Superficial Venous-Associated Inflammation from Direct IV Administration of RRx-001 in Rats

Area of Science:

• Pharmacology
• Toxicology
• Oncology

Background:

• RRx-001 is a novel small molecule inhibitor targeting the NLRP3 inflammasome, with demonstrated anti-CD47 and anti-angiogenic properties.
• Clinical trials indicated that direct intravenous (IV) infusion of RRx-001 led to painful infusion phlebitis (IP), a significant adverse event.
• The development of IP poses risks such as deep venous thrombosis and post-thrombotic syndrome, particularly in cancer patients.

Purpose of the Study:

• To evaluate the toxicological profile of RRx-001 administered via IV infusion in a preclinical setting.
• To assess the safety and tolerability of RRx-001, focusing on venous irritation and inflammatory responses.
• To provide data supporting alternative, safer administration methods for RRx-001.

Main Methods:

• A 13-week toxicology study involving once-weekly IV administration of RRx-001 to Wistar Han rats.
• A subsequent 28-day recovery period to monitor for persistent toxicities.
• Histopathological examination of venous tissues to assess inflammatory responses and thrombosis.

Main Results:

• The primary toxicity observed was a significant inflammatory response in the vein wall, consistent with superficial venous thrombosis.
• This inflammatory response mirrored the infusion phlebitis seen in human clinical trials.
• The findings indicate a direct correlation between RRx-001 administration and venous wall inflammation.

Conclusions:

• Direct IV infusion of RRx-001 is associated with significant venous toxicity, including inflammation and thrombosis.
• Co-administration with autologous blood, as explored in Phase 2, is a preferred method to mitigate these risks.
• These findings support the contraindication of direct IV infusion and the use of alternative delivery methods for RRx-001 in clinical practice.