Etokimab, previously known as ANB020, is an antibody that inhibits the activity of IL-33, a pro-inflammatory cytokine that multiple studies have indicated is a central mediator of atopic diseases, including atopic dermatitis, food allergies and asthma. IL-33 directly mediates release of disease-associated downstream cytokines, which recruit pro-inflammatory cells that mediate atopic disease. Because etokimab inhibits IL-33 function, and acts upstream broadly across the key cell types and cytokines involved in atopy, we believe that its mechanism has advantages in the treatment of atopic diseases over competing agents that block only a subset of the downstream cytokines responsible for atopic diseases. The role of IL-33 signaling in asthma has been recently genetically validated through human studies published in the medical literature.
A single and multiple ascending dose Phase 1 trial of etokimab in healthy volunteers reported a favorable safety profile and pharmacodynamic properties of etokimab, where a single dose was sufficient to suppress IL-33 function for 85 days post-dosing as measured by an ex vivo pharmacodynamic assay. We presented these results at the 2017 American Academy of Dermatology Annual Meeting and the American Academy of Allergy, Asthma and Immunology 2017 Annual Meeting in March 2017, (click here to download).
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We have subsequently completed a Phase 2a trial where a single dose of etokimab was administered to 12 moderate-to-severe adult atopic dermatitis patients that were inadequately controlled with topical corticosteroids. Each patient was dosed with placebo 14 days following enrollment, and subsequently administered a single 300mg intravenous dose of etokimab one week after placebo.
Etokimab was efficacious in all 12 patients enrolled in this Phase 2a trial with each patient achieving 50% or better improvement in their Eczema Area Severity Index (EASI) relative to enrollment baseline (EASI-50) on or before day 57 post-etokimab administration. Rapid clinical response was observed by day 15 post-etokimab administration with nine of 12 patients (75%) achieving EASI-50, of which three patients (25%) also achieved EASI score improvement of 75% relative to baseline (EASI-75). Day 29 results exceeded the primary efficacy objective of the trial with 10 of 12 patients (83%) achieving EASI-50, of which four patients (33%) also achieved EASI-75. Efficacy was sustained through day 140 following single dose administration of etokimab with five of 12 patients (42%) achieving EASI-50, of which three patients (25%) also achieved EASI-75. ANB020 efficacy was not limited by disease severity as etokimab was similarly efficacious in the seven of 12 enrolled patients treated with systemic immuno-modulators pre-study, which exhibited an average EASI baseline score of 36 upon enrollment, relative to the remaining five of 12 enrolled patients that did not require systemic immuno-modulators pre-study and exhibited an average EASI baseline score of 27. The average baseline EASI score upon enrollment across all 12 patients was 32. Investigator’s Global Assessment (IGA) scores of zero or 1 (clear/almost clear skin) were observed in three of 12 patients (25%). Other atopic dermatitis efficacy endpoints, including the SCORing Atopic Dermatitis (SCORAD) scale, Dermatology Life Quality Index (DLQI) and the 5-dimensional pruritus scale, demonstrated rapid and sustained single dose etokimab efficacy results in a similar manner to the aforementioned EASI results.
We also observed that clinical efficacy was consistent with certain biomarkers tested in this Phase 2a trial. Circulating blood eosinophil levels were reduced by a maximum of 40% at Day 29 post-etokimab administration relative to baseline, which is aligned with genotypic studies that associate lower eosinophil counts with human IL-33 loss-of-function mutations (see scientific publications page). In addition, clinical efficacy in this Phase 2a trial was consistent with an ex vivo pharmacodynamic assay measuring IL-33 mediated interferon-gamma release, where 98% inhibition was observed within 72 hours following etokimab administration and 86% inhibition was sustained at day 57 post-etokimab administration, which is consistent with the pharmacodynamic activity observed using the same assay in our prior Phase 1 trial of etokimab in healthy volunteers.
Etokimab was generally well-tolerated by all patients and no drug-related safety signals were observed. The most frequent adverse events reported were dizziness in 17% of patients post-placebo and headache in 25% of patients post-etokimab administration. A single serious adverse event of depression was reported on Day 140 post-etokimab administration, which was consistent with the patient’s pre-trial history of depression and was deemed not drug-related. We presented these results at the 2018 American Academy of Dermatology Annual Meeting on February 17th 2018 and the European Academy of Allergy and Clinical Immunology Congress on May 29th 2018, (click here to download).
As further development in atopic dermatitis, we are enrolling a Phase 2b randomized, double-blinded, placebo-controlled, multi-dose study in 300 adult patients with moderate-to-severe atopic dermatitis, also referred to as the ATLAS clinical trial, to assess different dose levels and dosing frequencies of subcutaneously-administered etokimab for a 16-week treatment period followed by an eight-week follow-up period, with data expected in the second half of 2019. Sixty patients are being randomized into each of the five arms in the ATLAS trial where dosing will occur as follows: (i) initial 600mg loading dose followed by 300mg monthly doses of etokimab, (ii) initial 300mg loading dose followed by 150mg monthly doses of etokimab, (iii) initial 300mg loading dose followed by 150mg doses of etokimab every eight weeks, (iv) monthly 20mg doses of etokimab and (v) monthly doses of placebo.
Based on our analysis of publicly available data sources and interviews with physicians and key opinion leaders in the field of atopic dermatitis, we estimate approximately 1.4 million adults in the United States are affected by atopic dermatitis, of which approximately 280,000 are diagnosed with a moderate-to-severe form of this disease.
In September 2018, we announced positive proof-of-concept topline data from an interim analysis of our ongoing Phase 2a trial of etokimab in severe adult eosinophilic asthma patients.
This Phase 2a proof-of-concept trial enrolled 25 adult eosinophilic asthma patients, who were randomized between a single 300mg intravenous dose of etokimab or placebo upon enrollment (Day 1) at six sites located in the United States and the United Kingdom. Upon screening, which occurred seven to 14 days prior to enrollment, patients were required to have a blood eosinophil count of at least 300 per microliter, confirmed clinical diagnosis of severe asthma according to the Global Initiative for Asthma (GINA) 2016, pre-bronchodilator FEV1 of less than 80 percent of predicted and at least one asthma exacerbation within the past 12 months requiring use of rescue medication. Patients were required to be stably maintained on high-dose inhaled corticosteroids (ICS) and long-acting beta-2-agonists (LABA) for at least three months prior to screening and were required to continue ICS/LABA therapy during the course of this trial. Baseline clinical assessments were conducted for each patient on Day 1 prior to etokimab or placebo dose, and patients completed follow-up clinical assessments on Days 2, 8, 22, 36 and 64 as of this interim analysis. The last follow-up visit for each patient will occur on Day 127 post-dose.
Patients administered with etokimab demonstrated rapid and sustained improvement of their Forced Exhaled Volume In One Second (FEV1), which is a measure of lung function. FEV1 rapidly improved in etokimab-administered patients to 8 percent over placebo at Day 2, and was sustained at 11 percent increase over placebo at Day 64. Blood eosinophil reduction, which is a biomarker illustrative of etokimab’s mechanistic breadth, was observed at 31 percent over placebo at Day 2 and sustained to 46 percent over placebo at Day 64. This reduction correlated with FEV1 improvement and was consistent with the blood eosinophil effects observed in our prior single dose etokimab Phase 2a trial in moderate-to-severe atopic dermatitis patients. Etokimab was generally well-tolerated by all patients and no serious adverse events have been reported to date. No treatment-emergent adverse events were deemed to be etokimab-related, and the most frequent treatment-emergent adverse events reported were single occurrences of moderate strep throat in two etokimab-dosed patients and single occurrences of mild vomiting in two placebo-dosed patients. No exacerbations or rescue therapy usage has been reported as of the interim analysis.
This Phase 2a trial is currently ongoing and the company plans to report full data from this trial at a medical conference in 2019 following trial completion. AnaptysBio plans to continue development of etokimab in eosinophilic asthma with a multi-dose Phase 2b randomized, double-blinded, placebo-controlled trial, which is expected to be initiated in 2019.
We estimate, based on our analysis of publicly available data sources and interviews with physicians and key opinion leaders focused on asthma, that asthma affects approximately 19.0 million individuals, of which approximately 1.1 million have severe disease that cannot be controlled by standard-of-care therapy.
Chronic Rhinosinusitis With Nasal Polyps
We have expanded development of etokimab into adult chronic rhinosinusitis with nasal polyps (CRSwNP), which is a debilitating atopic disorder associated with elevated IL-33 pathway signaling (see scientific publications page), affecting approximately 1.3 million adults in the U.S., and AnaptysBio estimates approximately 400,000 of these patients are inadequately controlled with standard-of-care.
We intend to initiate a randomized, placebo-controlled Phase 2 trial, also referred to as the ECLIPSE trial, in approximately 100 adult CRSwNP patients treated with two different multi-dosing frequencies of subcutaneously-administered etokimab or placebo, each in combination with mometasone furoate nasal spray as background therapy, for a treatment period of 16 weeks followed by an eight-week follow-up period. We plan to initiate the ECLIPSE trial by the end of 2018, and anticipates top-line data will be available in the second half of 2019.