Page 93 - Haematologica Vol. 110 - January 2025

ARTICLE - LP-118: a promising treatment for CLL
J. Ravikrishnan et al.
sponds to 10-fold reduced platelet toxicity for LP-118 in vivo. No thrombocytopenia was observed for LP-118 doses within the 5 to 20 mg/kg range in a 28-day repeat-dose non-GLP toxicity study (Online Supplementary Figure S1M). Lastly, a 25 mg/kg single dose study revealed the maximum concentra- tion of LP-118 in plasma (mean = 8 μg/mL) was reached 10 hr after treatment (Online Supplementary Figure S1N). A notable difference between venetoclax and LP-118 pharmacokinet- ics was seen at 30 hr post treatment where only venetoclax persisted in plasma, suggesting faster clearance for LP-118. In this study, the maximum reduction in platelets was 6%, 17%, and 97% for venetoclax, LP-118, and navitoclax, respectively. Therefore, LP-118 is an ideal candidate for clinical evaluation due to its minimal platelet targeting, and has a toxocity profile similar to that of venetoclax.
Xenograft mouse models depict superiority of LP-118 compared to venetoclax in vivo
We wanted to study the efficacy of LP-118 in vivo, in cells har- boring WT or G101V BCL2. Immunodeficient CB.17 SCID mice
A
were engrafted with RS4;11 cells with WT or G101VOE BCL2. After tumors reached an average size of 113 to 116 mm3, WT RS4;11 mice were treated orally once daily with vehicle (N=7), 6.25 mg/kg LP-118 (N=7), or 6.25 mg/kg venetoclax (N=7) for 28 days. Mice were removed from study when tumors reached an endpoint volume of 2000 mm3, or at 77 days, whichever occurred first. Upon stopping treatment, tumors from LP-118 treated mice did not show increased volume, while veneto- clax-treated mice relapsed and exhibited increased tumor growth (Figure 6A). Mice treated with LP-118 had a significant survival advantage over vehicle-treated mice (median survival = 31.4 days; LP-118 versus vehicle P=0.0005) and veneto- clax-treated mice (median survival = 59 days; LP-118 versus venetoclax P=0.0002) (Figure 6B). RS4;11 BCL2 G101VOE cells were engrafted in mice and treated with vehicle, venetoclax (100 mg/kg, q.d., N=7) or LP-118 (50, 100 and 150 mg/kg, q.d., N=7) after reaching a tumor size of 131-134 mm3. Contrary to venetoclax 100 mg/kg, mice treated with LP-118 at all doses exhibited a decrease in tumor growth (Figure 6C). All doses of LP-118 also resulted in a significant improved overall
BCD
Figure 3. LP-118 induces apoptosis in chronic lymphocytic leukemia cells supported by NK Tert stroma. (A) Representative flow of N=6 primary chronic lymphocytic leukemia (CLL) samples cultured with or without NK Tert stroma with in vitro treatment of venetoclax, LP-118, or navitoclax. IC50 calculated by Nonlinear Regression. Plots display mean ± Standard Deviation. (B-D) Western blot, and quantification of BCL2 and BCLXL expression normalized to GAPDH, in primary CLL patient samples cultured with or without NK Tert stroma (N=5).
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