S793 Full Target Engagement With Saturation of α4β7 Integrin Receptor Occupancy Resulting in Changes in Subset of Lymphocytes by MORF-057 Following 200 Mg Daily Dosing in Healthy Subjects

Introduction: MORF-057 is a potent and selective α4β7 integrin inhibitor being developed as an oral treatment for patients with inflammatory bowel disease. In a previously reported Phase 1 study in healthy subjects (NCT04580745) MORF-057 was well tolerated and demonstrated favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties at doses up to 100 mg twice daily (BID). This study evaluated second generation formulation and the multidose assessment to 200 mg BID. Methods: An immediate release formulation in capsules at dosage strengths of 25 and 100 mg was used for this study. This was a two-part healthy volunteer study where Part 1 investigated the safety and PK of a single administration of 25 mg (fasted) and 100 mg (fasted, fed) MORF-057. Part 2 investigated the safety, PK and PD of a single dose of 200 mg MORF-057 followed, after washout, by 14 days of repeat dosing at 200 mg BID. Blood samples to assess PK (Part 1 and 2) and receptor occupancy (RO; Part 2 only) of α4β7 and α4β1 integrins were obtained prior to the first dose and 12 hours post-dose. Changes in lymphocyte subsets (LS) and expression of C-C Motif Chemokine Receptor 9 (CCR9) mRNA in blood were also measured in Part 2 of the study. (Figure) Results: A total of 20 subjects were enrolled in the study (n=8 in Part 1; n=12 in Part 2). Three non-serious adverse events (AEs) were reported. No AEs were deemed related to MORF-057, and no safety signals were identified. Approximately dose proportional exposures of MORF-057 was observed following single administration at doses from 25 to 200 mg. MORF-057 was rapidly absorbed with a Tmax ranging from 2-4 hours. The high fat meal delayed the absorption resulting in a slight decrease in AUC (23%) and Cmax (49%) and an increase in Ctrough (46%). Saturating α4β7 RO (99%) was achieved at 12 hours following a single 200 mg dose and was sustained over multiple doses at 200 mg BID. α4β1 RO was below the limit of quantitation. The B cells and T cell subsets, and expression of CCR9 mRNA in blood, were elevated at Day 19 during BID dosing. (Table) Conclusion: Single and multiple dose MORF-057 was well tolerated in this study. Compared with data from a previous study, biomarker responses are consistent between 100 and 200 mg BID suggesting saturation of biomarker effect. MORF-057 demonstrated a favorable PK and PD profile supporting further clinical development.Figure 1.: α4β7 receptor occupancy (RO) Following Multiple Oral Administration of 200 mg BID MORF-057 Data presented as boxplots with central line representing the median value; α4β7 RO was measured at trough (12 h post dose) after a single administration (Day1_12h) and during repeat dose administration at 200 mg BID (Day6_12h, Day12_12h, Day19_12h). Table 1. - Summary of Plasma MORF-057 PK Parameters Following Single Dose Administration AUC, Cmax, and C12, values are presented as geometric mean (geometric CV%). Tmax is presented as median (min, max) PharmacokineticParameter (Unit) Part 1 Period 1100 mg MORF-057 IRCapsules (Fasted)(N=8) Part 1 Period 2100 mg MORF-057 IRCapsules (Fed)(N=7) Part 1 Period 325 mg MORF-057 IRCapsules (Fasted)(N=7) Part 2200 mg MORF-057 IRCapsules (Fasted)(N=9) AUC0-inf (h*ng/mL) 2050 (51.2) 1660 (41.1) 604 (36.5) 3770 (30.3) Cmax (ng/mL) 545 (45.9) 299 (48.7) 139 (38.6) 970 (46.6) C12 (ng/mL) 19.0 (81.9) 35.1 (98.6) 5.98 (61.8) 40.0 (44.1) Tmax (h) 2.01 (1.02, 4.02) 4.00 (1.50, 4.00) 1.50 (1.00, 2.50) 2.50 (1.52, 4.02) NA = Not Applicable.