Hereditary Hemochromatosis (HH) is one of the most common genetic disorders in the United States affecting1 million people primarily of Northern European descent. People with HH are unable to produce hepcidin and,as a result, experience excess absorption of dietary iron. Excess iron is stored in tissues and organs, causingclinical iron overload and severe health issues, including cirrhosis and heart failure. Phlebotomy is the primarytreatment for managing serum ferritin levels in patients with HH, with patients requiring maintenancephlebotomy treatments 4-6 times per year on average throughout their lifetime. While phlebotomy is safe, it isnot well tolerated by patients. This leads to poor long-term compliance, significant organ damage, andincreased risk of severe health conditions. Pharmacologic treatment offers an attractive alternative tomaintenance phlebotomy. However, while studies have explored the potential of pharmacologic interventionsfor iron overload (e.g., systemic iron chelation therapy, protein replacement therapy, gene therapy), few havebeen clinically translated and none have been commercialized for chronic management of iron overload dueto issues of safety and cost. As a result, there is a significant need for a safe, convenient intervention that isan effective alternative to phlebotomy for chronic maintenance of iron overload in patients with HH. In thisproject, we will develop an orally dosed, non-absorbed iron chelator, BBI-001, that binds dietary iron in thesmall intestine and eliminates it through fecal output for chronic maintenance of serum ferritin levels inpatients with HH. Preliminary studies of BBI-001 have validated its mechanism of action in a small animalmodel and demonstrated that it is non-absorbed and has high iron binding capacity, and selectivity with rapidkinetics for binding iron prior to absorption in the gastrointestinal tract. This Phase I SBIR study has twoSpecific Aims: In Specific Aim 1, we will complete a preclinical Maximum Tolerated Dose toxicity study in ratsto validate BBI-001's safety when multiple doses are given per day. Specific Aim 2 will focus on rapid clinicaltranslation of BBI-001 by preparing a package to support a pre-IND (Investigational New Drug) meeting withthe FDA for BBI-001 and by advancing Chemistry, Manufacturing, and Controls (CMC) strategy in preparationfor cGMP production. The long-term goal of this project is to commercialize BBI-001 as the first and only non-toxic iron chelation therapy and a safe and effective alternative to maintenance phlebotomy for chronicmaintenance of serum ferritin levels in HH patients. Chronic treatment of iron overload in HH patients withBBI-001 will result in improved compliance and more consistent maintenance of serum ferritin levels, leadingto lower risk of organ damage and related complications, reduced healthcare costs, and improved long-termoutcomes in patients with HH.
Public Health Relevance Statement: Project Narrative
Hereditary hemochromatosis is one of the most common genetic disorders in the United States. In this
project, we will develop the first and only non-toxic iron chelation therapy as a safe and effective alternative to
phlebotomy for chronic management of serum ferritin levels in patients with hereditary hemochromatosis. This
will result in improved compliance and more consistent maintenance of serum ferritin levels, leading to lower
risk of organ damage and related complications, reduced healthcare costs, and improved long-term outcomes
in patients with hereditary hemochromatosis.
Project Terms: dietary Fe ; Dietary Iron ; Hereditary hemochromatosis ; Severities ; Oral ; meetings ; experience ; iron chelation therapy ; Protein Replacement Therapy ; enzyme replacement therapy ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; Structure ; technological innovation ; Prevention ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Intervention Strategies ; interventional strategy ; Intervention ; Hepc peptide ; hepcidin ; Molecular Interaction ; Binding ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Dose ; Age-Months ; Data ; Pharmacological Treatment ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Preparation ; Cirrhosis ; cirrhotic ; Pathway interactions ; pathway ; Output ; pre-clinical ; preclinical ; cost ; design ; designing ; Outcome ; Chronic Care ; commercial application ; standard of care ; preclinical efficacy ; pre-clinical efficacy ; preclinical safety ; pre-clinical safety ; cGMP production ; clinical translation ; Genetic Diseases ; genetic condition ; genetic disorder ; iron absorption ; Fe absorption ; side effect ; Phase Ib Clinical Trial ; Phase 1b Clinical Trial ; absorption ; Affect ; Animals ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Chelation Therapy ; Chemistry ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Investigational Drugs ; Investigational New Drugs ; Enterobactin ; Enterochelin ; Europe ; Feces ; stool ; Ferritin ; Gastrointestinal tract structure ; Alimentary Canal ; Digestive Tract ; GI Tract ; Gastrointestinal Tract ; alimentary tract ; digestive canal ; Gel ; gene therapy ; DNA Therapy ; Gene Transfer Clinical ; Genetic Intervention ; gene-based therapy ; genetic therapy ; genomic therapy ; Goals ; Health ; Heart failure ; cardiac failure ; Small Intestines ; small bowel ; Iron Chelating Agents ; Iron Chelates ; Kinetics ; Maintenance ; Mus ; Mice ; Mice Mammals ; Murine ; Legal patent ; Patents ; Patients ; Pharmacology ; Polymers ; Publishing ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Risk ; Safety ; Time ; Tissues ; Body Tissues ; Translating ; United States ; Health Care Costs ; Health Costs ; Healthcare Costs ; Investigational New Drug Application ; base ; crosslink ; cross-link ; Organ ; improved ; Venous blood sampling ; Phlebotomy ; Chronic ; Clinical ; Phase ; Serum ; Blood Serum ; European ; Iron Overload ; Fe overload ; Fe element ; Iron ; Iron Binding Capacity ; Iron binding capacity measurement ;
