly with a superior ease of administration and safety profile.”
But because dosing plans are unclear and because there are few approved products, very few US allergists — likely less than 5% — offer sublingual immunotherapy to treat food allergies, making it far less available.
Since there are no FDA-regulated sublingual products for food allergy, “I never considered offering it,” says Jeff Weiss, MD, a private allergist in Riverdale, NJ, who also has two peanut-allergic children.
Jaclyn Bjelac, MD, an associate director of the Food Allergy Center of Excellence at the Cleveland Clinic in Ohio, thinks it “could be an option for the future” but wants to see more published data, particularly in older children, “because those are the kids who struggle more in [oral immunotherapy],” she says.
Compared with toddlers, older kids on this therapy have more side effects and systemic reactions.
John Wieck’s 4-year-old daughter started oral immunotherapy in the spring of 2018 to treat her peanut and milk allergies. Within 3 months, she went into anaphylaxis twice. She also had an allergic condition known as eosinophilic esophagitis (EoE), which forced her to discontinue the treatment. Eosinophilic esophagitis happens in about 2% to 6% of people who get oral immunotherapy and usually goes away after treatment is stopped.
For Wieck’s daughter, symptoms included choking, coughing, and prolonged hiccups.
This spring, she resumed food allergy treatment — sublingual immunotherapy this time — starting with wheat, with hopes of adding eggs, peanuts, and milk. She gets the drops twice a day and so far has had no allergic reactions.
“Had I gone back and done it all over again, I definitely would have started with [sublingual immunotherapy],” Wieck says.
The family’s allergist, Stacy Silvers, MD, of Aspire Allergy & Sinus in Austin, TX, started offering the therapy 3 to 4 years ago. He was already well-versed in oral immunotherapy, having learned the approach while working at Richard Wasserman’s practice in Dallas.
Wasserman, MD, of Allergy Partners of North Texas, was among the first U.S. allergists to offer oral immunotherapy. He and colleagues have since formed the Food Allergy Support Team, a group of doctors and other food allergy specialists that publishes best practices and meets annually to share experiences and protocols.
But while gaining experience with oral immunotherapy, Silvers saw “the good and the bad, and came to realize that [oral immunotherapy] is not for everyone,” he says.
In the meantime, promising data from sublingual trials was starting to emerge. Silvers spent about a year coming up with a sublingual protocol based on published studies and conversations with other allergists who were offering it to food allergy patients with good success.
Timing and schedule vary between people, but broadly speaking, food allergy patients can expect to complete 12-18 months of sublingual immunotherapy before trying a food challenge, 2 to 3 times longer than it takes with oral immunotherapy. Sublingual immunotherapy “is a longer, slower process for sure,” Silvers says. “But the majority of our patients are getting that level of protection, and the side effect profile is just so much better.”
Not only does oral immunotherapy increase a patient’s risk for allergic reactions, it can be hard for kids who dislike the taste of their allergen and have extracurricular activities that make it hard for them to avoid exercise for several hours after dosing each day.
But sublingual therapy has downsides, too. First, the extracts are expensive. Protocols from recent published trials — in which participants received up to 4 milligrams per day over 6 months and continued with a daily maintenance dose of 4 milligrams for 3 years — would cost a patient $10,000, says Sakina Bajowala, MD, of Kaneland Allergy and Asthma Center in the Chicago area.
With this dosing plan, food allergy sublingual therapy is unaffordable, she says. And “there’s no way to make it cheaper because that’s the raw materials cost. It does not include labor or bottles or profit at all. That’s just $10,000 in peanut extract.”
Owing to cost, Bajowala’s clinic generally uses sublingual therapy as a bridge to oral treatment. Her food allergy patients receive up to 1 milligram per day and stay at that dose for a month or so before transitioning to oral therapy, “for which the supplies are orders of magnitude cheaper,” she says.
Comprehensive sublingual clinics — such as Allergy Associates of La Crosse, WI, and Allergenuity Health Associates in Huntersville, NC — have seen success with lower doses.
Nikhila Schroeder, MD, an allergist and co-founder of Allergenuity Health, says there is evidence the treatment is effective at microgram and even nanogram doses — much lower than used in the recent food sublingual trials. Maintenance doses range from 50 nanograms to 25 micrograms a day to treat environmental allergies with sublingual therapy and 4 to 37 micrograms a day for food allergies, she says. The La Crosse method uses even lower dose ranges.
Another difficulty with sublingual therapy is that dosing protocols are hard to find. Schroeder, for instance, has spent years scrutinizing articles and compiling information from allergen extract suppliers, all while treating hundreds of sublingual patients.
“I have had to expend a lot of time and effort,” she says.
Silvers uses higher doses similar to those from published trials. Yet because his clinic gets steep discounts on extracts through a different manufacturer, his team can offer the sublingual drops to patients at a reasonable cost that “in many cases is pretty comparable” to oral immunotherapy, he says.
Wieck pays $800 for 42 weeks of sublingual treatment for his daughter. Vials arrive at their home every few months, and the family has video calls with Silvers twice a year with direct access to the allergist through a mobile phone app in the event of emergency reactions or questions.
Oral immunotherapy dosing is less expensive when using commercial food products, but the overall cost of treatment can be less predictable. It varies depending on the number of office visits and possible hospital trips for severe reactions.
“We had anaphylaxis, and that was three grand to the ER,” Wieck says.
Since the therapy doesn’t require you to ingest your allergens, anaphylaxis is much rarer with sublingual therapy, but this can pose other challenges: Success is less visible than it is for oral therapy patients, who build up to dosing with actual food.
“To a family who has a concern about their kid reacting, they can see them eating chunks of peanut in our office. That is really encouraging,” says Douglas Mack, MD, an allergist and assistant clinical professor of pediatrics at McMaster University in Ontario.
On the other hand, some families don’t mind that sublingual success may be harder to measure.
“I’m less concerned about that,” says Sapp, whose oral therapy-averse preteen daughter would consider the sublingual approach if she could get it locally.
“Because there’s no ingestion, that’s a perk for us,” she says. “She wants nothing to do with a peanut butter sandwich. We don’t want to go out and eat the stuff. For us, the end goal would just be so that if she accidentally did eat it, she wouldn’t end up in anaphylaxis.”
Because sublingual treatment is customized, “success” looks different from one family to the next. For Betsy Grider’s son who has a peanut allergy, a year on sublingual therapy at Allergenuity Health built enough protection for the family to stop scouring labels for cross-contamination.
That has freed him to eat cake at birthday parties and bread at restaurants and has made eating “generally less stressful,” says Grider, of Charlotte, NC.
For another Allergenuity patient, treatment brought a notable decrease in sneezing, itchy eyes, eczema flare-ups, and hives during meals. Those symptoms were once so strong that Julie Werry’s daughter had become anxious around doctors, testing, and food in general. Sublingual therapy helped the family achieve its main goal, which was to “improve her quality of life so she could be a kid and not let this completely define her,” Werry says.
Kim, who published the recent smaller sublingual trials, has tried to find partners to fund more research on sublingual immunotherapy for food allergies. (Researchers have studied sublingual therapy more extensively as a treatment for environmental allergies, and several sublingual tablets have gained FDA approval.)
In conversations with philanthropists and drug developers, Kim says they have found his food data promising. Yet with sublingual protocols and products already in the public domain, they “can’t see a commercial path forward,” he says. “And that’s kind of where many of my conversations end.”
At least one company is giving it a shot. Applying the sublingual principle of delivering food allergens to tolerance-promoting immune cells in the mouth, New York–based Intrommune Therapeutics is enrolling peanut-allergic adults for a phase I trial of its experimental toothpaste.
In a preliminary analysis reported by the company in late October, the toothpaste was well-tolerated by patients told to brush daily with higher and higher doses of the peanut immunotherapy. Based on these safety and dosing limits, Intrommune plans to start phase II studies of its toothpaste therapy next year.
“Research should be aimed at how the treatment could be formulated to be most effectively used in the real world for the majority of the patients,” Schroeder says. For example, studies could assess the minimum dosing and treatment time needed for practical benefits — such as milder hay fever symptoms and protection from cross-contamination or accidental ingestion — rather than trying to show what high, expensive doses can achieve.
Every now and then, maybe a couple of times a year, Sapp reads up on sublingual therapy and looks into potential providers. If the treatment were available locally, “I think there’s a good chance we would be doing it.”