Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.
The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. In tumor cells, the B cell lymphoma 2 (Bcl-2) protein family promotes cell survival through upregulation of anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL, Mcl-1 and Bcl-w. Clinical activity of the Bcl-2 inhibitor venetoclax has validated the approach of targeting this class of molecules, but additional value remains in jointly targeting Bcl-2 with other family members. AZD0466 is a novel drug-dendrimer conjugate, where the active moiety, AZD4320, is chemically conjugated to Starpharma's DEP® dendrimer platform, a 5-generation PEGylated poly-lysine dendrimer via a hydrolytically labile linker. AZD4320 is a potent dual Bcl-2/Bcl-xL inhibitor, with nanomolar affinity for both proteins1. AZD0466 has been optimized to maintain efficacy whilst mitigating anticipated on-target toxicities of AZD4320. The active moiety, AZD4320, was profiled in an unbiased 72 h cell proliferation screen of 764 cancer cell lines. The greatest degree of sensitivity to AZD4320 (IC50 value ≤0.1 µM) was observed in hematological and small cell lung cancer (SCLC) cell lines. AZD0466 demonstrated greater monotherapy activity than platinum/etoposide chemotherapy regimen or venetoclax monotherapy in 6 out of 11 SCLC PDX models. AZD0466 was also evaluated at different doses in the RS4;11 B-ALL xenograft model. Weekly intravenous dose of AZD0466 resulted in complete tumor regression at 34 and 103 mg/kg doses. Administration of a single dose of AZD0466 produced dose dependent induction of cleaved caspase 3 in tumors as measured by MSD ELISA, which was consistent with the concentrations of released AZD4320 measured in the tumor. All treatments were well tolerated. Anti-tumor activity of AZD0466 was also evaluated in the disseminated luciferase-tagged Ri-1-DLBCL tumor model. AZD0466 dosed weekly IV at 34 mg/kg showed approximately 82% inhibition of bioluminescence compared to vehicle treated animals, whereas 103 mg/kg and 340 mg/kg showed complete inhibition of bioluminescence. In the SUDHL-4 GCB DLBCL model, 103 mg/kg AZD0466 with 10 mg/kg Rituximab resulted in complete and durable regressions in 5/6 animals. Finally, combination of 103 mg/kg AZD0466 with 12.5 mg/kg BID Acalabrutinib, a Bruton's Tyrosine kinase inhibitor, was investigated in OCI-LY10 DLBCL model. While neither agent showed any demonstrable monotherapy activity the combination resulted in complete regressions in 8/8 mice in this model. These data show that AZD0466 has monotherapy activity and a differentiated response from Venetoclax in SCLC models. AZD0466 also has therapeutic potential as monotherapy and a combinatorial agent to increase the depth and duration of response to standard of care and BTK inhibitors in hematological tumors. 1Cidado, J; et al. AACR (2018) Citation Format: Srividya B. Balachander, Areya Tabatabai, Shenghua Wen, Francis D. Gibbons, Giulia Fabbri, Guangnong Sunny Zhang, Justin Cidado, Lorraine Graham, Marianne Ashford, Barry Davies. AZD0466, a nanomedicine of a potent dual Bcl-2/Bcl-xL inhibitor, exhibits anti-tumor activity in a range of hematological and solid tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 56.
AZD4635 is an orally administered, selective adenosine 2A receptor (A2AR) antagonist, being evaluated in patients with advanced solid tumors. In the phase 1 trial, safety and pharmacokinetics (PK) of AZD4635 nanosuspension (NS) was assessed as monotherapy or in combination with durvalumab. In the HV study, a single dose of AZD4635 was evaluated to assess relative bioavailability, effect of high fat meal and effect of proton pump inhibitor (PPI) on new capsule formulation (CF). Here we present PK results from both trials to provide dosing and formulation recommendation for ongoing clinical trials. Methods: Phase 1 Study in CP: An open-label, multicenter study in advanced solid malignancies (121 patients PK evaluable), AZD4635 was administered as a NS at various dose levels (125 mg BID, 75mg QD, 100 mg QD) as monotherapy or in combination (75 or 100 mg QD) with durvalumab (NCT02740985). The PK parameters of AZD4635 and its metabolites have been characterized in patients after single and multiple doses. Phase 1 Study in HV: An open-label, single-dose (50 mg), 2-part crossover clinical pharmacology study was conducted in 20 HV (non-smoking, male) (NCT03710434). Part A was a 2-period randomized crossover study of AZD4635 as NS or CF. Part B was a fixed-sequence crossover study to evaluate effect of high fat meal and co-administration of PPI (lansoprazole) on AZD4635 CF. PK and safety assessments were obtained for up to 120 h post-dose in each treatment period, and the treatments were separated with at least a 9-day washout period. Results: AZD4635 NS rapidly appeared in plasma after single or multiple oral administration with tmax of 1 h and Cmax were 594.13, 580.21, and 770.66 ng/mL and AUC were 4780.3, 4364.8, and 5972.89 ng•hr/mL at 75, 100 and 125 mg, respectively with a mean t1/2 of 13.1 - 18.1 h following a single-dose administration. There was minimal accumulation at steady state with high inter-individual variability (43 - 114%). Metabolites PK will be presented. In HV, administration of CF resulted in absorption rates similar to NS with tmax of 1.5 h and had 27% and 10% higher Cmax and AUC, respectively compared to NS. Administering AZD4635 CF after a high fat meal resulted in 56% and 12% decrease in Cmax and AUC, respectively compared to the fasted state. In the presence of PPI (lansoprazole), peak and overall exposures (Cmax, AUC and tmax) were similar to those for CF administered alone. Conclusion: Based on totality of exposure and safety data from ongoing Phase I study in CP at various doses of AZD4635 NS, and data from HV study for both NS and CF, a dose of 75 mg CF is proposed RP2D for further clinical studies. As food can mitigate gastrointestinal toxicities, and there was a lack of significant effect on AUC, the current fasting restrictions have been relaxed to allow patients to receive AZD4635 with or without food. No impact of PPI allows for better compliance as the target patient population may also be receiving gastric modifiers. Citation Format: Ganesh Moorthy, Gayle Pageau Pouliot, Lorraine Graham, Chris Wilks, Tinnu Sarvotham, Patrick Mitchell, Lindsey Jung, Yan Li, Wenlin Shao, Ganesh Mugundu. Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT168.
Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many hematological and solid tumors, but their clinical application has been limited by tolerability issues, including thrombocytopenia. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, showed good efficacy but encountered dose limiting cardiovascular toxicity in preclinical species, and had challenging physicochemical properties which prevented its clinical development. Nanocarriers can provide prolonged circulation time, controlled release, tumor accumulation and retention. Consequently, they have been explored to improve the therapeutic index of small molecules in oncology. This work describes the design and development of AZD0466, a novel drug-dendrimer conjugate, where AZD4320 is chemically conjugated to Starpharma's DEP® dendrimer platform, a 5-generation PEGylated poly-lysine dendrimer via a hydrolytically labile linker. Release of AZD4320 is through hydrolytic cleavage of the linker, which is characterized by a “release half-life”, defined as the time to release 50% of the active moiety. This release half-life can be modified through linker design. Initially, three drug-dendrimer conjugates with a range of AZD4320 release half-lives (from 1.7 h to 217 h) were synthesized and efficacy was investigated in C.B-17 SCID mice bearing RS4;11 tumors while cardiovascular parameters and tolerance were assessed in a telemetered rat model. A mathematical model was developed and used to optimize the desired release rate of the active moiety, AZD4320, from the dendrimer conjugate for maximal therapeutic index in terms of preclinical anti-tumor efficacy and cardiovascular profile. Based on this modeling, AZD0466, with a release half-life of 25.5 h, was synthesized and selected for further in vivo efficacy and tolerability assessment. Efficacy studies in the RS4;11 xenograft model showed similar efficacy to AZD4320, while cardiovascular studies in rat and dog demonstrated that AZD0466 was tolerated at doses of active-moiety that are more than ten-fold higher. In addition, it can be easily formulated for intravenous administration due to significantly enhanced solubility. The AZD4320-dendrimer conjugate, AZD0466, identified in this study has resulted in an improved therapeutic index and enabled progression of this promising Bcl-2/Bcl-xL inhibitor into clinical development. Citation Format: Marianne B. Ashford, Srividya B. Balachander, Lorraine Graham, Iain Grant, Francis D. Gibbons, Kathryn J. Hill, Alexander R. Harmer, Sonya Gales, Sean Redmond, Brian Kelly, William McCoull, Shenghua Wen, Martin Wild, Eric Gangl, David J. Owen, Barry R. Davies. Design and optimization of a dendrimer-conjugated dual Bcl-2/Bcl-xL inhibitor, AZD0466, with improved therapeutic index [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1718.
AimsTwo phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton‐pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635.MethodsStudy 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50‐mg capsule either following a high‐fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug‐drug interaction study), a 25‐mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine.ResultsIn Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high‐fat meal produced a 12% decrease in AUCinf, a ≥50% reduction in Cmax and delayed absorption (Tmax: 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N = 28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5‐fold increases in AUCinf, 2‐fold increases in Cmax and prolonged AZD4635 elimination half‐life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache.ConclusionsThe high‐fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.
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