IRAP: fighting diabetes through screening for risk

Over 325 million working-age people have diabetes, 50% of which are undiagnosed. We propose a novel and simple diagnostic tool.

The aim of this proposal is to fight the diabetes epidemic which has become a major health and socioeconomic burden especially in low-income areas and countries. Type 2 diabetes (T2D) is a progressive disease due to increasing resistance to insulin (IR), which is asymptomatic during its initial phase called prediabetes. Early management, based essentially on diet and lifestyle improvement or very low-cost drugs, is very effective as it generally stops the progression of the disease. Counseling and education leading to self-care should therefore allow to strongly reduce the incidence of diabetes.

The key issue is thus early diagnosis of IR through simple but reliable and cost-effective means. So far, the current tests are either too variable and therefore unreliable or too complicated and expensive to serve for large-scale population screening.

We have identified a novel biomarker of IR and developed a specific and quantitative assay for it in blood whose aim is to detect prediabetes thus allowing to enforce counseling and self-care campaigns for the affected populations.

- The prevalence of T2D has been estimated at 425 million people and prediabetes at around 35% of the population worldwide. T2D is expected to affect 520 - 830 million people by 2040. 

- Two thirds of the people affected by T2D are of working-age and the resulting disability exceeds 100 million corrected life years. T2D is responsible for 28% (Europe) to >75% of deaths under 60 years (Africa and S-E Asia). 

- The healthcare cost of diabetes has been estimated at 727 billion USD worldwide in 2017. 

         Apart from being the early phase of T2D, prediabetes itself is a serious disease as it strongly increases the cardiovascular risk similar to T2D.

         As stated above, the key to success in this fight, is an appropriate diagnostic test usable for population screening.

         Our novel IR biomarker is the circulating fragment of IRAP (Insulin-Regulated AminoPeptidase), which is secreted in the bloodstream in response to insulin. In IR, cells gradually lose their sensitivity to insulin and glucose levels in blood increase causing prediabetes and eventually diabetes (T2D). Concurrently, IRAP secretion decreases.

         We have developed and patented a robust, extremely sensitive and specific assay for IRAP in blood. Moreover, IRAP's stability allows samples to be stored prior to being assayed. Currently, the IRAP assay has been analytically validated, reference values for healthy individuals have been determined and pilot studies have confirmed our hypothesis. A multi-centric clinical trial is underway. 

Eventually, we are aiming at developing a point-of-care test to allow immediate diagnosis and subsequent management on location.

         We feel that this project fits with the spirit of Solve challenges as it should provide a solution for a major health and socio-economic threat to low-income and remote or secluded areas by procuring an easy and affordable screening tool to allow timely, local and simple management of prediabetes and hence prevention of T2D.

Despite the rapidly growing incidence of Type2 Diabetes (T2D), there is currently no simple and reliable test available for the diagnosis or screening of its cause, insulin resistance (IR), which is the key to any policy of preventive care. The same applies to T2D. 

We discovered a novel circulating biomarker of glucose uptake, IRAP. IRAP itself is directly involved in insulin-dependent glucose uptake through the regulation of GLUT4 translocation which makes it the first direct biomarker of insulin response.

We propose to use IRAP determination as a screening and diagnostic tool for IR and T2D in populations at risk.

The ELISA we developed uses custom-made recombinant human secreted IRAP protein for its calibration. Since the secreted extracellular domain of IRAP is heavily glycosylated (approx. 50 kDa of sugar residues for 110 kDa of amino acids), the expression system we developed is crucial in order to avoid aberrant glycosylation which would alter the the results.

In addition, this ELISA requires two specific monoclonal antibodies which we developed in order to obtain a highly specific and sensitive assay. Sensitivity is essential as IR and T2D are characterized by reduced IRAP concentrations.

1- To confirm the results of our pilot studies which indicated that IRAP levels correlate with insulin sensitivity:

   - A trial to determine IRAP values in healthy subjects according to sex  and age is expected to end by December 2018.

   - A multi-centric trial to compare the diagnostic value of IRAP versus OGTT in pre-diabetic patients (n = 100)  will be launched in September 2018. First results are expected by the end of 2019.

   - Launch a larger scale multi-national clinical trial on pre-diabetic and T2D patients in 2019

2- To diffuse the first results of the studies

Once the diagnostic value of IRAP will have been established, large-scale production and registration of IRAP ELISA kits through either licensing or partnership with an IVD company, or creation of a start-up company will be launched.

This will allow increased availability and reduction of costs for diagnostic and screening campaigns. 

Diabetes foundations and health authorities will be contacted 

Deployment will  occur essentially through two pathways:

   - Government health agencies and authorities

   - Medical and Diabetes foundations and societies

This should allow accessing targeted populations through screening and diagnosis campaigns

Retainment of customers will depend essentially on the success rate of the pilot campaigns

Currently only volunteers (n=200) enrolled in clinical trials

A few thousand essentially by increasing the size and number of clinical trials and pilot campaigns.

A major effort will be devoted to the evaluation of IRAP as screening and diagnostic tool in obese child and adolescent populations. The french government will launch a program focused on this particular issue and is interested by our assay.

We have an expertise the pathophysiology of insulin resistance and T2D

We have a longstanding expertise in the various skills required for the design of ELISAs:

   - recombinant protein production

   - antigen design and monoclonal antibody generation

   - assay design and optimisation

We have a longstanding expertise in setting up and coordinating clinical trials, both mono- and multi-centric 

There are essentially two options:

   - licensing to an existing IVD company. One of the three major IVD companies worldwide is interested by our assay and by a license once it will have been clinically validated.

   - launching a biotech start-up company. 

Considering the size of the diabetes care devices market, currently estimated at approximately 20 billion USD and expected to reach 26 billion USD in 2021 (CNBC), long-term sustainability and profitability should be ensured. The market for a screening and direct diagnostic test such as IRAP, which has no competitor, has been estimated between 0.5 and 1 billion USD/year.

Taking the increasing size of affected and at risk populations which will require diagnosis and follow-up monitoring, the market for IRAP is probably underestimated and should anyhow grow with time.

This growth should be supported by the will of most industrialized and emerging countries to establish preventive healthcare policies aimed at fighting the T2D "epidemic" which is becoming a major socioeconomic burden.

I am applying to Solve because of 

1° funding restrictions in France which make it very difficult to develop any large scale health and medicine project and 

2° the difficulty in getting in contact with foundations or industrial companies to try to establish partnerships.

I understand that one of Solve's major aims is to foster this kind of contacts and partnerships.

1° Insufficient funding for large scale multi-centric clinical trials

2° Lack of contacts with major industrial companies active in the field in order to establish partnerships

3°  Lack of contacts with major diabetes foundations and associations as well as with WHO

I feel that Solve can help me to meet key persons in these areas