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Informatics

Disruptive precision medicine technology conquering inflammation and diabetes

Synthetic IBD Patients

Synthetic patient cohorts are key components in the design of in silico clinical trials. A virtual population group ideally reflects the individual diversity and variability plus characteristics that represent a clinical cohort population. The virtual population can be extremely useful in identifying the broad range of responses which are otherwise hard to predict in a clinical trial.

The drug development and approval process

A larger synthetic population of patient avatars was generated based on an expert guided random variation from the typical cases of IBD patients undergoing treatments of placebo, GED-0301, Anti-TNF-alpha, and BT-11.

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Informatics

Disruptive precision medicine technology conquering inflammation and diabetes

iMed: intelligent Medicine

The advanced analytics platform, intelligent Medicine (iMED), is engineered to model from molecules and cells to clinical cohorts of patients with inflammatory bowel disease (IBD).

iMED system for accelerating precision medicine

iMED is the first multiscale modeling platform that ties together Ordinary Differential Equation (ODE), Stochastic Differential Equation (SDE), Partial Differential Equation (PDE), Agent-Based Model (ABM), and Artificial Intelligence (AI) modules into a single cohesive IBD model capable of parallel processing.

iMED system for accelerating precision medicine

iMed is able to elucidate hidden, unforeseen linkages between spatiotemporal simulation changes with clinical disease scoring methods through image analysis of endoscopies. Combined with expert image analysis of real patient’s gut endoscopic images, advanced machine learning algorithms provide a foundation for clinical utility of our iMED models.

iMED system for accelerating precision medicine

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Nutritionals

Safer and more effective medical foods and supplements from nature’s innovation

Gut Inflammation (PUA)

Major Health Problem

Gut Inflammation

  • In 2004 Crohn’s Disease was the cause of 57,000 hospitalizations.
  • Around 200,000 new cases of IBD have surfaced since 2011.
  • The US spent $1.84 billion on Crohn’s and UC in 2004.
  • It is estimated that 70% of Crohn’s patients eventually need surgery.
  • IBS affects 25-45 million people in the US.

Take Away

Despite this growing problem, pharmaceutical manufacturers have been unable to develop medications that are safe and highly effective. Common gut inflammation treatments are a combination approach of immunosuppressants and medications for individual symptoms. These treatments have demonstrated adverse side effects, some severe.

BTI Solution

PUA Supplement

  • PUA is a novel nutritional health ingredient for managing gut inflammation and necrotizing enterocolitis.
  • PUA is a safe and effective choice compared to current gut inflammation treatments.
  • PUA in the average diet is not enough to benefit health.
  • PUA supports digestive and immune health.

Definitions

Inflammatory Bowel Disease (IBD): A cluster of chronic, inflammatory conditions that involves all or part of the digestive tract. IBD primarily includes ulcerative colitis and Crohn’s disease.

Ulcerative Colitis (UC): An IBD that causes long-lasting inflammation and ulcers in the innermost lining of the large intestine and rectum.

Crohn’s Disease: An IBD that causes inflammation of the digestive tract. The inflammation can involve different areas of the digestive tract lining — the large intestine, small intestine or both.

Irritable Bowel Syndrome (IBS): A common disorder that affects the large intestine. Unlike IBD, IBS does not cause changes in bowel tissue or increase the risk of colorectal cancer.

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Nutritionals

Safer and more effective nutritional products from nature’s innovation

Glycemic Control (ABA)

Why ABA?
  • The naturally occurring Abscisic Acid (ABA) maintains healthy blood sugar levels.
What is ABA?
  • ABA is a hormone originally identified in plants that is naturally produced in humans and found in regular foods/diets. ABA regulates inflammation and blood glucose levels.

ABA Discoveries

  • ABA promotes glucose normalization in mouse models of disease.
  • Dietary ABA improves insulin sensitivity and reduces inflammation in white adipose tissue.
  • High glucose levels activate endogenous ABA production from pancreatic beta cells which stimulates glucose consumption by adipocytes and myoblasts
  • A single dose of ABA (extract) at approximately 1 ug/kg body weight lowered glycemia during a glucose tolerance test (GTT) study in human subjects

ABA Levels in Common Foods

ABA levels in foods table

Innovative Pathway - LANCL2

  • ABA binds to lanthionine synthetase C-like 2 (LANCL2) and signals through Akt/mTORC2.
  • Exerts anti-diabetic actions by up-regulating glucose transporter Glut4.

LANCL2

Significance

Major Health Problem

Metabolic Syndrome, Diabetes and Prediabetes Percentage with Diabetes

  • It is estimated that 34% of adults in the U.S. have metabolic syndrome.
  • About 28.3 million Americans have type 2 diabetes (T2D) and over 20% of middle-aged adults have prediabetes.
  • The total direct and indirect costs attributable to T2D in the United States is over $132 billion.
  • As the rates of obesity and T2D in the U.S. continue to rise, an increasingly large number of people are becoming reliant on expensive oral anti-diabetic drugs with demonstrated adverse side effect.

Take Away:

Despite this growing problem, pharmaceutical manufacturers have been unable to develop medications that are safe and highly effective. Additionally, there is an unmet need for medications targeting prediabetes.

BTI Solution

ABA GRAS Food Ingredient

  • ABA is an innovative health food ingredient that fills an unmet clinical need for the nutritional management of glycemic control.
  • ABA is a safe alternative to current treatments for addressing glycemic control.
  • ABA has numerous health benefits in diabetes and inflammation, and it was recently demonstrated that ABA is produced and released in brain tissue and may play a role in depression.


Definitions

Metabolic Syndrome: A grouping of biochemical and physiological risk factors – high blood pressure, high blood sugar, unhealthy cholesterol levels and obesity.

Prediabetes: A condition in which blood glucose levels are higher than normal but not high enough to be classified as diabetes.

Type 2 Diabetes: A metabolic disease in which the body does not properly process glucose due to inadequate insulin production and/or the body’s cells lack of response to insulin. This results in high blood glucose.

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Nutritionals

Safer and more effective nutritional products from nature’s innovation

Punicic Acid (PUA)

Why PUA?
  • Punicic acid (PUA) has demonstrated effectiveness in decreasing gut inflammation and improving digestive health.
What is PUA?
  • PUA is a dietary lipid found in pomegranate seed oil (PSO).

BTI Discoveries

  • Oral supplementation of PSO and its predominant bioactive constituent has demonstrated efficacy in suppressing gut inflammation.
  • The health benefits of PUA resemble those of conjugated linoleic acid (CLA).
  • PSO ameliorates intestinal inflammation in mouse models of Inflammatory Bowel Disease (IBD) and necrotizing enterocolitis (NEC).

Disease Activity Level graph

Innovative Pathway - NLRX1

  • PUA binds to nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1).
  • Involved in down-regulating inflammation during bacterial and viral exposure, acute non-infectious colitis, colorectal cancer and chronic pulmonary disease.
  • Demonstrated convergence between NLRX1, antimicrobial peptide production and altered microbiome ecology.
  • Loss of NLRX1 during colitis causes severe mucosal damage.

Significance

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Nutritionals

Safer and more effective nutritional products from nature’s innovation

Abscisic Acid (ABA)

Why ABA?
  • The naturally occurring Abscisic Acid (ABA) maintains healthy blood sugar levels.
What is ABA?
  • ABA is a hormone originally identified in plants that is naturally produced in humans and found in regular foods/diets. ABA regulates inflammation and blood glucose levels.

ABA Discoveries

  • ABA promotes glucose normalization in mouse models of disease.
  • Dietary ABA improves insulin sensitivity and reduces inflammation in white adipose tissue.
  • High glucose levels activate endogenous ABA production from pancreatic beta cells which stimulates glucose consumption by adipocytes and myoblasts
  • A single dose of ABA (extract) at approximately 1 ug/kg body weight lowered glycemia during a glucose tolerance test (GTT) study in human subjects

ABA Levels in Common Foods

ABA levels in foods table

Innovative Pathway - LANCL2

  • ABA binds to lanthionine synthetase C-like 2 (LANCL2) and signals through Akt/mTORC2.
  • Exerts anti-diabetic actions by up-regulating glucose transporter Glut4.

LANCL2

Significance

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Nutritionals

Safer and more effective nutritional products from nature’s innovation

Nutritionals Overview

BTI Nutritionals is a division of Biotherapeutics Inc. that develops nutritional products containing “Generally Recognized as Safe” (GRAS) ingredients of natural origins. BTI’s products improve and maintain health and well-being and are subjected to the highest levels of safety and quality.

Food Ingredients for Health Promotion

Glycemic Control

BTI’s active food ingredient, Abscisic Acid, has been thoroughly researched and scientifically proven to help maintain healthy blood sugar levels. ABA improves glucose tolerance and insulin levels in individuals with normal and high blood sugar.

Technology and Products

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Informatics

Disruptive precision medicine technology conquering inflammation and diabetes

Informatics Technology

The precision medicine informatics division at Biotherapeutics Inc has made it a priority to tackle the immensely complex challenge of discovering and validating new safer and more efficacious treatments for human diseases.

Problems with Current Drug Development Process

Developing a new medicine takes an average of 10-15 years. Of the tens of thousands of compounds screened, only one is approved.

The drug development and approval process

How We Solve It

Our informatics technology platform is constructed and maintained by a team of outstanding immunologists, data scientists, computational modelers, bioinformaticians and software developers in order to address the comprehensive needs of precision medicine and conquer diseases with data.

High-throughput multi-scale modeling using graph analytics

Under our informatics umbrella, we incorporate a systems-wide analysis of massively interacting networks incurred between diet, microbiome, metabolism, immunity, pharmaceuticals and nutritionals. In doing so, the BTI team strongly invokes a holistic approach to successfully advance drug discovery in the precision medicine era.

iMed: intelligent Medicine

The advanced analytics platform, intelligent Medicine (iMED), is engineered to model from molecules and cells to clinical cohorts of patients with inflammatory bowel disease (IBD).

iMED system for accelerating precision medicine

iMED is the first multiscale modeling platform that ties together Ordinary Differential Equation (ODE), Stochastic Differential Equation (SDE), Partial Differential Equation (PDE), Agent-Based Model (ABM), and Artificial Intelligence (AI) modules into a single cohesive IBD model capable of parallel processing.

iMED system for accelerating precision medicine

iMed is able to elucidate hidden, unforeseen linkages between spatiotemporal simulation changes with clinical disease scoring methods through image analysis of endoscopies. Combined with expert image analysis of real patient’s gut endoscopic images, advanced machine learning algorithms provide a foundation for clinical utility of our iMED models.

iMED system for accelerating precision medicine

EHR Data Mining and Synthetic IBD Patients

Using large-scale clinical data in the form of electronic health records (EHR) and claims data from insurance plans of IBD patients, BTI is developing synthetic IBD patient cohorts (i.e., human avatars that capture human diversity and variation) to perform in silico clinical trials and engineer personalized/precision medicine strategies tailoring individual patients.

Relational model

We use structured electronic health records of 11,325 IBD patients since 1996 to perform deep phenotyping through utilization of unsupervised machine learning methods. The data elements extracted include demographic information (including age, sex, race, age at diagnosis), laboratory measures (133 laboratory variables, including more common variables such as glucose level to less common variables such as cortisol levels in serum or plasma), medication history (medication name, dosage and timing), co-morbidities (complete list of ICD9/10 codes), as well as information from GI clinic visits. Using EHR, it is possible to build predictive models of diseases and response to treatments for unseen conditions. Integrating EHR data with other sources of clinical and preclinical data can provide valuable opportunities for knowledge discovery by providing venues for building models that can predict non-intuitive hypotheses.

AI

AI involves advanced computer algorithms that replace the traditional rule-based strategy with data-driven approaches capable of learning from positive and negative experiences. As opposed to traditional “one-size-fits-all” treatments, AI algorithms are driving the future of predictive, preventive, precision medicine and provide personalized healthcare support for diverse and dynamic patient populations. On average, the EHR of a four-year patient contains about 32 petabytes of data. The application of AI will leverage the volume and exponential growth of clinical data to translate clinical information into new unforeseen insights for safer, more effective and cost-efficient personalized healthcare.

The drug development and approval process

Synthetic patient cohorts are key components in the design of in silico clinical trials. A virtual population group ideally reflects the individual diversity and variability plus characteristics that represent a clinical cohort population. The virtual population can be extremely useful in identifying the broad range of responses which are otherwise hard to predict in a clinical trial.

Preliminary results A series of in silico clinical trials have been run based on de-identified clinical data of IBD cases. Data imputation was performed on the <250 samples of patient records. Machine learning (ML) methods were applied to predict INF-gamma, TNF-alpha, and CD Activity Index (CDAI) scores for the patients using profile information, lab measures, as well as medication history. A larger synthetic population of patient avatars was generated based on an expert guided random variation from the typical cases of IBD patients undergoing treatments of placebo, GED-0301, Anti-TNF-alpha, and BT-11. The EHR is used to create a training dataset for the prediction of CDAI scores of larger synthetic population of 10,000 patients using the optimized ML algorithm. From the different starting severity levels of CD, the statistically significant difference between the effects of the placebo versus all the drugs tested can be clearly seen (P < 0.05). For the highest range of initial CDAI scores from 450 to 500, BT-11 was statistically significant in outperforming GED-0301 and Anti-TNF-alpha in decreasing CDAI (P < 0.0001). These results suggest that BT-11 is the best drug option for treating the patients with moderate to severe IBD.

Personalized Nutrition

Around half of American adults have at least one chronic diseases, such as obesity and cardiovascular disease, which are often related to unhealthy diet and a sedentary lifestyle. Developing a healthy eating pattern in combination with an active lifestyle is vital to reduce the risk of disease and maintain health. Elevated blood glucose level is a major risk factor of diabetes. In a recent study, researchers from Weizmann Institute of Science measured responses (glucose levels) of 800 persons to 46,898 meals. It was found that the glucose levels can vary drastically in response to identical meals, indicating that the current, “one-size-fits-all”, dietary recommendations have limited value. Preliminary results Advanced analytics and big date related to nutrition, psychological sciences, and a growing demand from consumers for personalized products and services for improving human health lead to the need for personalized nutrition. We will leverage consumers’ data from food providers, distributors, retailers, smart devices, and healthcare provider to elucidate interactions among food/nutrition, human body (in particular human genome and intestinal microbiota), human behavior, and environment, based on which to prescribe food tailored to specific needs of the individual.

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Informatics

Disruptive precision medicine technology conquering inflammation and diabetes

Informatics Overview

BTI Informatics is a division of Biotherapeutics Inc. that advances novel precision medicine informatics to identify cures for infectious and inflammatory diseases and diabetes. Combining and analyzing massive amounts of data of different types can often provide insights of great value. BTI has streamlined a pipeline that fully integrates computational and experimental platforms to transcend current limitations in clinical research (www.modelingimmunity.org).

Precision Medicine

Precision medicine under the BTI Informatics division assists:

Patients

Patients

BTI’s informatics platform uses state-of-the art computing to improve the quality of diagnosis and minimize time-to-care for patients suffering from infections, inflammation, diabetes or metabolic syndrome. Enhanced diagnosis is synergized with clinicians’ increased understanding for best treatment options.

Clinicians

Precision Medicine Clinicians

BTI’s precision modeling platform empowers clinicians to define patient populations appropriate for precision medicine applications, while determining optimum treatment patient plans through management and interpretation of big data. Next generation sequencing data substantially increases the knowledge base for infectious, immune-mediated and inflammatory diseases.

Researchers

Researchers

BTI’s informatics platform seamlessly integrates diverse multi-parameter datasets to help researchers examine enormous amounts of data more efficiently and more accurately. This rigorous analysis helps researchers justify project leads, ensure reproducibility and advance along the drug discovery pipeline, and preemptively identifying safety and efficacy issues of products.

Technology

Our cutting-edge technology assembles data from the molecular, cellular, tissue and population levels using data-driven tools to provide answers to complex biological questions. BTI’s precision medicine and health strategies optimizes scalable and rigorous modeling and big-data analytics methods to gain mechanistic insights from molecules to health outcomes. BTI’s technology leverages the expertise gained through the Center for Modeling Immunity to Enteric Pathogens (www.modelingimmunity.org).

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