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Clinical Validation of a Novel Biomarker for the Prediction of Bone Metastasis in Early Stage Breast and Prostate Cancer

Periodic Reporting for period 1 - OSTEOMET (Clinical Validation of a Novel Biomarker for the Prediction of Bone Metastasis in Early Stage Breast and Prostate Cancer)

Reporting period: 2016-03-01 to 2016-08-31

Overall Business Innovation Project Objectives
Our overall goal is to introduce a new in vitro diagnostic device (IVDD), named OSTEOMET, in the market as a treatment guide to identify breast and prostate cancer patients who, according to their risk of developing bone metastases, would benefit from current treatments. OSTEOMET is based on a new proprietary biomarker (C-MAF) whose expression levels/gene amplification in primary tumour tissue are highly correlated with the risk of bone metastasis. C-MAF is a transcription factor that also acts as proto-oncogene. We will validate the prognostic and stratification value of the OSTEOMET test in breast and prostate cancer via prospective-retrospective analyses of banked samples from large clinical studies. The results of these studies will dictate the ultimate clinical positioning and provide guidance for discussions with regulatory agencies on the required regulatory path. Unmet Medical Need and Economic/Social Problem
Metastasis is responsible for 90% of cancer deaths in patients with solid tumours. Breast and prostate tumours metastasize mainly to bone. Approximately 20-25% of breast and prostate cancer patients reach the advanced stage of the disease characterized by the presence of metastatic lesions in distant organs with more than 70% and 90% of patients, respectively, present metastasis only in bone. Despite bone metastasis being the most frequent event of disease progression, there is no test to identify a patient’s risk of developing bone metastases in breast and prostate cancer. This implies that personalised surveillance is lacking and, as a preventive measure, aggressive treatments with systemic chemotherapy or hormonal therapy are indiscriminately being administered. This clearly results in overtreatment of many of the patients that are at no risk of relapse. Apart from the obvious impact on patients quality of life this carries a high economic burden.
Solution – Business Opportunity
Inbiomotion seeks to valorise these results by developing and commercializing a validated CE-marked diagnostic test (OSTEOMET) to personalize surveillance and rationalize the use of adjuvant treatment in breast and prostate cancer. We have already developed and technically validated prototype tests of OSTEOMET (based on immunohistochemistry (IHC) and Fluorescent in situ Hybridisation (FISH) technologies) for evaluating MAF expression levels. Using these tests, we have confirmed the association of MAF with the risk of bone metastasis with a very high negative predictive value (>95% in breast and prostate cancer related bone metastasis).
Expected Outcome
As clinical parameters have been proven insufficient for accurately defining disease risk, we expect that OSTEOMET will routinely become implemented in the standard of care, introducing a significant change in clinical management of breast and prostate cancer patients and even become a standard stratification tool during clinical development of existing and new treatment options. The outcome of our prospective biomarker validation studies will dictate the potential clinical uses of OSTEOMET, each implying an alternative route to market. The objective of this project is to further map out the business case in the different scenario’s to clearly illustrate the route to market and the project’s impact for each scenario.
Specific objectives feasibility study
1. To develop timelines and costs to develop CE-marked diagnostic assays for entry within the EU and US market for both the IHC and FISH assays
2. To assess, for each clinical application, the addressable market opportunity for the tests, including the total available patient market, growth and value potential.
3. To define a regulatory pathway to obtain registration for two indications with two potential technologies (FISH and IHC).
4. To perform an EU and US strategic market analysis to frame the commercial value proposition (most favorable positioning of MAF to benefit patients and serve unmet need). Identify clinical adoption, payer acceptance and overall stakeholder value perspectives for the OSTEOMET tests.
5. To develop an overall market, evidence development and reimbursement roadmap to deliver optimal coverage, reimbursement, and patient access for the tests.
6. To validate the market value of the C-MAF marker in a market assessment with expert interviews.
7. To fine tune the risk analysis
Phase 1. Bone Metastasis Diagnostic Assay Development & Validation Costs
Inbiomotion wishes to understand the cost and timing of partnering with an IVD diagnostic company to commercially develop an IHC and FISH cMAF assay with the potential to become a Companion Diagnostic (CDx). The data provided in this report is based on the following:
• Costs of assay development are typical fee-for-service by an IVD company to a Pharma CDx partner
• The development of a prognostic antibody has vastly different value implications to a diagnostic company compared to a CDx
• A prognostic test will likely become a value-added antibody where as a CDx can command a premium and be a portfolio leading product for the tests ability to select patients who will be likely to benefit from a specific therapy
• Companion Diagnostic partnership agreements are complex, typically negotiated between a Pharma company and an IVD diagnostic company
• Expect negotiations to be lengthy in a companion diagnostics agreement with the main driver being the clinical value of the diagnostic to the market and to the diagnostic company

CDx Pharma IVD deal structures, pricing and timing varies based on many factors including:
• The value of the test to the diagnostic company’s portfolio
• Clinical utility of the diagnostic to meet an unmet need not currently served
• Exclusivity of the biomarker to enable competitive differentiation for the IVD
• Size of the market being served

CDx partnership agreements typically cost the sponsor company (e.g. Pharma) between $8-12 M for a full business to business engagement including; CDx development, regulatory, clinical, and commercial partnership. In this report, we estimate the development portion of the cMAF assay to range between $1.5M for a prognostic antibody assay to approximately $6M for a fully validated companion diagnostic assay on an automated platform

Timing for the development of a cMAF assay can range from 12 months for a prognostic assay to 3 years for a fully developed CDx. Remove barriers prior to approaching diagnostic company to facilitate timing:
• The length of time required to integrate a new product in an already IVD company’s pipeline of products under development
• The ease of integration and transition of an assay from business development to development to production
• The clarity of the IP.

Phase 2. EU and US Regulatory Plan
This document describes several regulatory registration options for a commercially distributable device for the Osteomet program. The regulatory options are dependent on the clinical data that may be available, and the proposed Intended Use for the device.
In the US, all medical devices are classified by the FDA through a classification system which is based on risk to patient safety. In this system Class I represents the lowest risk, Class II represents moderate risk, and Class III - the most significant risk. Class III devices require the highest level of analytical and clinical validation, as well as a comprehensive review of a dossier that demonstrates that the device is safe and effective for its intended use.
The US FDA poses the most rigorous and well-defined registration system, and it is expected that if the program meets the regulatory requirements for the US, the same data can be used to support registration in the EU. Currently in the EU, in vitro diagnostic tests of this nature are self-certified IVD Directive (IVDD) 98/79/EC. Products are self-certified against a list of Essential Requirements, all of which are documented in a Technical File and kept on record at the manufacturer. A revision to the IVDD is expected sometime between 2016 – 2018 and is expected to align more closely with the US system. Therefore, defining the various registration pathways for a US filing has been a focus of this document, as they are also likely to be sufficient for a future EU filing.
FDA has clearly-defined parameters for immunohistochemistry devices (21CFR864.1860) covering all three classes of risk. For Osteomet, a Class I claim could include detection of biomarker expression only, with no link to therapy or clinical utility. A prognostic claim of clinical utility with no link to therapy, would be classified as a Class II medical device, requiring premarket notification. Lastly, a body of clinical validation data tying the use of the biomarker as essential for the safe and effective use of a therapy or drug, would be a Class III Companion Diagnostic device, requiring a premarket approval (PMA).
FDA has also established a defined registration pathway for a fluorescence in-situ hybridization (FISH) kit, (21CFR866.4700) that at a minimum, a FISH test is defined as a Class II device, requiring premarket notification. If an indication would include a link to a therapy, the device would be raised to significant risk, Class III, and require a PMA.
In the EU, the current In Vitro Diagnostic Directive is currently undergoing some major changes and will effectively soon become the In Vitro Diagnostic Regulation. The impact of the change will be that the Regulation will be implemented in all EU Member States directly. Previously, the Directive was implemented with the potential for different interpretations across Member States. Therefore, the overarching goal will be to provide more parity across the EU, with respect to the classification, regulation and oversight of these devices.
The new Regulations have introduced, among other things, a risk-based classification system, higher levels of clinical evidence, technical document review, device sampling, increased scope of oversight for Notified Body audits, increased manufacturer responsibilities as well as minimum qualifications for regulatory compliance staff. Therefore, as the level of risk increases with the intended use of the device, so will the level of scrutiny and expectations across the life-cycle of the product.
The intended use claims for Osteomet will ultimately be dictated by the clinical evidence available, which will subsequently drive the risk classification of the device. Therefore, the regulatory strategy and the respective registration pathway will be defined based on the level of risk of the device in both the EU and US. Since there is an ongoing effort in the EU to revise diagnostic regulations, it is expected that Osteomet will have opportunity to leverage development and clinical data to support both registration pathways.

Phase 3. Value Proposition Development & VOC Market Validation
Due to the rapidly emerging use of oncology biomarkers to drive treatment decisions, the IB cMAF biomarker is well positioned to fill an unmet need. This study determined that a bone metastasis biomarker is extremely relevant…
• General agreement that a bone metastasis biomarker was valuable in breast and prostate cancer
 This study provides directional data but additional oncologist data is needed to differentiate clinical utility in breast verses prostate cancer
• Due to limited biomarker data presented, oncologists desired a better understanding of the precise biomarker clinical utility and supporting studies for more definitive adoption feedback
 Oncologists understood the step-wise continuum to enter the market starting with a prognostic test to a risk of bone metastasis diagnostic with the highest barrier as a CDx to select patients for a potential therapy
 A few KOLs expressed a desire for access to the biomarker as soon as supporting data is available without a need to wait for the highest indication or FDA approval
• Although Oncologists cited the importance of having a bone metastasis test, there were caveats
 Treating bone metastasis preventatively raised concerns due to:
• Harsh side effects (jaw necrosis) of bisphosphonates
• Clinical studies showing limited effectiveness of Zoledronic acid
• Bone metastasis testing not adding value in osteolytic bone metastasis - only palliative treatment exists
 Like the Oncotype Dx risk tests, need to address the ethical and psychological issues of informing a patient they have high risk of bone metastasis similar to BRCA predisposition and Oncotype risk recurrence score tests

The information gathered during the projects has fine-tuned the strategic vision of Inbiomotion’s project in the following aspects:
• A sound strategic pathway to reach the market is now in place. This strategy is now the core of the new Business Plan of the company that we have built and constitutes the main deliverable of the project.
• A clear view of the pathway, timing and cost of developing OSTEOMET assay, from the prototype to reach the market.
• The regulatory requirements for EMA/FDA regulatory approval in the different clinical positioning of the assay. This complex regulatory environment will require close collaboration with Regulatory advisors, that we are currently selecting.
• The perception of the Oncologists and Pathologists, the final uses of the product, on the clinical utility of OSTEOMET assay and their wiliness to include a test as OSTEOMET in their clinical practice. The perception of these clinicians have been very favourable in terms of filling the gap of a medical need, easiness of the technology for adoption in the clinical routine and the benefits for patients, which ensures an essay adoption in the clinical setting.
• And finally we gain experience and communication tools on how to approach potential partners for commercialization of OSTEOMET by licencing the technology for worldwide Pharma or Diagnostic companies.
This new information has in implemented in a new Business Plan of the company, more focused on clinical applications, with a clear pathway to reach the market and the timing and costs of this process. In addition, the new study of potential marker based on the well defined clinical applications of the OSTEOMET assay predicts a large market size with large sales prediction even in the most conservative assumptions that guarantees the profitability of the project.
The fields of diagnosis and treatment of bone metastasis are virtually orphan of markers and specific drugs to control metastasis morbidity/mortality. OSTEOMET will address this unmet medical need by revealing if a patient has a high risk of developing bone metastases in breast and prostate cancer. This will be a valuable addition to the oncologists’ decision making aids allowing treatment focussed to patients at high risk. Particularly in breast and prostate cancer, where bone metastasis accounts for more than 72% and 90% of the metastatic events respectively, a negative OSTEOMET result could become implemented as an indicator of low risk of relapse reducing the use of aggressive preventive treatments. In addition, the test could identify patients who may be excluded from extended hormonal therapy, thereby allowing personalized decisions that contrast with current practice which is based on population criteria for risk assessment. We foresee that OSTEOMET will be included in the routine tumour analysis schemes in pathology labs.
A significant reduction of the expenditure in medical interventions is expected because only high-risk patients identified as OSTEOMET positive will be treated. Each patient from the prostate high-risk metastasis group that is excluded of treatment results in a reduction of over € 35,000 of direct healthcare costs (Schulman et al., 2007, CANCER , 109, 11), also avoiding treatment-related adverse events and their associated management costs, without compromising the patient’s outcome.
Based on our simulations, current general clinical risk stratification used by clinicians result in treating approximately half of the patients while only a minority of them would develop metastasis. However, basing their decisions on OSTEOMET data would result in only treating 10% of patiens with therapy, of which more than half would develop metastasis. This results in a massive reduction of overtreatment from 46% to 5%. This fact has a profound social and economic impact since in approximately 40% of patients, treatment could be avoided without compromising the patient’s outcome, implying €14M cost reduction for each 1000 prostate patients diagnosed. Translated to the 356,000 Intermediate/High risk prostate patients that are diagnosed each year in the more developed countries, this would add up to €5,289M in cost savings for health care systems (€2,340M EU only).
The feasibility study based on literature studies and stakeholder interviews, indicates that for breast and prostate cancer induced bone metastasis the predictive diagnostic scenario might become the lead scenario.