Safety, Pharmacokinetics, and Pharmacodynamics of the Novel Oral Peptide Therapeutic PN-10943 (alpha4beta7 Integrin Antagonist) in Normal Healthy Volunteers: 730

INTRODUCTION: Oral gut-restricted α4β7 integrin peptide antagonists represent a new therapeutic strategy for IBD. An example is PTG-100, which in a recent Phase 2 study was associated with higher rates of clinical and histologic remission relative to placebo in ulcerative colitis patients (Sandborn et al, UEGW 2018). PN-10943 is an oral, gut-restricted, potent, and highly selective α4β7 integrin antagonist peptide that has demonstrated preclinical superiority to PTG-100 (Mattheakis et al, DDW 2019). The purpose of this first-in-human Phase 1 study with PN-10943 was to assess safety, tolerability, PK, and PD activity in NHV and confirm previous preclinical observations. METHODS: A randomized, placebo-controlled Phase 1 trial of single (SAD) and multiple (MAD) ascending doses of PN-10943 was conducted in 70 male NHV. MAD regimen consisted of 14 daily doses. Subjects are monitored for safety and tolerability while undergoing serial plasma PK and blood PD evaluations as measured by integrin receptor occupancy (RO) and expression (RE) on circulating α4β7+ lymphocyte subsets. RESULTS: In the SAD portion of the study, 100, 300, 1000, and 1400 mg cohorts were dosed with no serious adverse events or dose-limiting toxicities. All adverse events were of mild to moderate severity and resolved without complication. In the MAD portion of the study doses studied were 100, 300, & 1000 mg for 14 days. Peak plasma concentration (Cmax) and area under the curve increased in a dose proportional manner and plasma pharmacokinetics were also time invariant between day 1 and day 14 in the MAD cohort. There was a significant dose dependent increase in RO of blood memory T cells (reaching >90% in the 1000 mg cohort). RE of α4β7 on blood memory T cells decreased in a dose dependent manner consistent with α4β7 internalization. The PD responses strongly correlated with plasma Cmax, and the binding activity from subject/time-matched RO on α4β7 memory T cells was comparable to that demonstrated in preclinical studies. CONCLUSION: Following oral administration in NHV, PN-10943 was well tolerated. As expected, plasma exposure was very low, and there was significant dose-related PD. The Phase 1 PK/PD relationship confirms previous preclinical observations in which PN-10943 demonstrated superiority to PTG-100. These Phase 1 PD data for PN-10943 together with the previous clinical activity of PTG-100 suggest that PN-10943 may potentially be an effective oral therapy for the treatment of UC.