The opioid crisis in the United States is a devastating public health issue, with over 70,000 overdose deaths annually, largely driven by the highly potent synthetic opioid fentanyl. The urgency to address this crisis has spurred the development of innovative therapies to prevent and reverse fentanyl overdoses. In this blog, we will explore the groundbreaking preclinical work on CSX-1004, a fully human monoclonal antibody with exceptional affinity for fentanyl and associated analogs, offering hope in the battle against opioid overdose deaths.
CSX-1004’s effectiveness in reversing the effects of fentanyl and carfentanil was demonstrated in a mouse study. These opioids induce severe respiratory depression, which can be fatal. Using emka & SCIREQ whole-body plethysmography (WBP) and IOX Software, CSX-1004 was found to reverse this respiratory depression more effectively than the standard opioid overdose reversal drug, naloxone (Figure 1), particularly in cases of carfentanil overdose, which are notoriously challenging to treat.
To better understand its potential in a more human-like context, CSX-1004 was tested in non-human primates (NHPs), specifically squirrel monkeys. emka & SCIREQ WBP and IOX Software enabled the measurement of breathing frequency, tidal volume, and minute volume in these NHPs. These experiments showed that CSX-1004 not only reversed respiratory depression (Figure 2) but also mitigated other fentanyl-related effects like antinociception and operant responding. Importantly, it did not affect non-fentanyl opioids such as oxycodone.
CSX-1004 demonstrated remarkable durability in NHPs, providing protection from repeated fentanyl challenges for up to three weeks after a single administration. As WBP allows for continuous monitoring of respiratory parameters, this further emphasizing the sustained impact of CSX-1004. This suggests that CSX-1004 could be administered less frequently, possibly on a monthly basis, making it a convenient and effective option for overdose prevention.
Toxicology studies in rats indicated no adverse effects of CSX-1004, and minimal antibody formation occurred. Additionally, there was no significant cross-reactivity with human tissues. These promising results pave the way for CSX-1004’s entry into clinical trials, where it is currently being evaluated for safety and pharmacokinetics.
The development of CSX-1004, a fully human monoclonal antibody with potent anti-fentanyl properties, represents a significant breakthrough in addressing the opioid crisis in the United States. Its efficacy in reversing and preventing fentanyl overdose, along with its favorable safety profile, holds promise for saving lives and reducing the devastating impact of the opioid epidemic.
Investigation of monoclonal antibody CSX-1004 for fentanyl overdose. (2023). Bremer, P., Burke, E.L., Barrett, A.C., & Desai, R.I. Nature Communications, 14: 7700
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