Randomized, Double‐Blind, Placebo‐Controlled, Single Ascending Dose Trial of Synthetic Preimplantation Factor in Autoimmune Hepatitis

Abstract

Preimplantation factor (PIF) is an evolutionary conserved peptide secreted by viable embryos which promotes maternal tolerance without immune suppression. Synthetic PIF (sPIF) replicates native peptide activity. The aim of this study was to conduct the first‐in‐human trial of the safety, tolerability, and pharmacokinetics of sPIF in patients with autoimmune hepatitis (AIH). We performed a randomized, double‐blind, placebo‐controlled, prospective phase I clinical trial. Patients were adults with documented AIH with compensated chronic liver disease. Diagnosis of AIH was confirmed by either a pretreatment International Criteria for the Diagnosis of AIH score of 15 or more, or a posttreatment score of 17 or more. Patients were divided into three dosing cohorts (0.1, 0.5, or 1.0 mg/kg) of 6 patients in each group. Three patients in each group had normal liver tests and 3 patients had abnormal liver tests. They were randomized to receive a single, subcutaneous dose of either sPIF or a matching placebo. Eighteen patients were enrolled, and all successfully completed the trial. There were no clinically significant adverse events and all doses were well tolerated. Ascending doses of sPIF produced a linear increase in the respective serum levels with a half‐life of 90 minutes. There were no grade 2, 3 or 4 laboratory abnormalities. No patient developed detectable anti‐sPIF antibodies. Conclusion: This first‐in‐human trial of the safety and pharmacokinetics of sPIF (a novel biologic immune modulatory agent) demonstrated both excellent safety and tolerability. The data support further studies of multiple ascending doses of sPIF in autoimmune hepatitis and potentially other autoimmune disorders.

Clinical management of autoimmune hepatitis

“…Other experimental strategies are aimed at increasing the pool and function of regulatory T‐cells, 49 for example by subcutaneous low‐dose interleukin‐2, which has proved to reduce inflammatory liver damage 50 , 51 . A phase I trial with subcutaneous synthetic preimplantation factor showed good safety and tolerability in AIH patients, but was not continued into phase II (source: NCT03593460) 52 …”

The core sequence of PIF competes for insulin/amyloid β in insulin degrading enzyme: potential treatment for Alzheimer's disease

“…Animal models of AD are currently being prepared but are beyond the scope of this manuscript. However, sPIF received a FDA Fast-Track Approval for first-in-human Phase I trial and orphan drug designation for autoimmunity, which was successfully completed [ 35 ]. Such observations together with the current evidence support PIF's potential protective role in AD or type II diabetes, where IDE plays a major role.…”

Review article: experimental therapies in autoimmune hepatitis

“…Pre‐implantation factor was awarded FAST‐TRACK status by the FDA, and a phase I placebo‐controlled study of pre‐implantation factor administration in 18 patients with AIH demonstrated minimal toxicity 126 . Pre‐implantation factor may now be taken forward to efficacy trials and represents a potential novel therapy for AIH, although a phase 2 trial was announced and then withdrawn as the manufacturer reported a change in the focus of drug development.…”

“…The advantages of pre‐implantation factor are that it is a naturally occurring peptide, with no evidence of anti‐pre‐implantation factor antibody formation in the phase I study. The required dosing interval is currently unknown, although with a half‐life of 91 minutes, 126 frequent subcutaneous dosing may be required.…”