Development of the anti-fentanyl monoclonal antibody, CSX-1004, for prophylaxis against fentanyl and fentanyl analog overdose - The opioid crisis in the United States has been dominated by illicitly manufactured fentanyl for a majority of the last decade, during which time over 400,000 Americans have died from unintentional overdose due to fentanyl or fentanyl analogs. The overdose reversal agent, naloxone, has been the cornerstone of opioid overdose management since 1971; however, the unique pharmacology of fentanyl, including the speed with which it can produce life-threatening respiratory depression and that some high-dose fentanyl effects (e.g., laryngospasm) are resistant to naloxone reversal, has contributed to decreased clinical utility of naloxone in the synthetic opioid era. Given the unique challenges posed by fentanyl and fentanyl analogs for reversing acute overdose, there is a pressing unmet medical need to develop novel therapies that offer prophylaxis against fentanyl overdose. We have developed a human IgG1 monoclonal antibody, known as CSX-1004, that is specific for fentanyl and structurally related fentanyl analogs. Preclinical data in nonhuman primates demonstrated that a single dose of IV CSX-1004 produced robust, durable, and selective blockade of fentanyl-induced respiratory depression for at least one month. A first-in-human pharmacokinetic and safety study indicated that IV CSX-1004 was well-tolerated and exhibited a multi-week half-life with predictable exposure across the dose range tested. CSX-1004 is therefore a Phase 2-ready molecule. In response to PAR-22-202, we propose to further advance the clinical development of CSX-1004 by first conducting a Phase 2, proof-of-concept, fentanyl challenge study in healthy subjects and subjects with Opioid Use Disorder (Aim 1). The ultimate target product profile is a fixed-dose, subcutaneous (SC) injection that can be rapidly and conveniently deployed in a variety of healthcare settings. Using this SC formulation, we will conduct a single-dose bioavailability study of SC vs. IV CSX-1004, and determine the multiple-dose safety, pharmacokinetics, and immunogenicity profile of the SC formulation (Aim 2). The collective data from Aims 1-2, along with prior nonclinical and clinical data, will form the scientific and regulatory framework for an End of Phase 2 Meeting with FDA (Aim 3), where we will solicit guidance from FDA on a pivotal Phase 2/3 study design and other requirements (e.g., any additional nonclinical studies, extent of safety database) for a successful BLA submission.
