CUE-221

IgE Therapies and Unmet Need

Immunoglobulin E (IgE) is a clinically validated, therapeutic target. Monoclonal antibodies that target IgE transformed the treatment of IgE-mediated allergic diseases, including CSU and Food Allergy.

CSU is a chronic inflammatory skin disease driven in part by type 2 inflammation, which causes sudden and debilitating hives and recurring itch. CSU is typically treated with H1 antihistamines, medicines that target H1 receptors on cells to control symptoms of itch and urticaria. However, the disease remains uncontrolled despite antihistamine treatment in many patients, some of whom are left with limited alternative treatment options. These individuals continue to experience symptoms that can be debilitating and significantly impact their quality of life.

Despite advances, significant unmet need remains, particularly in diseases characterized by very high IgE levels.

Food allergy illustrates this challenge affecting 33 million Americans with prevalence continuing to rise. The disease imposes a substantial burden on patients and families, with many individuals remaining at risk for severe, potentially life-threatening allergic reactions despite allergen avoidance and available therapies.

A distinguishing feature of food allergy is its high IgE burden, with patients exhibiting markedly elevated baseline IgE levels. This presents a challenge for therapies such as XOLAIR® (omalizumab) which works exclusively by neutralizing circulating IgE alone and is not indicated for use in patients with high IgE levels exceeding 1,850 IU/mL (Xolair USPI). As a result of these guidelines, only about 2/3 of patients can be treated. Among those who can be treated, protection against allergic reactions resulting from accidental exposure is limited to a maximum of up to 2-to-2.5 whole peanuts with similar limitations that apply to protection provided against other food allergens. As a result, there remains an opportunity for therapies that address IgE biology more comprehensively. In addition to neutralizing existing free IgE as with current marketed therapies, suppressing ongoing IgE production could provide deeper and more sustained reductions in IgE, potentially expanding treatment options for patients with the greatest IgE burden and address limitations associated with currently available therapies.

CUE-221 Proposed Mechanism of Action: A Differentiated Approach to Targeting IgE

CUE-221 is a novel anti-IgE antibody engineered with a proposed differentiated dual mechanism of action designed to address both existing IgE and the biology that drives continued IgE production.

Like first-generation anti-IgE therapies, CUE-221 binds to free IgE, preventing its interaction with the high-affinity IgE receptor (FcεRI) on mast cells and basophils (see figure 1 below). This blocks IgE-mediated allergic signaling while facilitating the removal of circulating IgE.

Importantly, CUE-221 was also designed to preserve signaling through the low-affinity IgE receptor, CD23 (FcεRII) (Kuo et al. J Clin Invest. 2022). CD23 serves as part of the body’s natural feedback mechanism for regulating IgE homeostasis, helping limit new IgE production when circulating IgE levels are elevated (see figure 2 below).

By preserving CD23 function while neutralizing free IgE, CUE-221 has the potential to both reduce existing circulating IgE and maintain the body’s natural ability to suppress ongoing IgE production. This differentiated mechanism is designed to potentially achieve deeper and more durable control of IgE biology than approaches based solely on neutralizing circulating IgE.

CUE-221 in the Clinic

CUE-221 announced positive topline results from the Phase 2 clinical trial in chronic spontaneous urticaria (CSU). See our press release for more details.

These findings support continued clinical development of CUE-221 as a drug product candidate for CSU in addition to our plans to enter development into food allergy. Subject to the FDA’s review of the data from the Phase 2 clinical trial of CUE-221 in CSU, we intend to initiate a global Phase 2 trial of CUE-221 in food allergy and a Phase 2b/3 trial in CSU.

CUE-221’s functionally distinct novel dual mechanism of action has the potential to address not only food allergy and CSU, but also other allergic diseases with significant unmet need, including atopic dermatitis, asthma, allergic rhinitis, and anaphylaxis.

Figures 1, 2: “Adapted from Wright et al., “Structural and Physical Basis for Anti-IgE Therapy,” Scientific Reports 5, 11581 (2015). Licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).”