A third ARIAD-discovered compound.

The latest candidate to enter ARIAD’s early-stage pipeline, AP26113, is a unique small-molecule that in preclinical studies has exhibited activity as a potent dual inhibitor of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR). Internally discovered by ARIAD scientists, this compound targets unique genetic features of cancer cells similar to ponatinib.

ARIAD announced the start of an international Phase 1/2 clinical trial of AP26113 in September 2011. The initial Phase 1 dose-escalation trial will include patients with advanced solid tumors, particularly those with NSCLC. Patients enrolled in this multicenter study will be either refractory to available therapies or have no standard treatment available to them. The primary objective of the Phase 1 segment of the Phase 1/2 trial is to determine the initial safety, tolerability, pharmacokinetic profile, recommended dose (anticipated to be once daily), and preliminary anti-tumor activity of AP26113. ARIAD expects to enroll approximately 30 to 50 patients in this portion of the trial.

The Phase 2 part of the trial is expected to begin in the second half of 2012 and will include four genetically defined patient cohorts, including:

• Patients with ALK positive NSCLC who have not previously received an ALK inhibitor
• Patients with ALK positive NSCLC who are resistant to at least one ALK inhibitor
• Patients with EGFR positive NSCLC who are resistant to at least one prior EGFR inhibitor
• Patients with other cancers expressing ALK or other known targets of AP26113

The Phase 2 trial is planned to enroll approximately 80 patients and will provide further data on the preliminary anti-tumor activity of AP26113 in these molecularly defined patient populations.

ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.

Epidermal growth factor receptor (EGFR) is another validated target in NSCLC. Unfortunately, mutation-based resistance at the T790M “gatekeeper” position is observed in approximately 50 percent of patients taking first-generation EGFR inhibitors. While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with native (endogenous or unmutated) EGFR inhibition. Therapies designed to target activated EGFR and the T790M mutation but avoiding native EGFR inhibition are another promising class of cancer therapeutics.

AP26113 Potential Against ALK

ARIAD scientists identified multiple compounds that potently inhibit ALK both in vitro and in vivo while maintaining significant selectivity over the highly homologous insulin-like growth factor-1 receptor and insulin receptor tyrosine kinases. Based on proprietary ARIAD chemistry, AP26113 was identified as the lead compound, potently inhibiting ALK-expressing tumor cells while having no effect on ALK-negative cells. In addition, this compound is active when administered orally in multiple mouse models of lymphoma and lung cancer with minimal effects on insulin or glucose levels.

In 2010, ARIAD announced results of preclinical studies on AP26113 showing potent inhibition of the target protein including mutant forms that are resistant to the first-generation ALK inhibitor, crizotinib. ARIAD scientists presented these data at the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C. in April. Full Press Release

ARIAD scientists used an in vitro assay to identify mutations in ALK that confer resistance to the investigational dual Met/ALK inhibitor developed by Pfizer, Inc., PF-02341066 (PF1066), or to AP26113. This resistance-profiling method has successfully predicted the specific mutations that confer clinical resistance to other tyrosine kinase inhibitors, such as the BCR-ABL inhibitors used in chronic myeloid leukemia (CML). Multiple mutations in ALK were identified that conferred resistance to PF1066, but not to AP26113. Three of these ALK mutants were also tested in mouse tumor models, and in each case, AP26113 potently blocked tumor growth while PF1066 was ineffective.

In a second study, ARIAD performed direct comparative studies on AP26113 and PF1066 in a series of ALK-dependent cell culture and in vivo models. In all models, AP26113 was at least ten-fold more potent than PF1066. In addition, AP26113 exhibited approximately 100-fold selectivity for ALK-positive cell lines compared with an approximate 10-fold selectivity for PF1066, and demonstrated excellent “drug-like” properties, including the potential for once-daily oral dosing.

AP26113 Activity Against EGFR

In 2011, ARIAD announced preclinical studies showing that AP26113 potently inhibited activated EGFR or its T790M mutant, both in cell culture and in mouse tumor models following once daily oral dosing. Importantly, the effective oral doses in these preclinical models were similar to those previously shown to be effective in resistant ALK models. When tested against the native form of EGFR, AP26113 lacked activity, indicating a favorable selectivity for activated EGFR. These data were presented at the International Association for the Study of Lung Cancer (IASLC) 14th World Conference on Lung Cancer. Full Press Release.

AP26113: a novel dual ALK and EGFR inhibitor

• ALK and EGFR are validated targets in non-small cell lung cancer (NSCLC)
• Targets mutation-based resistant cancer cells
• International Phase 1/2 clinical trial initiated in September 2011