Pipeline
VEGFR-3 ANTIBODY
Circadians partner, ImClone Systems, a wholly owned subsidiary of Eli Lilly & Co, is developing a fully human anti-VEGFR-3 antibody as a treatment for solid tumours. This antibody is designated as IMC-3C5. In April 2010 ImClone announced that it had commenced Phase I clinical trials. The trial is described in greater detail at www.clinicaltrials.gov under NTC01288989.
VGX-100
VGX-100 is a fully human monoclonal antibody targeting the VEGF-C protein. Preclinical studies have demonstrated that it inhibits the growth of a variety of tumour types including prostate, glioma, lung, ovarian and breast cancer. Additionally, VGX-100 has been shown to dramatically reduce the frequency of tumour metastatic spread in certain animal models. Formal IND enabling toxicology studies have identified no serious adverse effects of VGX-100 treatment in animals. VGX-100's IND was cleared by the FDA in October 2011. Phase 1 clinical trials commenced at two sites (UCLA and MD Anderson Cancer Centre) in January 2012, and are expected to be completed by H1 2013. Phase 2 studies are expected to commence in H2 2013. VGX-100 and its therapeutic uses are covered by a variety of US and international patents extending beyond 2023.
VGX-300
VGX-300 is a soluble form of VEGFR-3. It functions by capturing and blocking the activity of both VEGF-C and VEGF-D. VGX-300 consists of extracellular domains of human VEGFR-3 fused to the Fc-domain. In addition to cancer, Circadian is also evaluating VGX-300 in models of eye disease, in particular "wet" Age Related Macular Degeneration . Circadian’s patent protection covering soluble VEGFR-3 extends beyond 2025. The molecule is currently undergoing detailed pre-clinical testing. Circadian plans to initiate human clinical trials of VGX-300 in 2012/13.
CANCERS OF UNKNOWN PRIMARIES
Carcinomas of unknown primary (CUP) account for 3–5% of all malignancies. CUP is generally less well known and publicised than other cancer types. However, it is actually more common than leukaemia and is the fifth most common cause of death due to cancer in Australia.
Although the prognosis for patients with CUP is poor, identifying the primary site of the tumour can allow for more specific treatment selection and may prolong survival.
The diagnostic test method for CUP has been developed through a collaboration between Circadian, the Australian pathology company, Healthscope, the Peter MacCallum Cancer Centre, a leading specialty cancer centre based in Melbourne, Australia, and scientists at NICTA (National ICT Australia) and has been validated based on results obtained from biopsies taken from patients with multiple different different tumour types.
The CUP diagnostic methodology identifies a patient’s tumour type by comparing its pattern of gene expression to a database of known tumours. It is hoped that by correctly identifying a patient’s tumour type, clinicians can choose the most effective treatment strategy for the cancer. RNA is extracted from formalin fixed biopsy samples containing known metastatic tumours of various classes. Whole genome expression analysis is performed and a binary support vector machine utilising a proprietary algorithm is then used provide a probability weighted analysis of likely primary tumour type.
Healthscope, through its subsidiary Clinical Laboratories Pty Ltd, has rights to develop, clinically validate and market the test throughout Australia, New Zealand, Malaysia and Singapore. Circadian retains rights to market the test in the remainder of the world.
Healthscope launched the product as CUPGUIDETM in July 2012 in Australia, New Zealand, Singapore and Malaysia.
VEGF-D DIAGNOSTICS
VEGF-D has shown to be a very important prognostic indicator for survival in a number of different tumour types particularly gastric cancer. Circadian is currently developing a range of specific VEGF-D antibodies that can be utilised by pathology groups to undertake immunohistochemical analysis of tumour biopsies.
Additionally, Circadian in conjunction with the Cincinnati Children’s Hospital Medical Center markets a blood based VEGF-D diagnostic test in the USA as a laboratory test compliant with CAP (College of American Pathologists) /CLIA regulations. This is the first blood based diagnostic available to test for the disease lymphangioleiomyomatosis (LAM). The blood sample based diagnostic was developed by Cincinnati Children’s, using Circadian’s VEGF-D technology, following the discovery that high levels of vascular endothelial growth factor-D, or VEGF-D – to which Circadian owns intellectual property rights – holds the key to detecting the disease.
LAM is a serious lung disease that causes shortness of breath and lung collapse. It affects mostly women, often striking in their 30s or child bearing years, and the only known treatment is a lung transplant.
Although only a small number of patients have been diagnosed with LAM to date, the recent discovery of a link between LAM and genetic abnormality, Tuberous Sclerosis Complex (TSC), causing the disease, has led scientists to estimate that more than 250,000 women worldwide are unaware they have LAM. The availability of the test, and subsequent increasing knowledge of the disease amongst the general medical community, is predicted to increase screening for LAM in patients, with the number of tests estimated to exceed 25,000 within the next few years.
The findings of the diagnostic link between LAM and VEGF-D by the team of scientists at the University of Cincinnati (UC) and Cincinnati Children’s led by Dr. Lisa Young and Dr. Frank McCormack, Director of Pulmonary, Critical Care and Sleep Medicine at UC were published in the August 2010 edition of CHEST1.
Cincinnati Children’s provides the diagnostic test for LAM in the United States. Circadian retains the rights to the rest of the world and is working towards approval in other markets.
Circadian is also undertaking research studies to expand the use of VEGF-D blood based diagnostic tests to the oncology setting.
VEGF-C DIAGNOSTICS
Blood levels of VEGF-C have been widely described as a major prognostic indicator for disease progression and/or patient survival in a very wide array of different tumour types.
More recently, at ASCO 2011, a group at MD Anderson reported that, following analysis of a colorectal cancer patient cohort, that VEGF-C levels appear to be a predictive biomarker indicating resistance to Avastin.
These findings have identified a major diagnostic role for blood levels of VEGF-C to be used a diagnostic tool for various tumour types as well as monitoring the ongoing efficacy of particular drug therapies.
Circadian is currently developing VEGF-C diagnostics in collaboration with a number of groups worldwide with the aim of having a VEGF-C diagnostic publically available by H1 2013.
_________________________
1 Chest. 2010 Sep;138(3):674-81.