Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome.

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.

Quantifying survival in patients with Proteus syndrome.

PurposeProteus syndrome is a rare mosaic overgrowth disorder that is associated with severe complications. While anecdotal data have suggested that the life span of affected patients is reduced, this has not been measured. Mortality data on rare diseases is critical for assessing treatments and other interventions.MethodsTo address this we used the clinical research records of 64 patients in a longitudinal natural history cohort at the National Institutes of Health to ascertain the data in an organized manner and estimate survival using a Kaplan-Meier approach.ResultsThe median age of diagnosis was 19 months. Based on this analysis, there was 25% probability of death by 22 years of age. Ten of the 11 patients who died were younger than 22 years of age, and there was only a single death after this age.ConclusionThese data quantify the risk of premature death in Proteus syndrome, which can be used to support interventions and trials. Although the risk of death is substantial, the fact that only one patient died after 22 years of age supports anecdotal evidence that the disease process moderates after the end of adolescence. Interventions to reduce mortality should be targeted to the pediatric age range.