Our anti-BTLA agonist antibody, known as ANB032, is broadly applicable to human inflammatory diseases associated with lymphoid and myeloid immune cell dysregulation. ANB032 is anticipated to down-modulate the activity of T cells, B cells and BTLA expressing myeloid dendritic cells via several potential mechanisms: direct BTLA agonistic activity, stabilization of the interaction of BTLA and HVEM in cis which prevents pro-inflammatory signaling mediated by HVEM ligands such as LIGHT, and abrogation of pro-inflammatory HVEM signaling mediated by BTLA in trans. Genetic studies have demonstrated that BTLA pathway mutations increase human susceptibility to multiple autoimmune diseases and insufficient BTLA signaling can lead to dysregulated T or B cell responses. We presented preclinical data regarding ANB032 at the Federation of Clinical Immunology Societies meeting in October 2020.
We announced positive top-line data from a healthy volunteer Phase 1 trial, under an Australian Clinical Trial Notification (CTN), in April 2022. We anticipate filing an IND for a Phase 2 clinical trial with ANB032 in the second half of 2022.
A total of 96 subjects were enrolled in the randomized, double-blind, placebo-controlled healthy volunteer Phase 1 trial, where single ascending dose (SAD) cohorts received subcutaneous or intravenous single doses of ANB032 or placebo, while multiple ascending dose (MAD) cohorts received four weekly subcutaneous doses of ANB032 or placebo. Dose escalation was conducted subsequent to data safety monitoring board review of safety and tolerability parameters following each single and multiple ascending dose level.
ANB032 was generally well-tolerated, no dose limiting toxicities were observed and there were no discontinuations due to adverse events other than one patient quarantined for potential COVID infection. No serious adverse events (SAEs) were reported in subjects receiving single or multiple doses of ANB032 or placebo. Most adverse events were considered to be mild-to-moderate, of short duration, resolved without sequelae and occurred sporadically in a dose-independent manner. The most frequent adverse event reported among SAD cohorts was headache (24% 13/54 ANB032 and 33% 6/18 PBO) and URTI (15% 8/54 ANB032 and 6% 1/18 PBO), and these were all mild (with one moderate), of short duration, resolved without sequelae and occurred sporadically in a dose-independent manner. The most frequent adverse events reported among MAD cohorts were headache (28% 5/18 ANB032 and 33% 2/6 PBO), and URTI (17% 3/18 ANB032 and 0% PBO). The majority of these were mild, of short duration, resolved without sequelae and occurred sporadically in a dose-independent manner. Two subjects in a low dose MAD cohort had three severe adverse events (2 CPK elevations and 1 AST elevation), none of which were treatment-related, occurred in two subjects in a low dose MAD cohort. No infusion reactions or injection reactions were reported in the SAD cohorts. Three subjects had mild-to-moderate single injection site reactions of short duration reported in the MAD cohorts (mild ecchymosis (bruise); erythema; and pain).
Pharmacokinetic analyses demonstrated a favorable profile for ANB032 including an approximate two-week half-life for subcutaneous and intravenous routes of administration. Full BTLA receptor occupancy was observed rapidly within hours and was maintained for greater than 30 days following IV or subcutaneous ANB032 dosing. ANB032 pharmacodynamic activity resulted in reduction of cell surface BTLA expression on T cells and B cells following dosing. A portion of the cell surface BTLA was shed from the cells as soluble BTLA (sBTLA), while the residual approximately 60% of baseline BTLA on T cells and B cells remained occupied by ANB032. The duration of reduced BTLA expression correlated with receptor occupancy in a dose-dependent manner and was maintained for greater than 30 days following IV or subcutaneous ANB032 dosing. In addition, ANB032 demonstrated rapid and sustained target engagement on both T cells and B cells. Importantly, reduction of cell surface BTLA expression and the shedding of a portion of the cell surface BTLA as soluble BTLA, which was previously demonstrated to occur with ANB032 treatment in animal models of inflammation where robust efficacy was observed, confirmed the pharmacodynamic activity of ANB032 in humans. Based upon these data, we believe ANB032’s in vivo mechanism has the potential to broadly treat T and B-cell driven human inflammatory diseases.
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