Thursday, November 5, 2015

Drugs in Clinical Pipeline: Brigatinib

Brigatinib [5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine] is an oral, potent and selective inhibitor of anaplastic lymphoma kinase (ALK). Brigatinib is reported to show activity against the both wild type ALK (IC50 = 0.62 nM; Ki = 0.09 nM) as well as L1196M mutant (Ki = 0.08 nM) with about five-fold greater potency compared with Crizotinib {IC50 (ALK) = 3.6 nM; Ki (ALK) = 0.69 nM; Ki (L1196) = 8.2 nM} [1]. Brigatinib was profiled against greater than 250 kinases by Reaction Biology Corporation (Malvern, PA) using the Kinase Hotspot assay, which utilizes 10 µM [33P]-ATP, recombinant kinase domain, peptide substrate, and a single inhibitor concentration of 1 µM. Brigatinib inhibited eight kinases (FER, ROS, FLT3, FES, FAK, BRK, STK22D and CHK2) with IC50 between 1-10 nM; 22 kinases with IC50 between 10-100 nM. It inhibited EGFR with IC50 = 129 nM but ErbB4 with an IC50 value of 27 nM.

Brigatinib showed excellent preclinical activity against ALK and all 9 clinically-identified Crizotinib-resistant mutants tested [2].

Brigatinib is also a potent, reversible inhibitor of activated and T790M-mutant EGFR, yet it does not inhibit the native enzyme [3].

In October 2014, ARIAD Pharmaceuticals, Inc. announced that its investigational cancer medicine, Brigatinib, has received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who are resistant to crizotinib. This designation is based on results from the ongoing Phase 1/2 trial that show sustained anti-tumor activity of Brigatinib in patients with ALK+ NSCLC, including patients with active brain metastases.

The activity of Brigatinib is as follows:

IC50 (ALK enzyme assay) = 0.62 nM
IC50 (FER enzyme assay) = 1.3 nM
IC50 (ROS enzyme assay) = 1.9 nM
IC50 (FLT3 enzyme assay) = 2.1 nM
IC50 (FES enzyme assay) = 3.4 nM
IC50 (FAK enzyme assay) = 3.8 nM
IC50 (BRK enzyme assay) = 4.1 nM
IC50 (STK22D enzyme assay) = 4.3 nM

IC50 (CHK2 enzyme assay) = 6.5 nM

Common Name: Brigatinib
Synonyms: AP26113; AP-26113; AP 26113
IUPAC Name: 5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine
CAS Number: 1197953-54-0
Mechanism of Action: Kinase Inhibitor; ALK Inhibitor; Anaplastic Lymphoma Kinase Inhibitor; T790M Inhibitor
Indication: Various Cancers; Treatment of Non-Small Cell Lung Cancer
Development Stage: Phase I/II
Company: ARIAD Pharmaceuticals

The oncogenic fusion kinase echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) is present in ~4% of patients with non-small cell lung cancer (NSCLC). Chromosomal translocations involving ALK also occur in other cancers, including anaplastic large cell lymphomas and inflammatory myofibroblastic tumors. In all cases, the fusion partner (e.g., EML4) is believed to mediate ligand-independent oligomerization of ALK, resulting in constitutive ALK kinase activation. In cell line and genetically engineered mouse models, EML4-ALK serves as a potent oncogenic “driver,” and cancers with this translocation are highly sensitive to ALK kinase inhibition. Crizotinib (PF-02341066), a tyrosine kinase inhibitor (TKI) targeting ALK, was examined in a phase 1 trial where among 105 patients with EML4-ALK–positive NSCLC, crizotinib showed remarkable activity, with an objective response rate of 56% and a median progression-free survival of 9.2 mo. These results support the notion that lung cancers harboring EML4-ALK are highly susceptible to ALK-targeted therapies and demonstrate the properties of “oncogene addiction” to ALK [1].

Phase II Study {Anti-tumour Activity in ALK-positive NSCLC patients with Brain Metastasis} [5]

Concept: Central nervous system (CNS) progression has been observed in a significant proportion of patients treated with Crizotinib for ALK-positive Non-small cell lung cancer (NSCLC). More than 80% of patients with NSCLC and brain metastases achieved intracranial disease control after treatment with Brigatinib.

Methodology: Contrast-enhanced magnetic resonance imaging of the brain was done at baseline and at follow-up that was centrally reviewed by blinded independent neuroradiologists. Lesions having a longest diameter of 10 mm or greater were defined as measurable lesions. The post hoc analysis was done on data from 45 of the 49 patients identified with baseline brain metastases that had evaluable data at cut-off. The patients were among participants in a larger phase 1/2 single-arm, multicentre study of Brigatinib in patients with advanced malignancies. All patients received Brigatinib at total daily doses of 30 to 300 mg orally once daily.

The 49 patients identified with baseline brain metastasis and having evaluable data were on study a median of 56.1 weeks. Measurable brain metastases were reported for 16 patients and non-measurable brain metastases for 33 patients. Following treatment, 45 patients overall with brain involvement and a follow-up scan achieved median intracranial progression–free survival (PFS) of 22.3 months and the median duration of intracranial response in 16 patients with a response and a follow-up scan was 18.9 months.

Result: Intracranial response was reported for 8 (53%) patients with measurable brain metastases and for 9 (30%) patients identified with non-measurable lesions. Intracranial disease control was achieved by 13 (87%) patients with measurable and by 26 (87%) patients with non-measurable brain metastases.

Side-effects: Treatment-emergent adverse events were mild to moderate in severity and included nausea, diarrhoea, and fatigue that were reported by 29 (59%), 28 (57%) and 24 (49%) patients, respectively.

1. Shaw, A. T.; et. al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011, 108(18), 7535-7540.
2. Gettinger, S.; et. al. 1292P Alk Inhibitor Ap26113 In Patients With Advanced Malignancies, Including Alk+ Non-Small Cell Lung Cancer (Nsclc): Updated Efficacy And Safety Data. Ann Oncol 2014, 25(suppl 4), iv455.
3.  Camidge, D. R.; et. al. First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results. J Clin Oncol 2013, 31(15), 8031.
4. Wang, Y.; et. al. Phosphorous derivatives as kinase inhibitors. US20150225436A1 (for structure and synthesis of AP26113, Example 122)
5. Kerstein, D. LBA4. Evaluation of anaplastic lymphoma kinase (ALK) inhibitor brigatinib [AP26113] in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) and brain metastases. 2015 (article here)