Page 97 - Haematologica Vol. 110 - January 2025

ARTICLE - LP-118: a promising treatment for CLL
J. Ravikrishnan et al.
cytometry at the end point, determined by hind limb paraly- sis.26 Compared to vehicle, LP-118 and venetoclax significantly improved the survival of mice (P=0.0002) (Figure 6E). LP-118- and venetoclax-treated mice also maintained similar platelet counts throughout the course of treatment (Figure 6F). The data presented here indicate that LP-118 increases survival and decreases tumor growth in 2 leukemia xenograft models and can target cells harboring G101V mutant BCL2 in vivo.
Discussion
We characterized LP-118, a novel, highly potent, orally bioavailable, selective BCL2 inhibitor that also moderately targets BCLXL and can potentially overcome several vene- toclax resistance mechanisms. LP-118 retains high binding affinity to WT BCL2 and is a more potent inhibitor of G101V mutant BCL2 than venetoclax. It shows improved plate- let-sparing capability than navitoclax in human platelets ex vivo and Eμ-TCL1 mice in vivo.
There are multiple mechanisms of venetoclax resistance that have been well-characterized. We showed that LP- 118 is highly potent at inducing mitochondrial apoptosis in both treatment-naïve and venetoclax-relapsed CLL cells. BH3 profiling revealed that venetoclax-relapsed CLL may lose sensitivity to BAD peptide, which binds most tightly to BCL2. The observation that BCLXL targeting peptide HRK initiated apoptosis in some venetoclax-relapsed cells, but not in treatment-naïve CLL, suggests increased depen- dence on BCLXL at relapse. We also showed that LP-118 can induce apoptosis of venetoclax-resistant cell lines with high dependence on BCLXL, or with G101V BCL2 muta- tions. Additional studies are required to assess its potency against other BCL2 mutations, such as D103E which makes BCL2 more structurally similar to BCLXL.3,4 in vivo, LP-118 improves the survival of RS4;11 WT, RS4;11 G101VOE BCL2 and OSU-CLL xenografts. These results highlight the pre- clinical efficacy and success of LP-118 and warrant clinical evaluation to determine its potential to treat front-line or venetoclax-relapsed CLL.
A recent study described the few treatment options for patients who progress on venetoclax, and the limited and relatively ineffective therapeutic interventions for patients refractory to both BCL2 and BTK inhibitors.27 Inhibitors of multiple BH3 proteins are attractive to overcome venetoclax resistance and must be carefully designed to limit on-target toxicities. For example, targeting MCL1 amplification and overexpression, venetoclax resistance factors in lymphoid malignancies,7 will require strategies to circumvent cardiac side effects14,15 such as CDK9 inhibition.28 Clinical evaluation of first generation BCL2 / BCLXL inhibitors like navitoclax found on-target platelet toxicity leading to concentration-de- pendent thrombocytopenia that limit the clinical utility of these inhibitors.17,18 LP-118 has low platelet toxicity, similar to venetoclax in vitro and in vivo, in Eμ-TCL1 mice and dogs.
Therefore, we predict LP-118 to have clinically manageable side effects.
Dependencies on various antiapoptotic proteins of the BCL2 family have been identified in a wide range of hematologic malignancies and solid tumors; therefore, LP-118 may also be of clinical interest in other cancers. Venetoclax has been approved by the US Food and Drug Administration for both CLL and acute myeloid leukemia (AML) and is currently under investigation for other non-Hodgkin lymphomas, T-cell lym- phoma, acute lymphoblastic leukemia (ALL), and solid tumors. Moreover, in some solid tumors such as breast cancer29 and colon cancer,30 BCLXL is highly associated with resistance to therapy. Therefore, the high potency and broader activity of the BCL2 / BCLXL inhibitor LP-118 may have many areas of potential impact, surpassing more selective BH3 mimetics. These areas include ALL and venetoclax-resistant T-cell leukemia, as evidenced by the efficacy shown in RS4;11 and MOLT4 cells, respectively, among other cell lines.
While the preclinical data are encouraging, clinical trials will be required to determine whether the preclinical ad- vantages seen with LP-118 compared to venetoclax are relevant in patients. Pharmacokinetics and platelet toxicity must be monitored carefully. These preclinical data support the ongoing phase I evaluation of LP-118 in CLL, as well as other hematologic malignancies.
Disclosures
JAW received research support from Verastem, Karyopharm, Morphosys, and Schrodinger, and has consulted for Phar- macyclics, Janssen, AstraZeneca, Arqule, Abbvie, Beigene, Loxo, Newave, and Genetech. DS is on the advisory board for Newave Pharma. KAR received research funding from Genen- tech, AbbVie, Janssen, and Novartis, consults for Genentech, AbbVie, AstraZeneca, Innate Pharma, Pharmacyclics, and Beigene, and received travel funding from Beigene. JAW and KAR are clinical scholars of the Leukemia and Lymphoma Society. ASK consulted for Abbvie, Beigene, Bristol-Myers Squibb, and Janssen. MSD reports receiving grant support paid to his institution and consulting fees from Ascent- age Pharma, Astra-Zeneca, BMS, Genentech, MEI Pharma, Pharmacyclics, TG Therapeutics, and Verastem, and reports grant support paid to his institution from Surface Oncology, and consulting fees from AbbVie, Adaptive Biotechnologies, Aptitude Health, BeiGene, Celgene, Eli Lilly, Janssen, Merck, Research to Practice, and Takeda. JCB consulted for Acer- ta, AstraZeneca, Pharmacyclics, Astellas, Syndax, and Jazz Pharmaceuticals, and reports stock ownership in Vincerx Pharmaceutics. SAB consulted for Pharmacyclics, Janssen, Beigene, and Acerta / AstraZeneca. RL has membership on the Vincerx Pharma Inc. Board of Directors or advisory committees. YiC, SPA and YuC are employed by and hold a position on the Board of Directors of Newave Pharmaceu- tical Inc., the maker of LP-118, and report stock ownership in Newave Pharmaceutical Inc. YiC holds patents 10456397, 10377755, 10253029, 10239872, 10195200. YS and FT are em-
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