Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy

Abstract

BACKGROUNDIL-33, found in high levels in participants with allergic disorders, is thought to mediate allergic reactions. Etokimab, an anti-IL-33 biologic, has previously demonstrated a good safety profile and favorable pharmacodynamic properties in many clinical studies.METHODSIn this 6-week placebo-controlled phase 2a study, we evaluated the safety and the ability of a single dose of etokimab to desensitize peanut-allergic adults. Participants received either etokimab (n = 15) or blinded placebo (n = 5). Clinical tests included oral food challenges and skin prick tests at days 15 and 45. Blood samples were collected for IgE levels and measurement of ex vivo peanut-stimulated T cell cytokine production.RESULTSEfficacy measurements for active vs. placebo participants at the day 15 and 45 food challenge (tolerating a cumulative 275 mg of peanut protein, which was the food challenge outcome defined in this paper) demonstrated, respectively, 73% vs. 0% (P = 0.008) to 57% vs. 0% (ns). The etokimab group had fewer adverse events compared with placebo. IL-4, IL-5, IL-9, IL-13, and ST2 levels in CD4+ T cells were reduced in the active vs. placebo arm upon peanut-induced T cell activation (P = 0.036 for IL-13 and IL-9 at day 15), and peanut-specific IgE was reduced in active vs. placebo (P = 0.014 at day 15).CONCLUSIONThe phase 2a results suggest etokimab is safe and well tolerated and that a single dose of etokimab could have the potential to desensitize peanut-allergic participants and possibly reduce atopy-related adverse events.TRIAL REGISTRATIONClinicalTrials.gov NCT02920021.FUNDINGThis work was supported by NIH grant R01AI140134, AnaptysBio, the Hartman Vaccine Fund, and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University.

Keywords: Allergy; Clinical Trials; Immunology.

Conflict of interest statement

Conflict of interest: KN receives grant support from NIAID, Food Allergy Research & Education (FARE), End Allergies Together, Allergenis, and Ukko Pharma; personal fees from Regeneron, AstraZeneca, ImmuneWorks, and Cour Pharmaceuticals; research sponsorsip from Novartis, Sanofi, Astellas, and Nestle; and research sponsorship for clinical trials from Genentech, Aimmune Therapeutics, DBV Technologies, AnaptysBio, Stallergenes-Greer, Regeneron, and Adare Pharmaceuticals. She is a data and Safety Monitoring Board member at Novartis and NHLBI; she cofounded Before Brands, Alladapt Immunotherapeutics, and ForTra; and she is a director for FARE and World Allergy Organization (WAO) Center of Excellence. SC receives grant support from CoFAR NIAID, Aimmune, DBV Technologies, Astellas, AnaptysBio, Novartis, Regeneron, Stallergenes-Greer, and Boehringer Ingelheim and is a scientific advisory board member for Alladapt Immunotherapeutics. ML is currently an employee at AnaptysBio. DP was an investigator for the study and received funds from AnaptysBio.

Figures

Figure 1. Participant enrollment consort diagram.

EKG, electrocardiogram; SPT; skin prick tests. Asterisk indicates completed OFC.

Figure 2. Study Design.

OFC, oral food challenges; PK, pharmacokinetics; WBC, white blood cell count.

Figure 3. Oral food challenges.

(A) Number of participants who passed the standardized OFC to cumulative 275 mg peanut protein. (B) Number of participants who passed the standardized OFC to cumulative 375 mg peanut protein. (C) Participant-level spaghetti plot of CTD from baseline to day 45 for the active group. Fisher’s exact test was used to compare the proportion of participants who passed food challenge between groups at each time point. The Wilcoxon matched-paired signed rank test was used to compare the CTD between baseline and day 15. **P ≤ 0.01.

Figure 4. IgE and skin prick tests.

Measurements of (A) peanut-specific IgE, (B) total IgE, (C) peanut skin prick test wheal sizes, and (D) histamine skin test wheal sizes for placebo (blue) and active (red) groups at each time point. Solid circles indicate subjects who passed food challenge on day 15 and day 45. All participants in the placebo group failed food challenge. The Mann-Whitney U test was performed to compare the measurements between placebo and active groups at each time point. Mean ± SD is presented. *P ≤ 0.05.

Figure 5. IL-4 and IL-5.

Measurements of (A) IL-4+ cells of total CD4+ T cells, (B) IL-4+ of peanut-specific CD4+ T cells, (C) IL-5+ cells of total CD4+ T cells, and (D) IL-5 of peanut-specific CD4+ T cells. Solid circles indicate subjects who passed food challenge on day 15 and day 45. All participants in the placebo group failed food challenge. The Mann-Whitney U test was performed to compare the measurements between placebo and active groups at each time point. Mean ± SD is presented. *P ≤ 0.05, **P ≤ 0.01.

Figure 6. IL-9, IL-13, and ST2.

Measurements of (A) IL-9+ cells of total CD4+ T cells, (B) IL-9+ of peanut-specific CD4+ T cells, (C) IL-13+ cells of total CD4+ T cells, (D) IL-13+ of peanut-specific CD4+ T cells, (E) ST2+ cells of CD4+ T cells, and (F) ST2+ of peanut-specific CD4+ T cells for placebo (blue) and active (red) groups at each time point. Solid circles indicate subjects who passed food challenge on day 15 and day 45. All participants in the placebo group failed food challenge. The Mann-Whitney U test was performed to compare the measurements between placebo and active groups at each time point. Mean ± SD is presented. *P ≤ 0.05, **P ≤ 0.01.

Figure 7. CD4+ T cells.

Measurements of (A) CD4+ T cell out of total CD3+ cells and (B) peanut-specific CD4+ T cells for placebo (blue) and active (red) groups at each time point. Solid circles indicate subjects who passed food challenge on day 15 and day 45. All patients in the placebo group failed food challenge. The Mann-Whitney U test was performed to compare the measurements between placebo and active groups at each time point. Mean ± SD is presented.

Figure 8. Individual, median, and mean plot of sST2.

No change in sST2 was observed from baseline through day 15. There was also no statistical difference between the placebo and active groups at any of the time points. Solid circles indicate subjects who passed food challenge on day 15 and day 45.

Figure 9. Individual, median, and mean plot of basophil/leukocyte counts.

No change in basophils were observed from baseline through day 15. There was also no statistical difference between the placebo and active groups at any of the time points. Mean and median are presented. Solid circles indicate subjects who passed food challenge on day 15 and day 45.

Figure 10. Cmax and tmax.

Linear regression between (A) Cmax and total IgE, (B) tmax and total IgE, (C) Cmax and IL-13 level of total CD4+ T cells, (D) tmax and IL-13 level of total CD4+ T cells, (E) Cmax and CTD, and (F) tmax and CTD. There was no significant association between the measurements and Cmax or tmax. Open circles indicate subjects who failed food challenge on day 15; solid circles indicate subjects who passed food challenge on day 15.