David Xu

1. NCA to get initial estimates, Semicompartmental, Nonparametric via different routes (transdermal), or dual routes administration; 2. BE: Perform BE including highly HVD (RSABE) analyses for 2x2, 3x3 ,4x4, partial and full replicated and/or repeated treatment studies 3. PK patterning, modeling, prediction, simulation: IV/extravascular single/multiple disposition, linear/non-linear behaviors, baseline drift or endogenous counterparts, parent drug/metabolites and ratios, Tlag,Enterohepatic recirculation, peak shift, or cut-down by ADA after repeat doses, flip-flop phenomena , saturation and other potential nonlinearities. 4. PD patterning, modeling, prediction, simulation: PD (mRNA, SiRNA or RISC , Protein) or biomarker, a myriad of interactions (transport to biophase, binding to target, activation of target, or fractional or multiple transit turnover models, cascades downstream mediators, physiological response (tolerance and feedback), convex or concave curvature, clockwise or anticlockwise, Bell-shaped or upside down Bell-shaped or oscillatory pattern, stimulation build-up/loss, inhibitory build-up/loss etc.) 5. Population PK: FIH, ), RPD2, SAD, MAD, food effect, drug-drug interaction (DDI), renal/hepatic impairment, Herg/QTc, Juvenile/elder, popPK, Linear/nonlinear Absorption via single compartment/multiple compartments,EOP1 and EOP2 briefing documents, TMDD, MIDD plus covariates (age, weight, sex, race etc. on Ka, CL and V). 6. IVIVC: In vitro dissolution/In vivo PK prediction (convolution/deconvolution), transdermal (patch) (In vitro skin influx/In vivo PK prediction), and TDS scaling to oral dose and skip multiple and tiresome regimen and adverse effects. 7. Toxicokinetic analysis: including small molecules, siRNA and ASO (serum, urine), ADC/PDC/RDC (payload, Ab, linker, internal dissociation and trafficking/tumor penetration and killing dynamics) 8. Tools: WinNolin 8.5, R language (>2000 packages), R studio, RsNLME (Certara), Pirana-NONMEM

Recently consulting for non-clinical studies in rabbits, guinea pigs, Göttingen minipigs(pilot PK and skin irritation and sensitization), performing QSAR, HTS, risk assessment for drug and device excipients ICH M7, 3Q series, operating phase I clinical trials in Malaysia, Australia, China, India and US and clinical pharmacology including population PK, BE, IVIVC kit, PK-PD modeling by WinNolin 8.5 and GastroPlus 9.5; Preparing PND briefing books, IND submission (Module 2.4 and 2.6, 2.5 and 2.7 ), NDA submiss; Taking a lead in a new project for Radioligand Therapy (RDC) in treating neuroendocrine tumor and prostrate cancer etc.

1. Organized and submitted CpAM class I to treat HBV, and successfully got IND approved via eCTD (ICH M4). 2. Led and established Clinical trial group, deploying Phase I and serving SRC member, and taking the whole responsibility for clinical pharmacology, clinical population PK, supporting phase II with long term toxicity studies. 3. Projected preclinical studies in TLR7/8 agonist and antagonist pipelines for HBV, cancer and autoimmunity diseases (SLE), and shouldering optimization leading compounds, PCC determination etc. in general Tox, reproductive and developmental tox (segment I, II, III), immunogenicity in compliance with GLP. 4. Optimized and developed leading compounds and characterized of MetID via ADME Mass Frontier 7.0 and Compound Discover 2.1, PK/PD via WinNonlin 6.3, IND enabling for mono/bio-specific Ab, tumor mRNA Vaccines and ADC, SiRNA (sequence, linker, vehicle).

1. Directed double negative T cells (DNT) adoptive immunotherapy for treating refractory and recurrent Acute Myelocytic Leukemia (AML), and steered PK/PD modeling, as well as outsourced toxicity studies. 2. Headed for IND submission successfully of cell immunotherapy targeting AML, NHL and NSCLC , including proof of concept, pharmacometrics in NSG immunodeficiency mice, safety evaluation including in vitro and in vivo, as well as outsourcing studies in CRO. 3. Endorsed and led mon/bi-specific Ab and ADC to target cancers.

1. Responsible for drug safety evaluation, determine PK/TK (AUC, Cmax, Tmax,Vd, T1/2 etc.), bioequivalence, bioavailability, Biomarkers, PD, dose-response relationship, Xenograft, T/C%, general toxicity (acuet, subacute, subchronic and chronic toxicity studies, safety pharmacology in rodents and nonrodents. 2. Enlivened with Sponsors for conducting GLP studies in rodents and non-rodents, included Medical device system toxicity, biocompatibility, hemocompatibility, irritation and skin sensitization (ISO-10993 and ASTM) and drug discovery, familiar with FDA (CDRH, CDER), EMA, ARGMD and MHLW.

1. Implemented safety evaluation of Medical devices in biocompatibility (subcutaneous and Muscular), hemocompatibility, extraction or leachable or degradation, local irritation and skin sensitization, systemic toxicity, identification and quantizationof leachable/degradable medical devices. Responsible for surgical device implantation, including the jugular vein hemo-dialysis in compliance with ISO10993, ASTM, USP and MHLW. 2. Endorsed drug dosing ranging finding, MTD, short term, chronic general toxicity, safety pharmacology, developmental and reproductive toxicity, PK/PD Modeling with WinNonlin 6.3.

Responsible for : 1. Drive antitumor candidates (NCE) through preclinical studies to IND (FDA and SFDA) 2. PK/PD modeling with WinNonlin 6.3, Biomarker deveopment 3. Dose range finding studis (DRF): dose probe; up/down method,"Pyramiding" method, Limit test,Fixed dose method. 4. Acute toxicity studies: "Rolling" acute test,minimum acute toxicity test,complete acute toxicity test,supplemented acute test, acute toxiity test with nonrodent species. 5. Responsible for designing xenograft models for R&D Wnt inhibitors against gastric intestinal tumors, including leading compounds optimization, PD (in vitro/vivo), Biomarker development, Pre-clinical studies to define NOAEL, MTD, HED, STD10, HNSTD in compliance with FDA, CFDA, OECD and ICH guidelines. 6. Responsible for leading PK/TK analysis, ADME by using HPLC, LC/MS (AB SCIEX 4000, Analyst and Peak View 1.2 Software)

1. Enlivened with international clients for non-GLP or GLP studies on rodents and non-rodents (Primarily on Non-human Primates), particularly bio-products, blood products (proliferated NK cells) efficacy and safety evaluation. 2. Took overall responsibility for designing and conducting non-clinical studies contracted to Wuxiapptec by sponsors, including protocol design, study initiation, data collection, documentation, results interpretation and study reports. 3. Provided global regulatory affairs and scientific supports for Business Development, plus training staff, creating, revising or retiring SOPs, and validation of new programs. 4. Performed medical device safety evaluation, bio-comptibility, hemocompatibility, ISO 10993, PMA and 510K, interacting with CDRH (FDA). 5. Led a small PK group, helping trouble shooting auto-sampler, LC-MS including routine maintenance, cleaning and re- calibration, deploying internal data QC and control with Levey-Jennings charts and Westgard rules.

1. Serving a clinical study coordinator, helping PI to recruit participants, collect data and summarize, manage the events of projects, record and report severe adverse events (SAE); assistant for health check, drug administration, clinical Lab tests, human clinical pharmacology. 2. Cloned human Prox1 gene and knocked it into CHO cells, mapped alterations of signaling pathways; 3. Constructed shRNA and packaged into lentivirus to knock down Prox1 in small cell lung cancer cell lines. 4. Constructed tet-on system with expanding polyglutamine tract in PC12 cell lines. 5. Found new mechanism of Huntington’s disease, as overflow of cholesterol induced neurons apoptosis.

1. Created MEK1 knock in transgenic mice and connexin 50 and 46 knockout mice. 2. Found that rottlerin, a classical PKC- isoforms inhibitor, was an interesting calcium channel agonist .

MD