Project Grant R44DK121634

TARGETED LYMPHOABLATION AS AN ALTERNATIVE TO HSCT TO CURE T1D - PROJECT SUMMARY 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.