Research and Development
MDxHealth is a front runner in epigenetic research with a proven track record to identify, develop, validate and deliver molecular diagnostic assays. Leveraging our patented methylation specific PCR technology (MSP) and proprietary portfolio of genes, we have built a robust portfolio of biomarkers for diagnostic, prognostic and predictive molecular assays for prostate, colorectal, lung, bladder and brain cancers, among many others. In addition, MDxHealth has numerous proprietary biomarkers for other solid cancer types ready for development.
We endeavor to stay at the cutting edge of epigenetic solutions in the molecular diagnostics arena by continuously exploring and developing new and improved clinically relevant products, approaches and techniques. Since 2010, when we first announced the transition in our business model from a research and licensing company to a commercial clinical diagnostic company, we have been rationalizing our R&D efforts with the goal to narrow our focus on select number of core development projects to bring to the market. With our current focus on urologic cancers, we have either delayed, partnered or frozen many of our developemt programs previously identified in our product pipeline.
Our ongoing core research and development efforts include:
- Further enhancement of our ConfirmMDx for Prostate Cancer test
- New product development in other urologic cancers, such as bladder and kidney
- Discovery and development of new epigenetic biomarkers
- Technology platform development to increase throughput and economic efficiencies in our testing and laboratory operations
Our research and development efforts are not limited to specific technology platforms, biomarkers or methodologies. We seek to leverage current and future innovations in biomarker identification and measurement in developing future solutions. Over the past decade, MDxHealth has assembled a world-class scientific team and acquired unique experience in the application of Next-Generation and Deep Sequencing technologies for the identification and validation of powerful epigenetic biomarkers.
Enhancement of ConfirmMDx for Prostate Cancer Test
In addition to our ongoing and planned clinical studies to further support the negative predictive value (NPV) of our ConfirmMDx test, we have committed significant resources to further establish the actionability of a positive ConfirmMDx test result.
Although the ConfirmMDx test was developed to help reduce unnecessary repeat biopsies, by virtue of its high NPV, the test was also shown to be the most significant independent predictor for prostate cancer detection on repeat biopsy as reported in recent clinical validation studies. To further enhance the clinical utility of a positive test result, a risk score for ConfirmMDx methylation-positive men was developed to increase the positive predictive value (PPV), especially for those potentially harboring aggressive prostate cancer. A combined risk score based on clinical risk factors combined with epigenetic profiling strongly correlates with the detection of aggressive prostate cancer upon repeat biopsy.
At the 2014 ASCO Genitourinary Cancers Symposium in San Francisco, USA (January 30 - February 1, 2014), MDxHealth presented data demonstrating that epigenetic profiling of selected genes provided prognostic information, corresponding to Gleason score that could help to identify patients with aggressive prostate cancer. The results were reported on a selected panel of genes that MDxHealth had previously identified as exhibiting prognostic value, including the GSTP1, APC and RASSF1 genes from the ConfirmMDx for Prostate Cancer test.
At the recent 2015 ASCO Genitourinary Cancers Symposium in Orlando, USA (February 26-28, 2015), MDxHealth and our collaborators presented data demonstrating that the intensity of field effect hypermethylation of GSTP1, APC and RASSF1 in benign biopsy cores correlates with the level of hypermethylation present in the cancer cores from the same patient. In Gleason score 6 (GS6) cancer cores, the intensity of hypermethylation is higher in subjects who also have cores of GS7 than in subjects with GS6 cores only. These findings support the feasibility of an algorithm that is sensitive to the aggressiveness of undetected prostate cancer.
MDxHealth and our collaborators presented additional scientific and clinical data describing a risk score for ConfirmMDx methylation positive patients at the 2015 Annual American Urological Association meeting in New Orleans, USA (May 15-19, 2015). The data support a secondary algorithm, which combines clinical risk factors with epigenetic profiling to improve the identification of patients with a negative prostate biopsy but who may be at increased risk of harboring clinically significant prostate cancer.
Consistent with our focus in the urology market, MDxHealth is accelerating the development of our AssureMDx for Bladder Cancer test. The test is designed to rule-out bladder cancer in patients diagnosed with hematuria, who are traditionally followed with cytology and cystoscopy. Although cytology and cystoscopy are the standard of care, these methodologies are prone to miss small papillary bladder tumors, satellite lesions as well as carcinoma in situ. The AssureMDx for Bladder Cancer test is a non-invasive, urine-based test designed to help rule out the presence of cancer, sparing many patients invasive cystoscopy procedures, and aiding in the identification of high-risk patients requiring further examination.
The use of epigenetic markers for bladder cancer detection to improve on current diagnostic procedures, like cystoscopy, has been well studied and evaluated in more than 300 scientific publications. The Company has filed for patent protection on TWIST1, ONECUT2, OTX1 in combination with the mutation markers FGFR3, TERT and HRAS some of the most intensively studied and widely reported epigenetic and mutation biomarkers associated with bladder cancer diagnosis. We have recently completed a second clinical validation study and the results will be published in the Journal of Urology.1-3
Additionally, we are validating AssureMDx for Bladder Cancer to address the need for improved monitoring of patients treated for low grade superficial bladder cancer. More than 60% of early stage bladder cancer patients will have a recurrence following treatment and it is estimated that more than 300,000 Americans are currently under surveillance for recurrent bladder cancer.4
Bladder cancer is the fourth most common cancer in men and the eight most common cancer in women. Over 170,000 cases are diagnosed every year in the US and EU, with over 50,000 deaths. Worldwide, the incidence of bladder cancer varies substantially, with over 400,000 cases each year, and the highest rates in Europe and North America and in areas (e.g. North Africa) endemic with the parasite Schistoma heamatobium. Annually in the US, we consider that there are approximately:
- 7 million patients diagnosed with hematuria
- 1 million referrals to urologists
- 72,500 bladder cancer diagnosis
- 15,000 deaths(5,6)
More than 90% of bladder cancer patients in the EU and US have urothelial cell carcinoma (UCC), derived from the urothelium or lining of the bladder, most of whom initially present with superficial disease. These UCC’s have a high chance of recurrence (60-80%), requiring extensive and long-term monitoring for progression to more invasive disease. There are an estimated 1 million individuals in the US and EU living with a diagnosis or history of bladder cancer that require this life-long surveillance.(5,6,7,8)
Hematuria is the most common sign of bladder cancer, with 90% of bladder cancer patients presenting with macro or micro hematuria, however only 15-35% of patients with hematuria are diagnosed with bladder cancer. In the US, over 7 million people are diagnosed with hematuria each year. Under today’s standard of care, diagnosis and surveillance of bladder cancer consists of cystoscopy and cytology. A urine sample is obtained for cytopathology review to identify the cause of hematuria and to rule out bladder cancer. While cytopathology yields a high specificity of more than 90%, its sensitivity,at approximately 50%, is quite weak, leaving many patients without a definitive diagnosis and at risk for low grade bladder tumors. When the cause of hematuria remains unclear, patients are referred to a urologist for further evaluation, leading to about 1 million patient referrals each year. Cytopathologic review is often repeated, and if equivocal, a cystoscopy procedure will be performed.(1,5,6,8)
In 2010, MDxHealth published a validation study of a two-gene epigenetic bladder cancer test in the journal European Urology, reporting an NPV of greater than 95%. (Identification and Validation of the Methylated TWIST1 and NID2 Genes through Real-Time Methylation-Specific Polymerase Chain Reaction Assays for the Noninvasive Detection of Primary Bladder Cancer in Urine Samples, EUROPEAN UROLOGY 58 (2010) 96–104.) Analysis of urine samples from 466 subjects identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from bladder cancer patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. These results suggest that detection of the methylated TWIST1 and NID2 genes in urine sediments using methylation specific PCR provides a highly sensitive and specific, noninvasive approach for detecting primary bladder cancer in hematuria patients.1
Kidney and other Urologic Cancers
MDxHealth will continue to focus in urological oncology, and we intend to develop and validate tests for kidney cancer, also known as renal cell carcinoma. Early stage development work is underway with academic collaborators in the areas of diagnosis and prediction of response to therapy.
Biomarker Discovery and Development
With over a decade of cutting-edge epigenetics research and development experience, both internally and with a diverse range of academic and commercial collaborators, MDxHealth has amassed a proprietary portfolio of hundreds of epigenetic biomarkers and related expertise.
For cancer outside of our core urologic focus, we have sought to partner or out-license the commercialization of valuable biomarkers and technologies. The following represent certain of the key cancer types that MDxHealth has addressed:
- Colon: In 2010, MDxHealth entered into an exclusive licensing agreement with Exact Sciences Corporation for stool-based screening of colorectal cancer. Under the terms of the agreement, Exact Sciences obtained exclusive, worldwide rights to use MDxHealth’s NDRG biomarker in stool-based detection of colorectal cancer, as well as non-exclusive access to MDxHealth’s MSP platform technology for use with those biomarkers. Exact Sciences has obtained FDA approval and CMS coverage, and launched its Cologuard® test in H2 2014.
- Brain: MDxHealth holds exclusive rights to the MGMT biomarker, which has been extensively studied in glioblastoma and related brain cancers. Studies on thousands of clinical trial patients have demonstrated that methylation of MGMT can help oncologists identify newly diagnosed glioblastoma patients that are likely to respond to the most commonly used class of brain cancer drugs (alkylating agents). MDxHealth’s PredictMDx for Glioblastoma (MGMT) test was included in the 2013 National Comprehensive Cancer Network (NCCN) Senior Adult Oncology Guidelines and has been awarded a Tier 1 reimbursement code, 81287, by American Medical Association (AMA), which provides a clear basis for comprehensive reimbursement. MDxHealth’s strategy has been to partner with leading pathology service providers, such as the Laboratory Corporation of America (LabCorp) in the US, Teva Pharmaceutical Industries in Israel, and HistoGeneX in Belgium, to distribute the MGMT test to clinicians.
- Cervical: In 2014, MDxHealth granted oncgnostics GmbH of Jena, Germany, a limited, non-transferable, non-exclusive, worldwide license for its patented methylation specific PCR (MSP) technology for diagnostic applications in cervical cancer. In return, MDxHealth will receive upfront and milestone payments, and royalties on net sales. oncgnostics will utilize MDxHealth's epigenetic technology for the accurate and sensitive assessment of DNA methylation markers included in its GynTect® test, which is intended for the early detection of cervical neoplasias that may progress to cancer.
MDxHealth, in collaboration with University of Gent in Belgium, has established the NXTGNT (Epi)genomics research joint-venture, which brings together researchers with expertise in genomic and methylome sequencing and bioinformatics. The Laboratory for Bio-informatics and Computational Genomics (BIOBIX, FBW), the laboratory for Pharmaceutical Biotechnology (FFW), the IOF consortium Biomarked, together with a research team from MDxHealth are located within the Faculty of Pharmaceutical Sciences at University of Gent in Belgium. NXTGNT's core focus is the application of innovative technologies such as NextGen and Deep Targeted Sequencing for the discovery of novel biomarkers which improve the diagnosis and risk stratification of cancer patients, as well as the identification of potential targets for therapy. The mission is to accelerate the development and preclinical validation of new diagnostic and therapeutic products for personalized medicine.
Utilizing our experience in the development of methylation-specific deep sequencing technology, MDxHealth offers a discovery product to researchers and to pharmaceutical companies called EpiHealth. EpiHealth is a panel of hundreds of defined genes whose expression is controlled by DNA methylation. This concise panel allows collaborators to test xenografts, cell lines and primary material, and to focus on known published genes thereby decreasing the overall project development time. Knowledge gained from the profiles of the primary material allow for rapid downstream development of MSP assays for clinical application.
1. Renard et al.: Identification and Validation of the Methylated TWIST1 and NID2 Genes through Real-Time Methylation-Specific Polymerase Chain Reaction Assays for the Noninvasive Detection of Primary Bladder Cancer in Urine Samples, European Urology 58 (2010) 96–104.
7. Sylvester et al Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006 Mar;49(3):466-5; discussion 475-7.