1,1-DIETHYL-4-PHENYLHOMOPIPERAZINIUM (ASM-024), a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. ASM-024 is able to activate the α7 nAChR channel opening in the presence of the positive allosteric modulator (PNU-120596), indicating that ASM-024 behaves as a ‘silent agonist’ that places the receptor in a desensitized state. Compounds with similar properties have been shown to induce signal transduction pathways independently of ion channel activation. ASM-024 has demonstrated an antagonist effect on ACH-evoked activation at the M1, M2 and M3 muscarinic receptors expressed in Xenopus oocytes. 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. 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.

H3B-6527 is a highly selective covalent FGFR4 inhibitor with at least 250-fold selectivity over FGFR1-3. H3B-6527 inhibits FGFR4 signaling, proliferation, and leads to apoptosis in Hepatocellular carcinoma (HCC) cell line. Treatment on Hep3B cells leads to robust activation of caspase-3/7, an apoptotic marker, in a concentration-dependent manner, indicating FGFR4 inhibition by H3B-6527 leads to cell death in HCC cell lines. In the Hep3B human HCC xenograft mouse model, H3B-6527 shows dose-proportional plasma exposures and greater than dose-proportional tumor exposures within the dose range evaluated (30, 100, and 300 mg/kg). Oral treatment of H3B-6527, twice daily, inhibits xenograft growth in a dose-dependent manner in nude mice, with the 300 or 100 mg/kg twice daily, significantly inhibiting tumor growth in both Hep3B subcutaneous and orthotopic xenograft model and causing tumor regressions in the subcutaneous xenograft model.

ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum strains. ACT-451840 has been used in trials studying malaria. ACT-451840 appears to have a distinct mode of action that sets it apart from current antimalarial drugs, including artemisinins. It has a rapid onset of action as well as activity on all blood-borne (erythrocytic) stages, which is retained against multiple resistant parasites, including artemisinin-resistant strains. Unlike the majority of antimalarial agents, ACT-451840 has the potential to block disease transmission due to its activity on gametocytes. he antimalarial activity of ACT-451840 was studied in an experimental induced blood stage malaria clinical trial performed in collaboration with MMV Medicines for Malaria Ventures at the laboratories of Professor James McCarthy, MBBS, MD of the Royal Brisbane and Women's Hospital in Herston, Australia. In the trial, ACT-451840 was safe and well tolerated and showed clinical efficacy against the early stages of P. falciparum infections. The PK/PD model developed from this proof-of-concept study with eight healthy subjects enabled prediction of therapeutic effects, with cure rates following 1 week of therapy (single daily doses) predicted to be equivalent to artesunate monotherapy.