Source: FDA, National Drug Code (US) Revision Year: 2024
Pegulicianine is a prodrug that is optically inactive when intact and produces a fluorescent signal after its peptide chain is cleaved by cathepsins and matrix metalloproteases (MMPs). The levels of these enzymes are higher in and around tumor and tumor-associated cells than normal cells.
This enzymatic cleavage results in “fragment 2” and “fragment 3”, which are optically active metabolites that emit fluorescence, as well as “fragment 1” containing the fluorescence quencher that keeps the intact molecule optically inactive. “Fragment 2” and “fragment 3” absorb light in the visible light region with a peak absorption at 650 nm and fluoresce with a peak emission at 675 nm.
The relationships between the plasma concentrations of the optically active metabolites and the time course of pharmacodynamic response have not been fully characterized.
Pegulicianine is cleaved by cathepsins and matrix metalloproteases to the active metabolites “fragment 2” and “fragment 3.” Pegulicianine undergoes minimal hepatic metabolism in vitro.
Pegulicianine excretion pathway in humans is unknown. Observed blue/green discoloration of urine (chromaturia) in subjects receiving pegulicianine suggests that pegulicianine and/or its metabolites may be excreted renally.
Mild renal impairment (RI) does not appear to have a clinically meaningful effect on the pharmacokinetics, safety, and efficacy of pegulicianine and fragment 3; fragment 2 data are not available. The effect of moderate or severe RI on the pharmacokinetics, safety, and efficacy of pegulicianine, fragment 2, and fragment 3 has not been evaluated.
No studies in animals have been conducted to evaluate the carcinogenic potential of pegulicianine.
The nonfluorescent major metabolite of pegulicianine was not mutagenic in nonclinical tests, i.e., in vitro reverse mutation test in bacteria (Ames test), in vitro chromosomal aberration test in human peripheral blood lymphocytes, and in vivo (mice) micronucleus test after intravenous doses up to 11.24 mg/kg (225 times the pegulicianine clinical dose of 1 mg/kg).
No reproductive and developmental toxicity studies in animals have been performed to evaluate the effects of pegulicianine on fertility.
The efficacy and safety of LUMISIGHT for the intraoperative detection of cancerous tissue within the resection cavity following removal of the primary specimen during lumpectomy surgery in patients with breast cancer were evaluated in a randomized, multicenter, intra-patient controlled clinical trial (NCT03686215). A total of 406 adult patients with confirmed invasive breast cancer, ductal carcinoma in situ (DCIS), or both received 1 mg/kg LUMISIGHT by intravenous injection 2 hours to 6 hours prior to imaging with the Lumicell DVS. Among them, 357 patients underwent LUMISIGHT-guided imaging after completion of the standard of care lumpectomy procedure. Patients who received neoadjuvant chemotherapy or radiotherapy prior to surgery were excluded from study. After the standard of care (SOC) lumpectomy was completed, the lumpectomy cavity was divided into six regions based on anatomic orientation and each region was imaged with the Lumicell DVS. When positive fluorescence signal was detected, the tissue was resected with a cavity shave procedure and the region was re-imaged. A maximum of two LUMISIGHT-guided shaves were obtained from a single region. Histopathology analysis of excised tissue served as the reference standard. Cavity regions that did not have a LUMISIGHT-guided cavity shave or tissue from a second surgery for a reference standard were assigned the margin status of the corresponding outermost surface of the lumpectomy specimen or SOC cavity shave, with a positive margin defined as tumor on ink for invasive cancers (with or without DCIS) or within 2 mm of the inked margin for DCIS alone.
The mean age of patients was 62 years (range: 36 years to 83 years). Distribution by race was 82% White, 7% Black or African American, 6% Asian, and 5% other. Distribution by ethnicity was 3% Hispanic/Latino, 94% non-Hispanic/Latino, and 3% unknown or unreported. In the study group, 70% of patients had invasive ductal carcinoma (with or without DCIS), 20% had DCIS only, 10% had invasive lobular carcinoma (with or without DCIS), and <1% had both invasive ductal and invasive lobular carcinoma.
The study assessed the proportion of patients receiving LUMISIGHT who had residual cancer detected and removed using the Lumicell DVS after completion of SOC lumpectomy. One hundred and sixty-six (166) of 357 (46%) patients had at least one LUMISIGHT-guided shave. A total of 27 of 357 patients had residual cancer confirmed by histopathology in at least one LUMISIGHT-guided shave (7.6%; 95% CI: 5.0%, 10.8%).
Table 1 shows sensitivity and specificity of LUMISIGHT for residual breast cancer after completion of SOC lumpectomy calculated from the 2,346 evaluable images in the study. Regions of the lumpectomy cavity from which LUMISIGHT-guided shaves were taken contributed more than one image to the analysis.
Table 1. Image-level performance of LUMISIGHT for detection of residual breast cancer in the lumpectomy cavity after completion of standard of care lumpectomy:
| Reference Standard | Total | |||
| Positive | Negative | |||
| LUMISIGHT Imaging Result* | Positive | 34 | 337 | 371 |
| Negative | 35 | 1940 | 1975 | |
| Total | 69 | 2277 | 2346 | |
| Diagnostic Performance** (95% Confidence Interval) | Sensitivity 49.1% (36.4%, 61.9%) | Specificity 86.5% (84.5%, 88.3%) | ||
* Regions of the lumpectomy cavity from which LUMISIGHT-guided shaves were taken contributed more than one image.
** Sensitivity and specificity were calculated using a generalized estimating equation method to account for within-patient correlation.
A total of 155 of 357 (43%) patients had at least one false positive image, and 28 of 357 (8%) patients had at least one false negative image. Among the 166 patients with at least one LUMISIGHT-guided shave, the mean total LUMISIGHT-guided shave volume was 22 cm³ ± 20 cm³, accounting for 20% ± 15% of the total volume of resection.
After completion of SOC lumpectomy, prior to LUMISIGHT-guided tissue removal, 62 of 357 patients (17%) had at least one cancer-positive margin. After LUMISIGHT-guided surgery, 9 of these 62 (15%) patients changed to having all cancer-negative margins, and 2 of the remaining 295 (1%) patients changed from having all cancer-negative margins to having at least one cancer-positive margin.
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