Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome

Abstract

Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.

Trial registration: ClinicalTrials.gov NCT02594215.

Keywords: Proteus syndrome; connective tissue nevus; miransertib; mosaicism; overgrowth; phase I study.

Published by Elsevier Inc.

Figures

Figure 1

AKT Pharmacodynamic Inhibition with Miransertib Treatment Levels of pAKT and miransertib in the tissue and plasma of the participants. The histogram depicts the primary outcome measure, which is the pAKT signal determined by western blot analyses in lysates obtained from biopsies of affected tissue at C1D15 (blue bars) or C4D1 (red bars) as compared to the baseline value, normalized to 100% (green bars). Lysates were tested in two separate experiments; the first dataset is shown here and both datasets are shown in Figure S1. The plasma miransertib levels obtained at C1D15 and the tissue miransertib levels at C1D15 and C4D1 are also shown numerically at the bottom of the figure. The assays were performed as technical triplicates, averaged, normalized to the baseline, and the 90% confidence intervals of the measures were compared to the 50% reduction target.

Figure 2

Cerebriform Connective Tissue Nevus Changes with Miransertib Treatment Photographic quantitation of the cerebriform connective tissue nevi (CCTN) and pre-CCTN abnormal skin comparing baseline to pre-treatment period and pre-treatment to post-treatment periods. The visible area of the entire sole, the total lesional area (pre-CCTN and CCTN combined), and CCTN area alone were quantitated using ImageJ software. (A) shows the pre-treatment and post-treatment change in the CCTN and (B) shows the pre- and post-treatment change in the combined pre-CCTN and CCTN areas.

Figure 3

Pain Intensity Changes with Miransertib Treatment Results of Pain Intensity scores comparing pre-treatment to post-treatment self-report of pain from 0 (no pain) to 10 (worst pain ever experienced). Adult participants are designated in orange; pediatric participants are designated in blue.