P0984 Phase 1 Interim Results for XmAb942, a Potential Best-in-Class, Long-Acting Anti-TL1A Antibody for the Treatment of Inflammatory Bowel Disease

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) mediates a broad spectrum of pro-inflammatory and pro-fibrotic effects that have been linked to the pathogenesis of inflammatory bowel disease (IBD) and other autoimmune disorders. Recent clinical trials have demonstrated remission in IBD with the use of antibodies to TL1A. XmAb942 is an engineered anti-TL1A IgG1 antibody with ablated Fc-mediated effector function that incorporates Xtend™ half-life extension technology. XmAb942 binds trimeric TL1A with high affinity and specificity and is highly potent across multiple preclinical assays. Interim results from single ascending dose (SAD) and multiple ascending dose (MAD) cohorts of the Phase 1 portion of the XmAb942-01 trial are reported here. Methods In Phase 1, healthy volunteers were randomized to receive XmAb942 in 3:1 drug:placebo ratio in 6 SAD cohorts (3 cohorts with XmAb942/placebo administered intravenously [IV] and 3 cohorts with XmAb942/placebo administered subcutaneously [SC]) and 2 MAD cohorts (with XmAb942/placebo administered IV). Participants were followed for at least 140 days post last dose. Safety, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity assessments were performed per protocol. Results XmAb942 was found to be safe and well-tolerated. Treatment emergent adverse events were infrequent and mild or moderate in severity. There were no serious adverse events (including infections) and no deaths. XmAb942 demonstrated extended serum exposure, with an estimated terminal half-life of > 71 days based on pooled analysis of single-dose cohorts. Early multiple-dose PK data were consistent with single-dose cohort data, with no apparent impact of anti-drug antibodies on PK profile up to 16 weeks after single dose or up to 10 weeks after multiple doses given every 4 weeks. Dose-dependent and durable increases in drug complexed soluble TL1A for at least 16 weeks after IV and SC single dosing were observed. All IV and SC single dose levels led to rapid and sustained reduction of free soluble TL1A below lower limit of quantitation for at least 16 weeks. These data support lower frequency of dosing than first-generation TL1A inhibitors. Conclusion Interim results from the Phase 1 portion of the seamless Phase 1/2b XmAb942-01 trial demonstrate that XmAb942 was safe and well-tolerated in single or multiple doses in healthy volunteers, with enhanced target engagement and substantially longer half-life compared to first-generation TL1A inhibitors. The Phase 2b portion of the XmAb942-01 trial in patients with ulcerative colitis, XENITH-UC, is ongoing. Conflict of interest: Osterman, Mark: No conflict of interest Dr. Aggarwal, Sudeepta: No conflict of interest Kanodia, Jitendra: No conflict of interest Makaryan, Sahak: No conflict of interest Belouski, Shelley: No conflict of interest Rodriguez, Nicole: No conflict of interest Chaudhuri, Dipankar: No conflict of interest Karki, Sher: No conflict of interest Salama, Engie: No conflict of interest Ding, Ying: No conflict of interest Visonneau, Sophie: No conflict of interest Leone, Dane: No conflict of interest Dahiyat, Bassil: No conflict of interest Desjarlais, John R.: No conflict of interest