Mantle Biotech - Low-cost diagnostics for tuberculosis

25% of all incident tuberculosis (TB) cases in Bangladesh go undetected every year, and only 18% of detected cases are identified using rapid diagnostic assays that provide a same-day result. Most existing diagnostic methods are expensive and centralized, and are inaccessible for broad swaths of the patient population - effective control programs require a true point-of-care diagnostic which can be used in front-line detection campaigns. Over the past five years, our research has focused on the development of novel diagnostic assays which permit the detection of TB biomarkers in patient urine. These assays have been intentionally designed for use at the point-of-care: they use paper as a low-cost, mass-manufacturable substrate, and employ reagents sourced from hot springs to ensure assay stability. These novel assays would enable detection of TB by front-line clinicians, and may enable diagnosis of patients ill-served by existing sputum-based methods (e.g. children, the elderly, and the immunocompromised).

Globally, tuberculosis is the leading cause of death from a single infectious agent, and this occurs in large part because it goes undiagnosed in 36% of incident cases. Bangladesh has a slightly more effective case-finding apparatus, yielding a diagnostic efficiency of approximately 75%. However, this still leaves over 90,000 patients undetected every year. In Bangladesh, the typical path to care (60.7%) is via unqualified healthcare practitioners, 58% of whom prescribe medication without any laboratory examination. This contributes to the average health system delay of 68.5 days (compared to a global average of 28 days in other developing economies). This delay contributes to increased transmission of disease and missed diagnoses, and stems from a critical disconnect between the national tuberculosis control program and the informal community health workers that most patients visit first when seeking care. For most patients, the necessary diagnostic resources are too centralized and too expensive, and these informal healthcare practitioners aren't equipped with effective tools for disease detection. This diagnostic gap especially impacts marginalized populations living in migrant camps, crowded urban slums, and disconnected rural communities, and is particularly pronounced within certain patient populations (women, low-income patients with limited medical literacy, children under five, the elderly, and the immunocompromised).

In order to bring reliable diagnostic capabilities to these under-served patient populations, we are designing our assays for use by community healthcare workers, and are committed to actively engaging with these practitioners to ensure that our assay design meets their needs. For the past two years, we have received guidance and support from the Tata Center at MIT, and have traveled to India to learn about outstanding diagnostic needs identified by the medical community. This has informed our product design, prompting us to look for low-cost, heat-stable solutions that detect TB biomarkers in non-invasive patient samples. Likewise, through user-centered design interviews with patients and diagnostic manufacturers, we have identified critical design features that will be integrated into our assays (e.g. discreet reporting, the need for close collaboration with female accredited social health activists (ASHAs), clear yes-no results, connections to care following either a positive or negative diagnosis, and counseling from trained clinicians). We have also established an implementation partnership with Operation ASHA, a non-profit operating in Cambodia and India, and will conduct prototyping studies with ASHA workers to ensure that assays are designed for simple use and straightforward interpretation.

Researchers at the Forsyth Institute and the Boston Children's Hospital have identified a suite of five urine-based biomarkers of tuberculosis by screening urine samples from patients with confirmed active TB, and comparing these signatures to those of samples from healthy patients. In order to detect these disease markers, traditional diagnostic assays would employ a type of binding protein called an antibody to capture these markers from patient samples. However, antibodies are costly to develop and produce, and have poor thermal stability, making them ill-suited for low-cost diagnostics intended for use at the point-of-care. To address these limitations, we are producing a new class of diagnostic reagents which are based on proteins sourced from thermophilic microbes found living in hot springs. This original protein scaffold is stable up to 98 degrees Celsius, and can be readily produced in bacteria at low cost. We are able to develop new versions of this protein which recognize target disease markers by leveraging protein engineering techniques developed by the pharmaceutical industry. In short, we create billions of random variations based on this common protein scaffold. We then rapidly screen through this "library" to identify protein variants which bind specifically and strongly to disease biomarkers, and which retain the thermal stability of the original scaffold. Furthermore, we can use recombinant DNA technology to fuse these binding proteins to other functional proteins - in particular, we have fused our target-binding proteins to a cellulose anchoring domain in order to enable the straightforward manufacturing of paper-based diagnostic assays. This enables us to manufacture assays within 30 seconds (compared to the previous standard of 32 hours), making roll-to-roll mass-manufacturing of low-cost paper-based diagnostics feasible. We have developed a highly sensitive, specific, and urine-stable prototype for one of these five TB markers, and are in the process of completing development for the remaining four targets. Our aim is to incorporate these reagents into an integrated multiplexed assay which can be developed via the simple addition of a patient urine sample, and which will yield a diagnostic indication within 10-20 minutes. Based on preliminary results, we anticipate that this test would be shelf-stable for up to two years, and the tests could be conducted and interpreted in non-instrumented settings by community healthcare workers. 

Within the field of TB diagnostics, there is no point-of-care alternative which is suitable for the urine-based detection of TB markers in non-immunocompromised patients (e.g. 90% of the global patient population). This assay would enable disease detection in under-served patient groups, and would permit the decentralization of diagnostic services to rural and marginalized communities. Furthermore, we've found that these reagents can be rapidly produced at a price-point that is 100-1,000x lower than traditional antibodies, enabling the production of assays at a cost-of-goods of less than $0.50 per test. We have also developed manufacturing methods and assay formats which enable local manufacturing, further reducing distribution costs.These reagents are up to 275x more stable than antibodies, enabling the use of these assays in infrastructure-limited settings. Furthermore, our platform allows us to directly select for reagents which function in the sample context (e.g. in serum, urine, etc), as well as reagents which feature limited cross-talk (reducing the incidence of false-positive test results and enabling multiplexed detection of multiple disease markers within a single test). Our platform development has been informed by considerations of modularity - every format innovation can be easily adapted to address new disease targets, such that in the future we can extend accessible diagnostic testing to additional indications beyond tuberculosis. We are one of the only diagnostic ventures which can exercise precise control over our development process to readily produce reagents that can distinguish between diseases with highly similar disease markers. 

Our intervention is designed to enable front-line clinicians to perform their roles more effectively, identifying TB patients earlier in the course of disease progression and preventing disease transmission within families and local communities. It has been shown that an accurate triage test which can be used for all early-stage patients presenting with long-lasting coughs would prevent up to seven disease transmissions per tested individual. Studies have also demonstrated that a point-of-care diagnostic with no infrastructure requirements, 85% sensitivity (correctly detecting 85/100 TB patients), and 97% specificity (correctly detecting 97/100 healthy patients) could save over 290,000 lives every year, by connecting neglected populations to the continuum of care. Likewise, if an assay were decentralized and effectively deployed by community health care workers such that the average initial patient delay prior to seeking consultation was halved to ~3 months, TB incidence would be reduced by 65% over 10 years. Even if patients were not identified earlier, but instead private clinics were just provided with tools to diagnose self-presenting patients at twice their current level of accuracy, the health system delay would be drastically reduced, and disease incidence would decline by 45% over 10 years. Likewise, we see a tremendous need for diagnostics which don't rely upon the production of sputum - pediatric patients under the age of five are notoriously difficult to diagnose, because they are incapable of producing the high-quality sputum required by most other existing diagnostic methods. A urine-based diagnostic will enable diagnosis and treatment for this vulnerable population.

Currently we aren't actively serving anyone with our solution - we are in the prototype stage, and are beginning the process of seeking clinical validation for our developed prototype (as well as completing assay development for the remaining four urine-based biomarkers). In one year's time we hope to have finished our initial clinical validation through the Foundation for Innovative New Diagnostics (FIND), as well as our initial pilot study, conducted in collaboration with pulmonary clinics in India. We then plan to engage further with FIND and the WHO to initiate multi-site studies, to demonstrate the clinical efficacy of our assays in multiple patient populations. However, even within this year, we will not be directly serving patients - at best, our clinical pilot study will have provided the financial support required for the diagnosis of a limited number of patients (e.g. 50) via traditional means (using gold-standard assays as a basis for comparison for our own diagnostic intervention). Within five years we hope to have secured endorsement from the WHO and to have our assay integrated into the Global Drug Facility's portfolio of diagnostic offerings. Based on the WHO's endorsement, we hope that our assay will be integrated into the official diagnostic algorithms of WHO member countries, and that we can begin to address the 3.6 million TB patients (90,000 of which live in Bangladesh) who go undiagnosed every year, as well as the 6.4 million diagnosed patients (270,000 of which live in Bangladesh) who rely on expensive, centralized diagnostic methods.

Within the next year, we would like to secure early clinical validation of our point-of-care tuberculosis assays, and to have engaged with international governing bodies to initiate multi-site clinical trials. Pending promising clinical data, we anticipate that we would secure WHO endorsement in 2021, and significant uptake within Bangladesh and other countries by late 2021/2022. In the next five years, we would like to use this generalizable platform for the development of a broad range of low-cost, heat-stable point-of-care diagnostics - just as we can produce paper-based assays for the detection of urine-based markers of tuberculosis, we can produce point-of-care tests to diagnose a broad range of significant global health problems. A small selection of these addressable conditions include malaria, HIV, hepatitis B, pre-diabetes, latent TB, concussion, hypothyroidism, prostate cancer, heart attack, neglected tropical diseases such as leishmaniasis and chikungunya, water-borne diseases, and food-borne illness. For any health condition or environmental pathogen for which there is a well-defined, detectable biomarker, our platform would enable us to produce marker-specific reagents for the development of point-of-care assays. Our vision is to make the broad portfolio of diagnostic offerings that is available in the United States (through centralized labs such as LabCorp and Quest) accessible to under-served populations lacking medical resources and trained clinicians. We would like to enable clinicians to rapidly, accurately, and cost-effectively provide a suite of diagnostic services for patients, and to enable patients to monitor their own health for select health conditions.

There is an enormous number of challenges we will need to overcome in the coming years to execute on our vision of universally accessible diagnostic assays. From a technical perspective, we require initial clinical validation of our assays, and as we expand into additional disease indications, we will need to build out strategic partnerships with clinicians working on the discovery of clinically actionable biomarkers. We would also like to further develop our reagent production process in order to even more rapidly address new targets, and to demonstrate the capabilities of our platform in multiplexed contexts (i.e. detecting multiple disease markers simultaneously). These efforts (and the resultant clinical trials) will require substantial financial resources, as will mass manufacturing, marketing, sales, and distribution. In order to address problems on the global scale, we will need to establish manufacturing capacity on the order of tens of millions of tests every year. On the market access side, we require not only endorsement from the WHO (which will be based upon technical and clinical performance of these assays), but uptake and adoption from a diversity of national control programs and private clinic networks. This uptake will depend upon the demonstration of clinical efficacy, as well as an attractive price point which can be supported by the global health apparatus. Even then, there will be behavioral barriers to overcome (patient reticence due to social stigma, distrust of the point-of-care assay format and presumptive treatment, etc). 

We have a detailed technical plan for establishing the broader capabilities of this platform, and demonstrating its clinical capabilities for both funders and regulatory partners. Traditional capital sources may not be aligned with our impact-driven mission, and so we would pursue funding from the philanthropic and impact investor spheres. For our first critical clinical proof-of-principle, we are sourcing biobanked urine samples of TB patients from the WHO-affiliated Foundation for Innovative New Diagnostics, and would look to establish partnerships with research hospitals and clinics to pursue initial clinical validation for other indications. We will actively collaborate with the WHO and international partners to conduct multi-site trials, as well as to ensure consistent supply/distribution and market access for approved products. We have established research partnerships with corporations that we believe have the capacity to support mass manufacturing and assay distribution. These partnerships depend on licenses to critical IP elements, which we are currently pursuing.  At the country level, we will work with local NGOs to ensure diagnostic assays reach the intended end users and are used appropriately to inform patient care. We will design assays specifically with patient privacy and emotional well-being in mind. All clinical trial data will be published in peer-reviewed journals in order to credibly establish the clinical efficacy of these assays. Where possible, positive controls will be included with assays in order to further boost patient and clinician confidence. 

Just as we plan to do in India, we intend to conduct a local clinical pilot study in Dhaka, in collaboration with the TB Screening and Treatment Center and BRAC (the world's largest non-governmental development organization, based in Bangladesh). We have initiated manufacturing and distribution negotiations with India's largest in vitro diagnostics manufacturer, and would likely source our assays from the regional production facility in Delhi. In Bangladesh, we see a market opportunity in that the medical apparatus is well-developed (with centralized clinics offering gold-standard diagnostic techniques), but lacks the point-of-care resources needed to identify TB patients in crowded urban slums and itinerant communities. We believe that our solution can serve as the preferred front-line diagnostic method for the detection of all of the 360,000 annual cases of tuberculosis (at the significant procurement overages required to identify positive TB cases against a backdrop of other pulmonary conditions and communicable diseases). Likewise, with Bangladesh's swelling middle class and urban population, we believe that this frontier market must be served with accessible point-of-care diagnostic interventions addressing a range of health conditions beyond tuberculosis. A 2018 report states that 5.7 million Bangladeshis have been driven into poverty by catastrophic health expenditures, and we believe that our portfolio of offerings could enable early detection and timely intervention, preventing these outcomes.

While we are not currently incorporated, we anticipate pursuing a hybrid for-profit/non-profit business model.

Our initial team consists of four people - one full-time member and two part-time members. We are also supported by a formal advisor with a long career in the medical device industry, and a constellation of informal advisors through translational programs here at MIT. 

Eric Miller is a fresh graduate of the Chemical Engineering PhD program here at MIT, and has spent the last 6 years developing the capabilities of our diagnostic platform. Among protein engineers and biochemists working within the diagnostics industry, he is one of the few individuals who is well-versed in leveraging this powerful discovery platform, and he has conducted extensive research into the capabilities of these reagents, with seven published papers and three pending patents. Likewise, Professor Hadley Sikes (his PhD advisor and faculty co-founder) has spent her career operating at the interface of medical diagnostics and protein engineering, and is able to leverage her extensive academic, clinical, and corporate networks to build strategic partnerships. Aditi Trehan is a clinical researcher with a deep background in disease diagnosis, having worked in the NIH Undiagnosed Disease Program. She has a master's degree in biotechnology, and currently works at the Broad Institute conducting biomarker identification studies and exploring the etiology of disease. John Frick is a veteran of the medical device industry, having helped numerous medical start-ups secure funding and establish critical partnerships. Eric and Aditi have both spent significant amounts of time in India, and have a broad professional network within the global health space, ranging from stakeholders at the WHO and FIND, to academic researchers, to philanthropic stakeholders at the Tata Trusts and Bill and Melinda Gates Foundation.

We are supported by a broad range of funding organizations, including the Tata Center for Technology and Design, the Deshpande Center, the Sandbox Program at MIT, the PKG Center at MIT, the National Science Foundation, and the National Institutes of Health. We have initiated a preliminary manufacturing research collaboration with a Fortune 100 company with significant manufacturing capacity, and are currently securing access to biobanked clinical samples from the Foundation for Innovative New Diagnostics. We have also established an implementation partnership with Operation ASHA, and have spoken with a broad range of stakeholders in India, ranging from prospective clinical partners (the National Institute for Tuberculosis and Respiratory Disease, and the Indian Council on Medical Research), governmental stakeholders (the Revised National Tuberculosis Control Program), and non-governmental organizations that have been instrumental in the roll-out of previous diagnostic assays (the Clinton Health Access Initiative, PATH, The Union). One of our team members will be attending the annual TB conference in Hyderabad in October, and we hope to confirm these partnerships in order to lay the groundwork for an efficient transition into clinical pilot studies.

We will provide point-of-care tuberculosis diagnostics to the Bangladeshi government, as well as to international NGO partners and private clinics. We anticipate a low price point for these assays (with sales subsidized by the Global Fund), and thus we will need to scale our business to financial sustainability by establishing significant volume (both in terms of the number of tests sold and the number of different disease conditions addressed). In the short-term, our key impact metrics will be successful disease diagnoses (or cases ruled out), particularly within communities previously lacking access to the formal medical system. Our hope is that these assays will extend the reach of the medical system to traditionally under-served populations, reducing disease transmission and ultimately incidence, and enabling patients to play a more proactive role in their own health at an accessible price point. In Bangladesh and other geographies, we would partner with local clinics, non-profits, pharmacies, and governmental agencies to ensure effective distribution of these assays, and will engage with local manufacturing partners where possible to minimize logistical expenditures and support local workers. As we further develop the capabilities of our development platform and clinical apparatus, we would look to expand into additional diagnostic indications and additional geographies.

We anticipate that financial sustainability will not come easily through product sales alone (particularly given the long lead times for clinical validation, regulatory approval, and market acceptance, and the low price point of our assays). We would like to eventually develop integrated assays and products for developed markets where revenues can sustain our broader activities in the global health sector. In the interim, while we are building out that development and manufacturing capacity and pursuing regulatory approval in those geographies, we will rely heavily on grants from philanthropic and governmental organizations, as well as select investments from the impact investor community. We plan to apply for development grants from the NSF, USAID, UNITAID, NIH, and CDC, and will pursue SBIRs to fund our early development activities. Where possible, we will also pursue corporate partnerships, including corporate venture firms. As we develop a broad portfolio of low-cost assays (replicating the diagnostic capabilities of developed markets in frontier markets), we anticipate that the significant volume of this business will lead to self-sustaining operation.

Our vision is to produce a robust, sensitive, and affordable portfolio of point-of-care assays that enable universal access to medical diagnostics, regardless of proximity to medical infrastructure or socioeconomic means. This is a tremendous undertaking, and each new geography that we look to enter will come with its own unique set of challenges and hurdles that we will have to address. We currently stand at the precipice of producing and clinically validating the first of many interventions based on this diagnostic platform, and we see the medical system in Bangladesh, the entrepreneurial ecosystem, and the potential for impact within under-served communities, as well-suited for our initial product roll-out. With support from the Tiger Challenge, we believe that we can initiate the clinical validation process for our first generation of diagnostic assays, identify local partners for distribution and implementation, and assess the diagnostic needs of Bangladesh and the broader global health community to develop an expansive pipeline of affordable diagnostic products. Our success hinges on us finding sustainable financial support and capable local partners, as well as mentors to navigate the complex medical landscape and regulatory systems in Bangladesh.

We would love to partner with the World Health Organization to coordinate multi-site clinical trials and assay distribution. We would also like to establish a relationship with BRAC as an implementing partner. Their shasthyashebikas act as front-line community health workers whose needs would ultimately inform the design and capabilities of our diagnostic assays. BRAC also plays a key role in coordinating the efforts of over 40 Bangladeshi NGOs operating in the public health sector. We would also like to make contact with the National TB Control Program (NTP), as well as to connect with potential clinical partners (e.g. the TB Screening and Treatment Center).