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EPIGEN: A New Predictive Response Test for Non Small Cells Lung Cancer Treatment

Periodic Reporting for period 1 - EPIGEN (EPIGEN: A New Predictive Response Test for Non Small Cells Lung Cancer Treatment)

Reporting period: 2015-09-01 to 2015-10-31

The EPiGen Project final goal is the commercialization of the EPiGen test under CE-IVD mark as a new predictive response test to lead clinicians towards Non Small Cell Lung Cancer (NSCLC, the 80% of lung cancer diagnosed cases) personalized treatment. The key of the test is based on the measurement of the methylation percentage of the biomarker IGFBP-3, which value allows stratifying patients in terms of his potential resistance to the standard treatments: chemo and/or radiotherapy. For product commercialization first in Europe, the approval by regulatory agencies (Spanish Agency of Medicine, AEMPS, which follows European Medicament Agency (EMA) Regulatory Guidelines) is required. In the EPIGEN project we aim at validating the EPiGen technology and the IGFBP-3 biomarker in a prospective clinical study with huge statistical power (>99.9%) to provide evidence that the analysis of the EPiGen test supports the intended use.

The business opportunity is based on the need for a tool that could help clinicians stratifying patients in terms of their potential resistance to standard NSCLC treatment, which implies chemo and/or radiotherapy. The Project itself is the materialization of the clinicians claims for the development of an efficient tool that could guide them toward NSCLC personalized treatment. This support will prompt EPiGen test to be positioned leading the Cancer IVD Devices Market, being a key resource for the oncologist. EPiGen will not only improve patient health, but also will save cost for the overall healthcare system. In 2014, 1.8M patients were diagnosed with lung cancer worldwide, and are potential beneficiaries of EPIGEN test technology. Moreover, the overall mean treatment for NSCLC cost ranges from €13.218 to €16.120 per patient, but after failed treatment this mean increases up to €34.631-€42.234. These cost differences will be avoided by implementing EPIGEN test in prescription protocols. Accurate lung cancer predictive response test as EPiGen will benefit the patients, avoiding severs side effects of ineffective treatments; clinicians, leading for the best treatment option, and also will benefit the whole healthcare systems, through substantial costs reductions in management of NSCLC.
1) Technical feasibility study

The key of the EPiGen test is based on quantifying the DNA methylation status of the IGFBP-3 epigenetic biomarker of the tumour sample through Quantitative Methylation Status PCR technique (qMS-PCR), by using for quantifying our fluorescent patented probe. The DNA methylation status of IGFBP-3 was correlated with the tumor exposure to cis platinum based chemotherapy (hereafter CDDP) and to radiotherapy in three clinical retrospective studies. The final data provided from the analysis of the patient tumor sample, processed with the reagents included in the EPiGen test, is a report for the clinician that includes the recommendation for the therapy based on patient susceptibility to CDDP and radiotherapy. The tumor sample comes from the biopsy needed for the NSCLC diagnosis, therefore any other patient test will be required in addittion to the current tests carried out in the general diagnosis process. The protocol for diagnosis involves imaging test (X-ray image, CT scan), blood test, Sputum cytology, and tissue sample or biopsy. The technical task to carried out in the feasibility study included defining the clinical parameters required for the EPiGen test validation (clinical data needed, including patient typology). We also designed the experimental protocols to ensure a high level of performance in handling samples found in routine clinical use in order to guarantee the clinical standars for ensuring the CE-IVD marking and its proper implementation in diagnosis protocols before prescription.

2) Commercial feasibility study

- KOLS STRATEGY FOR BOOSTING EPIGEN COMMERCIALIZATION AND DISSEMINATION. The KOLs are clinicians who influence their peers' medical practice, including but not limited to prescribing behavior. The KOLs need not be in formal positions of authority, but have a strong influence on Health Managers buying decisions. The ultimate decision for purchasing EPiGen is not taken directly by KOLs but by Health Managers as last resort, but this decision really relies on KOLs. Therefore, for the EPiGen project, it is essential understanding KOLs influence as a potent marketing tool. To ensure a successful outcome, during the feasibility study at IGEN BIOTECH we have analyzed how to establish the basis for creating a favorable opinion of the EPiGen test in the European health community supported by KOLs. Our KOLs strategy starts in Spain through the main validation clinical study and rise to Europe with “satellite” clinical demonstration studies. The core of the biomarker validation study will be performed in a number of selected hospitals in Spain, and therefore we will engage several Spanish KOLs with different roles. The results from this main clinical study have been strictly designed to generate sufficient data for the obtaining of the CE-IVD marking. Additionally, as a commercialization strategy that will boost the market entry in Europe, we have planned to conduct smallest additional clinical studies that will be performed at the targeted European countries selected in the previously explained market study: France, Germany and UK. From a technical point of view, these punctual clinical trials are considered as additional support for our project, but are designed as demonstration studies rather than validation. The satellite studies have been specially designed in order to convince KOLs about the EPiGen test effectiveness, and this convincement will open up a KOL network with favorable opinion that will certainly influence health managers buying decisions, boosting the market entry at this European countries.

- GEOGRAPHICAL LOCATION OF POTENTIAL TARGETED USERS. During the feasibility study we have analysed the trends in the lung cancer therapeutics market in several European countries to detect which country is the most interesting for EPiGen. In terms of market share based upon manufacturer prices, the selected countries are Germany, France and UK. Additionally, we have investigated about the EU’s reimbursement environment related to CE-IVD marketed medical technology. As it is not uniform, because each member state has its own policies with reimbursement being approved by either private or public insurance companies, the most sense for us was to analyse the reimbursement policies at hospitals, our main clients, of the previously selected countries. We have also identified and selected several hospitals in each of these countries with which we plan to collaborate.

- COMMERCIALIZATION STRATEGY BASED ON DISTRIBUTORS. To avoid possible obstacles related to unfamiliar marketplace mechanics or shifting regulations of each country, at IGEN BIOTECH we have decided that market strategy based mainly on distributors makes the most sense for our needs, since a strong in-market representation is critical to export success. In addition, to dealing directly with EPiGen clients and helping us you to grow our sales, distributors will be a relevant partner that can provide us with a number of benefits. The benefits of strong in-market representation through distributors include access to local knowledge, on-going market intelligence about competitors, dealing directly with EPiGen clients in helping grow the export sales, in-market customer support for queries, support and warranty and established sales network. Overall, distributors will help us to save development marketing costs and time. In the European area, we have identified and reported during the feasibility study a number of candidates which are currently distributing similar products to the EPiGen.

3) Financial Feasibility Study.

Selling price of EPiGEN. To estimate the selling price of EPiGen during the feasibility study we performed a research about prices of current employed genetic test based on genetic mutations to personalize NSCLC treatments. These tests are based on ALK, FISH and EGFR biomarkers. These tests just target a very specific niche of patients, covering the 25% of diagnosed cases maximum stratified as potential beneficiaries of the biomarker therapy regimen, always involving a drug therapy regimen. Despite EPiGen targets the 100% of patients and its impact on patients’ outcome and also on the health care system will be certainly higher, at this stage of the project we have consider appropriately assessing the EPiGen price under these test prices.

Business Plan. Based on the activities performed above and other key issues we have elaborated a business plan and the market strategy for EPIGEN. It includes targeted commercialization strategy based on KOLs and distributors as key stakeholders. We also established Epigen Price, functionalities, countries for exploitation and key issues related to IP protection. Once analysed all these parameters we have envisaged the EPIGEN sales forecast and the estimated funding requirements for EPIGEN successful commercialization in 2019.
Personalized treatments through evidence-based guidelines are a cost-effective strategy for delivering care to patients with NSCLC, but currently there are only some recently developed approaches based on genetic markers. These approaches just provide a solution for those patients with specific genetic mutations (biomarkers) which are below 25% of total NSCLC diagnosed patients, and are linked to a drug. It means, a genetic test is performed once the patient is diagnosed, and if the biomarker (genetic mutation) is found, the patient can benefit of a special drug regimen, but even in this cases chemo and/or radiotherapy are prescribed at any rate. The EPiGen test will offer a tool based on epigenetic factors, rather than punctual genetic mutations, and therefore will allow determining how the 100% of the patients will respond to chemo/radiotherapy treatments. It has been demonstrated that the average care cost per patients on a personalized pathway is up to 35% less compared with patients treated without considering its potential response to the treatment. In the case of NSCLC, this cost difference will be driven predominantly by significantly lower costs for chemotherapy (up to 7.179€ per patient). These cost differences will be avoided by implementing EPiGen test in prescription protocols. Regarding the EPiGen market, the test fits in the Cancer In vitro Diagnosis Market, which is expected to increase significantly over the forecast period across the leading eight developed nations, from €5.1B in 2014 to €7.9B in 2020. In 2014, 1.8 M patients were diagnosed with lung cancer worldwide, and are potential beneficiaries of our technology. The solution that we offer through the EPiGen Project will benefit the patients, avoiding severs side effects of ineffective treatments; clinicians, leading for the best treatment option, and also will benefit the whole healthcare systems, through substantial costs reductions in management of NSCLC. In this sense, we seek positioning IGEN BIOTECH S.L. as a leading player of Cancer In vitro Diagnosis Market, as we will offer the only tool in the market capable to overcome these challenges.