SBIR-STTR Award

With insulin being the only approved treatment of Type 1 diabetes mellitus (T1DM), there is a very large unmet medical need for a definitive cure for pediatric and adult patients. Increase in obesity, unhealthy diet, and physical inactivity are driving the prevalence of diabetes among all ages. In the U.S., diabetes currently affects 14% of the population of all ages, and it is the seventh leading cause of death, with an estimated cost of $237 billion every year to the healthcare system. The medical community has recognized diabetes as an autoimmune disease and proposed different immunotherapeutic approaches to cure it. However, only hematopoietic stem cell transplantation (HSCT) after reset of the immune system with toxic chemotherapy, has so far shown temporary restoration of insulin independence. The mission of AVM Biotechnology is to develop a disruptive solution for diabetes based on a novel regimen for immunologic reset that safely removes the complete autoimmune pathophysiologic substrates from diabetes patients and can be safely re-administered in case of relapse. The goal of this project is to establish proof-of-concept data for AVM0703, a novel proprietary oral formulation for the treatment of diabetes. In our early-stage preclinical validation, we verified that a single oral dose of AVM0703 induces complete non-myeloablative lymphodepletion without side effects. In this Phase I application, we have two specific aims: (1) Determine the optimal doses of AVM0703 for immunologic reset in the pre-clinical Non-Obese Diabetic (NOD) mouse model. (2) Assess the therapeutic effect AVM0703 in NOD mice and compare it with the one of other standard immunosuppressive medications. We expect to identify one concentration of AVM0703 that is able to safely remove >97% of autoimmune pathophysiologic substrates within 48 hours from its oral administration in NOD mice (Aim1), and that AVM0703 treated mice will achieve normal urine glucose levels within 20 days from dosing preventing insulitis in more than 95% of the cases (Aim2). The successful conclusion of the proposed phase I studies will lay a solid foundation for IND-enabling PK and PD studies in the SBIR phase II period that will lead to clinical trials to evaluate the effects of this novel therapeutic lead in recent-onset juvenile type I diabetes patients.

Public Health Relevance Statement:
Novel safe immunomodulation strategies to arrest diabetes progression are a global necessity to combat the rising incidence of diabetes to the epidemic proportion. This project proposes the feasibility assessment of an innovative best-in-class lymphodepleting regimen for diabetes that removes the associated autoimmune pathophysiologic substrates. The project is expected to introduce a novel lead therapeutic for diabetes and hopefully other autoimmune diseases.

Project Terms:
Oral Glucose Tolerance Test; OGTT; Pancreatic; Pancreas; Pancreatitis; Patients; Peyer's Patches; Structure of aggregated lymphoid follicle of small intestine; plasmocyte; Plasmacytes; Blood Plasma Cell; Plasma Cells; Relapse; Researchers; Investigators; Research Personnel; Risk; Safety; Spleen Reticuloendothelial System; Spleen; Staining method; Stains; Progenitor Cells; Stem cells; thymus derived lymphocyte; T-Cells; T-Lymphocyte; Testing; Upregulation; Up-Regulation; Urine Urinary System; Urine; Measures; nonobese diabetic (NOD) mice; non-obese diabetic (NOD) mice; Nonobese Diabetic Mouse; Non-Obese Diabetic Mice; NOD Mouse; Inbred NOD Mice; Mediating; base; Area; Acute; Solid; Clinical; Phase; Medical; Adolescent; juvenile human; juvenile; Adolescent Youth; Evaluation; Serum; Blood Serum; Childhood; pediatric; Individual; diabetic; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell Transplant; HSC transplantation; Therapeutic; Prediabetes syndrome; prediabetic; pre-diabetic; pre-diabetes; Prediabetic State; Prediabetes; Hour; Oral; Peritoneal; Autoimmune Process; Autoimmune; System; restoration; Ablation; age group; experience; receptor; Receptor Protein; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; immunoregulation; immunoregulatory; immunomodulatory; immunologic reactivity control; immune regulation; immune modulation; Immunomodulation; novel; Cell surface; Pharmacodynamics; Modeling; Immunotherapeutic agent; immunotherapy agent; immunotherapeutics; immunologic preparation; immune-based therapeutics; Intervention; interventional strategy; Intervention Strategies; diabetes mellitus therapy; diabetes therapy; Inflammatory Response; preventing; prevent; Dose; Data; National Institute of Diabetes and Digestive and Kidney Diseases; NIDDK; Pre-Clinical Model; Preclinical Models; Small Business Innovation Research Grant; Small Business Innovation Research; SBIR; Validation; Immunologics; Immunologically; Immunological; Immunologic; Immunochemical Immunologic; Monitor; Process; Therapeutic Effect; symptom management; manage symptom; pre-clinical; preclinical; autoreactivity; cost; novel strategies; novel strategy; novel approaches; new approaches; Population; Prevalence; innovation; innovative; innovate; Impairment; chemotherapy; novel therapeutics; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; mouse model; murine model; type I diabetic; type 1 diabetic; combat; novel therapeutic intervention; novel therapy approach; novel therapeutic approach; new therapy approaches; new therapeutic strategies; new therapeutic intervention; new therapeutic approach; clinical practice; phase 1 study; Phase I Study; Regimen; physical inactivity; lack of physical activity; Formulation; procedure cost; procedural costs; Unhealthy Diet; side effect; infection risk; pharmacokinetics and pharmacodynamics; PK/PD; Oral Administration; intraoral drug delivery; Oral Drug Administration; Adoption; Adrenal Cortex Hormones; Corticosteroids; Corticoids; Adult; adulthood; Adult Human; 21+ years old; Affect; Aftercare; post treatment; After-Treatment; After Care; Age; ages; Autoimmune Diseases; autoimmune disorder; Autoimmunity; Autoimmune Status; Automobile Driving; driving; B-Lymphocytes; B-cell; B-Cells; B cells; B cell; B blood cells; Biotechnology; Biotech; Blood; Blood Reticuloendothelial System; Blood Cells; Peripheral Blood Cell; Blood Platelets; Thrombocytes; Platelets; Marrow platelet; Body Weight; Bone Marrow; Bone Marrow Reticuloendothelial System; Bone Marrow Transplantation; Marrow Transplantation; Bone Marrow Transplant; Bone Marrow Grafting; Cause of Death; Cell Body; Cells; Clinical Trials; Communities; Complete Blood Count; Cyclosporines; Cyclosporins; Dexamethasone; diabetes; Diabetes Mellitus; type one diabetes; type I diabetes; ketosis prone diabetes; juvenile diabetes mellitus; juvenile diabetes; insulin dependent diabetes; Type I Diabetes Mellitus; Type 1 diabetes; Type 1 Diabetes Mellitus; T1DM; T1D; T1 diabetes; T1 DM; Sudden-Onset Diabetes Mellitus; Ketosis-Prone Diabetes Mellitus; Juvenile-Onset Diabetes Mellitus; IDDM; Brittle Diabetes Mellitus; Insulin-Dependent Diabetes Mellitus; Diffusion; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Epidemic; Excipients; flow cytophotometry; Flow Microfluorometry; Flow Microfluorimetry; Flow Cytofluorometry; Flow Cytofluorometries; Flow Cytometry; Foundations; Dextrose; D-Glucose; Glucose; Goals; Health; Health Care Systems; Healthcare Systems; Modern Man; Human; allergic/immunologic organ system; allergic/immunologic body system; Immune system; immune suppression; Immunosuppressive Effect; Immunosuppression Effect; Immunosuppression; immunosuppressive; Immunosuppressants; Immunosuppressive Agents; Incidence; Regular Insulin; Novolin R; Humulin R; Insulin; heavy metal lead; heavy metal Pb; Pb element; Lead; lymph gland; Lymph node proper; Lymph Node Reticuloendothelial System; lymph nodes; Mission; Murine; Mice Mammals; Mice; Mus; Neutropenia; Polymorphonuclear Neutrophils; Polymorphonuclear Leukocytes; Polymorphonuclear Cell; Neutrophilic Leukocyte; Neutrophilic Granulocyte; Marrow Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Neutrophil; neutrophil; obese population; obese person; obese people; obese; corpulentia; corpulency; corpulence; adiposity; Obesity

With insulin being the only approved treatment of Type 1 Diabetes (T1D), there is a very large unmet medical need for a definitive cure for pediatric and adult patients. In the U.S., diabetes currently affects 14% of the population of all ages, and it is the seventh leading cause of death, with an estimated cost of $237 billion every year to the healthcare system. The medical community has recognized T1D as an autoimmune disease and proposed different immunotherapeutic approaches to cure it. However, only hematopoietic stem cell transplantation (HSCT) after reset of the immune system with toxic chemotherapy, has so far shown temporary restoration of insulin independence. Antigen-specific immunotherapies (Teplizumab) are offering partial therapeutic benefits with only 5-6% of the patients showing two-year insulin independence. AVM Biotechnology (AVM) is developing a new approach for T1D based on a novel immunomodulatory formulation (AVM0703) that mobilizes "Supercharged" Natural Killer T-Cells for safe removal of autoreactive lymphocytes responsible for T1D. Results from Phase I activities show that AVM0703 administered alone can prevent diabetes in 45%, or delay its onset by 20-31 weeks in 55% of mice in the NOD model of T1D. AVM0703 may represent a safe standalone curative option for 50% of the patients based on preclinical mouse data, providing them an expected window of insulin independence of 3-30 years. In case of relapse, the safety profile of AVM0703 will allow repetitive dosing up to 8 times as currently approved by the FDA for an ongoing clinical trial in relapsed refractory lymphoid malignancies (NCT04329728). For patients not showing remission, AVM0703 is expected to reinforce other immunotherapies allowing a wider range of T1D patients to achieve insulin independence, for instance, combinatorial therapy with Teplizumab (anti-CD3). This SBIR Phase II project has been designed as a randomized, placebo-controlled multi-center pre-clinical trial to obtain solid data which, with the already available toxicology information for AVM0703 and potential companion agents such as Teplizumab, will expedite IND approval and pave the way to clinical trials. Activities in Aim 1 will be directed to perform a pre-clinical dose- finding and mechanism of action study in NOD mice in three scenarios: pre-diabetic, new-onset, and established diabetes. Results from Aim 1 will be used to determine the AVM0703 dose to be used in the pivotal efficacy study for reversal of new-onset diabetes and established diabetes in Aims 2 and 3. An IND application will be filed at the end of the project.

Public Health Relevance Statement:
PROJECT NARRATIVE There is an urgent need for a safe therapeutic solution granting insulin independence to Type 1 Diabetes (T1D) patients. This project will generate IND enabling data for an innovative therapeutic approach for T1D enabled by a novel Dexamethasone Sodium Phosphate (DSP) formulation able to mobilize a nonconventional NKT cell population that removes T1D autoreactive lymphocytes. The project is expected to unveil important insights on the mechanism of action of suprapharmacological doses of DSP which will benefit other autoimmune diseases as well.

Project Terms:
Longevity; Length of Life; life span; lifespan; Lymphocyte; Lymphatic cell; Lymphocytic; lymph cell; Marketing; Mus; Mice; Mice Mammals; Murine; Patients; Pharmacology; Production; Program Development; Relapse; Risk; Safety; Cell-Mediated Lympholytic Cells; Cytolytic T-Cell; Cytotoxic T Cell; killer T cell; Cytotoxic T-Lymphocytes; Testing; Time; Toxicology; Translating; Treatment Protocols; Treatment Regimen; Treatment Schedule; Universities; sodium phosphate; Inbred NOD Mice; NOD Mouse; Non-Obese Diabetic Mice; Nonobese Diabetic Mouse; non-obese diabetic (NOD) mice; nonobese diabetic (NOD) mice; Businesses; Healthcare; health care; CD3 Antigens; CD3; CD3 Complex; CD3 molecule; OKT3 antigen; T3 Antigens; T3 Complex; T3 molecule; base; Procedures; Solid; Clinical; Refractory; Phase; Medical; pediatric; Childhood; insight; Individual; diabetic; HSC transplantation; Hematopoietic Stem Cell Transplant; Hematopoietic Stem Cell Transplantation; Therapeutic; Companions; Intravenous; Prediabetes; Prediabetic State; pre-diabetes; pre-diabetic; prediabetic; Prediabetes syndrome; C2B8 Monoclonal Antibody; MabThera; Rituxan; rituximab; Scientist; Oral; restoration; Remission; Disease remission; experience; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; novel; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; lymphoid cancers; lymphoid malignancy; Malignant lymphoid neoplasm; Modeling; drug development; immune drugs; immune-based therapeutics; immunologic preparation; immunologic therapeutics; immunotherapeutics; immunotherapy agent; Immunotherapeutic agent; Anti-CD3 Antibody; HuM291; MoAb HuM291; Monoclonal Antibody HuM291; preventing; prevent; Length; Dose; Data; randomisation; randomization; randomly assigned; Randomized; Clinical Trials Design; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Process; symptom management; manage symptom; Placebo Control; placebo controlled; pre-clinical; preclinical; preclinical study; pre-clinical study; early onset; autoreactivity; design; designing; novel strategies; new approaches; novel approaches; novel strategy; Non obese; Nonobese; Population; innovation; innovate; innovative; Impairment; combinatorial; chemotherapy; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; FDA approved; insulin dependent diabetes mellitus onset; type 1 diabetes onset; Regimen; Formulation; preclinical trial; pre-clinical trial; experimental study; experiment; experimental research; efficacy study; clinical development; anti-CD20; cost estimate; cost estimation; Adoption; Adult; 21+ years old; Adult Human; adulthood; Affect; Age; ages; Antigens; immunogen; Autoimmune Diseases; autoimmune condition; autoimmune disorder; Autoimmunity; Autoimmune Status; Biotechnology; Biotech; Blood Glucose; Blood Sugar; Cause of Death; Cells; Cell Body; Clinical Trials; Communities; Dexamethasone; Diabetes Mellitus; diabetes; Insulin-Dependent Diabetes Mellitus; Brittle Diabetes Mellitus; IDDM; Juvenile-Onset Diabetes Mellitus; Ketosis-Prone Diabetes Mellitus; Sudden-Onset Diabetes Mellitus; T1 DM; T1 diabetes; T1D; T1DM; Type 1 Diabetes Mellitus; Type 1 diabetes; Type I Diabetes Mellitus; insulin dependent diabetes; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; type I diabetes; type one diabetes; Drug Industry; Pharmaceutic Industry; Pharmaceutical Industry; Excipients; Florida; Glucocorticoids; Grant; Health; Healthcare Systems; Health Care Systems; Human; Modern Man; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; Immunosuppressive Agents; Immunosuppressants; Immunosuppressive drug; Immunosuppressive treatment; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Insulin; Humulin R; Novolin R; Regular Insulin; Leadership