ARIAD Pharmaceuticals Announces Results of Preclinical Studies on Brigatinib at the American Association for Cancer Research Annual Meeting
Apr 21 15
ARIAD Pharmaceuticals Inc. announced the results of a series of preclinical studies on its investigational tyrosine kinase inhibitor (TKI), brigatinib (AP26113) at the American Association for Cancer Research (AACR) Annual Meeting 2015. Brigatinib is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC), who are resistant to crizotinib. Oral Presentation on Brigatinib Discovery: An oral presentation describes, for the first time, the design and chemical structure of brigatinib, discovered using ARIAD’s structure-based drug design platform. With the goal of designing a selective ALK inhibitor with broad-based activity against crizotinib-resistant mutants, ARIAD scientists advanced a series of novel compounds culminating in the identification of brigatinib. Brigatinib incorporates unique chemical-design features, including the distinctive use of a recognition element that confers favorable pharmacologic properties. Brigatinib has at least 10-fold greater potency than crizotinib against ALK+ NSCLC cell lines and was broadly active against clinically relevant crizotinib-resistant mutants in preclinical models. New Preclinical Data on Brigatinib in Poster Presentation: A poster presentation shows that brigatinib, at clinically achievable concentrations, has potent anti-tumor activity against a panel of 17 distinct ALK mutants known to confer resistance to other ALK inhibitors. In a separate study designed to model the occurrence of brain metastases in ALK+ lung cancer patients, brigatinib significantly reduced the tumor burden in mice with ALK+ brain tumors compared to the tumors in mice treated with crizotinib. Survival of brigatinib-treated mice was also markedly enhanced compared to the survival duration of crizotinib-treated mice.
ARIAD Pharmaceuticals, Inc. Presents Updated Clinical Data on Brigatinib in Patients with ALK+ Non-Small Cell Lung Cancer
Apr 17 15
ARIAD Pharmaceuticals Inc. announced updated clinical data on its investigational tyrosine kinase inhibitor, brigatinib (AP26113), in patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. The new results include an analysis of safety and efficacy for patients treated at select doses of brigatinib and an evaluation of intracranial central nervous system (CNS) antitumor activity. The updated results were presented at the 2015 European Lung Cancer Conference (ELCC) being held in Geneva, Switzerland. Phase 2 dose sub-analysis: The data presented at ELCC focused on the 98 patients treated at doses of 90 mg/day (n=18), 90 mg/day for 1 week followed by escalation to 180 mg/day (n=32), and 180 mg/day (n=48) in the Phase 2 portion of the trial. All patients receiving these doses were evaluated for safety, and patients with ALK+ NSCLC (n=65) were evaluated for efficacy. The presentation at ELCC is based on patient data as of January 19, 2015 with a median follow-up of 40 weeks (range, 0.1 – 150+ weeks). Key data from the study update include: Safety Summary: The most common adverse events (AEs) of any grade, regardless of treatment relationship, were nausea, diarrhea, and fatigue and were similar in incidence across all three dose-cohorts, as follows: At 90 mg/day (n=18): nausea (44%), headache (44%), diarrhea (39%), fatigue (39%), cough (39%), and increased amylase (33%); At 90 mg to 180 mg/day (n=32): diarrhea (44%), nausea (41%), fatigue (38%), headache (28%), cough (28%), and increased amylase (28%); At 180 mg/day (n=48): nausea (63%), diarrhea (38%), fatigue (31%), headache (31%), cough (25%), and increased amylase (15%). Serious AEs, regardless of treatment relationship, occurring in 4% or more patients, were dyspnea, hypoxia, and pneumonia, as follows: At 90 mg/day (n=18): dyspnea (1 patient, 6%), hypoxia (2 patients, 11%), and pneumonia (2 patients, 11%); At 90 mg to 180 mg/day (n=32): dyspnea (2 patients, 6%), hypoxia (1 patient, 3%), and pneumonia (1 patient, 3%); At 180 mg/day (n=48): dyspnea (2 patients, 4%), hypoxia (2 patients, 4%), and pneumonia (2 patients, 4%). As previously observed and reported, fewer early-onset pulmonary events, including dyspnea, hypoxia, and new pulmonary opacities, were reported with a starting dose of 90 mg (2/50 patients, 4%) vs. 180 mg (6/44 patients, 14%). Importantly, no early-onset pulmonary events were observed in the 32 patients started at 90 mg and escalated to 180 mg after 7 days. Response Summary: The median time on study for patients dosed at 90 mg/day was 33.5 weeks (range, 0.7-150+ weeks), 50.3 weeks (range, 0.1-70+ weeks) for the 90 mg to 180 mg/day cohort, and 31.4 weeks (range, 0.1-135+ weeks) for the 180 mg/day cohort. Brigatinib was active at each of the three dosing regimens with similar efficacy among the cohorts: Objective response rate (ORR) among the 14 evaluable ALK+ NSCLC patients dosed at 90 mg/day was 79% (11 patients, 7 confirmed). Among the 26 evaluable ALK+ NSCLC patients dosed at 90 mg/day for 1 week followed by 180 mg/day, ORR was 81% (21 patients, 19 confirmed), including 3 patients (12%) with a complete response (CR). Among the 25 evaluable ALK+ NSCLC patients dosed at 180 mg/day, ORR was 68% (17 patients, 16 confirmed), including 2 patients (8%) with a CR. Median duration of response was 11.2 months for the 90 mg/day cohort, not yet reached for the 90 mg to 180 mg/day cohort, and 9.2 months for the 180 mg/ay cohort. Median progression-free survival (PFS) was 12.9 months for the 90 mg /day cohort, not yet reached for the 90 mg to 180 mg/day cohort, and 11.1 months for the 180 mg/day cohort. Phase 1/2 analysis of CNS antitumor activity: separate evaluation of the efficacy and safety of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also presented at the ELCC meeting. In an independent central radiological review of brain Magnetic Resonance Imaging (MRI) scans, 49 of 79 ALK+ NSCLC patients in the Phase 1/2 trial were identified to have intracranial CNS metastases at baseline. Of these 49 patients, 16 had measurable intracranial CNS metastases (15 evaluable) and 33 patients had only non-measurable intracranial CNS metastases (30 evaluable). AEs in patients with CNS metastases occurred at a similar incidence as in the broader study population. In this post-hoc analysis of centrally reviewed brain MRI, brigatinib demonstrated intracranial CNS antitumor activity with responses in ALK+ NSCLC patients with intracranial CNS metastases at baseline. Objective response rate (ORR) was 53% in evaluable patients with measurable lesions (n=15), including 1 (7%) CR. In evaluable patients with non-measurable lesions (n=30), ORR defined as disappearance of all lesions was 30% (9 patients). For patients with a response and at least one follow-up MRI scan (n=16), median (Kaplan-Meier [KM] estimate) duration of intracranial response was 18.9 months. For patients with a follow-up MRI scan (n=45), median (KM estimate) intracranial PFS was 22.3 months. Median time on study for ALK+ NSCLC patients with intracranial CNS metastases at baseline was 56.1 weeks (range, 0.1-150+ weeks). Pivotal phase 2 ALTA trial enrolling patients: A separate, pivotal global Phase 2 trial of brigatinib (AP26113) in patients with locally advanced or metastatic ALK+ NSCLC who have progressed on crizotinib continues to enroll patients. The ALTA (ALK in Lung Cancer Trial of AP26113) trial is designed to determine the safety and efficacy of AP26113 in refractory ALK+ NSCLC patients. The trial will enroll approximately 220 patients including those with brain metastasis. Patients are randomized 1:1 to receive either 90 mg of brigatinib once per day continuously or a lead-in dose of 90 mg/day for 7 days followed by 180 mg/day continuously.
Ariad Pharmaceuticals Inc. Announces Approval of Iclusig (as Ponatinib Hydrochloride) in Canada
Apr 6 15
ARIAD Pharmaceuticals Inc. announced that Health Canada has approved the use of Iclusig™ (as ponatinib hydrochloride) in Canada for the treatment of adult patients with all phases of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive, or where there is prior TKI resistance or intolerance. Iclusig is approved under the Notice of Compliance with Conditions (NOC/c) policy based on promising evidence of clinical effectiveness following review by Health Canada. Products approved under this policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness, and have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, these products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. The Health Canada decision was based on two-year data from the pivotal Phase 2 PACE trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation of BCR-ABL. Iclusig demonstrated anti-leukemic activity, achieving a major cytogenetic response (MCyR) in 56% of chronic-phase CML patients and in 70% of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint of the PACE trial for chronic-phase patients. In patients with advanced disease, 57% of accelerated-phase CML patients and 31% of blast-phase CML patients achieved a major hematologic response (MaHR) with Iclusig. MaHR within the first 6 months was the primary endpoint in the trial for patients with advanced disease. In patients with Ph+ ALL, 41% achieved MaHR. ARIAD’s upcoming dose-ranging trial to evaluate three starting doses of Iclusig in patients with refractory, chronic-phase CML who are resistant to at least two approved TKIs -- planned to begin in mid-2015 -- will serve as the confirmatory trial for the Health Canada approval.