PMID- 32019723 OWN - NLM STAT- MEDLINE DCOM- 20210920 LR - 20210920 IS - 1873-460X (Electronic) IS - 1056-8727 (Linking) VI - 34 IP - 5 DP - 2020 May TI - A novel non-PPARgamma insulin sensitizer: MLR-1023 clinicalproof-of-concept in type 2 diabetes mellitus. PG - 107555 LID - S1056-8727(19)30928-6 [pii] LID - 10.1016/j.jdiacomp.2020.107555 [doi] AB - AIM: MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes. METHODS: Type 2 diabetes patients (18-75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC(0)(-)(3h)) in a mixed meal tolerance test (MMTT) at day 29. Secondary endpoints included changes in fasting plasma glucose (FPG), insulin, HbA1c, lipids and body weight and adverse events. ANCOVA model was used for efficacy analysis. RESULTS: The placebo-corrected least-squares mean differences (DeltaLSM) in MMTT PPG AUC0-3 h (mmol/L) were -5.96 and -5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected DeltaLSM in FPG (mmol/L) was -2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (DeltaLSM, -0.56 mmol/L, p = 0.07 and -0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%). CONCLUSIONS: MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Lee, Moon-Kyu AU - Lee MK AD - Sungkyunkwan University School of Medicine, Samsung Medical Center, (06351) 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, South Korea. Electronic address: leemk@skku.edu. FAU - Kim, Sin Gon AU - Kim SG AD - Korea University Anam Hospital, Goryeodae-ro Seongbuk-gu, Seoul 02841, Republic of Korea. Electronic address: k50367@korea.ac.kr. FAU - Watkins, Elaine AU - Watkins E AD - ProSciento, Inc., 855 Third Ave #3340, Chula Vista, CA 91911, USA. FAU - Moon, Min Kyong AU - Moon MK AD - Seoul Metropolitan Government Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Sindaebang-dong, Dongjak-gu, Seoul, South Korea. Electronic address: mkmoon@snu.ac.kr. FAU - Rhee, Sang Youl AU - Rhee SY AD - Kyung Hee University Medical Center, 23, Kyung Hee Dae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. FAU - Frias, Juan P AU - Frias JP AD - National Research Institute, 2010 Wilshire Blvd Ste 302, Los Angeles, CA 90057, USA. Electronic address: Juan.Frias@nritrials.com. FAU - Chung, Choon Hee AU - Chung CH AD - Yonsei University Wonju Severance Christian Hospital, 20 Ilsan-ro, Ilsan-dong, Weonju, Gangwon-do, South Korea. Electronic address: cchung@yonsei.ac.kr. FAU - Lee, Seung-Hwan AU - Lee SH AD - The Catholic Univ. of Korea, College of Medicine, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul, Republic of Korea. FAU - Block, Bradley AU - Block B AD - Compass Research East, LLC, 100 West Gore St # 202, Orlando, FL 32806, USA. Electronic address: docblock@oviedomedicalresearch.com. FAU - Cha, Bong Soo AU - Cha BS AD - Yonsei University Severance Hospital, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: bscha@yuhs.ac.kr. FAU - Park, Hyeong Kyu AU - Park HK AD - Soon Chun Hyang University Hospital, 22, Daesagwan-gil (657 Hannam-dong), Yongsan-gu, Seoul, Republic of Korea. Electronic address: hkpark@schmc.ac.kr. FAU - Kim, Byung Joon AU - Kim BJ AD - Gachon University Gil Hospital, 21 Namdong-daero 774beon-gil, Guwol 1(il)-dong, Namdong-gu, Incheon, South Korea. Electronic address: kbjoon4u@gilhospital.com. FAU - Greenway, Frank AU - Greenway F AD - Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808, USA. Electronic address: Frank.Greenway@pbrc.edu. LA - eng SI - ClinicalTrials.gov/NCT02317796 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200202 PL - United States TA - J Diabetes Complications JT - Journal of diabetes and its complications JID - 9204583 RN - 0 (Hypoglycemic Agents) RN - 0 (PPAR gamma) RN - 0 (Pyrimidinones) RN - EC 2.7.10.2 (lyn protein-tyrosine kinase) RN - EC 2.7.10.2 (src-Family Kinases) RN - MU3JD8E9IS (5-(3-methylphenoxy)-2(1H)-pyrimidinone) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Diabetes Mellitus, Type 2/*drug therapy/physiopathology MH - Double-Blind Method MH - Female MH - Humans MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Insulin Resistance MH - Male MH - Middle Aged MH - PPAR gamma MH - Pyrimidinones/pharmacology/*therapeutic use MH - Treatment Outcome MH - Young Adult MH - src-Family Kinases OTO - NOTNLM OT - Fasting glucose OT - Insulin sensitizer OT - Lyn kinase agonism OT - Mixed meal tolerance test OT - Tolimidone OT - Type 2 diabetes COIS- Declaration of competing interest All other authors have no conflicts of interest to declare. EDAT- 2020/02/06 06:00 MHDA- 2021/09/21 06:00 CRDT- 2020/02/06 06:00 PHST- 2019/09/26 00:00 [received] PHST- 2020/01/27 00:00 [revised] PHST- 2020/01/27 00:00 [accepted] PHST- 2020/02/06 06:00 [pubmed] PHST- 2021/09/21 06:00 [medline] PHST- 2020/02/06 06:00 [entrez] AID - S1056-8727(19)30928-6 [pii] AID - 10.1016/j.jdiacomp.2020.107555 [doi] PST - ppublish SO - J Diabetes Complications. 2020 May;34(5):107555. doi: 10.1016/j.jdiacomp.2020.107555. Epub 2020 Feb 2.