2016 ANNUAL REVIEW Ministry of Science and Technology

2. National Research Program for Biopharmaceuticals The National Research Program for Bio- pharmaceuticals has the overall objective of strengthening mid-stream development work, employing pre-clinical trials or clinical trials to perform verification and add value, and promote the industrialization of R&D results. The following major results were achieved in 2016: (1) Research teams: Mission-oriented research projects a. The novel adenocarcinoma candidate drug DBPR112: After using EGFR as a molecular target and obtaining a series of compounds, researchers at the National Health Research Institute's Institute of Biotechnology and Pharmaceutical Research found that DBPR112 can inhibit EGFR's overactivation of cancer cell growth, and is also effective in the case of cancer cells resistant to Gefitinib and Erlotibnib. While Afatinib was shown in animal experiments involving mice to have a significant anti-cancer effect, DBPR112 possesses better pharmacokinetic characteristics, and consequently offers development potential. K i l og r am- g r ade p r oduc t i on o f t he ac t i ve pharmaceutical ingredients for the quantity of this candidate drug needed for preclinical and clinical trials was completed in early 2016, and preparation of the drug for preclinical toxicology tests and preparation for clinical trials was also completed. The investigational new drug (IND) application passed review in Taiwan and the United States during 2016, and clinical trials are expected to get underway during the second quarter of 2017. b. The novel diabetes candidate drug DBPR211: Apart from causing death, type 2 diabetes also induces many complications, including ca r d i ovascu l a r d i sease and neu r o l og i ca l pathologies. The type 1 cannabinoid receptor (CB1) controls appetite via the central nervous system, and also regulates lipid and sugar metabolism and synthesis in peripheral tissue. As a consequence, peripheral CB1 is a potential target for treatment of type 2 diabetes. DBPR211 is a CB1 antagonist, can significantly improve insulin resistance in obese and diabetic rodents, and can reduce weight and alleviate fatty liver. Global patent protection for this drug is currently pending. Kilogram-grade production of the active pharmaceutical ingredients for this candidate drug was completed in early 2016, batches of the drug preparation to be used clinical toxicological tests and clinical trials have been produced, and the drug's US IND application has been approved. c. The anti-cancer multi-target kinase inhibitor DBPR114: Conventional targeted therapy drugs typically have a single, specific molecule as a target, and block signal transmission pathways fostering the existence of tumor cells. Most drug resistance can be attributed to tumor cells' multiple proliferation mechanisms, which makes it difficult for a single targeted drug to effectively inhibit tumor growth. The multi-target kinase inhibitor DBPR114 can not only effectively inhibit at least 15 types of carcinogenic kinases, but also demonstrates significant efficacy against the growth of various types of tumors in animal models, including stomach cancer, colorectal cancer, pancreatic cancer, oral cancer, acute myelogenous leukemia, liver cancer, and bladder cancer. This candidate drug has obtained seven domestic and foreign patents, kilogram-grade production of the active pharmaceutical ingredients has been completed, and production of a preparation for preclinical toxicology tests and clinical trials is underway. It is expected that IND applications will be made in the US and Taiwan during the first half of 2017. d. Use of an innovative subretinal biological scaffold in the treatment of human retinal diseases: The research team in this project developed and produced a "new multifunctional retinal biomimetic implantation scaffold" that can carry single- layer retinal pigment epithelial cells derived from stem cell differentiation, and also possesses the ability to inhibit abnormal blood vessel proliferation. This product, which can facilitate retinal repair and the treatment of ophthalmological diseases, has passed biosafety/compatibility testing administered by a third-party certification company, which indicates that it can be feasibly used in clinical research. The R&D team has also formed a strategic alliance involving domestic pharmaceutical and biotech firms. The team plans to apply this therapeutic model to the treatment of retinal maculopathy, which is prevalent among middle-aged and older persons and currently lacks effective treatment methods. (2) Preclinical development group: New biomolecular target drug research and development Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes produced many lead compounds and three novel candidate drugs between 2014 and 2016, which have entered the drug development or IND application stage. These candidate drugs consisted of the anti- cancer multiple-target kinase inhibitor DBPR114, the stem cell mobilizer DBPR215, and opioid receptor allosteric modifier DBPR116. The results of other MOST Ministry of Science and Technology Ministry of Science and Technology 52 2016 ANNUAL REVIEW