Overview/Mechanism of Action
Miransertib (ARQ 092) is an orally available, selective, pan-AKT (protein kinase B) inhibitor that potently inhibits AKT 1, 2 and 3 isoforms. Additionally, it binds both the active and inactive forms of AKT which directly inhibits and prevents membrane localization, respectively. 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. We are currently initiating a registrational trial in both Proteus syndrome and PIK3CA-Related Overgrowth Spectrum (PROS) and further information related to these diseases and trials can be found in our orphan disease-focused presentation, PROS and PS Primer 2019.
The AKT1 mutation is believed to play a role in multiple cancers and overgrowth diseases, such as Proteus syndrome and PROS. 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. 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.
- PIK3CA-Related Overgrowth Spectrum (PROS)
PIK3CA-Related Overgrowth Spectrum is a group 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 recently published data from a phase 1 dose escalation trial of miransertib for Proteus syndrome to establish safety, PK, PD, and clinical benefit. We are currently initiating a registrational trial in both Proteus syndrome and PIK3CA-Related Overgrowth Spectrum (PROS) and further information related to these diseases and trials can be found in our orphan disease-focused presentation, PROS and PS Primer 2019.
- AKT Pathway Driven Cancers
Prevalence of AKT pathway mutations in cancer varies from 3-5%, depending on tumors. The tumor types with the highest prevalence of AKT1 mutations are breast, bladder, endometrial, ovarian and cervical cancers. PIK3CA (the gene that codes for an important subunit of PI3K) mutations are even more prevalent in multiple solid tumors, such as colon (32%) and brain (27%), etc. ArQule is currently conducting a phase 1b trial in endometrial cancer with AKT and PIK3CA mutations to determine the safety, PK, PD and clinical activity of miransertib in combination with anastrozole. In addition, we are conducting a phase 1b trial with our second generation AKT inhibitor, ARQ 751, in patients with solid tumors harboring AKT, PIK3CA or PTEN mutations.
Current Clinical Trials
- Recruiting: Study of ARQ 092 in Patients with PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
This open label, phase 1/2 study of oral ARQ 092 administered to patients at least 2 years of age with PIK3CA-related Overgrowth Spectrum (PROS) and Proteus syndrome (PS).
More info: https://clinicaltrials.gov
Identifier on clinicaltrials.gov: NCT03094832
- Available: Expanded Access to Provide ARQ 092 for the Treatment of Overgrowth Diseases and/or Vascular Anomalies
ARQ 092 is being investigated for patients with overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway and may be available for patients who are ineligible for an ongoing ARQ 092 clinical trial or have other considerations that prevent access to ARQ 092 through an existing clinical trial.
More info: https://clinicaltrials.gov
Identifier on clinicaltrials.gov: NCT03317366
- Active, not recruiting: 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 Anastrozole
This open-label phase 1b, dose escalation study of oral ARQ 092 administered in combination with carboplatin plus paclitaxel (Carboplatin Plus Paclitaxel Arm) or in combination with paclitaxel alone (Paclitaxel Arm), in subjects with advanced, inoperable metastatic and/or recurrent solid tumors, or in combination with anastrozole (Anastrozole Arm) in subjects with ovarian or endometrial cancer.Enrollment in the Carboplatin plus Paclitaxel Arm and Paclitaxel Alone Arm is now closed. Enrollment in the Expansion Cohort for the Anastrozole Arm continues for patients with endometrial cancer.
More info: https://www.clinicaltrials.gov/
Identifier on clinicaltrials.gov: NCT02476955