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NEOSONICS – First non-invasive screening medical device for infant meningitis.

Periodic Reporting for period 1 - NEOSONICS (NEOSONICS – First non-invasive screening medical device for infant meningitis.)

Reporting period: 2018-06-01 to 2018-08-31

Broad need and problem
Certain type of infections occurring in superficial body fluids such as CSF or peritoneal fluid may cause death in a matter of hours if they are not detected promptly . Besides, they may present with very unspecific symptoms or signs challenging early diagnosis, which worsens prognosis of the disease. Some of these killing infections are meningitis, peritonitis, septic arthritis, chorioamnionitis or pleuritis.
Detection of meningitis: the unmet need
Infant meningitis is where we have identified the need is most urgent. On one hand, meningitis may appear with unspecific symptomology that can easily be confused with the flu or other more common diseases or infections. However, meningitis may kill in a matter of hours and cause life-long disabilities in 25% of patients, if not detected promptly. On the other hand, within the higher risk groups, infants (<12 months) are the most vulnerable population because their immunologic systems are still being developed and have limited communication capabilities. Consequently, Paediatricians respond very conservatively and suspect meningitis in cases where newborn patients (<28 days) present with only a fever, irritability, vomiting or bad appearance but also with older infants having other infections (sepsis, pulmonary or urine infection) . This results in a huge and daily challenge to physicians who need to exhaustively screen many vulnerable patients, with unspecific symptoms and varied clinical conditions, and make sure they do not miss and early detect the few cases with meningitis. Accordingly and in order to rule in or out the presence of the disease, these patients immediately undergo exhaustive diagnostic interventions, which is no surprise given the magnitude and relevance of the devastating effects of the disease according to WHO and UNICEF:
• 1.7 million meningitis cases, 300.000 deaths (50.000 new-born deaths).
• One of the top ten causes of death under 20.
• With advances in medical practices and vaccination, the incidence and mortality have declined over the past 40 years; however, morbidity remains unchanged.
• Up to 50% of infants suffer neurological impairment, 30% severe life-long disabilities.
• In developed countries, the incidence of neonatal bacterial meningitis is 0.2-1 per 1000 live births and, in under-resourced countries, 0.8-6.1 per 1000 live births. This is likely an underestimation of the true incidence, however.
• In developed countries, mortality from neonatal meningitis ranges from 10–15%. It reaches 40-58% in under-resourced countries.
With all these alarming figures it is unconceivable that today the only method for meningitis detection is the realization of a LP for CSF analysis determined by risk of infection due to unspecific symptoms of the infant.
The problem related to screening with LP
The current screening process taken as standard to detect the presence or absence of meningitis in suspected patients is lumbar puncture (LP), a medical procedure for diagnostic testing that collects CSF which envelopes the brain and spinal cord. The first thing to be checked is the level of WBC in it because if increased, that is a clear sign of infection and broad-spectrum antibiotic treatment should be immediately administered. The sample is then sent for bacteriologic analysis and results are obtained after 72 hours. The type of organism causing infection determines duration of the treatment, which may vary from 14 to 21 days. LP is an invasive technique not exempt of risk, painful despite the use of local anaesthetics and difficult in the infant. More specifically, LP is a cumbersome technique because:
• It takes not less than 1 hour to be performed (parent approval, materials preparation, complications…)
• Two (nurse and paediatrician) or three (2 nurses and paediatrician) professional are needed to perform an LP.
• It is blindly performed, meaning that the user cannot see where the needle is heading. This explains that in up to 50% of cases the needle damages a capillary and blood contaminates the sample, turning WBC count unreliable. In this frequent situation, double-dose preventive antibiotic is administered while waiting for CSF bacteriologic results, available in 72 hours. Patients with negative blood/urine infections that could be discharged earlier often remain at the hospital while waiting for CSF results.
• Critical patients who cannot move, patients who are unstable, who have raised intracranial pressure, coagulopathies or immunodeficiency do not tolerate an LP. Consequently, when meningitis is suspected, these patients are treated as if they had meningitis, which may unnecessarily trigger treatment & hospitalization.
• LP is negative 95% of times: 95% of patients receiving a LP for suspected meningitis do not have meningitis.
• The number of unnecessary lumbar punctures in EU is 250.000 each year (90% of total LPs), with 300 on average in large-size hospitals (>1.000 beds). On top of that, contaminated samples (30% of LPs also add to the pain cost of hospitals.
• Inefficient diagnosis of meningitis via LP costs hospitals in EU 1.5B€, 43M€ in Spain.
The problem related to the screening process is not unique to meningitis. As a matter of fact is a recurrent problem happening in other infections taking place in other superficial fluids of the body, such as the peritoneal fluid in the abdominal area, the amniotic fluid that surrounds the fetuses, the synovial fluid that surrounds the joints (knee, elbow), and the pleural fluid that surrounds the lungs. Early detection is also required for patients at risk of infection of these fluids but the current standard is again an invasive puncture. Because these infections are more frequently associated to the adult population, with a fully developed immunologic system, the need is less urgent than in the case of infant meningitis. However, the rate of negative punctures is also about 90-95% and the number of cases is 4 (pleuritis) to 20 (peritonitis) times larger.
Physicians often opt to conservatively administer prophylactic antibiotics and extend hospital stay, which altogether are safe yet highly undesirable consequences both for the patient health and the sustainability of health care systems.
From July 2018 until August 2018 we executed the Phase 1. The outcome of the work performed and main results are explained below:
1. Technology development and validation
We have improved overall system's sensitivity to accomplish a clinical study where we show that no false negatives are generated. The two main components that drive sensitivity are the sensor and the excitation, digitization and filtering electronics. We have tested several transducers and electronics and ultimately selected those meeting the technical specifications required to reach the needed level of sensitivity but also that provide a higher versatility so that we can test different configurations that optimize signal to noise ration from obtained clinical data during the studies. Theses upgraded components have implied a 100-factor amplitude improvement with which we have generated evidence that our system's sensitivity will overcome expected fontanel attenuation levels to detect any WBC concentration in the CSF. In addition to this reassuring evidence, it is important to highlight the fact that 99% of diagnosed meningitis cases present with CSF WBC in excess of 100 WBC/µL. This means that it is very rare to detect meningitis with concentrations even close to the diagnostic neonatal threshold of 20 WBC/µL. We have updated cell count algorithms to perform consistently in the 0-100 WBC/µL range and have assessed strategies for higher concentrations, when the echoes from cells start overlapping. These algorithms, together with tissue segmentation algorithms, will be refined with clinical data. Finally, we have identified different coupling materials (consumables) and determined the specifications from a technical and a user perspective.
2. Definition of pilots
We have analysed and defined the tasks to achieve technological validation in operational environments. They are included as part of the tasks to be undertaken during Phase 2 as shown in the Work Plan. They will include clinical proof of concept, clinical validation and clinical validation assessment for new applications. Infant meningitis studies have already been approved by the Ethical Committees of the collaborating hospitals. The design of the studies has been carried out together with the clinical collaborators and their respective biostatistics departments.
3. Market assessment and Business Model Assessment
Through the market study we got to the conclusion that NBS is facing a market valued between €20B and €40B worldwide. While having analysed several markets we have rationally deduced that superficial body fluids market can be regarded as the intersection of three general markets: Medical device consumables, diagnostic ultrasound and healthcare Business Intelligence. The TAM for Neosonics corresponds to its application for meningitis: the infant meningitis market. It is our immediate TAM because it is where the need is most urgent given that patients (babies) are most vulnerable. This explains that awareness has been raised among KOLs and potential first clients as stated in our LOIs. Particularly, EU will be the first region where we will be able to sell after clinical validation and CE mark. Our most conservative estimation of TAM predicts €20B by 2024. We have relied on the following assumptions to size the market: i) we will sell 3 units to large hospitals, 2 units to medium hospitals and 1 unit to small hospitals, ii) selling 3 consumables for each LP performed, iii) unit price of €10,000 for the device and €50 for the consumables. Taking into account a penetration factor of 90% for large hospitals, 80% for medium size hospitals and 75% in small hospitals we have quantified a Global TAM of €1B. In Europe there are 353 large hospitals (>1,000 beds), 1,139 medium hospitals (500-1,000 beds) and 9,836 small hospitals (51-500 beds). Our Serviceable Available Market (SAM) is i) geographically defined by Europe, ii) and is limited to small, medium and large hospitals. We have estimated the SAM by quantifying the total potential benefits of Neosonics in Europe, achieving a potential of €378.6M by 2024. Thanks to the market assessment, cost-utility study and willingness-to-pay study we have been able to gather the needed information and validate our market opportunity and the business model we had initially presented. We have also initiated discussions with University Hospital Bellvitge (Barcelona, Spain) and Hospital Sanitas (part of Bupa group, Barcelona in Spain) to conduct feasibility studies to show the applicability of the technology and scalability of the business in peritonitis and arthritis, respectively. These studies are planned for 2019.
4. Legal Assessment and IPR study
During the execution of Phase 1 we have defined the legal and regulatory requirements to be taken into account for the development of the entire system, consumables, design and algorithms. In addition to the protected PCT patent with application number PCT2016072125, we have contracted the patents attorney Isern Patentes y Marcas to conduct an FTO study for the markets of Spain, UK, Germany, France, Italy and USA. As a result of the FTO study, 32 patents have been analysed and they have been classified as according to its infringement risk level against Neosonics. Next, an infringement study for the 11 patents showing a higher risk of infringement has been accomplished concluding there is no perceived infringement in the studied countries. Nonetheless, two patents have claims that might be disputed and these deserve a deeper analysis that will be conducted in early 2019. In the worst case scenario, we might need to reach a (licensing) agreement with the patent owners but this fact has not been discouraging for the investment funds that have analysed the business and recently made two investment offers.
5. Operational Capabilities Assessment
We have analysed the tasks to be undertaken and the resources to be assigned in order to develop our Work Plan. As a result, we have internalized key activities relating to the characterization, performance and quality of the prototypes as well as for the development and refinement of algorithms and data analysis. For this, we have reached an agreement with CSIC (research collaborating institution) for the transferability of the activities that until now had being developed in their facilities. We have already get to an agreement to recruit two new team members that will lead experimentation and data analysis activities as well as quality and performance system tests. Industrial experts in medical devices manufacture have been interviewed and one will be recruited as advisor in early 2019
6. Work Plan and Business Plan
Through the feasibility study of the Neosonics project, we defined a realistic and attainable work program to ensure that all the objectives are met, focusing our attention on specific technical and commercial obstacles that could present limitations to our market introduction. The WP descriptions were organised in a way to secure that they will be completed within their time frame, and to minimize time-to-market. For this reason, we understood which tasks will be performed by our own staff, as well as which activities will be externalized; all in order to guarantee the success of the project within the set timeframe.
Implications of the project and SME Instrument phase 1
Thanks to the funds of EC SME Instrument Phase 1 we have been able to develop a technical and commercial feasibility assessment and a business plan for the Neosonics project. In the final report of Phase 1 execution we present the results of a three months detailed feasibility assessment, including: a market analysis, a technical feasibility assessment, a legal framework assessment, the definition of a business plan and the Work Plan for Phase 2 H2020 proposal. The conclusions extracted allows us to believe that Neosonics development and further commercialization activities after the conclusion of the project will be successful and that New Born Solutions has an updated and detailed business plan to achieve the objectives envisaged in the project. We will continue with the Neosonics project now having included the advances and learnings presented in this report. Importantly, we have quantified the internal and external support needed to continue with the project and we have defined the key partnerships needed to make of Neosonics a complete success as the first medical product to noninvasively screen for infant meningitis.

Impact of SME Phase 2 and expected results
We will continue to pursue our vision to become the company that will enable quick, easy, painless and cost-effective detection and monitoring of superficial body fluid infections to help save lives, improve patient care and healthcare systems sustainability. We aim to achieve a SME Instrument Phase 2 to ease the development of Neosonics. With Neosonics we have the potential to reduce by 95% the number of LPs performed for suspected meningitis, a huge impact in the health sector and for society. We have estimated that this would account for a reduction up to 56% of current costs associated to unnecessary LPs, laboratory tests, antibiotics and hospitalization stay. We are requesting EC funding Phase 2 to fully develop, prove in clinical trials and industrialise our technology to reach the market by Q1 2021.
We want to offer a unique non-invasive product to the health sector that will improve current techniques and procedures for body fluid infections detection (€17B-€34B market), starting with infant meningitis (€1B globally, €350M in EU), thanks to the applied innovation. Firstly we will address medium and large hospitals in Europe (10% of 15.000 hospitals), aiming to a potential use on 2,5M patients. We envisage a B2B business model, based on new IP generation and protection, with sales of the device (€10,000) and consumables (€50/unit) in the short term and of data in the longer term allowing further escalation of technology potential by addressing other infections in our scope (peritonitis, septic arthritis, amnionitis, pleuritis). Our sales channels will be direct only to stay close to strategic clients and improve the quality of our products (1%) and mostly indirect via local and global distributors (99%).
Receiving EC funds will allow us to focus on technology development, will allow us to shorten time-to-market, and will increase our NPV from €27M to €37M.