Prof. Howard Lee proposed health insurance reimbursement for the combination therapy of DPP4 inhibitors and SGLT2 inhibitors, irrespective of their labels as approved by the Korea Ministry Food and Drug Safety (MFDS), at a special session organized by the Korean Diabetes Association (KDA), in association with its Spring Conference 2019, held on May 9-11, 2019, at the HICO, Kyeongju, Korea. Unlike other countries including the USA, EU, and Japan, MFDS in Korea has approved the combination therapy of SGLT2 inhibitors with other oral hypoglycemic agents, particularly with DPP4 inhibitors, only on the basis individual drugs, not on the therapeutic class. This unique regulatory approval has contributed to the delayed reimbursement of various combination therapies involving SGLT2 inhibitors since their approvals. 

The delayed reimbursement has caused a lot of debates not only between the pharmaceutical industry and the Health Insurance Review and Assessment Service or HIRA, but also among clinicians. With this background, the KDA asked Prof. Lee to share his perspectives from the points of drug regulatory science if the reimbursement for the combination therapy of DPP4 inhibitors and SGLT2 inhibitors on the basis of therapeutic class, not on the individual drug, has any scientific and clinical rationale. Prof. Lee, based on an intensive systematic literature review focusing on the pharmacokinetics, drug-drug interactions, clinical efficacy, and safety profiles of the combination treatment with DPP4 inhibitors and SGLT2 inhibitors, discussed that it is highly unlikely any combination of the two classes would interact in a clinically meaningful and significant way. Furthermore, Prof. Lee argued that it is very likely for every combination of a DPP4 inhibitor with an SGLT2 inhibitor to result in an additional, significant, and clinically meaningful decrease in HbA1c or glycated hemoglobin. However, since not every combination has been studied for its safety profiles although it is likely to be similar to those of monotherapy, Prof. Lee proposed to perform a real world data study under the auspice of KDA, sponsored by the pharmaceutical industry, to explore and confirm the safety and efficacy profiles of the combination therapy.      

Reflecting the interest in the reimbursement issue, the conference room was full of clinicians, industry representative, and journalists even though the session was presented early in the morning on Saturday. More detailed information on the session can be found here. 

Prof. Howard Lee presented the results of a first-in-human phase I study in healthy volunteers with Hyleukin-7, a human hybrid Fc-fused IL-7, to assess its tolerability, pharmacokinetics and biological properties at the 2019 annual meeting of the American Association of Cancer Research or AACR2019, held March 29 - April 3, in Atlanta, Georgia, US. Prof. Lee was the Principal Investigator for the phase 1 study, which showed that Hyleukin-7 after a single subcutaneous and intramuscular administration was well-tolerated, increased T cells in a dose-dependent manner, particularly killer and memory T cells. T cells have been known to play a crucial role in anti-tumor response, particularly when dosed with the immune checkpoint inhibitors such as Keytruda and Opdivo. 

The poster presentation by Prof. Lee was well-attended, and received media attention too. You may find more details about the study and its implications can be found at here (in Korean) or here (in English). 

Four CCADD members attended the SNU-Hokkaido University joint symposium held in Sapporo, Japan. On the second day of the symposium, professors and students of the Graduate School of Convergence Science and Technology of Seoul National University  met members of the Graduate School of Information Science and Technology of Hokkaido University and shared their research ideas, experiences, and results. The participants from the two universities introduced their research progress on a variety of topics, varying from computer-human interaction study to the development of new drug entities using machine learning technology. 

Dr. Soohyun Kim of CCADD gave an oral presentation, where she discussed if therapeutic drug monitoring (TDM) of vancomycin is cost-effective in elderly patients. According to Dr. Kim, the cost-effectiveness of vancomycin in this population might not be so cost-effective as was previously anticipated, but could be cost-effective in patients admitted to the intensive care unit. In the following poster session, Dr. Jeong-An Gim presented the results of a pharmacoepigenomic research (Difference in DNA methylation and pharmacokinetics parameters of tacrolimus between two periods of a bioequivalence test with tacrolimus). Dr. Kim tried to provide a basis for tacrolimus pharmacoepigenomics and may provide a clue to the different dose of tacrolimus through his research. Yoomin Jeon, a PhD student at CCADD, introduced a new research project, entitled "A Dimensionality Reduction Model to Increase the Efficiency and Accuracy of Clinical Trial Feasibility Assessment Using Electronic Medical Records." Yoomin’s poster was associated with a new grant CCADD received recently from the National Research Foundation (PI: Prof. Howard Lee). Another PhD student, Siun Kim, presented his research with Dr. Soohuyn Kim about the validity of the equivalence margin in the phase 3 trial with CT-P13, an Infliximab biosimilar. He had an opportunity to discuss the implication and the future plan of the study with researchers of Hokkaido University.

Those attending the symposium from CCADD were able to meet with many young Japanese professionals and researchers in various fields. They  look forward to seeing them again at a joint symposium at Seoul National University next year.

Dr. Jeong-An Gim has been awarded a government grant from the National Research Foundation (NRF) of Korea on September 1, 2018 to study epigenetic/epigenomic changes after drug treatment. The grant will cover a year and the total research funding is $40,000 or ~40 million Korean Won. The title of Dr. Gim's research was "An Association Study Between the Pharmacoepigenomic Patterns of Drug-metabolizing Enzymes and the Pharmacokinetics of Tacrolimus", which aimed to identify several sensitive genetic regions associated with the pharmacokinetics of tacrolimus, an immunosuppressive agent frequently used in transplant patients. Blood samples for this proposed study have been already collected from two previous studies ( Choi et al., Kim et al., 2017 ), and the samples will be outsourced to Theragen Etex for the next generation sequencing (NGS) analysis. 

The proposed study is the first of its kind applying the state-of-the-art technologies to investigating the epigenetic/epigenomic effect on the exposure to tacrolimus in humans. Dr. Gim has been interested in finding an optimal epigenetic state to maximize the efficacy of a drug while minimizing potential adverse events, and tacrolimus will be his first bet. 

Prof. Lee congratulated Dr. Gim, saying "Converging the principles of clinical pharmacology, genomics, and eipgenetics/epigenomics, we will have a much better understanding how humans handle the administered drug." Prof. Lee added, "Dr. Gim's approach is innovative, and his research exemplifies how convergent approaches can be adopted to solve problems in drug development." 

The best model for humans is human. Drug development has long been suffering from the lack of translatability and predictability of the preclinical animal experiments to humans. Dr. Richard Klausner, former Director of the US National Cancer Institute, commented in 1998, “the history of cancer research has been a history of curing cancer in the mouse. … and it simply didn’t work in humans.” Twenty years fast forward, drug development scientists are still struggling with the same issue.

Microtracing/microdosing is an innovative technology that can revolutionize the current paradigm of clinical drug development. Typically, a very small amount of the drug, i.e., ‘microdose’, which is less than 100 micrograms (or 30 nmoles for proteins), is administered to humans. Since this is much smaller than 1/100 of the pharmacologically active dose, microtracing/microdosing technology can be employed at a very early stage of clinical drug development even when there is limited animal toxicology data. Furthermore, in order to trace minute doses, an accelerator mass spectrometer (AMS) is required and the compound should be labeled, typically with ¹⁴C. The microtracing/microdosing study allows clinical drug development scientists for generating the intravenous pharmacokinetics, mass balance, metabolite profiling, and absolute bioavailability data much easier, faster, and at a lower cost.  

Dr. Howard Lee has spearheaded the employment of microtracing/microdosing technology for drug development in Korea since 2012, supported by three government grants. Dr. Lee has successfully d a new research ecosystem for the microtracing/microdosing study, which helped him perform the first microtracing/microdosing study under a full investigational new drug (IND) application in 2014. The result of this study was published at the most reputable journal in the field. Dr. Lee has conducted two additional microtracing/microdosing studies, and has recently won a two-year grant of $1 mil, in which microtracing/microdosing technology will be applied to a new drug development study with biologics.

Kim Y, Kim A, Lee S, Choi SH, Lee DY, Song JS, Lee H, Jang IJ, Yu KS. Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate After Single-Dose Administration in Healthy Korean Male Subjects. Clin Ther. 2017. Sep;39(9):1849-1857, ePub 2017 Aug 31.

Lee H, Chung H, Lee S, Lee H, Yang SM, Yoon SH, Cho JY, Jang IJ, Yu KS. LBEC0101, A Proposed Etanercept Biosimilar: Pharmacokinetics, Immunogenicity, and Tolerability Profiles Compared with a Reference Biologic Product in Healthy Male Subjects. BioDrugs. 2017 May 27. doi: 10.1007/s40259-017-0230-9. [Epub ahead of print]

Choi Y, Jiang F, An H, Park HJ, Choi JH, Lee H. A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform. The Pharmacogenomics Journal. 2017;17(2):174-179

Yoon S, Shin D, Lee H, Jang IJ, Yu KS. Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects. Drug design, development and therapy. 2015;9:5033-5049.

Kim TE, Lee H, Lim KS, Lee S, Yoon SH, Park KM, Han H, Shin SG, Jang IJ, Yu KS, Cho JY. Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers. Br J Clin Pharmacol. 2014;78(3):556-564.

Kim A, Chung I, Yoon SH, Yu KS, Lim KS, Cho JY, Lee H, Jang IJ, Chung JY. Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos. 2014;42(7):1174-1179.