Miransertib (ARQ 092) is an orally available, selective, pan-AKT (protein kinase B) inhibitor that potently inhibits AKT1, 2 and 3 isoforms. Dysregulation of AKT has been implicated in a variety of rare overgrowth diseases and cancers; however, there are currently no approved inhibitors of AKT. AKT inhibitors, either as single agent or combination therapy, show significant promise in molecularly defined patient populations. Miransertib is currently in a Phase 1/2 company-sponsored study for overgrowth diseases, a Phase 1 study for ultra-rare Proteus syndrome conducted by the National Institutes of Health (NIH), and a Phase 1b study in combination with the hormonal therapy, anastrozole, in patients with advanced endometrial cancer with AKT and PI3K mutations.
Miransertib has demonstrated inhibition of tumor growth and downstream AKT signaling in vivo in tumors whose growth is driven by these targets. Single agent activity with miransertib was observed in Phase 1a and Phase 1b studies as well as reductions in expression levels of relevant biomarkers. Publications support AKT1 as a viable target in oncology and Proteus syndrome.
Mechanism of Action
Miransertib is a potent small molecule pan-AKT inhibitor that suppresses the AKT pathway via two modes of action. First, miransertib binds inactive AKT, preventing membrane localization and subsequent AKT activation. Second, miransertib binds active AKT, resulting in direct inhibition.
The AKT1 mutation is believed to play a role in a number of cancers and overgrowth diseases, such as Proteus syndrome and PROS (PIK3CA-related overgrowth spectrum).
The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers and non-oncology indications. Preclinical research has demonstrated that miransertib suppresses PIK3CA/AKT1 mutant dependent kinase signaling and demonstrates anti-tumor activity in molecularly defined tumor models.
A landmark discovery by researchers from the National Human Genome Research Institute at the NIH demonstrated that a somatic mosaic mutation in the AKT1 oncogene is the underlying genetic alteration that causes Proteus syndrome. A spontaneous point mutation – a single-letter “misspelling” in the DNA of the genetic code — in the AKT1 gene during embryological development is responsible for activating the tissue growth characteristic of Proteus syndrome. The identification of the causal mutation of Proteus syndrome allows for the development of molecularly targeted treatments.
Planned/Ongoing Clinical Trials
- Proteus syndrome
Proteus syndrome is an ultra-rare condition characterized by the aberrant overgrowth of multiple tissues of the body. Patients with Proteus syndrome experience changes in the shapes of certain body structures over time, including abnormal, often asymmetric, massive growth (overgrowth) of the skeleton, skin, adipose tissue and central nervous system out of proportion to the rest of the body. Although patients may have minimal or no manifestations at birth, the disease develops and becomes apparent in early childhood (6-18 months) and rapidly progresses with intense growth in the first 10 years of life. The worldwide incidence is believed to be approximately one in a million. There are currently no approved medicinal treatments for Proteus syndrome, leaving patients with minimal treatment options to manage the disease and a mortality of 25% by age 22.
- Overgrowth Diseases
Overgrowth disease is a term used to refer to a spectrum of rare diseases identified by somatic mutations in the PIK3CA gene, that result in excess growth in certain areas of the body. While the individual diseases that fall within the overgrowth spectrum have similar symptoms, each disease is defined by unique characteristics. Diseases that are part of the overgrowth spectrum include PROS diseases (PIK3CA-related overgrowth spectrum) and Proteus syndrome. The implementation of genetic sequencing has led to the identification of the underlying genetic mutations that drive these overgrowth disorders, allowing for the development of medicines that target the specific causes of disease. As an example, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis) is a disease that is part of the PROS family of diseases. The NIH is currently sponsoring a Phase 1 dose escalation trial of miransertib for Proteus syndrome to establish safety, PK, PD, and clinical benefit. ArQule is conducting a Phase 1/2 expansion trial to externally validate the NIH proof of concept data in overgrowth diseases, including Proteus and PROS. Current plans are geared towards the initiation of a global registrational program.
AKT1 Driven Cancers
Prevalence of AKT1 mutations in cancer varies from 1-6% depending on tumor types. The tumor types with the highest prevalence of AKT1 mutations are breast, bladder, endometrial, ovarian and cervical cancers. ArQule is currently conducting a Phase 1b trial in endometrial cancer with AKT and PI3K mutations to determine the safety, PK, PD and clinical activity of miransertib in combination with anastrozole.
evalence of AKT1 mutations in cancer varies from 1-6% depending on tumor types. The tumor types with the highest prevalence of AKT1 mutations are breast, bladder, endometrial, ovarian and cervical cancers.
Current Clinical Trials
- Recruiting: Study of ARQ 092 in Patients with Overgrowth Diseases and/or Vascular Anomalies
This open label, Phase 1/2 study will assess the safety of oral miransertib (ARQ 092) administered to patients at least 2 years of age with overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway.
More info: https://clinicaltrials.gov
Identifier on clinicaltrials.gov: NCT03094832
- Enrolling by invitation: Dose Finding Trial of ARQ 092 in Children and Adults with Proteus Syndrome
This Phase 1 trial, conducted by the NIH, will determine the safety, tolerability and recommended dose of miransertib as a single agent in patients with Proteus syndrome.
More info: https://clinicaltrials.gov
Identifier on clinicaltrials.gov: NCT02594215
- COMPLETED: Phase 1b in Oncology – Single Agent
This open label Phase 1b trial will assess the safety, tolerability, pharmacology of miransertib as a single agent in patients with lymphoma, endometrial cancer and AKT1 E17K mutations and define a recommended Phase 2 dose of miransertib.
More info: https://clinicaltrials.gov/
Identifier on clinicaltrials.gov: NCT01473095
- Recruiting: Open-label Phase 1b Study of ARQ 092 in Combination with Carboplatin Plus Paclitaxel, in Combination with Paclitaxel, or in Combination with Anastrozole
This open-label Phase 1b study will evaluate the safety, pharmacology and activity of miransertib in combination with carboplatin plus paclitaxel, in combination with paclitaxel, or in combination with anastrozole in subjects with selected solid tumors. The anastrozole arm of this study will evaluate the safety, pharmacology and activity of treatment in patients with endometrial cancer with AKT and/or PI3K activating mutations.
Identifier on clinicaltrials.gov: NCT02476955