FDA staff gave generally high marks to an oral peanut-protein powder, called Palforzia (previously AR101), to be reviewed Friday by the agency's Allergenic Products Advisory Committee to reduce peanut allergy in children and teens.
Clinical studies showed substantial efficacy in cutting incidence and severity of allergic reactions, including anaphylaxis, according to a . But the document also noted that half of participants developed reactions to Palforzia itself, a few needing epinephrine treatment.
The committee will be reviewing Aimmune Therapeutics' Biologics License Application for Palforzia, seeking approval for use in patients age 4-17 with confirmed peanut allergy. Patients would still need to carry an epinephrine injector even if treatment is considered successful, the company noted.
Oral desensitization therapy for peanut allergy -- exposing severely allergic children to progressively larger amounts of peanut in controlled settings in hopes of inducing tolerance -- has generated substantial excitement in the field over the past decade. The startlingly simple concept promises to remake the lives of kids and their parents, who have had to restrict what they can eat and where they can go.
A , reported in 2009, found that oral immunotherapy succeeded in allowing many children, who had previously suffered anaphylaxis from exposure to small amounts of peanut, to eat several whole peanuts without incident. Other researchers enthusiastically took up the approach, and it wasn't long before clinicians began offering it in their practices.
But those early studies and clinical applications used store-bought peanut powder, with varying amounts of peanut allergens and no standardized protocol. Many in the field became concerned that the risks hadn't been adequately evaluated.
That -- along with the profit motive -- opened the door for private companies including Aimmune Therapeutics to develop proprietary peanut-protein formulations that could offer consistency and also pass muster with the FDA.
In materials prepared for the advisory committee, that make one batch of Palforzia identical to the next.
Its active components are 12 "Ara h" peanut proteins thought to be the principal allergens. The end product is a powder packaged in pull-apart capsules or sachets, to be mixed into age-appropriate foods such as applesauce or pudding, the company explained.
The treatment protocol involves three stages: initial dose escalation, "up-dosing," and maintenance. Dosing begins at 0.5 mg and increases to 6 mg the first day, with patients under close supervision for reactions. The next day, patients return to begin the up-dosing, with 3 mg as the starting dose. At intervals of at least 2 weeks, doses escalate in 10 steps to 300 mg/day, also under supervision. The planned maintenance dose is 300 mg/day, which patients will take indefinitely.
In a phase III trial that underpins Aimmune's marketing application, 499 patients age 4-17 were randomized 3:1 to Palforzia or matching placebo. The primary endpoint was ability to tolerate at least 600 mg of peanut protein with at most mild allergic symptoms at the end of the 6-month maintenance phase. (One peanut has roughly 200 mg of protein.)
Efficacy was impressive: 67% of patients met the primary endpoint in intention-to-treat analysis, compared with just 4% of the placebo group (P<0.0001). A less stringent endpoint, tolerating 300 mg with no or mild symptoms, showed response rates of 77% for Palforzia versus 8% of the placebo group.
But it wasn't all rainbows and ponies for Palforzia in the clinical program, which also included two phase II studies and a total of about 1,000 patients. Adverse events, mainly allergic reactions, were substantially more common with active treatment. During maintenance treatment, 51% of those taking Palforzia developed an adverse event related to the therapy, versus 22% on placebo.
Overall, 29 severe or life-threatening allergic reactions developed in patients receiving Palforzia versus four in the placebo groups. Many of these were repeat incidents in the same patients, and not all were considered to have been triggered by the therapy. Still, four serious events related to Palforzia were seen; none were attributed to placebo.
Also, epinephrine use was roughly four times more common with Palforzia, and most doses "were administered outside of clinical facilities," FDA staff noted. Another concern they raised was that three patients receiving the product developed eosinophilic esophagitis, which was not seen in placebo patients.
Advisory committee members will be asked to vote on whether the data support a favorable benefit-risk judgment on Palforzia, noting that peanut allergy is a potentially lethal condition. The FDA is not obliged to follow its advisors' recommendations but it usually does.