In a landmark vote on Friday, an advisory panel recommended Aimmune’s peanut allergy immunotherapy for FDA approval. The treatment, which desensitizes patients by giving them gradually increasing doses of peanut protein, could be a game-changer in the food allergy field, where avoidance is the most common treatment.
The panel voted 7-2 that the efficacy data presented supported the treatment's FDA approval. Known as AR101 and to be marketed as Palforzia it would be approved to “reduce the incidence and severity of allergic reactions, including anaphylaxis, after accidental exposure to peanut” in children and adolescents with a confirmed diagnosis of peanut allergy.
The panel voted 8-1 in favor of a safety plan called Risk Evaluation and Mitigation Strategies, or REMS, proposed by the FDA, to support the use of Palforzia in children aged 4 to 17. This plan includes that any patient prescribed Palforzia has a valid prescription for injectable epinephrine, caregivers/patients attest to carrying injectable epinephrine while taking Palforzia and the initial dose escalation and the first dose of each up-dosing level must be given at a certified site capable of treating systemic allergic reactions. Though the panel vote is not binding, the FDA generally tends to follow committee recommendations.
Aimmune set up shop in 2012 to develop approved treatments for food allergy—it is the result of a group of parents, advocates, researchers, and members of the FDA that were frustrated by the dearth of regulated treatments for life-threatening allergies.
The idea behind Palforzia is not new. Doctors have been using immunotherapy to treat other types of allergies, such as those to bee venom, ragweed and pollen for years. It involves injecting patients with gradually increasing doses of what they are allergic to in the hope of reaching a point where their immune system can tolerate it.
"What I would say about Palforzia, once approved, is it does exactly what other immunotherapy does. You start at low doses, slowly escalating, charging up the immune system with the same thing you’re trying to mount an immune response against,” Aimmune CEO Jayson Dallas told FierceBiotech.
The difference is delivery.
“In the case of food allergy, it’s a little bit riskier to do something like that with injections, so Aimmune did this as an oral immunotherapy,” Thomas Casale, M.D., the chief medical adviser of Food Allergy Research & Education (FARE), told FierceBiotech. FARE provided early funding for Aimmune and Casale was the lead investigator of the Palforzia phase 3 study in Tampa Bay, Florida.
The BLA package for Palforzia includes data from two phase 3 studies and their follow-on studies. The year-long PALISADE trial, tested the treatment against placebo in 555 patients aged 4 to 55. The vast majority of them were children and adolescents, the age group for which Aimmune is seeking approval.
At the start of the trial patients could not tolerate 100mg or less of peanut protein—that’s a fraction of a single peanut, which weighs in at about 300mg. Patients were given a higher dose of the treatment every two weeks until they reached a maintenance dose of 300mg. After one year of treatment, 67% patients in the intent-to-treat population could tolerate 600 mg of peanut protein, about two peanuts or a small bite of a peanut butter sandwich, compared to 4% of patients who received placebo.
"What we're actually trying to protect folks against in the real world is about half a peanut," Aimmune CEO Jayson Dallas told FierceBiotech. "About 125 mg is the median dose that causes an accidental exposure to result in a systemic allergic reaction that may be life-threatening when people are out in the real world trying to avoid peanuts."
A pair of panelists, Erica Brittain, a statistician with the National Institutes of Health, and Soheila Maleki food allergy researcher at the U.S. Department of Agriculture raised the issue that Palforzia may be a lifelong treatment.
“[The fact that] we don’t have long-term follow-up of pats gives me pause,” Brittain said.
Aimmune is working on that. More than 90% of the patients who completed PALISADE rolled over into the follow-on study.
“Our goal is to keep treating them until they essentially go into remission of their allergy and if they discontinue treatment, they are no longer allergic,” Dallas said.
If immunotherapies for grass pollen or bee venom are any indication, one year on Palforzia is nowhere near enough to wean patients off treatment, added Steve Tilles, senior director of medical affairs at Aimmune.
“With grass pollen allergy shots or bee venom immunotherapy, if we stop therapy after the second year, the allergy will reaccumulate and the patient is as sensitive as they were before we started,” Tilles said. “The magic number with those two types of immunotherapy is three years.”
One of the two dissenting panelists, John Kelso, M.D., an allergist at the Scripps Clinic in San Diego, echoed concerns about the safety data. In the phase 3 study, patients taking Palforzia had a higher rate of allergic reactions, epinephrine use and study dropouts than the placebo group: 89.1% versus 57.5%.
“The question asks about reducing reactions to accidental exposures [which are] not directly assessed and would be very difficult to directly assess,” Kelso said. “I understand the rationale of substituting this surrogate of passing the food challenge, but I think that because the treatment itself represents a [food] challenge every time a dose is given and the end result being patients on therapy are twice as likely to have a reaction requiring epinephrine, that the effectiveness of the treatment has in fact not been demonstrated. It may be demonstrated on the day that food challenge was done. But the rest of the time, patients are getting challenge every day in the form of a dose of medication that doesn’t decrease but increases a chance of a reaction."
However, Casale and Dallas pointed out that these reactions are happening under the supervision of physicians and parents, and that patients and their caregivers are taught to recognize and treat the symptoms of an allergic reaction quickly.
“[It] is a lot different in my mind than having an allergic reaction when you’re not expecting it, if your child is at a party and you’re not there with them and they don’t have epinephrine to treat them if they have an accidental exposure,” Casale said.
What’s more, if Palforzia is approved, allergists can take steps to reduce the likelihood of a reaction to the treatment,” Dallas said.
The two-week up-dosing schedule should be seen as a “speed limit,” he said.
“In clinical practice, patients can take as long as they need on each of the intermediate dose steps to get to 300mg. This is exactly what allergists do today in the up-dosing of immunotherapy for grass and pollen allergy,” he said.
Doctors may also use an antihistamine alongside Palforzia to “blunt down” allergic reactions and gastrointestinal disturbances that may happen.
In all, it’s “probably not a perfect therapy,” Casale said. “But it’s a first step and I think that is what is generating a lot of excitement. Very few physicians right now are offering this type of therapy in practice because we don’t have a good handle on exactly how to do it... Approving this product will provide an impetus for a lot more allergists to use [oral immunotherapy] in practice, so hopefully patients will have access to it and be able to make an informed decision whether this is right for them, if they’d rather wait for something else, or if they’d just rather practice avoidance.”
Editor's note: This story has been updated to clarify that that the advisory committee voted 7-2 that the efficacy data for Palforzia were adequate to support its approval and 8-1 that the safety data, along with a safety plan, were adequate to support the treatment for approval.