CUE-221 Hits Primary and Key Secondary Endpoints in Phase 2 Chronic Spontaneous Urticaria Trial
核心洞察
Cue Biopharma reported positive topline Phase 2 results for CUE-221 (搜索) in 145 patients with moderate to severe chronic spontaneous urticaria (搜索) uncontrolled by H1 antihistamines.
The primary endpoint of complete hive resolution at week 12 was dose-responsive and met at all three dose levels, with p-values below 0.005 at 4 mg/kg and 2 mg/kg versus placebo.
Complete response on UAS7 was statistically significant at the 4 mg/kg dose, and benefit persisted 12 weeks off treatment with a 36% advantage over omalizumab in post hoc analysis.
Cue Biopharma reported positive topline results from a Phase 2 trial of CUE-221 (搜索) (UB-221) in moderate to severe chronic spontaneous urticaria (搜索) (CSU), with the primary endpoint and a key secondary endpoint both met and a safety profile the company described as favorable. The multicenter, randomized, double-blind, placebo and active comparator-controlled study was conducted in China by Genesis Life Sciences (搜索), a related company of Ascendant Health Limited (搜索), and enrolled 145 participants whose disease remained inadequately controlled despite treatment with H1 antihistamines.
The trial randomized patients in a 2:2:2:1:1 ratio across five groups to subcutaneous CUE-221 (搜索) at 4 mg/kg, 2 mg/kg or 1 mg/kg every four weeks, placebo every four weeks, or omalizumab 300 mg every four weeks. It included a 16-week treatment period and a 20-week post-treatment follow-up. The primary endpoint was the proportion of patients achieving HSS7=0 at week 12, and a key secondary endpoint assessed complete response, defined as the proportion achieving UAS7=0 at week 12. The study was designed to test superiority over placebo, and omalizumab was included to enable comparative efficacy without planned statistical testing.
Dose-Responsive Hive Clearance at Week 12
Complete resolution of hives at week 12 occurred in 54% of patients at 4 mg/kg (N=35), 53% at 2 mg/kg (N=36) and 43% at 1 mg/kg (N=37), compared with 11% on placebo (N=18) and 41% on omalizumab 300 mg (N=17). The primary endpoint was dose-responsive and met at all dose levels, with p-values versus placebo of p < 0.005 at 4 mg/kg and 2 mg/kg and p < 0.05 at 1 mg/kg. P-values were based on Fisher's exact test with Clopper-Pearson 95% confidence intervals.
On the key secondary endpoint of complete response (UAS7=0) at week 12, rates were 46% at 4 mg/kg, 39% at 2 mg/kg and 38% at 1 mg/kg, versus 11% for placebo and 29% for omalizumab. The endpoint was dose-responsive and reached statistical significance at the 4 mg/kg dose (p < 0.05).
Benefit Persists After Dosing Stops
The percentage of participants achieving HSS7=0 continued to rise beyond the week 12 primary endpoint, peaking at week 22 across all CUE-221 (搜索) dose groups at 69% (4 mg/kg), 61% (2 mg/kg) and 57% (1 mg/kg), against 11% for placebo and 41% for omalizumab. After the last dose was administered to all groups at week 16, clinically meaningful benefit was maintained for up to 12 weeks off treatment through week 28 at the 4 mg/kg dose level, where 60% of patients had complete hive resolution versus 31% at 2 mg/kg, 24% at 1 mg/kg, 11% for placebo and 24% for omalizumab.
A post hoc analysis at week 28 showed a statistically significant difference versus omalizumab (delta = 36%, p < 0.05), which the company said supports the premise of a fundamental difference between CUE-221 (搜索) and omalizumab in their impact on disease biology. Demographics and baseline disease characteristics were generally well balanced across treatment groups.
Safety Profile and Mechanism
CUE-221 (搜索) demonstrated a favorable safety profile, with no treatment-related serious adverse events and no cases of hypersensitivity reactions including anaphylaxis. Injection site reactions were infrequent, only one was greater than grade 1, and none led to study discontinuation.
CUE-221 (搜索) is a humanized anti-IgE (搜索) IgG1 monoclonal antibody engineered with a dual mechanism of action. It binds IgE at sites distinct from the binding sites of other anti-IgE monoclonal antibodies, which preserves the capacity of total IgE to bind the CD23 (搜索) receptor on the surface of B cells and results in reduced IgE synthesis. The design is intended both to neutralize free IgE with high potency and to prevent the synthesis of new IgE.
"The results of the Phase 2 CUE-221 (搜索) study in patients with CSU are particularly notable," said Dale Umetsu, M.D., Ph.D., Clinical Professor of Medicine and former Chief of the Allergy and Immunology Division at Stanford University, Clinical Professor of Pediatrics at the University of California, San Francisco, and prior Global Lead for XOLAIR development. "First, the results after 12 weeks of treatment, after three doses, appear to indicate that CUE-221 was better than XOLAIR for CSU at all dose levels tested. Moreover, there was persistent improvement with the 4 mg/kg dose at week 28, which was 12 weeks off treatment, significantly better than that off of standard XOLAIR dosing."
Dr. Umetsu added that CUE-221 (搜索), like XOLAIR, is designed to prevent IgE (搜索) from binding to FceR1 (搜索) but unlike XOLAIR allows IgE to bind to CD23 (搜索), and that the effects on IgE function could result in efficacy in CSU that persists for several months after dosing ends. He noted the improvement may be directly relevant for food allergy (搜索), another area where XOLAIR is the standard of care.
"I am very pleased to see these outstanding results from the UB-221 Phase 2 CSU trial," said Tse-Wen Chang, Ph.D., innovator of XOLAIR as well as UB-221 and an international expert in IgE (搜索) biology. "The UB-221 data provide clear clinical evidence validating the molecule's design to not only directly neutralize IgE, but also to create a next-generation approach to eliminate the production of new IgE over time. This fundamental difference in biological mechanism that is now clinically evident cannot be reached by giving higher doses or more potent IgE neutralization."
Development Plans and Licensing Structure
Shao-Lee Lin, M.D., Ph.D., President and Chief Executive Officer of Cue Biopharma, said the company believes the results establish CUE-221 (搜索) as a potential best therapeutic option for patients with CSU and that it is working toward rapid initiation of a Phase 2b/3 study in CSU while continuing to advance a planned Phase 2 study in food allergy (搜索). Cue Biopharma expects to present the complete data set, including pharmacokinetic and IgE (搜索) analyses from the 36-week study, at an upcoming scientific meeting.
CUE-221 (搜索) (Ascendant-221, UB-221) was innovated by Dr. Chang while serving as a Fellow of Academia Sinica and was originally developed by United Biopharma (Holdings) Co., Ltd., with rights allocated between two related companies: Genesis Life Sciences (搜索), which holds rights in China, Hong Kong, Macau and Taiwan and continues development under the name UB-221, and Ascendant Health Limited (搜索), which holds rights for the rest of the world. Under an exclusive license agreement with Ascendant, Cue Biopharma obtained exclusive development, manufacturing and commercialization rights in Ascendant's rest of world territories.
CSU is a chronic inflammatory skin disease driven in part by type 2 inflammation that causes sudden and debilitating hives and recurring itch. It is typically treated with H1 antihistamines, which target H1 receptors on cells to control itch and urticaria, but the disease remains uncontrolled in many patients despite this treatment, leaving some with limited alternative options and symptoms that can significantly affect quality of life.