Proof of Mechanism for an inhaled anti-TSLP fragment antibody, AZD8630/AMG104, in a phase 1 study in healthy adults and asthma patients

<bold>Aims:</bold> Thymic Stromal Lymphopoietin (TSLP) is a clinically-precedented target for treatment of asthma. AZD8630/AMG 104 is a fragment antibody (Fab) targeting TSLP, formulated for delivery as a dry powder inhaler. Here we report target engagement (TE) and pharmacodynamic (PD) biomarker results from the first-in human study (<ext-link>NCT05110976</ext-link>). <bold>Methods:</bold> The study comprised a single-blind study in 104 healthy subjects evaluating single and multiple ascending doses and a double-blind, randomized, placebo-controlled study in 75 patients with uncontrolled, moderate-to-severe asthma. TE in serum was measured using high-sensitivity immunoassays (Meso Scale Discovery) for free TSLP and TSLP/drug complexes. PD effects of AZD8630/AMG104 were measured by changes from baseline of Fractional exhaled Nitric Oxide (FeNO) and serum inflammatory biomarkers using mixed longitudinal models. <bold>Results:</bold> Levels of free TSLP were reduced and TSLP/drug were dose-dependently increased in serum following daily inhaled drug dosing, compared to placebo, in healthy subjects and asthma patients consistent with TE and pharmacokinetics in the circulation. There was a statistically significant reduction in FeNO in asthmatics following AZD8630/AMG104 dosing (23% vs placebo, one-sided p-value 0.037). that was evident from day 7 day to the end of the treatment (day 28). Serum IL-5 and -13 showed trends for lower levels following drug dosing, compared to placebo. <bold>Conclusion:</bold> Results demonstrate proof of mechanism for AZD8630/AMG104 and support further development as a potential treatment for asthma. Future work will confirm TE and broaden understanding of PD responses in the airway of asthmatics.