Clinical Research. |Valued Cooperations. For Improved Diagnostics.

With over a decade of cutting-edge clinical research and development experience, both internally and with a diverse range of academic and commercial collaborators, numares has gained a proprietary portfolio of several metabolic constellations and related expertise.

 

 

We endeavor to stay at the cutting edge of metabolomics solutions in the clinical diagnostics arena by continuously exploring and developing new and improved medically relevant products, approaches and techniques. Get to know numares’ clinical research unit in this section.

Our Vision. |Precision Diagnostics.

numares is an innovative diagnostics company, focusing on the discovery, development and the clinical integration of in-vitro diagnostic (IVD) tests that are based on metabolomics and our proprietary MGS® technology. Using these highly innovative approaches, we set out to establish IVD tests that meet current diagnostic challenges, improve patient care and easily fit into clinical routine.

Diagnostics relying on single biomarkers frequently fail to address medical needs that are still unmet today. Metabolomics offers the possibility to identify biomarker patterns in the metabolism, we call it metabolic constellations, whose dynamics and relation to each other allow non-invasive and reliable diagnostics, considering the complete individual features of the patient: just precision diagnostics.

Our clinical development unit focuses on the discovery and development of metabolic constellations for various clinical indications, including cancer diagnosis and staging, kidney transplant rejection and kidney function, multiple sclerosis and cardiovascular diseases.

With our AXINON® technology platform and associated diagnostic tests we offer the medical community - a sophisticated feature for an improved risk prediction of diseases.

 

Our Mission. |Improve Patient Care.

We are committed to advance medical progress by diagnostic products in various indications, such as cardiovascular diseases, liver and bladder cancer, multiple sclerosis, kidney function and renal transplant rejection– all being rising health issues worldwide.

Our clinical development unit ensures, that the developed metabolic constellations are carefully evaluated in the clinical context. Our concepts of individual medical use cases derive from daily clinical practice where therapeutic decisions are based on various diagnostics along with additional patient information (anamnesis). Therefore, we conduct our clinical studies to systematically record these relevant clinical data which serve as a basis for a scientifically sound developed IVD. By waiving external CROs, we retain control, avoid interface losses and thus remain flexible and adaptable in the choice of the respective study design. Furthermore the close collaboration throughout the course of the study allows a deeper understanding of the challenges in clinical routine and opens up the possibility of continuous improvement of our approach.

Our Competence. |Respectful collaborations.

The carefully designed studies on which our product developments are based are an essential and integral part of our research and development process. They would not be possible without the highly appreciated contributions of our valuable partners and collaborators. It is our central concern to treat our collaborators with greatest respect not only to support their valuable work to the best of our knowledge, but also to make the implementation of clinical studies compatible with clinical routine shores. In order to succeed, we support our partners with concentrated strength and experience, providing:

  • Interdisciplinary team with a strong scientific and clinical background
  • Proven track of record in supporting IVD development with suitable clinical studies
  • Clinical expertise and compliance acc. to ISO 13485, GCP & IVD EU regulations
  • All-round support: study set-up, contracting & logistics
  • Management of regulatory affairs & ethical approval
  • Integrity, reliable and resilient commitments
  • Joint scientific dissemination

Our Success. |Innovative Diagnostic Products.

Project: RENUM – Renal Function Assessment by Nuclear Magnetic Resonance based Metabolomics

Objective:
Development and validation of an NMR based metabolic constellation determining glomerular filtration rate for a more accurate picture of the underlying kidney function.

“A diagnostic test as precise as mGFR, as simple as eGFR, and fit for clinical routine“,
Dr. Eric Schiffer, Head of Clinical Development, numares AG

The glomerular filtration rate (GFR) is the most important parameter in assessing kidney function. The gold standard to determine GFR is inulin clearance [1, 2], but other substances have been explored for measuring GFR (mGFR) as well [3]. Although very precise, mGFR methods are expensive, time-consuming and therefore impractical in routine. Therefore, GFR is mostly estimated by a simple serum creatinine analysis (eGFR) [4]. However, serum creatinine levels strongly depend on patient’s individual features, i.e. muscle mass, age or physical activity level. Thus, this approach is associated with a distinct imprecision. There exist more than 50 eGFR equations illustrating the degree of uncertainty associated with the approach [5]. Based on these facts, there is a clinical need for a test system that combines precision of mGFR approaches with the easy accessibility of eGFR.

Study design:
RENUM is a retrospective multi-center observational study

Material:
Biobanked serum samples of patients with broad spectrum of primary renal diseases and degrees of renal impairment

Reference standard:
mGFR

Approach:
The scientific literature indicates that there is a connection between increasing/ decreasing concentrations of endogenous blood metabolites and the GFR. To establish a combination of endogenous metabolites with creatinine to a metabolic constellation reflecting GFR, numares uses its precise, fast and flexible analytical AXINON® System, which allows simultaneous detection of metabolites in a highly reproducible single analytical step.

Phase 1:
The association of endogenous serum metabolites with GFR will be tested. Quantitative NMR signals of both, literature reported candidates and proprietary metabolic markers, will be correlated with mGFR reference data. Candidates significantly associated with GFR will be used to model renal clearance based mGFR. 

Phase 2:
The diagnostic performance (trueness and precision) of the obtained model(s) will be tested in a further, independent sample set (not used for discovery or modelling).

Success:
Our efforts will result in a novel, simple blood test that will be available for clinical routine in early 2019: AXINON® Clearance Check.

References: 
1. Smith, H.W., The kidney: Structure and function in health and disease. Oxford University Press Inc, New York, 1951.
2. National Kidney, F., K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis, 2002. 39(2 Suppl 1): p. S1-266.
3. Stevens, L.A. and A.S. Levey, Measured GFR as a confirmatory test for estimated GFR. J Am Soc Nephrol, 2009. 20(11): p. 2305-13.
4. Kemperman, F.A., R.T. Krediet, and L. Arisz, Formula-derived prediction of the glomerular filtration rate from plasma creatinine concentration. Nephron, 2002. 91(4): p. 547-58.
5. Johnson, D. and I. Caring for Australians with Renal, The CARI guidelines. Evaluation of renal function. Nephrology (Carlton), 2005. 10 Suppl 4: p. S133-76.

*numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.

Project: PARASOL – Detection of Renal Allograft Rejection by NMR-based Urine Metabolomics

Objective:
Quantitative evaluation of the diagnostic accuracy (AUC value, sensitivity, and specificity) of AXINON® renalTX-SCORE-U100® for the detection of acute renal allograft rejections

“A non-invasive diagnostic test for close-monitoring of kidney transplant patients and minimizing the number of potential graft-harming biopsies for earliest therapy intervention to preserve the kidney“,
Dr. Eric Schiffer, Head of Clinical Development, numares AG

Kidney transplantation is the treatment method of choice for patients with terminal kidney failure [1]. Transplant patients require frequent follow-up examinations to detect potential complications at an early stage. Therefore, biopsies are performed during aftercare. They are generally considered to be safe, but it remains an invasive procedure with a risk for complications, at worst of losing the transplant [2; 3]. A metabolite based, non-invasive test for the detection of acute rejection after transplantation would improve clinical detection of asymptomatic rejection to arrange a control biopsy or to supplement the physician’s assessment of patients with non-specific symptoms such as fever.

Study design:
PARASOL is an open-label multicenter prospective observational (non-interventional) study w/o follow-up

Partners:
Regensburg University Hospital (Prof. Dr. Bernhard Banas); Medical University Vienna (Prof. Dr. Georg Böhmig); Institute for Clinical and Experimental Medicine Prague (Prof. MUDr. Ondřej Viklický, CSc.); Centre Hospitalier Universitaire Grenoble Alpes (Prof. Dr. Lionel Rostaing); Bellvitge University Hospital Barcelona (Dr. Oriol Bestard)

Material:
Urine samples from renal allograft patients ≥14 days after transplantation

Reference standard:
Routine kidney biopsy

Approach: 
Metabolomics studies make it possible to analyze the entire metabolite spectrum (metabolome) to detect rising and falling concentrations of endogenous substances and associate them with pathological processes. Previous results from the UMBRELLA study, which was performed in collaboration with Bernhard Banas and co-workers from the Department of Nephrology at the University Hospital Regensburg, showed that it is possible to diagnose acute renal allograft rejection from urine using alanine, citrate, lactate, and urea normalized to urine creatinine. This metabolic constellation is further validated in the PARASOL study in a pan-European multicentre study. The diagnostic accuracy for the metabolic constellations will be determined based on their AUC value, sensitivity, and specificity depending on the cut-off value.

Success:
In 2017, numares launched the AXINON® renalTX-SCORE-U100®* for use in clinical routine. 

References:
1.    Suthanthiran, M. and T.B. Strom, Renal transplantation. N Engl J Med, 1994. 331(6): p. 365-76.
2.    Schwarz, A., et al., Safety and adequacy of renal transplant protocol biopsies. Am J Transplant, 2005. 5(8): p. 1992-6.
3.    Furness, P.N., et al., Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates. Transplantation, 2003. 76(6): p. 969-73.

*numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.

Project: BLADE – Bladder Cancer Detection using Metabolomic Evaluation of Urine and Blood

Objective:
Development and Evaluation of a metabolic constellation for the diagnosis of bladder cancer in patients with persistent microhaematuria.

“A minimal invasive diagnostic test for a reliable detection of bladder cancer.“
Dr. Eric Schiffer, Head of Clinical Development, numares AG

Urinary bladder cancer (BCa) is a malignant tumour that usually develops in the mucous membrane (urothelial carcinoma) of the bladder. The symptoms are relatively unspecific. One of the earliest cardinal symptoms of BCa is microscopically detectable haematuria, so-called microhaematuria, [1]. However, microhaematuria commonly has benign causes, such as infection, benign prostate enlargement or kidney stones, and is caused by malignant tumors only in 2 - 5 % of cases [2]. The key issue in the management of microhaematuria is therefore to reliable detect rare malignant bladder tumors among common benign diseases [3]. Since urinary cytology and current available urinary markers lack sufficient clinical reliability, cystoscopy in combination with biopsy and trans-urethral resection of the bladder (TURB) are considered the gold standard for the diagnosis of bladder tumors [4,5] and frequently used for urologic evaluation of persistent microhaematuria. However, these examinations are invasive, expensive [1] and unnecessary for the majority of patients with microhaematuria. Those would greatly benefit from a non-invasive, metabolomics-based test that reliable detects bladder cancer in microhaematuria and – when used as triage to cystoscopy – would help reduce unnecessary diagnostic procedures.

Study design: 
BLADE is a multicentre, two-step adaptive prospective observational study

Partners: 

  • Outpatient urological specialist practices
  • Joint specialist practices
  • University hospitals

Material: 
Urine and serum samples from patients scheduled for cystoscopy or TURB due to persistent microhaematuria 

Reference standard:
Bladder cystoscopy in combination with biopsy or trans-urethral resection of the bladder (TURB)

Approach:
Over the past 20 years, a variety of molecular markers has been proposed for the detection of BCa in patients with persistent microhaematuria to meet the medical need for a triage test to reduce unnecessary cystoscopies [3]. None of the new markers is currently well established in clinical routine. Transferred to a heterogeneous patient population with multiple causes of microhaematuria, only a pattern with multiple markers is likely to provide sufficient diagnostic accuracy to exclude bladder cancer as a cause of microhaematuria. With the AXINON® platform, numares has a reliable, fast and flexible analysis system for the simultaneous acquisition of several hundred metabolites in a single analytical step. The metabolomics approach will now provide initial insights into the processes and metabolic changes in in bladder cancer. This will be the basis for developing a non-invasive, metabolomics-based test for bladder detection in microhaematuria.

Success: 
In-house preliminary work identified a metabolic constellation that allows detection of BCa by NMR analysis of urine.

References:
1.    Schwartz, G.L., Proper evaluation of asymptomatic microscopic hematuria in the era of evidence-based medicine--progress is being made. Mayo Clin Proc, 2013. 88(2): p. 123-5.
2.    Elias, K., et al., High-risk patients with hematuria are not evaluated according to guideline recommendations. Cancer, 2010. 116(12): p. 2954-9.
3.    Schmitz-Drager, B.J., et al., Immunocytology in the assessment of patients with asymptomatic hematuria. World J Urol, 2008. 26(1): p. 31-7.
4.    Babjuk, M., et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder. Eur Urol. 2017 Mar;71(3):447-461
5.    Davis, R., et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol. 2012. 188:2473-81

numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.

Project: HERMES – Hepatocellular Carcinoma Recognition by Metabolomics Analysis of Serum

Objective: 
Development and validation of a metabolic constellation in serum for early detection of hepatocellular cancer.

“A diagnostic screening test for early detection of hepatocellular cancer to supplement abdominal sonography in HCC surveillance.“
Dr. Eric Schiffer, Head of Clinical Development, numares AG

Hepatocellular carcinoma (HCC) is an aggressive tumor of the liver with annual incidence of 1-6% in at risk patients with liver cirrhosis [1, 2]). Most patients have symptoms only in advanced stage HCC, impeding early detection of the tumor. The 5-year survival rate is <10% if HCC is diagnosed after symptoms occur in advanced stage [3].However, 5-year survival rates of 50 – 70% are possible when the tumor is diagnosed at an early stage [4]. Therefore, current guidelines recommend to enroll patients with liver cirrhosis in HCC surveillance programs using semiannual abdominal sonography [4,5]. Unfortunately, the sensitivity of sonography for detecting early stage HCC in liver cirrhosis is less than 50% according to a recent meta-analysis [6]. Addition of the widely used serum biomarker AFP (alpha-feto protein) to sonography only marginally improved sensitivity for early HCC and is not recommended in HCC surveillance due to its low sensitivity and specificity. Thus, there is a strong clinical need for a non-invasive test to supplement abdominal sonography in HCC surveillance to improve detection of early stage HCC.

Study design: 
HERMES follows a two-step approach with development and initial testing of the metabolite constellation in retrospective case-control cohorts and a subsequent validation including transfer to the target population in a prospective multicenter study**.

Material: 
Serum samples of cirrhotic patients with and without HCC

Reference standard: 
High-resolution imaging with liver biopsy if necessary

Approach: 
Metabolomics studies allow the analysis of the entire metabolite spectrum (metabolome) of a biospecimen to detect rising and falling concentrations of endogenous substances and to associate them with pathological processes. numares uses its precise, fast and flexible analytical AXINON® System, which allows simultaneous detection of metabolites in a highly reproducible single analytical step without predefined selection criteria. Using this untargeted metabolic analysis, numares has identified a metabolite constellation in serum for detection of early HCC using a retrospective case-control data set. In an independent sample set not used for biomarker discovery, the metabolite constellation was able to detect early HCC in high-risk patients with liver cirrhosis. Moreover, preliminary work suggests that this metabolite constellation, in combination with abdominal sonography, can provide significant added value over sonography alone. In a first step, the metabolite constellation will be tested in additional retrospective case/control cohorts. In a second step, these results will be validated further and transferred to the actual surveillance setting in a prospective multicentre study**. 

**The prospective multicentre study is sponsored by the German Federal Ministry of Education and Research, field of action “Gesundheitswirtschaft im Rahmenprogramm Gesundheitsforschung”, contract number 13GW0307.

Success: 
numares successfully identified a metabolic constellation in serum for detection of early stage HCC*. 

References:
1.    Forner, A., M. Reig, and J. Bruix, Hepatocellular carcinoma. Lancet, 2018. 391(10127): p. 1301-1314.
2.    Ioannou, G.N., et al., Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol, 2007. 5(8): p. 938-45, 945 e1-4.
3.    Llovet, J.M., A. Burroughs, and J. Bruix, Hepatocellular carcinoma. Lancet, 2003. 362(9399): p. 1907-17.
4.    European Association for the Study of the Liver. Electronic address, e.e.e. and L. European Association for the Study of the, EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol, 2018.
5.    Heimbach, J.K., et al., AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology, 2018. 67(1): p. 358-380.
6.    Tzartzeva, K., et al., Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology, 2018. 154(6): p. 1706-1718 e1.

*numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.

Project: MUSE – Multiple Sclerosis Biomarker Evaluation

Objective:
Development and Validation of an NMR-based metabolic constellation that early indicates the transition of relapsing-remitting (RRMS) to secondary progressive multiple sclerosis (SPMS). 

“A serum-based test for early diagnosis of the RRMS-to-SPMS transition to allow timely therapy adjustment”
Dr. Eric Schiffer, Head of Clinical Development, numares AG

Multiple sclerosis (MS) is considered to be an immune-mediated disease in which the body’s own defence cells attack the central nervous system. MS involves inflammatory and neurodegenerative processes that damage the insulating myelin sheaths of nerve fibers and the nerve cells themselves.  While about 10-15% of patients begin the disease with primary progressive MS (PPMS) showing continuously worsening of symptoms from disease onset, the majority of patients are initially diagnosed with relapsing-remitting MS (RRMS)  [1,2]. In RRMS, patients experience attacks of neurological symptoms (relapses) followed by periods of complete or partial remission. Most RRMS patients will eventually transition to a secondary progressive course (SPMS) with continuous worsening of symptoms and accumulation of disability. The RRMS-to-SPMS transition requires a change in therapy as most MS medications are not effective in SPMS [3].  Currently, there is no diagnostic test for SPMS and clinical diagnosis of SPMS transition is difficult and time-consuming, as it requires retrospective evaluation of neurological exams and results from magnetic resonance imaging (MRI) of the brain of the last 12 months [1]. A diagnostic test that reliably identifies patients at early transition from RRMS to SPMS would improve management and long-term outcome of MS patients.

Study design:
Two-center, prospective, observational study

Material:
Serum samples from patients with RRMS or SPMS

Reference standard: 
Brain MRI in combination with retrospective evaluation of disease course and disability in neurological exams

Approach: 
University of Oxford and numares started a joint development program to develop metabolomics-based diagnostics tests in multiple sclerosis. In previous work, University of Oxford has discovered metabolic biomarkers for discriminating RRMS from SPMS patients using nuclear magnetic resonance (NMR)-based analysis of blood samples [4]. Oxford University and numares are currently conducting a prospective observational study to validate the identified biomarkers and combine them to a metabolic constellation that reliably indicates early transition from RRMS to SPMS. numares provides its Magnetic Group Signaling (MGS®) technology and NMR-based AXINON® IVD system to translate the biomarker constellation into an in vitro-diagnostic (IVD) test.

Success:
In 2017, Oxford University and numares initiated a prospective observational study for validation of previous work. 

References:
1.    Lublin, F.D., et al., Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology, 2014. 83(3): p. 278-86.
2.    Multiple Sclerosis Society. Types of MS. www.mssociety.org.uk/what-is-ms/types-of-ms
3.    Shirani A, Okuda DT, Stuve O. Therapeutic advances and future prospects in progressive forms of multiple sclerosis. Neurotherapeutics 2016; 13: 58–69.
4.    Dickens, AM, et al. A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology 2014. 83:1492-9

numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.