Discussion
ureteral injuries, renal impairment, proteinuria, hypersensitivity
URETER, RENAL IMPAIRMENT, HYPERSENSITIVITY, COMPLICATIONS
Results of this phase 2, dose-ranging study show that IV administration of pudexacianinium leads to enhanced anatomical visualization of the ureter under NIR-F conditions at all doses. Sustained enhancement of ureter visualization was observed for five of the six patients who received the 1.0-mg dose and all three patients who received the 3.0-mg dose during surgery. According to the visualization data and PK findings, plasma pudexacianinium concentrations and urinary pudexacianinium excretion increase in a dose-dependent manner. Results of the quantitative assessment of color contrast showed that the CEF was notably less for the 0.3-mg dose than for the 1.0-mg or 3.0-mg dose of pudexacianinium, indicating that the higher doses provide greater assurance of enabling the surgeon to visualize the ureter consistently. Ureters were visualized at the end of surgery for all except two participants (one received the 0.3-mg dose and one received the 1.0-mg dose). It is important to note that BMI is an important factor to consider when assessing optical visualization of vessels beneath the tissue surface. In the current study, participants who received pudexacianinium 1.0 mg had higher mean and median BMIs than participants in the other dose cohorts.Pudexacianinium appeared to be safe and well tolerated in this study. One case of proteinuria grade 1 was considered related to pudexacianinium (1.0-mg dose) administration, and the few serious AEs that occurred were not related to pudexacianinium and consistent with the underlying indication of colorectal surgery. It is also important to note that no AEs observed were suggestive of hypersensitivity or anaphylactic reactions, which have been reported in isolated cases immediately following administration of high doses of ICG [Published rates of IUI varied by surgery type and may be higher than previously reported [The 1.0-mg pudexacianinium dose provided visualization throughout the duration of surgery for five of the six participants. The surgeon survey on clinical benefit showed that benefits of visualization (6/6 questions) were apparent in all participants at the 1.0 mg and 3.0 mg doses. By comparison, the 0.3-mg dose provided reduced fluorescence intensity and shorter duration of visualization that was considered inadequate for intraoperative ureter visualization, while the 3.0-mg dose provided stronger fluorescence intensity over the 1.0-mg dose.Taken together with previous findings to date on pudexacianinium, we anticipate that this imaging agent will provide clinical benefit by addressing the unmet medical need for improved ureter identification using a safe, noninvasive, intraoperative visualization agent. Moreover, the benefits of avoiding intraoperative stents should minimize ureteral injuries and associated complications, potentially decrease operating times, avoid repeat surgeries, and reduce the possibility of increased medical costs from side effects.This study was limited by the small sample size with descriptive statistics used to evaluate differences between doses. Additionally, no participants with renal impairment were included in the study, so it remains to be determined whether slower renal elimination might impact fluorescence intensity and duration of ureter visualization. An investigation of the safety and tolerability and of the PK parameters of pudexacianinium in individuals with renal impairment is currently planned (NCT05495581).In conclusion, this phase 2 study demonstrated that administration of the novel fluorescent imaging agent pudexacianinium, at doses of 1.0 mg and 3.0 mg, provides ureteral visualization for the full duration of minimally invasive, laparoscopic colorectal procedures. The CEF threshold of 1.5 for dye identification is relevant based on ureter identification and visualization that occurred at CEF values above the threshold. Both qualitatively and quantitatively, data indicated that there was a direct relationship between signal intensity and pudexacianinium dose. High proportions of patients in the 1.0-mg (89.7%) and 3.0-mg (95.2%) dose groups had CEF values above 1.5, with potential benefit of the 3.0-mg versus 1.0-mg dose based on the higher proportion of patients above the dye identification threshold. Pudexacianinium, across studies to date, has demonstrated a consistent and desirable safety, tolerability, and PK profile. In the current study, all doses of pudexacianinium were tolerable and had good safety profiles.