The Pharmacological and Clinical Evidences of a Multi-herbal Drug Product - Dantonic (T89) Indicated for the Prevention and Treatment of Chronic Stable Angina - for FDA Registration

[Speaker] He (Henry) Sun:1,2
[Co-author] Guo Zhixin (Jason):1, Li Lingyan (LeAnn):1, Xijun Yan:1, Naifeng Wu:1, Kaijing Yan:1
1:Tasly Research Institutes, Tasly Group Co. Ltd. and Tasly Pharmaceuticals, Inc., USA, 2:Center for TCM Research, Columbia University, NY, USA

Background: Angina (A) in heart disease patients causes disability and reduced Quality of Life (QoL). Patients may still have AP despite revascularization and/or use current anti-angina drugs (AAD). AAD with new mechanism of action would improve AP treatment. T89 is a 3-herb traditional Chinese Medicine completed its US phase 2 and 3 developments ready for New Drug Application to the FDA.
Methods: For FDA registration, pre-IND meetings outlined the entire development track for Dantonic (T89). Full scaled pharmacology/toxicology studies were completed and accepted according to Special Protocol Agreements with the FDA alone with all chemistry, manufacture, and control info. The pivotal randomized, placebo controlled global phase 3 clinical trial in 8 countries and 127 clinical centers was successfully completed and presented to the FDA recently.
Results: T89 acts on several pathological targets including promoting antioxidant, energy metabolism and lipid peroxidation; preventing cholesterol plaque; inhibiting platelet aggregation and adhesion; suppressing thrombus development, and etc. Chronic use of T89 is not characterized by tachyphylaxis or severe toxicities particularly useful in long-term prevention and treatment of A. In vivo Cooperstown 5+1 Cocktail drug-drug interaction (DDI) studies showed no apparent pharmacokinetic DDIs with any of those P450 metabolic substrates or current AAD. T89 did not elevate INR when dosed with warfarin. There was no Peak-Trough effect. The onset of action takes ~2 weeks but was able to maintain at high level without tolerance. Phase 2 and 3 clinical trials show that T89 significantly improves the Total Exercise Duration (TED) compared with placebo in 1,154 patients aged 40-80 yrs with Canadian Cardiovascular Society angina class 2 or 3 on Treadmill. Time to ST Depression, Time to Chest Pain, and QoL were significantly improved (p<0.05) with a time- and dose- response trend. There were >85% reduction of weekly A and Nitrate dose. Adverse effects from all trials were rare, miner and similar in all arms. No QT prolongation was indicative on any treatment days.
Discussion: The successful registration of T89 with FDA will pave a new path for traditional Chinese Medicine to go global and stimulate the worldwide interest in multi-herbal drug discovery and developments.
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