This document provides a summary of Brian R. Boettcher's career experience and accomplishments. It outlines his 23 years of experience in drug discovery at Novartis, where he led projects that advanced 5 drug candidates into human clinical trials. It also details his technical expertise in areas like protein design and disease knowledge in diabetes/metabolism. His accomplishments include conceiving projects that generated drug candidates and initiating the first Novartis therapeutic protein projects using novel approaches.

1. BRIAN R. BOETTCHER
PROFILE:
• Twenty three years drug discovery experience in the pharmaceutical industry, resulting in
development candidates for both biological and chemical drug candidates
• Consistent record of innovation in advancing projects
• Technical expertise in protein design, biochemistry and enzymology
• Strong disease area knowledge in diabetes, metabolism and obesity
• Project team and line leadership as both Group Leader and Head of Cardiovascular and
Metabolism Disease Area (CVM DA) Biologics group
• Experienced in management of successful collaborative projects between therapeutic area
and internal and external partners
ACCOMPLISHMENTS:
• Conceived/championed 5 projects producing 18 compounds for development
• 5 human Proof of Concept (PoC) trials initiated
• Initiated and led/co-led all CVM DA’s therapeutic protein projects in development up to 2013
• Co-inventor for all CVM DA’s therapeutic proteins (FGF21 and GLP-1-FGF21 fusion
proteins; both as PEG modified and Fc fusion proteins) in development up to 2013
• Led first Novartis therapeutic protein projects that used a disulfide library screening approach
for lead optimization
• Led first Novartis therapeutic protein projects that fully integrated protein design,
developability assessments and predictive immunogenicity analysis
• Led first Novartis project to produce a clinical development compound (cevoglitazar; PPAR-
α/γ dual agonist; Phase 2) from a “virtual”, i.e. computationally-derived, screening hit
EXPERIENCE:
• Focus on therapeutic targets and approaches most likely to achieve superior efficacy in
humans and differentiation from competition:
- Single molecules with multiple, complementary modes of action (cevoglitazar and GLP-1-
FGF21 fusion proteins)
- Targets having pleiotropic efficacies (PPARs, FGF21 and GLP-1)
• Validation of differentiation strategy shown in cevoglitazar clinical trials
• Success and productivity in drug discovery achieved through a focus on depth rather than
breadth in project selection and implementation
• Proven ability to focus resources and balance biochemical, cellular and in vivo pharmacology
approaches effectively
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2. BRIAN R. BOETTCHER
Director: Novartis Institutes for Biomedical Research (NIBR), Cambridge, MA. Have held
positions of increasing responsibility from Lab Head to Group Leader, Unit Head and Director
throughout career in Novartis. Line responsibility for up to 14 people.
• Group Leader and Unit Head: Responsible for Lab Head and Associate recruiting and
development as well as support of biochemical and cellular assays for both low molecular
weight and biological projects for the Cardiovascular and Metabolism Disease Area (CVM
DA). Other responsibilities included development of new capabilities, e.g. semi-automation
of protein expression and purification as well as group’s budget.
• Project Team Leader (PTL) for the fibroblast growth factor 21 (FGF21) therapeutic protein
project and co-leader (collaboration with Genomics Institute of the Novartis Research
Foundation (GNF)) for the GLP-1-FGF21fusion protein; co-leader (GNF collaboration) for
the tropomyosin receptor kinase B (TrkB) monoclonal antibody project; PTL for the
peroxisome proliferator-activated receptor-α/γ (PPAR-α/γ) and PPAR-α projects in CVM.
The teams consisted of up to 20 core multidisciplinary team members and a number of
Research and Development colleagues: Computer Assisted Molecular Modeling, Structural
Biology, Magnetic Resonance Imaging, Global Imaging, Drug Metabolism and
Pharmacokinetics, Preclinical Safety, and Chemical and Pharmaceutical Development.
Biological projects:
• Proof of Concept (PoC) trials achieved for FGF21-PEG and Fc-FGF21
• Candidate Selection Phase (CSP) achieved for GLP-1-Fc-FGF21 fusion protein
• CSP achieved for TrkB agonist monoclonal antibodies
• Led first Novartis therapeutic protein projects that successfully implemented a disulfide
library screening approach for lead optimization
• Led first Novartis therapeutic protein project (GLP-1-FGF21 fusion protein) that
successfully utilized multiple receptor interactions with a single molecule to improve
potency and efficacy
• The success of the FGF21 and GLP-1-FGF21 fusion protein projects required effective
communication and leadership across multiple departments (CVM, GNF, Preclinical
Safety (PCS), Biologics Research (NBC), and Biologics Development (IBP)) and across
three sites (San Diego, CA, Cambridge, MA and Basel, Switzerland).
Small molecule projects:
• 3 PoC trials with cevoglitazar initiated in parallel: dyslipidemia, type 2 diabetes and
obesity
• Positive PoC for dyslipidemia achieved with cevoglitazar
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3. BRIAN R. BOETTCHER
• Clinical results validated the team’s drug design strategy focused on compound
differentiation. Cevoglitazar has limited adipose exposure and does not cause weight gain
and edema like typical PPAR-γ and PPAR-α/γ agonists that target adipose tissue.
• Clinical results with cevoglitazar also demonstrated potential cardiovascular benefits not
described with other PPAR ligands.
1. Increased ghrelin levels observed. Ghrelin improves endothelial function in
metabolic syndrome patients (Tesauro et al. Circulation 112: 2986-2992 (2005))
and increases heart function and exercise capacity in patients with heart failure
(Nagaya et al. Circulation 110: 3674-3679 (2004)).
2. HDLc changes are consistent with an increase in hepatic SR-BI mediated by
PPAR-γ (Ahmed et al. Endocrine 35:233-242 (2009) and Zhang et al. PPAR Res
DOI:10.1155/2011/164295). Increased SR-BI will improve HDL function and
cholesterol flux leading to reduced coronary heart disease based on human
genetic results with SR-BI loss-of-function variant P376L (Zanoni et al. Science
351: 1166-1171 (2016)) and results with SR-BI gene manipulation in mice
(Trigatti, B. L. et al. Arterioscler Thromb Vasc Biol 23:1732-1738 (2003) and
Zhang, Y. et al. J Clin Invest 115:2870-2874 (2005))
• Cevoglitazar was the first Novartis clinical development compound derived from a
“virtual”, i.e. computationally-derived, screening hit; Highly efficient project – Lead
compound to development candidates in only 9 months with 8 chemistry FTEs.
• Selection of PoC (sPoC) achieved with a PPAR-α compound
• CSP achieved for multiple PPAR-α compounds
• PPAR-α was among the first projects in Novartis in which the majority of lead
optimization chemistry activities were carried out with an external partner (Chembiotek
in India)
Senior Research Chemist, Chevron Chemical Company, Richmond, CA
Postdoctoral Fellow, Cornell University Medical College, New York, NY
EDUCATION:
• Ph.D. in Chemistry, University of Notre Dame, Notre Dame, Indiana
Dissertation: "Preparation of a Half Active Hybrid and 13C and 19F Magnetic Resonance
Probes for Active Site Symmetry in Dimeric Aspartate Aminotransferase."
• B.S. (with honors) in Chemistry, University of Texas, Austin, Texas
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4. BRIAN R. BOETTCHER
PATENTS:
Boettcher BR, Loew A, Caplan SL, Daniels D, Geierstanger BH, Hamamatsu N, Licht S and
Weldon SC “Methods of Treating FGF21-Associated Disorders” US20160051628 A1; Feb. 25,
2016.
Boettcher BR, Caplan, SL, Daniels D, Hamamatsu N, Licht S, and Weldon SC “Methods of
Treating Metabolic Disorders with an FGF21 Variant” US9266935 B2; Feb. 23, 2016.
Boettcher BR, Caplan SL, Daniels D, Geierstanger BH, Hamamatsu N, Licht S, Loew A and
Weldon SC “Fibroblast growth factor 21 mutations”. US9023791 B2; May 5, 2015.
Boettcher BR, Caplan, SL, Daniels D, Hamamatsu N, Licht S, and Weldon SC “Fibroblast growth
factor-21-Fc fusion proteins” US9006400 B2; April 14, 2015.
Boettcher BR, Caplan, SL, Cellitti, SC, Daniels D, Geierstanger BH, Hamamatsu N, Licht S, Loew
A and Weldon SC “Dual function proteins for treating metabolic disorders” US20130129724 A1;
May 23, 2013.
Caplan SL, Boettcher BR, Slosberg ED, Connelly S, Kaleko M, Desai UJ “Methods and
Compositions for Treatment of Diabetes and Related Conditions via Gene Therapy”. US6608038
B2; August 19, 2003.
INVITED REVIEW:
Shechter I, Guan G, Boettcher BR “Squalene Synthase” in Comprehensive Natural Products
Chemistry, Isoprenoids Including Carotenoids and Steroids, Volume 2, Chapter 9, DHR Barton and
K Nakanishi, Editors-in-Chief, DE Cane, Volume Editor, pp 245-266, Elsevier (1999)
PUBLICATIONS:
Chen H., Dardik B., Qiu L., Ren X., Caplan SL., Burkey B., Boettcher BR., Gromada J.
“Cevoglitazar, a novel PPARα/γ dual agonist, potently reduces food intake and body weight in
obese mice and cynomolgus monkeys” Endocrinology 151: 3115-24 (2010)
Laurent D. Gounarides JS. Gao J. Boettcher BR. “Effects of cevoglitazar, a dual PPAR alpha/
gamma agonist, on ectopic fat deposition in fatty Zucker rats” Diabetes, Obesity and Metabolism
11: 632-36 (2009)
Hu S, Boettcher BR, Dunning BE. “The mechanisms underlying the unique pharmacodynamics of
nateglinide”, Diabetologia 46 [Suppl 1], M37-M43 (2003)
Slosberg ED, Desai UJ, Fanelli B, St Denny I, Connelly S, Kaleko M, Boettcher BR, Caplan SL
“Treatment of type 2 diabetes by adenoviral-mediated overexpression of the glucokinase
regulatory protein”, Diabetes 50, 1813-20 (2001)
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5. BRIAN R. BOETTCHER
Desai UJ, Slosberg ED, Boettcher BR, Caplan SL, Fanelli B, Stephan Z, Gunther VJ, Kaleko M,
Connelly S “Phenotypic correction of diabetic mice by adenovirus-mediated glucokinase
expression”, Diabetes 50, 2287-95 (2001)
Hu S, Wang S, Fanelli B, Bell PA, Dunning BE, Geisse S, Schmitz R, Boettcher BR “Pancreatic
beta-cell K-(ATP) channel activity and membrane-binding studies with nateglinide: A
comparison with sulfonylureas and repaglinide”, J Pharm Exp Therap 293; 444-52 (2000)
Xue, S, Green, MA, LoGrasso, PV, Boettcher, BR, Madison, EL, Curtiss, LK, Miles, LA “Comparison
of the Effects of Apo(a) Kringle IV-10 and Plasminogen Kringles on the Interactions of
Lipoprotein(a) with Regulatory Molecules”, Thromb Haemost 81, 428-35 (1999)
Wattanasin, S, Boettcher BR, Scallen T “N-Hydroxyglycine Derivatives as Novel Inhibitiors of
Squalene Synthase”, Bioorganic and Medicinal Chemistry Letters, 7, 3039-44 (1997)
Mikol, V, LoGrasso PV, Boettcher BR "Crystal Structures of Apolipoprotein(a) Kringle IV37 Free and
Complexed with 6-Aminohexanoic Acid and with p-Aminomethylbenzoic Acid: Existence of Novel
and Expected Binding Modes”, J Mol Biol 256, 751-61 (1996)
Kumaravel G, Boettcher BR, Shapiro MJ, Petter RC "Peptide Mimics of Glycylproline as Inhibitors of
Prolidase" Bioorganic & Medicinal Chemistry Letters 5, 2825-28 (1995)
Soltis DA, McMahon G, Caplan SL, Dudas DA, Chamberlin HA, Vattay A, Dottavio D, Rucker ML,
Engstrom RG, Cornell-Kennon SA, Boettcher BR "Expression, Purification and Characterization
of Human Squalene Synthase: Use of Yeast and Baculoviral Systems." Arch Biochem Biophys 316,
713-23 (1995)
LoGrasso PV, Cornell-Kennon S, Boettcher BR "Comparison of the Inhibition of Yeast, Rat, and
Human Squalene Synthetase", Bioorg Chem 22, 294-99 (1994)
LoGrasso PV, Cornell-Kennon S, Boettcher BR "Cloning, Expression, and Characterization of Human
Apolipoprotein(a) Kringle IV37", J Biol Chem 269, 21820-27 (1994)
LoGrasso PV, Soltis DA, Boettcher BR, "Overexpression, Purification, and Kinetic Characterization of
a Carboxyl-Terminal Truncated Yeast Squalene Synthetase", Arch Biochem Biophys, 307, 193-99
(1993)
Shechter I, Klinger E, Rucker ML, Engstrom RG, Spirito JA, Islam MA, Boettcher BR, Weinstein DB,
"Solubilization, Purification, and Characterization of a Truncated Form of Rat Hepatic Squalene
Synthetase", J Biol Chem 267, 8628-35 (1992)
Johnson C, Boettcher B, Cherpeck R, Dolson M, "Design and Synthesis of Potent Inhibitors of
Glutamine Synthetase. 1. Cyclic Analogs of Phosphinothricin", Bioorg Chem 18, 154-59 (1990)
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6. BRIAN R. BOETTCHER
Boettcher B, Meister A "Synthesis of L-2-oxothiazolidine-4-carboxylic Acid", Methods in Enzymology
113, 458-60 (1985)
Boettcher B, Meister A "Synthesis of L-2-oxothiazolidine-4-carboxylic Acid", Anal Biochem 138,
449-50 (1984)
Williamson JM, Boettcher B, Meister A "Reversal of Acetaminophen Induced Hepatic Glutathione
Depletion by Administration of L-2-oxothiazolidine-4-carboxylate", Proc Nat Acad Sci US 79,
6246-49 (1982)
Boettcher B, Meister A "Regulation of E. coli Carbamyl Phosphate Synthetase. Evidence for Overlap
of the Allosteric Nucleotide Binding Sites", J Biol Chem 257, 13971-76 (1982)
Boettcher B, Meister A "Conversion of UMP, an Allosteric Inhibitor of Carbamyl Phosphate
Synthetase, to an Activator by Modification of the UMP Ribose Moiety", J Biol Chem 256, 5977-80
(1981)
Boettcher B, Meister A "Covalent Modification of the Active Site of Carbamyl Phosphate Synthetase
by 5'-p-Fluorosulfonylbenzoyl adenosine: Direct Evidence for Two Functionally Different ATP
Binding Sites", J Biol Chem 255, 7129-33 (1980)
Boettcher B, Martinez-Carrion M "Magnetic Resonance Relaxation Rates in the Study of Complexes
of Ligands of Spin Labeled Aspartate Transaminase", J Biol Chem 253, 4642-47 (1978)
Martinez-Carrion M, Slebe JC, Boettcher B, Relimpio AM "Flourine 19 as a Covalent Active Site-
Directed Magnetic Resonance Probe in Aspartate Transaminase", J Biol Chem 251, 1853-58 (1976)
Boettcher B and Martinez-Carrion M "Itemizing Enzyme Ligand Interactions in Native and Half
Active Hybrid Aspartate Transaminase to Probe Site Site Relationships", Biochemistry 15, 5657-64
(1976)
Martinez-Carrion M, Boettcher B, Churchich JE "Fluorescence Energy Transfer Between Active Sites
in Aspartate Transaminase", Biochem and Biophys Res Comm 67, 1480-87 (1975)
Boettcher B, Martinez-Carrion M "Glutamate Aspartate Transaminase Modified at Cysteine 390 with
Enriched Carbon13 Cyanide", Biochem and Biophys Res Comm 64, 2833 (1975)
Boettcher B, Martinez-Carrion M "Hybridization of Glutamate Aspartate Transaminase. Investigation
of Subunit Interaction", Biochemistry 14, 4428-31 (1975)
McCullough T, Allaire PN, Boettcher B "Determination of Chloride, Bromide, and Iodide Following
Sodium Fusion", J. Chem. Ed. 47, 217 (1970)
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