LP-118, a Novel BCL2 Inhibitor, Shows Potent in Vitro Anti-Myeloma Activity

Targeting anti-apoptotic proteins has been an effective therapeutic strategy in a subset of multiple myeloma (MM) patients who show lymphoid characteristics and/or who have t(11;14) translocations. The use of venetoclax has demonstrated excellent clinical activity in these patients, but prolonged treatment commonly leads to therapeutic resistance.

LP-118 is a novel BCL-2/BCL-XL inhibitor, which has a modified structure with fine-tuned BCL-XL activity that minimizes platelet toxicity, associated with other BCL-XL inhibitors, such as navitoclax. Here we report results from a preclinical study evaluating anti-tumor effect of LP-118 on human MM cells. We compared this compound's activity to venetoclax through single and combination drug assays on both MM cell line models and primary patient samples. Cell viability was measured using either luminescent cell viability assay or Annexin V flow cytometry staining. We also performed proteomic analysis after treatment of a human myeloma cell line, KMS-12-PE, with both drugs at 3h, 6h and 9h time points.

LP-118 showed strong anti-myeloma activity in both venetoclax-sensitive cell lines and primary MM cells, with significantly increased potency when compared to venetoclax. We tested a total of 14 MM cell lines, and on average LP-118 was around a 10-fold more potent than its counterpart (0.45 - 80.07 nM versus 0.08 - 0.93 nM in venetoclax and LP118 treated cell lines, respectively; p <0.001). A similar pattern was seen in the primary MM patient samples. Induced apoptotic activity was strongly associated with the previously described BCL-2/BCL-XL ratio. Through time-series proteomic analyses of venetoclax treated KMS-12-PE cells, we observed a compensatory upregulation of BCL-2 levels within 9 hours of treatment, an effect not seen within the same time frame in cells treated with LP-118 (Figure 1). Characteristically, within the same time frame there was an initial decrease of Mcl-1 at the 3-hour time point, followed by an expected increase by hour 6.

Resistance to venetoclax in MM has not been associated to mutations in the Bcl-2 protein as has been seen in other hematological malignancies. Instead, resistance has been linked to upregulation of compensatory anti-apoptotic proteins, such as Mcl-1, and through other complex metabolic mechanisms not fully understood. To determine whether resistance could be overcome with directed drug combinations, we further treated cell lines using the more-potent LP-118 in combination with other anti-MM drugs.

Co-treatment of LP-118 with bortezomib or dexamethasone showed strong synergistic activity in venetoclax-sensitive cell lines. In cell lines with acquired venetoclax resistance, the combinations of LP-118 with bortezomib or dexamethasone also showed promising synergistic activity, but requiring higher doses of both compounds in comparison to their venetoclax-sensitive counterparts. Based on recent literature showing a direct link of venetoclax sensitivity to electron transport chain activity, co-treatment with IACS-010759, a mitochondrial complex I inhibitor, was also tested, showing moderate enhancement of anti-BCL-2 activity. However, best results were seen when targeting the compensatory upregulation of MCL-1 with S63845, an MCL-1 inhibitor. The combination showed very strong synergistic activity, requiring very low doses of both compounds; well below their IC-50 as in single-drug assays.

Together, our results show LP-118 has promising in vitro activity in MM cell lines and primary samples. The significantly increased potency when compared to venetoclax, would potentially allow treatment with substantially lower doses. An ongoing phase 1 dose-escalation trial (NCT04771572) is underway evaluating safety and tolerability in patients with relapsed or refractory hematological malignancies. Future in vitro and in vivo animal studies will continue to evaluate drug combinations that best overcome drug resistance to anti-apoptotic treatment.

Bergsagel:Oncopeptides: Consultancy; Janssen: Consultancy; GSK: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Chesi:Pfizer, Novartis.: Consultancy; Abcuro, Palleon Pharmaceuticals, Pi Therapeutics.: Patents & Royalties: Genetically engineered mouse model of myeloma.. Chen:Newave Pharmaceuticals: Current Employment. Tan:Newave Pharmaceuticals: Current Employment. Anthony:Newave Pharmaceuticals: Current Employment. Chen:Newave Pharmaceuticals: Current Employment. Shen:Newave Pharmaceuticals: Current Employment. Dai:Newave Pharmaceuticals: Current Employment. Fonseca:Bayer: Consultancy; BMS/Celgene: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; H3 Therapeutics: Consultancy; Oncopeptides: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; AbbVie: Consultancy; Regeneron: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy; Takeda: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Juno: Consultancy; GSK: Consultancy; Amgen: Consultancy; OncoMyx: Membership on an entity's Board of Directors or advisory committees.

Venetoclax is used as an off-label treatment for a subset of multiple myeloma patients.