How CUE-221’s Phase 2 Results In CSU Could Translate To Food Allergy

Disclosure: The author holds a beneficial long position in Cue Biopharma (NASDAQ: CUE) and no position in any other company mentioned. This article is for informational and educational purposes only and is not financial advice. Although the author is a physician, this content is commentary on the underlying science and does not constitute medical advice, diagnosis, or treatment recommendation. The author receives no compensation for this article and has no business relationship with the companies mentioned. Biotech investing is extremely risky and can quickly lead to a total loss of principal. See the full Legal Information and Disclosures section below.

Countless feedback loops maintain homeostasis in living organisms, so it shouldn't surprise that IgE regulates its own synthesis, partly via CD23. Omalizumab blocks IgE binding to CD23 and may thereby interrupt this negative feedback, while CUE-221 is designed to bind IgE at a site distant from where IgE interacts with CD23, so CUE-221-IgE complexes might still engage CD23. However, so far only lab measurements reported by Kuo et al. in 2022 support this "dual mechanism" of the anti-IgE antibody CUE-221. No clinical measurement of total IgE, free plus complexed, that could provide direct evidence for the mechanism appears to have been published.

Kuo et al. proposed the CD23 mechanism on the basis of data showing that UB-221, as CUE-221 was then called, binds CD23-bound IgE and that UB-221-IgE complexes bind CD23, and of one functional assay, IgE synthesis in peripheral blood mononuclear cells stimulated with IL-4 and an anti-CD40 antibody, which UB-221 suppressed more than omalizumab did.

On September 20, Cue Biopharma reported topline results from the phase 2 trial of CUE-221 in chronic spontaneous urticaria (CSU), which an affiliate of Cue's licensor Ascendant Health ran in China with 145 patients. Cue's main target for CUE-221, however, is food allergy, which it calls its "global beachhead indication."

Cue has submitted an IND and intends to start a phase 2 in food allergy, subject to the FDA's review of the sufficiency of the CSU data. The phase 2 in CSU is so far the only randomized comparison of CUE-221 with omalizumab, which the FDA already approved in food allergy in February 2024. Until IgE data are presented, we have little more than these phase 2 results in CSU as a proxy for how CUE-221 performs in an IgE-driven condition. It should be clear though that the informative value of translating efficacy in CSU to food allergy is inherently limited.

In August I had argued that the IgE levels from this trial would be the part worth reading for assessing CUE-221's potential in food allergy. I doubted that CUE-221 would beat omalizumab in CSU, which appears to have been a bit too pessimistic. All three doses met the primary endpoint, with 54, 53 and 43 percent of patients hives-free (HSS7=0) at week 12 on 4, 2 and 1 mg/kg every four weeks, against 11 percent on placebo and 41 percent on omalizumab 300 mg. The omalizumab arm of 17 patients was included, in the words of the release, "to enable comparative efficacy without planned statistical testing," whatever that intention means.

In principle these are encouraging results for a phase 2. The release reports no treatment-related serious adverse events and no hypersensitivity reactions at any dose, with a single injection site reaction above grade 1. Cue's investor presentation calls them the first clinical evidence supportive of CUE-221's proposed dual mechanism. The release also quotes Tse-Wen Chang, who developed the anti-IgE approach behind omalizumab at Tanox and later UB-221 at Academia Sinica. In his words, the results are "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."

One possible reason why no IgE data from the phase 2 have been released yet is that the samples may be analyzed in one batch after the trial has ended, so the measurements might simply not be complete. Nevertheless, it is a red flag in my view when the very data a narrative is built on are delayed. Cue plans to present the IgE and pharmacokinetic data at an upcoming scientific meeting. Without IgE data, hives severity and activity scores may not separate tighter IgE binding from an effect of the proposed CD23 mechanism, since both could lower free IgE, which tracked symptom relief in the earlier phase 1.

At week 12 the 1 mg/kg arm "matched" omalizumab, with 43 against 41 percent hives-free and a mean UAS7 reduction of 22 against 23 points. The mean body weight in this arm was 69.5 kg, so the mean dose should be on the order of 70 mg of CUE-221, roughly a quarter of the 300 mg of omalizumab given per dose in the trial. CUE-221 is a humanized IgG1 antibody, as is omalizumab, so a quarter of the mass should translate to roughly a quarter of the molecules. This "match" in clinical effect between 1 mg/kg CUE-221 and omalizumab 300 mg comes, however, from small arms of 37 and 17 patients. The CUE-221 dose that "matches" omalizumab could therefore be lower or higher than 1 mg/kg.

Kuo et al., who described UB-221 (CUE-221) in 2022, measured pure IgE neutralization of UB-221, in serum without any cells, so this result reflects binding to IgE alone. In atopic dermatitis sera with lower IgE levels, omalizumab needed 4.3 μg/mL to neutralize 90 percent of IgE, against 1.1 μg/mL for UB-221. Surface plasmon resonance showed the same roughly fourfold difference in affinity, with a KD of 59 pM for UB-221 against 230 pM for omalizumab.

The clinical data thus suggest that CUE-221 has the same effect in CSU as omalizumab at roughly a fourth of the dose, which matches the binding potency and fits the affinity for IgE Kuo et al. measured in vitro. But is there any signal for the CD23 mechanism at work in the phase 2 results?

The only potential signal for the CD23 mechanism comes from the 4 mg/kg cohort. Hive resolution in all three CUE-221 arms peaked at week 22, six weeks after the last dose, at 69, 61 and 57 percent, while omalizumab had already fallen from 53 percent at week 16 to 41 percent. With dosing every four weeks, this peak may still reflect antibody in circulation rather than protection off drug. At week 28, twelve weeks after the last dose, 60 percent of patients on 4 mg/kg were still hives-free against 24 percent on omalizumab. Since no statistical testing against the omalizumab arm had been planned, this is a post hoc comparison, which the company reports as significant (Fisher’s exact test, p<0.05). The 2 and 1 mg/kg arms had fallen to 31 and 24 percent by week 28.

Cue reads this difference in durability against omalizumab, which works through IgE binding alone, as clinical evidence for the “dual mechanism”, and the CD23 mechanism would indeed predict longer protection off drug. If less new IgE is produced while the antibody is present, free IgE should return more slowly after the antibody has been cleared, and symptoms with it.

If the IgE binding of 1 mg/kg CUE-221 “matches” that of omalizumab 300 mg, however, as the week 12 results suggest, it should be no surprise that four times that dose has a longer-lasting effect. Complete responses in omalizumab’s registration trials in CSU were dose dependent and rose from 11.7 and 15.9 percent on 75 mg to 35.8 and 44.3 percent on 300 mg. With dose-proportional exposure, an antibody that works through IgE binding alone, dosed at 4 mg/kg, should stay above any given serum concentration for roughly two half-lives longer than at 1 mg/kg, the dose whose clinical effect matched omalizumab. This is 32 to 44 days at the 16- to 22-day half-life reported in the phase 1.

Notably, that half-life was measured in the phase 1 after single intravenous doses and could be longer after repeated subcutaneous dosing as in the phase 2. The 1 mg/kg arm lost its effect between week 22 and week 28, falling from 57 to 24 percent hives-free. An antibody that works through IgE binding alone would therefore be expected to lose its effect at 4 mg/kg 32 to 44 days later, that is between about week 27 and week 34. After the last dose, the delay of 32 to 44 days, about five to six weeks, should show at every point of the two curves and not only when the effect is lost. At any week off drug, the 4 mg/kg arm should look like the 1 mg/kg arm looked five to six weeks earlier. At week 22, six weeks after the last dose, 57 percent of patients on 1 mg/kg were hives-free. At week 28, six weeks later, 60 percent of patients on 4 mg/kg were hives-free, as this delay predicts. The 4 mg/kg arm then fell from 60 percent hives-free at week 28 to 46 percent at week 30 and 26 percent at week 36. This decline began inside the predicted window of week 27 to week 34.

Omalizumab reaches its maximum free IgE suppression three days after the first dose, but in its registration trials the median time to a complete response on 300 mg was 12 to 13 weeks. Complete responses thus lag far behind free IgE, which may be because the clinical effect depends on slower steps downstream of IgE binding, such as the fall in FcεRI-positive cells in the skin that went along with the plateau of clinical improvement. If the step from free IgE to symptoms takes weeks after the first dose, the reverse may also take weeks after the last one. A response that deepens or holds for weeks after the last injection may therefore follow from the kinetics of the response itself rather than from a second mechanism of CUE-221.

The phase 2 follow-up ended at week 36 and the window is wide, so the topline cannot show or exclude a (modest) CD23 contribution. Suppressed IgE synthesis might still contribute within the window, as might deeper FcεRI downregulation, spontaneous remission, with the placebo arm at 6 to 17 percent hives-free through the follow-up, or chance in this rather small trial with 35 patients on 4 mg/kg and 17 on omalizumab. The week 28 result might therefore be at most a weak signal for a CD23 mechanism at work. Only IgE measured against drug levels in the data Cue plans to present could shed light on this.

In a series of 113 patients, non-responders to omalizumab had lower total IgE at baseline than partial or complete responders. The patients whose IgE should have been easiest to neutralize thus did worst, which a disease model purely based on stoichiometric IgE neutralization would not predict. Low total IgE has, however, been linked to type IIb autoimmune CSU, in which IgG autoantibodies against IgE or FcεRI activate mast cells. Baseline IgE levels from the phase 2 have not been reported yet. Until they are, it cannot be told whether the omalizumab arm of 17 patients contained more of the low-IgE patients who respond poorly to omalizumab than the CUE-221 arms did.

Free IgE has a serum half-life of about two days, while omalizumab-IgE complexes clear more slowly. In omalizumab's CSU registration trials, as summarized in the Australian product information, average predose total IgE at week 12 was two- to threefold higher than before treatment. Binding alone should raise total IgE on CUE-221 as well. A smaller rise in total IgE than on omalizumab could therefore be a signal for the CD23 mechanism, pointing to suppressed IgE synthesis or to the CD23-mediated clearance of CUE-221-IgE complexes that Kuo et al. proposed but did not test.

Kuo et al. expected any CD23-mediated downregulation of IgE to become apparent only under repeat dosing over a long period. One reason may be that long-lived CD23-negative plasma cells that already secrete IgE may continue to do so for some time. After sixteen weeks of dosing, a clear difference in total IgE may therefore be unlikely even if the CD23 mechanism works as proposed. For this reason I would not completely dismiss the CD23 mechanism on the basis of the phase 2 results, even if the IgE data show no clear trend.

In food allergy, omalizumab is dosed by serum total IgE and body weight, at 75 to 600 mg every two or four weeks, while in CSU dosing does not depend on IgE or body weight. At the top dose of 600 mg, each administration takes two 2 mL injections from prefilled syringes, or four injections from vials. Patients with a baseline IgE above 1,850 IU/mL fall outside the label's dosing table. In OUtMATCH, which enrolled mostly children, 66.9 percent of participants on omalizumab tolerated at least 600 mg of peanut protein against 6.8 percent on placebo after 16 to 20 weeks, so about a third of them did not tolerate this dose of peanut protein under therapy.

Even without clear evidence for the CD23 mechanism, CUE-221 might have a case in food allergy if it binds IgE about fourfold more potently than omalizumab, as the dose comparison in CSU and the measurements by Kuo et al. suggest. It could then neutralize the same amount of IgE with a smaller dose, possibly in fewer injections, and might even reach patients above omalizumab's IgE limit. In the atopic dermatitis sera that Kuo et al. tested, however, the advantage was about fourfold only below 4,800 ng/mL of IgE, roughly 2,000 IU/mL, and narrowed to about twofold above that. For patients above omalizumab's limit of 1,850 IU/mL, the advantage of CUE-221 might therefore be closer to twofold than fourfold.

Ligelizumab, which Kuo et al. found as potent as UB-221 in neutralizing serum IgE, though with little engagement of CD23, may indicate how strongly the effect of an antibody that works through IgE binding alone depends on the dose in food allergy. In a phase 3 that enrolled adolescents and adults with peanut allergy, 45 percent of participants on 240 mg tolerated at least 600 mg of peanut protein after three months, against 16 percent on 120 mg and 4 percent on placebo. The trial was stopped early after a blinded efficacy review indicated that some patients might benefit from an improved dosing regimen. In the published report, the investigators state that the trial was terminated early because blinded data reviews indicated that the target efficacy would not be met. In CSU, by contrast, 2 and 4 mg/kg of CUE-221 gave almost the same share of hives-free patients at week 12. The CSU trial may thus say little about the dose CUE-221 would need in food allergy, where deeper IgE suppression might still help some patients who do not sufficiently respond on omalizumab.

Ozureprubart, a half-life extended anti-IgE antibody that binds the same epitope as omalizumab, is being tested every 8 and 12 weeks in the phase 2b prestIgE trial in food allergy. GSK, which acquired its developer RAPT Therapeutics in March, expects data from this trial in 2027. Cue's July presentation argues that a longer half-life "may improve convenience, not efficacy."

CUE-221's potency could offer another route to longer dosing intervals, since a dose equal in mass to omalizumab's would be roughly four times the matching dose and should add about two half-lives, or 32 to 44 days, of exposure. In patients with high IgE, where the advantage may be closer to twofold, this gain would shrink to about one half-life. Part of the gain could also be lost to clearance if the 16- to 22-day half-life from the phase 1 holds, since omalizumab's half-life in CSU is 24 days. At a mean body weight of 66.6 kg, the 4 mg/kg arm in CSU received about 270 mg of CUE-221 per dose, close to the 300 mg of omalizumab. The two doses were in fact nearly equal per kilogram, since the mean body weight in the omalizumab arm was 77.2 kg, so its weight-adjusted dose was 3.9 mg/kg. At this dose, 60 percent of patients were still hives-free twelve weeks after the last injection, against 24 percent on omalizumab.

With ligelizumab matching the potency of UB-221 (CUE-221) in serum and ozureprubart tested at intervals of up to 12 weeks, the proposed CD23 mechanism could differentiate CUE-221 in food allergy. Kuo et al. argued that at high IgE levels, neutralization alone may not bring free IgE, and with it allergen-specific IgE, sufficiently down unless new IgE synthesis is also kept under control. The mechanism could matter especially in the high-IgE patients who fall outside omalizumab's dosing table.

A phase 2 trial in food allergy that runs longer than sixteen weeks and reports total and allergen-specific IgE could test CUE-221's proposed CD23 mechanism more directly than this CSU trial. If this yields clear evidence for an effect on IgE synthesis, CUE-221 could be differentiated from omalizumab and ozureprubart by its mechanism as well as by its potency in binding IgE.

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General Disclaimer & No Financial Advice: The author is not a registered investment advisor or financial analyst, and nothing here is financial, legal, tax, or investment advice, a personal recommendation, an assessment of suitability for any investor, or an offer, solicitation, or recommendation regarding any security. This is not a securities research report and was not prepared under the requirements designed to promote the independence of investment research. It has not been peer-reviewed or audited, represents the author's opinion as of the publication date, and may change without notice. Readers should conduct their own due diligence and consult a certified financial professional before making any investment decision. Readers act on this content at their own risk, and to the fullest extent permitted by applicable law the author accepts no liability for any loss or damage arising from reliance on it.

Medical Disclaimer: The author is a physician, but this article discusses clinical trials and drug mechanisms as general scientific and educational commentary. It is not medical advice, diagnosis, or a treatment recommendation, and it establishes no physician-patient relationship. Readers should never disregard or delay professional medical advice because of anything written here, and should consult a qualified healthcare provider about any medical condition.

Accuracy and Third-Party Data: The cited sources are believed reliable but are not guaranteed complete, current, or correct. The CUE-221 phase 2 results are topline data from Cue Biopharma's press release and investor presentation, not peer-reviewed and partly read from slides. Their response rates keep all 143 dosed patients in the denominator at every time point although 40 of them did not complete the 36-week study. Cue has not stated how it handled the missing data. The molecule comparison assumes a molecular weight similar to omalizumab's, since none appears to have been published for CUE-221. Despite the author's efforts to verify the sources cited, this article may contain errors of fact or interpretation.

Disclosure of Interest: The author holds a beneficial long position in Cue Biopharma, Inc. (NASDAQ: CUE), and holds no position, long or short, in any other company mentioned. The author reserves the right to buy or sell securities of Cue Biopharma at any time without further notice. He received no compensation for this article, maintains no business relationship with any company mentioned, and has no access to non-public trial data, unblinded interim results, or internal company information. His position in Cue creates a potential for confirmation bias in interpreting the underlying science.

Forward-Looking Statements & Risk: Statements here about regulatory outcomes, clinical results, and market potential are predictions subject to significant risks and uncertainties, and actual results may differ materially. The planned phase 2b/3 in CSU and phase 2 in food allergy have not been initiated, depend on the FDA's review of the phase 2 data, and may change in design, endpoints, dose, and timing. Comparisons with omalizumab's trials in CSU and food allergy, with the ligelizumab trial in peanut allergy and with observational series in other patient populations are cross-trial and non-randomized. Extrapolations from CSU to food allergy, a different disease with different endpoints, are untested. The in vitro and ex vivo findings for CUE-221 come from a single laboratory and are unproven in patients. In its quarterly report for the period ended June 30, 2026, Cue Biopharma stated that it will need substantial additional capital. Readers should check its latest SEC filings. Biotechnology and pharmaceutical investing carries a high degree of risk, including total loss of principal, and past performance does not indicate future results.

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