ARIAD Pharmaceuticals, Inc. announced results of preclinical studies on its investigational Anaplastic Lymphoma Kinase (ALK) inhibitor, AP26113, showing that AP26113 has a novel profile as a dual inhibitor of ALK and Epidermal Growth Factor Receptor (EGFR), an additional validated target in Non-Small Cell Lung Cancer (NSCLC). In addition to inhibition of ALK and its mutant forms, AP26113 was shown to inhibit the EGFR T790M mutant that is resistant to available EGFR inhibitors. These data will be summarized at ARIAD's Analyst and Investor Day in New York City.
Activating mutations in EGFR are found in approximately 10 per cent of NSCLC in Western populations and 30 per cent of Asian NSCLC patients. The clinical utility of first-generation EGFR inhibitors, such as erlotinib, is limited by the development of resistance, linked in about 50 per cent of patients to the emergence of the T790M “gatekeeper” mutation. This represents a potential target patient population of 125,000 resistant NSCLC patients globally, in addition to another 40,000 patients with ALK-positive NSCLC. Second-generation EGFR inhibitors targeting T790M are in development, but clinical efficacy has been limited due to toxicity related to the co-inhibition of native (unactivated) EGFR.
Preclinical studies show that AP26113 potently inhibited activated EGFR or its T790M mutant, both in cell culture and in mouse tumour 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 favourable selectivity for activated EGFR.
“The EGFR inhibitory activity of AP26113 substantially changes its profile, significantly expanding the potential target patient population and commercial value of this tyrosine kinase inhibitor,” stated Timothy P Clackson, PhD, president of research and development and chief scientific officer at ARIAD. “Resistant forms of EGFR-mutant lung cancer represent a large unmet medical need with no available therapies. We will be filing the IND for AP26113 this month and look forward to moving AP26113 into a phase I/II clinical trial in the third quarter of this year.”
Data on the EGFR activity of AP26113 will be presented at the upcoming International Association for the Study of Lung Cancer (IASLC) 14th World Conference on Lung Cancer, to be held July 3 to 7, 2011, in Amsterdam. The mini oral presentation and electronic poster entitled, “AP26113: a potent ALK inhibitor, is also active against EGFR T790M in mouse models of NSCLC,” will be presented on Tuesday, July 5, 2011.
ARIAD's internally discovered drug candidate, AP26113, exhibits unique preclinical activity as a potent dual inhibitor of ALK and EGFR. Coupled with desirable pharmacologic properties, these characteristics confer a best-in-class potential in NSCLC. ARIAD expects to file an IND for AP26113 in 2Q11 and to begin a phase I/II clinical trial based on patients' molecular diagnoses in 3Q11.
Aberrant ALK expression is a key feature of certain non-small cell lung cancers, neuroblastomas, sarcomas and lymphomas. As an ALK inhibitor, AP26113 overcomes mutation-based resistance in NSCLC models. Multiple mutations in ALK were identified that conferred resistance to crizotinib, but not AP26113, including the L1196M “gatekeeper” mutation which has now been observed clinically in patients who initially responded to crizotinib and then relapsed.
AP26113 also inhibits activated EGFR, including the T790M “gatekeeper” mutant that confers resistance to current EGFR inhibitors. Constitutive EGFR activity due to activating mutation is a key feature of certain non-small cell lung cancers, and the T790M mutation causes resistance to inhibitor therapy in approximately 50 percent of these cases. In preclinical studies, AP26113 was shown to be specific for mutated EGFR and avoids inhibition of native (endogenous or unmutated) EGFR; such inhibition is thought to be associated with the toxicity of other EGFR inhibitors.
ARIAD's vision is to transform the lives of cancer patients with breakthrough medicines. It's mission is to discover, develop and commercialize small-molecule drugs to treat cancer in patients with the greatest and most urgent unmet medical need - aggressive cancers where current therapies are inadequate.