Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome

Abstract

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1 Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the 5-yr follow-up of an 18-yr-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-wk phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well-tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to 5 years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. Although an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.

Trial registration: ClinicalTrials.gov NCT00001403 NCT02594215.

Keywords: bone pain; connective tissue nevi; multiple skeletal anomalies; overgrowth.

© 2021 Ours et al.; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.

Serial photography of the left (A) and right (B) feet showing the progression of the cerebriform connective tissue nevus (CCTN) occurring more rapidly before initiating miransertib and a slowing of the involvement of the plantar surface during miransertib treatment.

Figure 2.

Measurement of the percent of cerebriform connective tissue nevus (CCTN) involvement on the plantar surface. The CCTN development and growth were observed prior to miransertib. A decrease in the annual growth rate is observed following initiation of miransertib and was sustained during the treatment period.

Figure 3.

Patient-reported outcome measures improved during the treatment period. (A) Impact of Pediatric Illness (IPI), (B) Pain Interference Index (PII), (C) PROMIS Mobility, and (D) NRS-11 scale of most severe pain in past 7 d.