On February 20th, Aimmune Therapeutics released topline data from its pivotal Phase III PALISADE trial assessing the efficacy and safety of its oral immunotherapy drug, AR-101, for the treatment of peanut allergy in patients ages four to 17 years. Similar to the Phase II trial for AR-101, PALISADE far surpassed its primary and secondary efficacy endpoints. In comparison to placebo, 81% of patients who completed the 12-month AR-101 treatment protocol (N = 296) were able to tolerate a 600mg dose of peanut protein (equivalent to about two peanuts) during the exit food challenge. Though efficacy was definitely stellar, the patient discontinuation rate was high: 20.4% (N = 76) of AR-101 patients dropped out of the study before treatment was complete—12.4% were related to adverse events. For investors, these safety data are likely made all the more worrying by news of DBV Technologies’ positive pre-Biologics License Application (BLA) meeting with the FDA. DBV’s epicutaneous immunotherapy (skin patch) for peanut allergy, Viaskin Peanut, may be less effective than AR-101, but is notably safer. GlobalData believes that improving the side effect profile of AR-101 will ensure its long-term success and posits that the company is well on its way to addressing the issue.
Immunotherapy protocols involve direct, controlled exposure of a patient to proteins that cause allergic inflammation. Because of this, treatment emergent adverse events are typically expected. In both Aimmune’s PALISADE trial and DBV’s Phase III PEPITES trial, treatment emergent adverse events affected over 95% of patients. However, while the majority of reactions to Viaskin Peanut were local to the site of patch administration, reactions to AR-101 included more intolerable GI symptoms and systemic hypersensitivity reactions. This is likely why dropout due to adverse events in the PEPITES trial was only 1.1%—ten times less than that in the PALISADE trial.
In order to compete with DBV’s Viaskin Peanut, it is clear that Aimmune needs to focus on improving patient safety and comfort. Though there is certainly room to grow, Aimmune has already begun to make significant strides toward that goal. Firstly, Aimmune needs to develop biomarkers or clinical guidelines that help identify patients likely to respond poorly to oral immunotherapy. In a conference call with investors, Aimmune described their plan to dig through the enormous PALISADE database to hopefully pinpoint longitudinal biomarkers that could be used to predict patients best suited for the therapy. Aimmune is taking the biomarker search a step further through a sub-study within their European Phase III ARTEMIS trial that seeks to correlate patients’ longitudinal salivary transcriptomes with select clinical variables, including the frequency and severity of adverse events involving the GI tract.
In addition to more careful selection of patients for treatment with AR-101, Aimmune needs to add flexibility to its dosing protocol in order to accommodate patients struggling with adverse events. Efforts to do this in the PALISADE trial (allowing patients to postpone up-dosing or return to a lower dose of peanut protein) may have contributed to decreased patient dropout compared to the Phase II ARC001 trial (12.4% vs. 21%). In its conference call with investors, Aimmune stressed the importance of building in this flexibility as the therapy goes forward, remarking that the suggested protocol for AR-101 should be viewed as a “speed limit,” not a required rate. Finally, Aimmune also needs to explore adjunctive therapies that will help to mitigate the severity of side effects. Aimmune is beginning to explore this strategy through a collaborative study with Sanofi/Regeneron exploring a treatment protocol combining AR-101 oral immunotherapy with the anti-IL4RA antagonist drug Dupixent (dupilumab). This trial is expected to begin at the end of 2018.