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 five-year follow up of an 18-year-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-week 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. He 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 five 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. While 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.

Barriers to Genetic Testing in Vascular Malformations

“…[22][23][24] Other drugs, such as trametinib (Mekinist; Novartis) and cobimetinib, which target MEK, and miransertib, which targets AKT, are in clinical trials or are in early development. 1,[25][26][27][28][29][30] Despite growing evidence that targeted therapies are an important component of comprehensive care for patients with VM, the results of the present survey underscore the difficulties in accessing genetic testing for this group of disorders. Respondents, most of whom were PHOs, universally noted that the obstacles in getting genetic information were unique to VM and were not similar to issues they often faced in obtaining molecular testing for patients with cancer.…”

“…Alpelisib (PIQRAY and Vijoice; Novartis), a drug that targets the PIK3CA gene, was approved in April 2022 by the US Food and Drug Administration for the treatment of a specific group of VM disorders: PIK3CA -Related Overgrowth Spectrum . Other drugs, such as trametinib (Mekinist; Novartis) and cobimetinib, which target MEK, and miransertib, which targets AKT, are in clinical trials or are in early development …”

“…Notably, VACs of all sizes sent specimens (including tissue) to Invitae, a laboratory that is not validated for variant allele frequencies less than 20%. Such sequencing methods, although adequate for cancer evaluation, may miss detection of sequence variations at the low variant allele frequencies seen in many VMs . Standard sequencing techniques for oncological diagnosis can fail to identify low-frequency somatic variants in VM, which can result in missed identification of relevant variants .…”

Updates on Diagnosis and Treatment of PIK3CA-Related Overgrowth Spectrum

“…35 Two children given a diagnosis of PROS were treated with miransertib and achieved reductions in soft tissue volume and seizure frequency. 37 Although miransertib is likely to interfere with the regulation of glycogen synthesis kinase-3 and disrupt the synthesis and metabolism of hepatic glycogen, 6 referring to the long-term follow-up results of using miransertib for other diseases, it might cause only brief, milder hyperglycemic responses, 38 which could be mediated by dietary modification.…”

Multimodal ocular imaging in Proteus syndrome

“…Recent studies suggest an overall improvement in symptoms and quality of life of PS patients treated with Miransertib, by slowing or arresting uncontrolled tissues" growth. 10,11 Case #2 patient developed a LGSOC, and genetic analysis demonstrated AKT1-E17K gain-of-function mutation on affected connective tissues and ovarian tissue. Considering the benefits of AKT-inhibitors in both PS patients and AKT-mutant cancers, the patient was treated with Miransertib on a compassionate basis for more than 3 years.…”