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Scientific Approach and Background Information
The lead compound, ASM-024, a non-steroidal small synthetic molecule was initially developed for the treatment of chronic lung disorders such as asthma and COPD characterized by airway obstruction and inflammation. ASM-024 is an acetylcholine (cholinergic) receptor modulator which blocks both nicotinic and muscarinic receptor activation and demonstrated anti-inflammatory and bronchodilation properties in in vitro and in vivo preclinical models. Acetylcholine, the main neurotransmitter in the nervous system, is also a signaling mediator in many non-neuronal cells involved in the regulation of several physiological responses through interaction with both nicotinic and muscarinic receptors. These receptors are also expressed by a variety of non-neuronal cell types, including immune and structural cells and most common cancer cells derived from epithelial and endothelial origin. These findings support the involvement of acetylcholine or exogenous ligands in the regulation of cell functions such as proliferation, immune regulation, locomotion, secretion, bronchomotor tone and cell differentiation.
A comprehensive nonclinical safety program was conducted with ASM-024 including pharmacokinetic and metabolism studies, safety pharmacology studies, toxicology and genotoxicity studies. In all, seven clinical studies were completed to evaluate the safety, tolerability and clinical activity of ASM-024. Three Phase I and four Phase II clinical trials were conducted on healthy subjects and patients with mild allergic asthma, stable moderate asthma and subjects with COPD. Altogether, ASM-024 has been safely administered to more than 200 subjects via the oral and inhalation delivery, i.e. nebulized solution and dry powder inhalation. However, the outcome of two phase II pilot studies in patients failed to demonstrate sufficient efficacy of ASM-024 in asthma and COPD. Thus, further work on ASM-024 on pulmonary diseases was stopped.
Inhibitory Potential of ASM‐024 on Cancer Cell Growth
Most common cancer cells derived from epithelial and endothelial origin express nicotinic and muscarinic receptors. Some examples include lung cancer, colon cancer, basal and squamous skin carcinomas, gastric carcinomas, breast cancer, ovarian carcinomas. Many cancer cells synthesize and secrete acetylcholine, which acts as an autocrine/paracrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. Similarly, several studies have suggested that nicotine can enhance the growth and spread of pre-existing tumors through direct activation of nicotinic acetylcholine signaling pathways. There is increasing evidence in the literature that both muscarinic and nicotinic antagonists inhibit cancer cell growth (for review: Russo P. et al., Cholinergic Receptors as Target for Cancer Therapy in a Systems Medicine Perspective. Current Molecular Medicine 2014, 14, 1-13)
In light of the findings that ASM‐024 blocks both nicotinic and muscarinic receptor activation, it is believed that ASM-024 will be a potent inhibitor of cell growth. These properties may have the potential to reduce the development or progression of tumors expressing these receptors.
Based on a greater knowledge of the unique pharmacological mechanisms of action of ASM-024 developed at Asmacure, Odan is exploring the potential therapeutic role of ASM-024 in the treatment of selected oncology diseases. These studies include the in vitro anti-proliferative properties against a panel of various cancer cell lines and the in vivo anti-tumor activity in selected mouse models. Overall, the most significant inhibitory effect on in vitro cell proliferation was observed on the following cell lines: human lung adenocarcinoma, breast cancer, brain neuroblastoma, prostate adenocarcinoma and malignant melanoma. Preliminary data from a mouse model of lung carcinoma (Lewis Lung Cancer) using a slow infusion delivery method that ASM-024 treatment reduces the size and number of tumor nodules in the lung.
In addition the potential therapeutic synergism between ASM-024 with commonly used chemotherapeutic agents will be investigated. Cisplatin and the taxanes (e.g. paclitaxel or Taxol) are commonly used chemotherapeutic agents, but their use is limited by their toxicity rates and innate or acquired resistance to these drugs. The concomitant effect of ASM-024 and cisplatin or Taxol on the proliferation of tumor cells will be assessed in vitro and potentially in in vivo mouse models.
In the long term, Odan will consider to pursue the development of ASM-024 in a solution formulation administered intravenously (IV) in conjunction with the commonly-used cancer chemotherapeutic agents, for the growth inhibition and possibly regression of tumors in cancer patients.