Just a few doses of a pill used to treat blood cancers prevented allergic reactions to peanuts in adults with a severe allergy, a recent study finds.
The drug, acalabrutinib, is one in a class of medications called BTK inhibitors, short for Bruton’s tyrosine kinase. These medications block BTK, a signaling enzyme found in various immune system cells.
Though it’s still early days, researchers say the medications are very effective and work rapidly, which presents intriguing possibilities for eventual real-world use.
Blocking BTK signaling likely prevents not just peanut reactions, but IgE-mediated allergic reactions to any food, medication, or insect venom, says study co-author Dr. Bruce Bochner.
“That’s the exciting part. Pre-medication with this drug can protect you from an anaphylactic reaction,” says Bochner. “They are incredibly effective,” says the allergist-immunologist and professor emeritus at Northwestern University’s Feinberg School of Medicine in Chicago.
The peanut study was small and more research with BTK inhibitors in food and other allergies is needed. However, getting a BTK medication approved to treat another condition associated with allergies – chronic spontaneous urticaria (CSU) – may not be far off. Drug maker Novartis has released top-line results showing a BTK inhibitor was effective in treating CSU hives and itch in two Phase 3 trials.
Peanut Study Shows Promise
The Phase 2 study on peanut allergy included 10 adults who reacted to about 29 milligrams (mg) of peanut, or about 1/10th of a peanut, at the start. Participants, who were highly reactive, received four doses of acalabrutinib over two days.
They then underwent a food challenge to peanuts. Seven of the 10 could consume over 4,000 mg of peanut without reacting. That’s 16 to 20 peanuts, and was the maximum amount tested. Three participants could consume significantly more peanut after receiving the drug – 444 mg, 1,044 mg, and 3,044 mg.
“After the fourth dose of acalabrutinib, we found people’s tolerance to peanut had increased dramatically,” says senior study author Dr. Melanie Dispenza. The assistant professor of medicine at Johns Hopkins University in Baltimore notes: “This is truly groundbreaking for the field because the onset of action is so rapid, within hours to days.”
What Do BTK Enzymes Do?
BTK is found in several types of immune system cells, including B cells (a type of white blood cell), mast cells and basophils.
When an allergenic protein binds to receptors on mast cells and basophils, it triggers a response inside the cells. This can lead to the release of histamines and inflammatory molecules called cytokines. BTK is a key enzyme inside the cell involved in that chain reaction.
“The theory was, if you could interrupt that, the mast cell and basophil would just sit there,” Bochner says. Early research in the lab showed that when they treated mast cells and basophils with a BTK inhibitor and then exposed them to an allergen, “sure enough that’s exactly what happened.”
In 2013, the FDA approved the first BTK inhibitor, ibrutinib, for use in cancer patients. It is used to treat B-cell cancers, such as certain lymphomas and leukemia. In cancer patients, BTK inhibitors help stop defective B cells from multiplying.
Allergy Testing Cancer Patients
Bochner and his colleague, Dr. Jennifer Regan, figured that people taking ibrutinib for cancer would probably notice that their allergies got a lot better. The drug approval gave them the chance to test that.
A few years ago, they published a study on two cancer patients – one allergic to cats and one to ragweed. Each patient had an allergy skin test before their first dose of a BTK inhibitor. They were tested again at one week and 28 days after starting the medication. After one week on the inhibitor, one had a negative skin test and the other’s skin test was markedly reduced. By two months, both had negative skins, and blood tests showed that their basophil activation was also dramatically reduced.
“That was the first publication that suggested patients taking this medication for their malignancy had reduced allergic responses to IgE [antibodies] and the IgE receptors in the basophils and mast cells,” Bochner says.
Future Uses for BTK Blockers
Since the approval of ibrutinib for cancer, several others BTK inhibitors have been approved, including acalabrutinib, made by AstraZeneca. Several others are in development.
So what of the future for BTK inhibitors for food allergies, or drug or venom allergies?
Bochner and Dispenza see a range of possibilities. Taking a BTK inhibitor could enable people with an IgE-mediated drug allergy to an antibiotic or chemotherapy agent to take those medications without reacting.
A BTK inhibitor could potentially be used to reduce food allergy reactions during the oral immunotherapy (OIT) buildup phase. With OIT, allergic individuals are desensitized to their allergen by eating daily doses of an allergenic food, in gradually increasing amounts over several months. While the therapy can be effective for many, allergic reactions are common, especially during the buildup.
Or, an allergic individual could take a BTK inhibitor before they travel. This could “allow a food allergic child to go on vacation without having to worry about a life-threatening reaction,” Dispenza says. (Currently, there are no BTK inhibitors approved for use in children.)
Because they work so quickly and likely for all allergens, BTK inhibitors have the potential to be “paradigm-shifting for how we manage food and medication allergies,” Dispenza says.
No additional studies of acalabrutinib and food allergies planned. However, research involving other BTK inhibitors and allergic conditions is underway. For instance, Novartis has launched a Phase 2 study using its BTK inhibitor, remibrutinib, to prevent peanut allergy reactions.
That trial is enrolling 110 peanut-allergic adults who will be randomly assigned to receive a low, medium or high dose of remibrutinib, twice a day, for one month. Or, they will receive a placebo dose for three weeks and a low dose of remibrutinib for one week. There is also a placebo-only arm. The FDA has not yet approved remibrutinib.
After a month, participants will undergo a food challenge to see how much peanut protein they can tolerate before starting to react, up to 3,000 mg. Study results are expected in 2026.
BTK Blocker Costs and Chronic Hives
Novartis’ Phase 3 trials of remibrutinib for chronic urticaria enrolled 925 adults in two separate double-blind, placebo-controlled trials. It found those taking a 25 mg dose, twice daily, showed an improvement in hive and itch symptoms as soon as two weeks after starting treatment, and at 12 weeks. Patients will continue to take the drug for a year. Novartis will submit for drug approval in 2024.
Genentech’s Phase 2 trial on its BTK inhibitor, fenebrutinib, for chronic hives also showed promising results.
“It wouldn’t surprise me if at least one of those drugs makes it onto the market,” Bochner says. “And they should work for other allergies as well. The question is at what cost, and are they safe to use on a long-term basis?”
High costs are an issue. Right now, “these are cancer drugs. They are on the order of $500 a day, which is $15,000 a month,” Bochner says.
If a BTK inhibitor is marketed for chronic urticaria or another allergic condition, a drug maker will likely have to price it lower than a cancer drugs, he says. As the pills do have side effects, he expects any approval in food allergies would apply to shorter-term use.
In cancer patients, the side effects with BTK inhibitors tend to be fewer than with traditional chemotherapy, Dispenza says. Still, there are some. Side effects in cancer patients can include fatigue, rash, nausea, diarrhea, bleeding, bruising, irregular heartbeat, and a drop in white blood cells, raising infection risk. Cancer patients who take BTK inhibitors tend to stay on them for years.
The newer BTK inhibitors are more “selective” than the first BTK inhibitors, meaning they are better at targeting BTK and only BTK, which generally means fewer side effects, she says. Also, BTK inhibitors for allergic conditions may require lower doses than cancer patients need to take.
Looking out even farther, Bochner’s lab and others are investigating nanoparticles to deliver a medication directly to cells you’d want to target. In the case of allergic diseases, that could be a BTK inhibitor targeting mast cells, but sparing the B cells. Eventually, there could there even be a BTK inhibitor nose spray or eye drops to treat seasonal allergies.
“If these work as well as I think they will, you may see a whole wave of drugs in the allergy space being developed,” he says.