Positive Topline Results Announced in Type 1 Diabetes Clinical Trial

A clinical trial investigating a possible novel treatment of early-onset type 1 diabetes last month met the primary endpoint assessing the safety and tolerability of a new class of microbe-based therapeutic agents. Precigen ActoBio is evaluating this therapy — AG019 ActoBiotics — as a monotherapy and in combination with teplizumab.

AG019 is formulated as an oral capsule consisting of engineered Lactococcus lactis specifically modified to deliver autoantigen human proinsulin (hPINS) and the tolerance-enhancing cytokine human interleukin-10 (hIL-10) to the mucosal lining of the gastrointestinal tissues. Administration of AG019 is designed to induce specific regulatory T cells (Tregs) that could reduce or eliminate the destruction of insulin-producing cells, potentially stabilizing or improving insulin production.

The Phase 1b open-label portion of the study evaluates the safety and tolerability of AG019 administered as a single dose and repeated daily doses as a monotherapy in adult and adolescent patients. The primary endpoint for assessing safety and tolerability is treatment-emerging adverse events (TEAEs) reported up to six months after treatment initiation. Nineteen patients were treated in the Phase 1b monotherapy portion of the study and 17 patients were evaluated at six months. The Phase 2a portion of the study is currently ongoing and investigates the safety and tolerability of AG019 in combination with teplizumab (PRV-031), which is currently under investigation in the PROTECT Phase 3 study for the treatment of newly diagnosed T1D.

Key findings from the Phase 1b AG019 monotherapy portion study for patients six months after treatment initiation include:

• The study met its primary endpoint demonstrating safety and tolerability. No serious or severe TEAEs were reported in any of the patients treated with AG019 monotherapy, and no patient discontinued treatment.
• Eight-week treatment with AG019 monotherapy was safe and well-tolerated in daily dosages up to 6 x 10¹¹ CFU (colony-forming units) in adult and adolescent patients with T1D.
• There was no evidence for systemic exposure of bacteria and proteins (hPINS/hIL-10) in the circulation, confirming the safety profile of AG019. The analysis of fecal samples confirmed gastrointestinal exposure of AG019 in most treated patients.
• C-peptide levels, a common biomarker used to measure pancreatic beta cell function, demonstrate slower decline in C-peptide levels in 67% of adult patients (6 out of 9) receiving AG019 monotherapy with 44% of these adult patients (4 out of 9) showing stabilization of mean four hours C-peptide area under the curve (AUC) levels at six months (within 9.7% of the baseline level). This was based on the comparison of the median percent decline in mean four hours C-peptide AUC from baseline between patients receiving AG019 monotherapy and patients who received placebo from previous studies.

Furthermore, in a preliminary analysis performed by the Immune Tolerance Network, a leading independent research group, AG019 monotherapy shows an increase in the frequency of islet-specific Tregs expressing inhibitory receptors, a potential mechanistic indicator of therapeutic activity, for patients three months after treatment initiation.

“Though preliminary, C-peptide data for the Phase 1b AG019 monotherapy is encouraging in this limited data set,” says Kevan Herold, MD, professor of Immunobiology and of Medicine at Yale University and principal investigator for the AG019 Phase 1b/2a clinical study. “The positive topline data from the Phase 1b monotherapy portion of study provides compelling rationale for continued clinical development of this promising investigational therapeutic candidate.”