Preparing BBI-001 as an oral, non-absorbed iron chelator for prevention of iron overload

PROJECT SUMMARY/ABSTRACT Hereditary Hemochromatosis (HH) is one of the most common genetic disorders in the United States affecting 1 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, causing clinical iron overload and severe health issues, including cirrhosis and heart failure. Phlebotomy is the primary treatment for managing serum ferritin levels in patients with HH, with patients requiring maintenance phlebotomy treatments 4-6 times per year on average throughout their lifetime. While phlebotomy is safe, it is not well tolerated by patients. This leads to poor long-term compliance, significant organ damage, and increased risk of severe health conditions. Pharmacologic treatment offers an attractive alternative to maintenance phlebotomy. However, while studies have explored the potential of pharmacologic interventions for iron overload (e.g., systemic iron chelation therapy, protein replacement therapy, gene therapy), few have been clinically translated and none have been commercialized for chronic management of iron overload due to issues of safety and cost. As a result, there is a significant need for a safe, convenient intervention that is an effective alternative to phlebotomy for chronic maintenance of iron overload in patients with HH. In this project, we will develop an orally dosed, non-absorbed iron chelator, BBI-001, that binds dietary iron in the small intestine and eliminates it through fecal output for chronic maintenance of serum ferritin levels in patients with HH. Preliminary studies of BBI-001 have validated its mechanism of action in a small animal model and demonstrated that it is non-absorbed and has high iron binding capacity, and selectivity with rapid kinetics for binding iron prior to absorption in the gastrointestinal tract. This Phase I SBIR study has two Specific Aims: In Specific Aim 1, we will complete a preclinical Maximum Tolerated Dose toxicity study in rats to validate BBI-001’s safety when multiple doses are given per day. Specific Aim 2 will focus on rapid clinical translation of BBI-001 by preparing a package to support a pre-IND (Investigational New Drug) meeting with the FDA for BBI-001 and by advancing Chemistry, Manufacturing, and Controls (CMC) strategy in preparation for 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 chronic maintenance of serum ferritin levels in HH patients. Chronic treatment of iron overload in HH patients with BBI-001 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 HH.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.