Abstract 2596: ACP-196: a novel covalent Bruton's tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients

Abstract

Ibrutinib, a first generation Btk inhibitor, is approved for the treatment of CLL and mantle cell lymphoma; known toxicities include atrial fibrillation, diarrhea, rash, arthralgia and bleeding events (1). Recent reports show ibrutinib's off target effects may negatively impact its potential for combined therapy with anti-CD20 antibodies (2,3). Here we describe the pharmacologic characterization of ACP-196 a potent, novel second generation Btk inhibitor, which binds covalently to Cys481 with improved selectivity and in vivo target coverage. Compared to ibrutinib and CC-292, ACP-196 demonstrated higher selectivity for Btk when profiled against a panel of 395 non-mutant kinases (1 μM) in a competitive binding assay. IC50 determinations on 9 kinases with a Cys in the same position as Btk showed ACP-196 to be the most selective. The improved selectivity is related to the reduced intrinsic reactivity of ACP-196's electrophile. Importantly, unlike ibrutinib, ACP-196 did not inhibit EGFR, Itk or Txk. Phosphoflow assays on EGFR expressing cell lines confirmed ibrutinib's EGFR inhibition (EC50: 47-66 nM) with no inhibition observed for ACP-196 at 10 μM. These data may explain the ibrutinib-related incidence of diarrhea and rash. Ibrutinib's potency on Itk and Txk may explain why it interferes with cell-mediated anti-tumor activities of therapeutic CD20 antibodies and immune-mediated killing in the tumor microenvironment (2,3). In human whole blood, ACP-196 and ibrutinib showed robust and equipotent inhibitory activity on B-cell receptor induced responses in the low nM range, whereas CC-292 was 10-20 fold less potent. In vivo, oral administration of ACP-196 in mice resulted in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg compared to 0.91 mg/kg for ibrutinib. A similar model was used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg. ACP-196 and ibrutinib inhibited CD86 expression >90% at 3h and ∼50% at 24h postdose. In contrast, CC-292 inhibited ∼50% at 3h and ∼20% at 24h postdose. An ELISA based Btk target occupancy assay was developed to measure target coverage in preclinical and clinical studies. In healthy volunteers, ACP-196 at an oral dose of 100 mg QD showed >90% target coverage over a 24h period. Btk occupancy and regulation of the PD markers (CD69 and CD86) correlated with PK parameters for exposure. In CLL patients, after 7 days of dosing with ACP-196 at 200 mg QD, 94% Btk target occupancy was observed compared with ∼80% reported for ibrutinib at 420 mg QD (4). In conclusion, ACP-196 is a novel Btk inhibitor with key pharmacologic differentiators versus ibrutinib and CC-292. ACP-196 is currently being evaluated in clinical trials. 1. IMBRUVICA package insert 2014 2. Rajasekaran Blood 2014 Abstr # 3118 3. Da Roit Haematologica 2014 4. Byrd NEJM 2013 Citation Format: Todd Covey, Tjeerd Barf, Michael Gulrajani, Fanny Krantz, Bart van Lith, Elena Bibikova, Bas van de Kar, Edwin de Zwart, Ahmed Hamdy, Raquel Izumi, Allard Kaptein. ACP-196: a novel covalent Bruton's tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2596. doi:10.1158/1538-7445.AM2015-2596

Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells

“…Differential effect of these two drugs on T-cells was further evidenced in Jurkat T-lymphoblastic cell line for ITK and PLCγ1 (Figure 6C-E). Consistent with these data, previous studies with acalabrutinib demonstrated minimal effects on EGFR, Tec, or ITK signaling, and no inhibition of thrombus formation in vivo at clinically relevant concentrations (32,51). …”

<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

“…7 Acalabrutinib was developed as a selective BTK inhibitor when compared to ibrutinib with the goal of achieving similar therapeutic outcomes in patients with CLL without the off-target effects on other kinases such as TEC, EGFR, and ITK. [7][8][9] Several pre-clinical studies have demonstrated the efficacy of acalabrutinib inhibition of BTK is similar to that seen with ibrutinib. These findings led to a phase 1/2 study to evaluate the efficacy and side-effect profile of acalabrutinib in CLL.…”

“…2,17,18 Acalabrutinib, a second generation, irreversible BTK inhibitor, was developed as a selective BTK inhibitor to avoid the off-target side effects seen ibrutinib. [7][8][9] Zanubrutinib, a next-generation, irreversible BTK inhibitor, was developed as a selective BTK inhibitor and has received approval for treatment of relapsed refractory mantle cell lymphoma. 19 Studies are ongoing in evaluating the drug's safety and efficacy in CLL.…”

“…5,6 Acalabrutinib, a second generation and more selective Bruton's tyrosine kinase (BTK) inhibitor, was developed to maximize efficacy while minimizing ibrutinib-associated adverse events hypothesized to be secondary to ibrutinib's off-target effects. [7][8][9] This review will summarize the development, pre-clinical evaluation, and key clinical trials that have demonstrated acalabrutinib's efficacy and toxicity profile in CLL.…”

Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor

“…However, ibrutinib has untoward effects, such as bleeding, rash, and atrial fibrillation, which could be partly due to the bystander effects on targets other than BTK [ 10 , 13 , 15 , 17 , 18 ]. Therefore, more selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored [ 19 – 23 ]. Acalabrutinib, also known as ACP-196, is a novel irreversible second-generation BTK inhibitor that was rationally designed to be more potent and selective than ibrutinib [ 19 , 24 – 28 ].…”