Scientific Collaborators

We are collaborating with The Ohio State University on the clinical development of ARQ 531, an orally available, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor rationally designed and selected for its ability to inhibit both wild type and C481S-mutant BTK. We recently published data in collaboration with researchers at Ohio State University that demonstrated superior efficacy of ARQ 531 compared to ibrutinib in a mouse model of chronic lymphocytic leukemia (CLL) and that ARQ 531’s spectrum selective targeting may expand the patient population for treatment and the potential use of ARQ 531 into many other B-cell malignancies1.

With Ohio State University as the lead investigator, we initiated a Phase 1a dose escalation study with ARQ 531 in hematologic malignancies. The goal of this study is to assess the safety, PK, PD, and clinical activity of ARQ 531 in patients with relapsed or refractory CLL, Mantle cell, Waldenstrom’s macroglobulinemia and B-cell non-Hodgkin’s lymphoma. Interim data presented at the 2018 European Hematology Association Congress demonstrated a dose proportional PK supporting once daily dosing, dose proportional target engagement and promising signs of activity, even in a C481S mutant setting, despite dosing below the anticipated efficacy range.

References

1http://cancerdiscovery.aacrjournals.org/content/early/2018/08/09/2159-8290.CD-17-1409

We are currently collaborating with the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) in Proteus syndrome, a rare disease characterized by overgrowth of the skeleton, skin, adipose tissue and central nervous system. Our proprietary, orally available, selective pan-AKT (protein kinase B) inhibitor, miransertib (ARQ 092), is being tested in a Phase 1 study to establish clinical proof of concept and to determine the safety, tolerability and recommended dose of miransertib as a single agent in Proteus syndrome patients. The study, which is the first ever clinical trial for Proteus syndrome, is enrolling by invitation.

In 2011, an NHGRI team led by Dr. Leslie G. Biesecker discovered that the somatic single (point) mutation in the AKT1 oncogene causes Proteus syndrome¹. Subsequently, the NHGRI team presented at the 2014 meeting of the American Society of Human Genetics (ASHG, Abstract # 2180M²), data that demonstrate that treatment with ARQ 092 caused a rapid decrease of AKT signaling and a reduction in the viability of Proteus syndrome cells taken from patients compared to untreated diseased cells. These findings provided preclinical proof-of-concept for advancement of miransertib into clinical testing for Proteus syndrome.

Our agreement, signed with the NIH in November 2014, is built upon preclinical data from NIH research and our own research in oncology demonstrating AKT signaling and the reduction of cell viability. The collaboration provides the opportunity to clinically investigate the therapeutic impact of miransertib in a rare, genetic disorder that has no approved medicinal therapy. The NIH is currently conducting a Phase 1 trial of miransertib for Proteus syndrome.

Related Links

http://ghr.nlm.nih.gov/condition/proteus-syndrome

http://www.nih.gov/news/health/jul2011/nhgri-27.htm

http://www.proteus-syndrome.org

http://www.proteus-syndrome.org.uk

References

Repression of ATK signaling by ARQ 092 in cell and tissues of patients with Proteus syndrome

1N Engl J Med 2011; 365:611-619, August 18, 2011

2http://www.ashg.org/2014meeting/pdf/2014_ASHG_Meeting_Poster%20Abstracts.pdf 

We are collaborating with Memorial Sloan Kettering Cancer Center on the clinical development of miransertib (ARQ 092), an orally available, selective, pan-AKT (protein kinase B) inhibitor that potently inhibits AKT1, 2 and 3 isoforms. Recent molecular characterizations of endometrial cancers support the rationale for targeting the PI3K/AKT pathway. Preclinical studies with miransertib showed suppression of PIK3CA/AKT1 mutant dependent kinase signaling and anti-tumor activity in endometrial tumor models.1,2

With our collaborators at Memorial Sloan Kettering, we initiated an expansion cohort for miransertib in combination with anastrozole (hormonal therapy) in patients with endometrial cancer harboring AKT and/or PI3K mutations. This study is an open-label Phase 1b trial to assess the safety, pharmacology and tumor response of miransertib in patients with endometrial cancer with AKT and/or PI3K activating mutations.

 

References

1http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140479

2https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00619

3http://cancerres.aacrjournals.org/content/78/13_Supplement/CT035

We are currently collaborating with The University of Texas MD Anderson Cancer Center on the clinical development our AKT inhibitor, ARQ 751.

ARQ 751 is an orally available, highly selective, next-generation pan-AKT (protein kinase B) inhibitor that potently inhibits AKT1, 2 and 3 isoforms. Dysregulation of AKT has been implicated in many cancers, making AKT an attractive target for cancer therapy.

Our Phase 1 clinical study with MD Anderson Cancer Center is a dose escalation study in adults with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations and PTEN-null, or other known actionable PTEN mutations. The goal of this study is to assess safety and tolerability, PK, PD and clinical activity of ARQ 751 in patients with advanced solid tumors.

Related Links

https://www.mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2016-0212.html

We are collaborating with the University of Texas Southwestern Medical Center on the clinical development of ARQ 761, an intravenously administered prodrug of Beta-lapachone, a naturally occurring substance. ARQ 761 is an NQO1 inhibitor that has demonstrated the potential to enhance the effect of chemotherapy and other cancer therapies.

In vitro testing showed activity against a wide range of tumors. Phase 1a testing with ARQ 761 identified anti-cancer activity as measured by tumor responses that occurred exclusively in a portion of the patient population with high levels of NQO1, the mechanistic target of the compound.

Related Links

http://www.utsouthwestern.edu/research/fact/detail.html?studyid=STU%20042011-005

http://www.utsouthwestern.edu/newsroom/center-times/year-2012/august/nanoparticles.html

https://www.arqule.com/pipeline/btk-inhibitor-arq-531-2/

The Ohio State University
National Institute of Health (NIH)
Memorial Sloan Kettering Cancer Center
The University of Texas MD Anderson Cancer Center
University of Texas Southwestern Medical Center

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