OIT Therapy Gets Ready for Prime Time

By:
in Features, Peanut & Tree Nut
Published: July 18, 2016

Peanut oral immunotherapy in a capsule is close to approval, bringing hope – not of a cure – but of lives lived with less vulnerability.

Alex Thomas 11Immunotherapy study participant Alex Thomas, 11.
FOR MORE than seven years, Alex lived like most kids with peanut allergies: he strictly avoided the legumes. His mom, Sarah Thomas, read food labels, grilled restaurant staff, and sent safe cupcakes for Alex to eat at birthday parties.

When Alex was young, Thomas heard about oral immunotherapy experiments, in which allergists were attempting to retrain the immune system to tolerate peanuts by feeding patients gradually increasing amounts of the allergen. But they were taking place at Duke University in North Carolina, more than three hours away from their home in Chesapeake, Virginia. She recalls putting her son on a waiting list, but it was realistically too far to go for treatment.

Starting Treatment

Then, when Alex was 9, the family moved to southern California, met their new allergist, and learned that she was also conducting peanut oral immunotherapy trials. This time, however, the studies weren’t being done for academic purposes. A company called Allergen Research Corp. was developing a standardized treatment that the founders hoped would be approved by the Food and Drug Administration. Alex had the opportunity to take part in one of the trials of a Phase 2 clinical study of what is essentially a new drug regimen – featuring carefully calibrated dosages of peanut proteins.

At first, Alex was in the group placed on a placebo (although his family didn’t know that), but after six months, he was moved onto treatment. Over six months, the boy was able to consume 300 milligrams (mg) of peanut protein, then succeeded at passing a challenge at 443 mg, or about one and a half peanuts. (Alex is now in a continuation of the study.)

As Alex and the rest of the people in this study (it initially enrolled 55 patients aged 4 to 21 at eight locations) continue to be monitored, the company, which has changed its name to Aimmune Therapeutics, is moving on to a large-scale Phase 3 trial. At press time, the researchers were busily working to recruit 500 patients, ages 4 to 55, to participate in about 60 study sites in the United States, Canada and Europe. [Editor’s update: A report on the completed trial is here.]

“What we’re trying to do is to take patients who are at risk from accidental exposure to even really small amounts of peanut protein and get them to a level of desensitization where they are protected against accidental exposure,” explains Stephen Dilly, Aimmune’s CEO.

If all goes well with the Phase 3 trials, by 2019, there could finally be an FDA-approved, widely available treatment for peanut allergy, the modern-day epidemic that tripled in size among U.S. children between 1997 and 2008. While not a cure, the aim of this standardized OIT regime is to make patients significantly less allergic to peanuts – and greatly reduce the odds of life-threatening anaphylaxis from an accident with food, whether at a restaurant, a friend’s home – or even in the allergic person’s own kitchen.

Standardized OIT Therapy

RESEARCHERS have been devising theories of how oral immunotherapy could work for more than a decade. It is peanut-allergic kids – whose parents will do almost anything to decrease their worry that one wrong bite could have severe consequences –who have been the guinea pigs. As successes emerged, some allergists started doing OIT, privately, in their clinics, while other leaders in the field cautioned this was premature, that there was still a lot to learn about how and for whom the desensitization therapy works best. There were treatment risks: patients sometimes experienced stomach pains or hives and in some cases needed epinephrine to stop allergic reactions.

Then in 2011, the allergy group Food Allergy Initiative (now FARE) hosted a research retreat with more than 40 researchers, government officials and industry and advocacy leaders. Out of that, a mission became clear: OIT was a therapy that had the potential to help the millions with food allergies. But for them to have safe access to it, large-scale research needed to happen. From there, Allergen Research Corp., which later turned into Aimmune, was formed.

“We’ve stood on the shoulders of people who have been working in this field for a long time and come up with what we found to be the best in dosing protocols out there,” says Dilly, who has a background of bringing pharmaceutical treatments to market.

What’s Different About AR101?

There are some clear differences between Aimmune’s process, and what other OIT trials and private OIT practitioners are doing. For one, rather than using off-the-shelf peanut flour, the new therapy, called AR101, uses peanut flour with a very consistent level of protein, which is precisely analyzed for a protein signature based on three key allergenic proteins.

Considered a biologic drug, AR101 is produced in a facility in Clearwater, Florida, with strict quality control. The company’s formula, which contains all of the peanut proteins, is put into a capsule at a fixed ratio. The patient breaks the capsule open and mixes the contents into food – such as apple sauce, Sunbutter or ketchup. It’s a standardized treatment: each patient starts on the same dose and is built up at the same pace, with increases usually every two weeks, until the person reaches 300 mg of protein. Then, you stay on a maintenance dose – forever – to maintain the level of desensitization.

OIT pillsAR101 capsules lined up by dose size. From left: 0.5 milligram, 1 mg, 10 mg, 20 mg and 100 mg. For maintenance, there are 300 mg sachets.

The FDA has granted Aimmune its “Breakthrough Therapy Designation,” which means it walks with the company side-by-side throughout the development process. “We are in constant dialogue with the FDA,” says Dilly. “We’re doing something new here, which is taking something that’s grown in the ground and turning it into an FDA-regulated biologic.”

Another key difference between Aimmune’s lastest version of AR101 oral immunotherapy and other regimens is that in the build-up and maintenance phase, you’re never taking a daily dose higher than 300 mg of peanut (approximately one peanut). Dilly contends this design improves safety, while still providing a good level of desensitization.

Stephen DillyAimmune CEO Stephen Dilly: therapy protects against food accidents.

Phase 2 Success

In early March 2016 at the AAAAI allergists’ conference, Aimmune released final results from its Phase 2 study, as well as from continuations of that research. Out of 55 original participants, including young Alex, 40 completed the up-dosing to 300 mg and maintenance dosing of 300 mg. All of them were able to tolerate 443 mg, or about one and a half peanuts. Ninety percent were able to tolerate 1,043 mg, which equals about four or five peanuts, and 60 percent were able to safely consume 2,043 mg of peanuts – which is two grams. “We’re in that range of real clinical relevance that can impact daily life, quality of life and the ability to have a normal childhood,” says Dilly.

And what happened to the other 15 participants? Eleven of them dropped out because of gastrointestinal issues, typically a dull ache in the gut. (One person also had a more serious reaction requiring epinephrine and others left due to compliance and scheduling issues).

Dr. Brian Vickery, an assistant professor of pediatrics at the University of North Carolina-Chapel Hill who also works at Aimmune part-time, says the results are in line with what has been seen in other OIT studies, and indicates that for some patients, oral immunotherapy just won’t be effective. “This will be something that will work in about four patients out of five,” adds Dilly. “The good news is if it’s not going to work, it declares itself early.”

Therapy a Big Commitment

THE QUESTION IS, if treatment with AR101 ensures you can tolerate a peanut and a half, is it enough of a benefit for patients to go through the hoops, stressful moments, and time commitment of treatment, as well as taking a dose every day for the rest of their lives?

“On the surface it has huge mass appeal, then once you get down to the details I think families will think much harder about it,” says Dr. Robert Wood, a leading oral immunotherapy researcher whose clinic at Johns Hopkins Children’s Center in Baltimore is one the sites of the Phase 3 trial.

Nevertheless, Wood is hopeful that AR101 will be approved, giving him and other allergists an FDA-sanctioned treatment to offer patients with peanut allergies.

“It will be very nice to have something to offer. There are going to be parents who will say, ‘My child is doing quite well with his or her life and did not have a reaction in the last five, eight, 10 or 12 years, and we’re perfectly happy with strict avoidance.” And there will be others whose lives are being greatly consumed by fear of the next reaction who would take a huge amount of comfort having some level of protection.”

Wood also notes that by the time AR101 is approved, there’s a good chance DBV Technologies’ Viaskin peanut patch will also have FDA approval – taking the food allergy community from years of having zero sanctioned options to two approved therapies. “Then it will be a matter of treatment with either, or neither,” he says.

Peace of Mind the Goal

sarah thomas and familySarah Thomas with sons from left) Alex, Benjamin and Byron.
FOR ITS PART, Aimmune says the goal is to protect from accidental reactions, and that the desensitization level of 443 mg of peanut is sufficient. Vickery points to research showing that accidental reactions typically happen after exposures of between 50 and 100 mg of peanut.

Dilly says the real promise of the AR101 therapy is moving away “from having to be obsessive about avoiding every single trace of peanut protein to saying: ‘Avoid eating foods that contain peanuts, and you’ll be fine.’” (You would still need to carry epinephrine in case you did accidentally eat some- thing containing peanuts.)

So far, Aimmune’s research has been focused on children older than 4 years old. Company researchers believe kids aged 1 to 3 can be treated with AR101 as well. They are awaiting important data from other studies, to see if there’s the potential for actually turning off the disease if it’s treated soon enough in life. “Then we’ll know what our objective is in young kids, whether it’s to do like the rest of the population and protect and desensitize long-term, or if we can actually go for the brass ring and try to use the “cure” word in those cases,” says Dilly.

Caution, Even if Approved

For now, rather than a cure, Aimmune will have to settle for peace-of-mind for the masses. And even that will come at a cautious pace. Dilly says that, presuming the FDA approves the therapy, the company will roll it out carefully. It needs to make sure allergists are trained properly, and will continue to monitor patients to study the impact on their lives and watch for any accidental reactions.

At this point, it’s unclear what the cost of the therapy will be, or how soon insurance companies will pay for it. The company will only say that it’s “actively working on market access and reimbursement.” But Aimmune is planning for an eventual large market: “There are millions of patients who can benefit from this, and we need to make it available,” says Dilly. “The way that we’re building the factory in Florida is to have the capacity to produce large amounts.”

In the Thomas house, Sarah is happy that she can loosen up some restrictions around Alex, and he’s pleased to be allowed to eat ice cream. “Even though we tried to make him feel included, he often felt that he was missing out or different,” she says. Still, Alex also has a tree nut allergy, so worry is only partly off the table.

But there is hope for people with allergies other than peanut: Aimmune plans to keep tackling them, including tree nuts, milk, and shellfish. The next target allergen is egg.

Related Reading: Panel Backs FDA Approval of OIT Drug