ADX-324: An Investigational siRNA Therapeutic for Hereditary Angioedema

I. Executive Summary

ADX-324 is an investigational short-interfering RNA (siRNA) therapeutic agent under development by ADARx Pharmaceuticals, Inc., primarily for the prophylactic treatment of Hereditary Angioedema (HAE).[1] The therapeutic strategy of ADX-324 centers on the specific targeting and reduction of plasma prekallikrein (PKK) production, a pivotal protein in the pathophysiological cascade leading to bradykinin generation and subsequent angioedema attacks characteristic of HAE. This is achieved through the RNA interference (RNAi) mechanism, where ADX-324 is designed to silence the KLKB1 messenger RNA (mRNA).[2]

A key feature of ADX-324's development is its utilization of ADARx Pharmaceuticals' proprietary RNA targeting platform. This platform incorporates technologies for liver-directed delivery, primarily through N-acetylgalactosamine (GalNAc) conjugation (referred to as PLR™ - Preeminent Liver RNA, or CTD™ - Cell-Targeted Delivery technology), and advanced oligonucleotide optimization strategies (known as SPE™ - Sequence Specific Platform Enhancement, or MST™ - mRNA Silencing Technology) to enhance potency, stability, and duration of action.[1]

Preclinical investigations, notably studies conducted in non-human primates, have provided encouraging data supporting the potential for ADX-324 to be administered via a long-acting, low-volume subcutaneous dosing regimen, possibly on a bi-annual or even annual basis.[1] Such a dosing schedule would represent a significant advancement in convenience and treatment burden reduction for HAE patients. Pharmacodynamic data from these preclinical efforts were presented at the Annual Scientific Meeting of the American College of Allergy, Asthma & Immunology (ACAAI) in November 2023, signaling progress in understanding the drug's activity profile.[8]