Peanut immunotherapy uses synthetic peptides for safety, durability
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Key takeaways:
- The activation of peanut-sensitized basophils was negligible.
- There were no treatment-related hypersensitivity events.
- Results persisted through 18 months after treatment.
An immunotherapy comprising seven synthetic peptides may provide a safe and durable alternative to immunotherapies based on whole peanuts, according to a study published in Allergy.
This is the first peptide-based immunotherapy designed to improve upon current oral immunotherapies that has been administered to patients with food allergy, Sara Prickett, PhD, cofounder and chief scientific officer of Aravax, and colleagues wrote.
“The key limitations of OIT for peanut allergy are that OIT uses natural extracts from peanuts, which can trigger allergic reactions and drive further allergic inflammation during treatment,” Prickett told Healio.
“OIT, therefore, requires indefinite daily dosing and onerous precautions to manage the short-lived treatment effect and the risk for treatment-induced systemic reactions,” she continued.
The peptides in PVX108 (Aravax) represent four immunodominant CD4+ T-cell epitopes in Ara h 1 and three from Ara h 2.
“PVX108 does not contain the peanut proteins which put patients at risk of serious side effects,” Prickett explained. “Rather, it contains short peptides mimicking key regions from those proteins, which can be used to retrain the immune system to tolerate peanuts but are too small to trigger allergic reactions.”
The researchers expect PVX108 therapy to be safe and convenient to initiate, with monthly rather than daily dosing, along with durable effects.
Study design, safety
The double-blind, placebo-controlled phase 1 study included 67 adults with peanut allergy, with 21 receiving placebo and 46 receiving PVX108, as well as 97 doses total for the cohort. Treatment ran for 21 weeks.
Stage 1 of the study included 49 patients, 31 of whom had experienced previous anaphylaxis and 16 of whom had asthma. During this stage, 33 received between 0.01 nmol and 150 nmol of PVX108, and 16 received placebo.
Treatment rolled out in cohorts of six, including four receiving a single dose of PVX108 and two receiving single doses of placebo.
“For each new cohort, the dose was increased once the previous dose was confirmed to be safe,” Prickett said. “Dosing continued to the maximum feasible dose, 150 nmol, in cohort 8.”
Eight of the members of the treatment group and seven in the placebo group did not have any adverse events. Also, 34 participants in the full cohort reported 68 adverse events, including 57 mild and eight moderate treatment-emergent adverse events.
Further, 31 of these treatment-emergent adverse events in the treatment group and 11 in the placebo group were related to the treatment, the researchers said, including 24 injection-site reactions that were mild (n = 23) or moderate (n = 1).
“There were no adverse events of clinical concern,” Prickett said.
Stage 2, which followed up with 18 participants 18 months after stage 1, included 11 with previous anaphylaxis to peanut and eight with asthma. Thirteen received at least one 150 nmol dose of PVX108, and five received placebo.
“In stage 2, a new cohort received six doses of the highest (150 nmol) PVX108 dose or placebo over 16 weeks,” Prickett said.
All the patients in stage 2 experienced at least one adverse event, with 150 total, including 146 that were treatment-emergent adverse events. There were 120 mild and 24 moderate events as well as two severe events that were not related to treatment.
Specifically, 94 of the treatment-emergent events were related to treatment, including 87 in the treatment group and seven in the placebo group, along with 72 injection-site reactions that were mild in 64 patients or moderate in eight patients.
When the researchers tested PVX108 in the whole blood of 185 adults with peanut allergy and confirmed basophil reactivity, 184 of the samples had no activation. The highest concentration of PVX108 tested, 100 nmol/mL, produced the single, low-level activation that occurred.
Mechanisms of outcomes
Through 18 months, the treatment group experienced a significant increase in the frequency of peanut-reactive regulatory T (Treg) cells in their total CD4+ memory T-cell population, but the placebo group did not. Peanut-reactive effector T helper (Th) cells also had a significant increase in the treatment group but not in the placebo group.
“Repeat PVX108 dosing (stage 2) induced clinically relevant changes in peanut-specific immune cells (T cells), which progressed off treatment, becoming more pronounced at 14 months post-treatment compared to just after dosing,” Prickett said.
Previous studies have found correlations between similar changes and efficacy during peanut OIT, Prickett said. But unlike PVX108, she added, these changes plateaued during OIT and reversed as soon as treatment was stopped. Clinical efficacy reversed as well.
“These results exceeded our expectations, especially after only six doses,” Prickett said. “We believe that longer treatment courses will improve immune modulation and clinical effects.”
Except for the Th2A subset, all the peanut-reactive Th subsets increased in the treatment group, with Th17 cells experiencing the largest and most significant increases. Patterns were similar but consistently less pronounced in the placebo group.
There were changes in the balance of phenotypes within the total peanut-reactive Th population over time in the treatment group but not in the placebo group as well.
In particular, the decreases in the percentage of Th2A, conventional Th2 and Th1 cells as well as the increases in the percentage of Th17 cells in the peanut-reactive Th population were significant in the treatment group but not in the placebo group.
The percentages of cells that expressed ST2 and CRTH2, which are associated with Th2, and CCR6, which is associated with Th17, saw similar changes in this population, the researchers said.
Compared with pretreatment profiles, the researchers characterized the differences between the groups in all these subsets as well as in GARP+ Treg as consistently more distinct at 18 months. However, none of them fell below a P value of .05.
The changes in Th2A and Th17 percentages in peanut-reactive Th cells exhibited the most pronounced differences between the treatment and placebo groups, reaching significance for the Th2A subsets.
Also, ST2+ cells expressed genes related to Th2, and CCR6+ cells expressed genes related to Th17 in addition to FOXP3 and TGFB, which Th17 subsets with regulatory properties express.
These gene expressions remained consistent, the researchers said, indicating that Th17 or Th17/Treg cells increased instead of the expression of CCR6 on T cells of another phenotype.
Gene expression changes in the total peanut-reactive Th cell population indicated a shift between Th2 and Th17 populations, including a gradual decrease in expression related to Th2A and increases in expression related to Th17.
Additionally, there was a combination of genes that were differently expressed at week 21 and/or month 18 in the treatment group in further analysis of the full data set of more than 10,000 genes.
Broadly, these genes clustered into groups that had distinct directional and/or kinetic changes, including genes associated with the differentiation of Th17 or Treg cells.
Neither the treatment group nor the placebo group had any changes in total IgE, peanut-specific IgE, or the ratio of peanut-specific IgG4 and IgE.
The treatment group experienced subtle increases in peanut-specific IgG4 levels through month 18, primarily after week 21, but the placebo group did not. Additionally, there were no consistent changes in wheal sizes in skin prick tests at the group level, although five of nine patients in the treatment group had decreased responses at 18 months.
Conclusions, next steps
Calling PVX108 the first peptide-based immunotherapy administered to patients with food allergies, the researchers touted the treatment’s lack of treatment-related hypersensitivity events as well as its absence of any adverse events of clinical concern.
The researchers further believe that this treatment may overcome long-standing safety and convenience issues associated with conventional allergen immunotherapy.
“Phase 2 studies are now underway to evaluate proposed therapeutic regimens in children with peanut allergy,” Prickett said.
This trial will evaluate the safety and efficacy of 12 doses of PVX108 administered over 44 weeks. It will be conducted in Australia and the United States as an investigational new drug.
“Enrollment of the first cohort of adolescents aged 12 to 17 is complete, and recruitment of children aged 4 to 11 (n = 66) is now underway,” Prickett said. “Topline results are anticipated in early 2026. Details can be found on Aravax’s website.”
For more information:
Sara Prickett, PhD, can be reached at sara.prickett@aravax.com.au.