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8/2/2017
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We will begin momentarily at 2pm ET
Slides available now! Recordings available as an exclusive ACS member benefit.
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ChemIDP.org
An individual development planning tool for you!
• Know your career options • Develop strategies to strengthen your skills • Map a plan to achieve your career goals
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The NSF Graduate Research Fellowship
Program (GRFP) recognizes and supports
outstanding graduate students in science,
technology, engineering, and mathematics
(STEM) disciplines who plan to pursue
research-based master’s and doctoral
degrees. GRFP Fellowships are awarded to
senior undergraduates and graduate students
through a national competition.
Awardees receive three years of funding
($34,000 stipend + $12,000 cost of
education allowance per year) over a five-
year period; the funds may be used at any
accredited institution in the U.S.. In addition,
awardees are eligible to participate in
international research and national internship
opportunities.
REGISTER TODAY @ http://bit.ly/GRFPwebinar 10
Speaker: Dr. Joerg Schlatterer, Manager,
ACS Graduate and Postdoctoral Scholars
Office, and Former NSF GRFP Program
Director (2014–2017)
Please send questions or comments to the Graduate and
Spinal Muscular Atrophy: Novel Approaches for Treatment Co-produced with the ACS Medicinal Chemistry Division and AAPS
Kevin Hodgetts, Director of LDDN and Head of Medicinal Chemistry, Assistant Professor of Neurology at Brigham and Women's Hospital and Harvard Medical School
Caesar’s Last Breath and the Fascinating Science and History of the Air We Breathe Co-produced with Chemical & Engineering News
Sam Kean, New York Times bestselling author
Celia Arnaud, Senior Editor, Chemical & Engineering News
12
What is the Heroes of Chemistry Award?
Heroes of Chemistry is an annual award sponsored by the American Chemical Society that recognizes talented industrial chemical scientists whose work has led to the development of successful commercialized products ingrained with chemistry for the benefit of humankind.
G-025897 IV 1 mg/kg Dog TKRG-025897 IV 1 mg/kg Dog CXVG-025897 IV 1 mg/kg Dog IGTG-025897 PO 2 mg/kg Soln Dog TKRG-025897 PO 2 mg/kg Soln Dog CXVG-025897 PO 2 mg/kg Soln Dog IGTG-025897 PO 2 mg/kg Susp Dog TKRG-025897 PO 2 mg/kg Susp Dog CXVG-025897 PO 2 mg/kg Susp Dog IGT
PO 2mg/kg solution
PO 2mg/kg suspension
PO solution and suspension
curves are equivalent to IV
GDC-0449
Vismodegib
IV dose
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Vismodegib is Efficacious in
Medulloblastoma Allograft Model
0
500
1000
1500
2000
2500
3000
3500
0 1 2 3 4 5 6 7 8
time (days)
tum
or
vo
lum
e (
mm
3)
Vehicle (MCT)
50
25
12.5
6.25
BID
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Favorable In Vitro ADME Properties
Metabolic Stability
Hepatocytes
Cl projected (ml/min/kg)
Human – 4.6 (S)
Mouse – 3.3 (S)
Cyno – 26 (L)
Dog – 0.73 (S)
Rat – 1.8 (S)
CYP IC50 (µM)
1A2 36.5
2C8 24.1
2C9 29.3
2C19 26.7
2D6 42.9
3A4 >50.0
Plasma Protein Binding
Mouse 91%
Rat 97%
Cyno 98%
Dog 95%
Human 97%
Permeability (Caco)
Papp A to B (cm/s) = 39.5 E-06
Papp B to A (cm/s) = 39.1 E-06
(B to A)/(A to B) ratio = 0.99
MW = 412 g/mol
cLogP = 3.0
Potency
IC50 (HEPM) = 3 nM
IC50 (S12) = 20 nM
GDC-0449
(Vismodegib)
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Medchem Synthesis of Vismodegib
Robarge, K. D.; et al. Bioorg. Med. Chem. Lett. 2009, 19, 5576. 47
Primary Objectives
• Evaluate the safety, tolerability, pharmacokinetics (PK),
pharmacodynamics (PD), and maximum tolerated dose (MTD) of GDC-0449
administered orally on a continuous once-daily schedule in patients with
advanced solid malignancies
• Determine the recommended Phase II dose and schedule of GDC-0449
Secondary Objective
• Make a preliminary assessment of tumor response
Vismodegib Phase I Trial
GDC-0449 is being developed under collaboration agreements between Genentech, Curis, and Roche. 48
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Mean ± SD Concentration - Time Profiles
After a Single Dose of GDC-0449
Day of Study T i m e ( D a y )
0 1 2 3 4 5 6 7
0
2
4
6
8
1 0
1 5 0 m g ( N = 7 ) 2 7 0 m g ( N = 9 ) 5 4 0 m g ( N = 4 )
Vis
modegib
Tota
l P
lasm
a
Concentr
ation (
uM
)
49
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Median Concentration: Time Profiles of Stage 1 Patients (multi-dose)
Stage 1- Median Plot
Time (Day)
0 7 14 21 28 35 42 49 56 63
GD
C-0
44
9 C
once
ntra
tion
(µM
)
0
10
20
30
40
50
60
150 mg (N=7)
270 mg (N=9)
540 mg (N=4)
(Error bars represent 25th and 75th percentiles)
Vis
modegib
Concentr
atio
n (
μM
)
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Vismodegib Adverse Events from Phase I
As reported by 01 April 2008
• No dose-limiting toxicities were observed with Vismodegib
• The most frequently observed AEs (regardless of relationship to drug):
Fatigue, dysgeusia (altered taste), nausea, anorexia, cough, abdominal pain, diarrhea, hyponatremia, decreased weight, back pain, and decreased appetite
• Grade 3 drug-related AEs consisted of reversible
Fatigue (n=2)
Asymptomatic hyponatremia (n=1)
Rudin et al., EORTC-NCI-AACR 2008
Data cutoff 6/1/08 51
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49 year old with Multiple Large,
Invasive Lesions of Skin
Baseline After 3 months
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Vismodegib in locally advanced BCC
Week 24 Baseline
Week 24: no residual BCC on biopsy
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67 year old with BCC Metastatic to Lung, Liver, and Bone
Baseline At 8 months (confirmed PR)
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Pivotal Phase 2 Study of Metastatic and Locally Advanced BCC Patients
What makes the Hh pathways such a great drug target?
• Genetic link to disease – translation
• Inhibition in models results in tumor regression - efficacy
• Major role in development, less active in the adult – safety
• SMO drug target is GPCR like – drugability
• …with few homologs – safety / selectivity
• Defects in pathway accounts for most BCCs – patient
selection
And for the drug discovery of vismodegib?
• Robust and relevant models (meduloblastoma allograft)
• Potent, drug-like starting point with a modular synthetic
scheme allowed the team to focus on ADME properties
• Combination of favorable PK and safety profile ensures
maximum coverage of target throughout dosing
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Acknowledgements – it takes a village / small town
Chemistry (Genentech)
Jim Marsters
Kirk Robarge
Vickie Tsui
Janet Gunzner
Mike Koehler
Mark Stanley
Shumei Wang
Georgette Castanedo
Rich Goldsmith
Kim Malesky
Kevin Lau
Liang Bao
Michael Dina
Rebecca La Londe
Chemistry (Evotec)
Shirley Brunton
Andy Boyd
Colin Mackinnon
Assays, PK and
Informatics (Curis)
Chang Qian
Oivin Guicherit
Alysia Parkes
Biology (Genentech)
Fred de Sauvage
Stephen Gould
Tracy Tang
Hua Tian
Suzie Scales
Derek Marshall
Lesley Murray
Leslie Lee
Michelle Nannini
Beth Blackwood
Biology (Curis)
Lee Rubin
Karen Kotkow
Christian Dibble
Melissa Chenard
Guizhi Yang
Assays (Genentech)
Dave Peterson
Christine Chang
Susan Keating
Brooke Hashimoto
James Ernst
Chemistry Process Dev (Genentech)
Mark Reynolds
Scott Savage
Shrinivasan Babu
Remy Angelaud
PK/Metab (Genentech)
Cyrus Khojasteh
Harvey Wong
Bilin Chou
Jason Halladay
Laurent Salphati
Young Shin
Hank La
Susan Wong
Savita Ubhayaker
Emile Plise
Sharmin Merchant
Mike Reich
Formulations (Genentech)
Minli Xie
Zedong Dong
Yong Cui
Toxicology (Genentech)
Hong Wang
Kelly Flagella
Eric Morinello
Clinical PK (Genentech)
Sravanthi Cheeti
Rick Graham
Laurent Vernillet
Bert Lum
Diagnostics (Genentech)
Bob Yauch
Ling Fu
Chris Callahan
Walter Darbonne
Ward Kadel
Kelly DuPree
Thomas Holcomb
Regulatory (Genentech)
Bao Truong
Miki Yamamoto
Project Management (Genentech)
Amel Lamrad
Emily Leong
59
Acknowledgements
Special thanks to all our patients and their families.
Translational Genomics Research Institute (TGen) and Scottsdale Healthcare
Daniel Von Hoff, Steve Anthony, Lisa Blaydorn, Mitesh Borad, Molly Downhour, Gayle Jameson,
Ronald Korn, Katy Schroeder, Raoul Tibes, Glenn Weiss, Erica White
Johns Hopkins University
Charles Rudin, Barbara Coleman, Christine Hann, Rosalyn Juergens, Heather Schneitzinger
Karmanos Cancer Institute, Wayne State University
Patricia LoRusso, Elisabeth Heath, Lisa Malburg, MaryJo Pilat, Carolyn Shearer, Andrea
Smoots, Denise Weiss, Jie Zhang
Genentech BioOncology
Jennifer Low, Josina Reddy, Lisa Nelson, Howard Mackey, Amita Joshi, Kenn Zerivitz, Jorge
DiMartino, Brandon Arnieri, Joanne Benedict, Alexandra Carrillo, Ilsung Chang, Susan Eng,
Rachael Garlick, Chris Hendricks, Sho-Rong Lee, Harald Loeffler, Hilary Nelson, Dale Posner,
Danny Shih, Dana Shriver, Tamar Steinmann, Annabel Vaghar, Janice Warner
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www.acs.org/acswebinars Slides available now! Recordings are an exclusive ACS member benefit.
This ACS Webinar was co-produced by ACS Industry Member Programs, C&EN, and ACS Committee on Corporation Associates
“Discovering Vismodegib in the Fight Against Skin Cancer” Session 7 of the 2017 Industry Science Series
Dan Sutherlin Principal Scientist and Director,
Discovery Chemistry, Genentech
Mark Jones Executive External Strategy and
Communications Fellow, Dow Chemical
62
What is the Heroes of Chemistry Award?
Heroes of Chemistry is an annual award sponsored by the American Chemical Society that recognizes talented industrial chemical scientists whose work has led to the development of successful commercialized products ingrained with chemistry for the benefit of humankind.
Spinal Muscular Atrophy: Novel Approaches for Treatment Co-produced with the ACS Medicinal Chemistry Division and AAPS
Kevin Hodgetts, Director of LDDN and Head of Medicinal Chemistry, Assistant Professor of Neurology at Brigham and Women's Hospital and Harvard Medical School
Caesar’s Last Breath and the Fascinating Science and History of the Air We Breathe Co-produced with Chemical & Engineering News
Sam Kean, New York Times bestselling author
Celia Arnaud, Senior Editor, Chemical & Engineering News
64
www.acs.org/acswebinars Slides available now! Recordings are an exclusive ACS member benefit.
This ACS Webinar was co-produced by ACS Industry Member Programs, C&EN, and ACS Committee on Corporation Associates
“Discovering Vismodegib in the Fight Against Skin Cancer” Session 7 of the 2017 Industry Science Series
Dan Sutherlin Principal Scientist and Director,
Discovery Chemistry, Genentech
Mark Jones Executive External Strategy and
Communications Fellow, Dow Chemical
8/2/2017
33
65
“I really enjoyed getting a basic overview of LinkedIn and how to best use it as a tool for networking. Plenty of time was left for specific questions, which was essential to understanding how we can apply what we learned in the presentation to our own individual needs.”
Dr. Amanda Grennell, ACS member for 8 years strong!
Be a featured fan on an upcoming webinar! Write to us @ [email protected]
How has ACS Webinars benefited you?
®
66
Next Month’s Industrial Science Series Webinar!
http://bit.ly/ChemStats
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youtube.com/acswebinars
Search for “acswebinars” and connect!
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Benefits of ACS Membership
http://bit.ly/benefitsACS
Chemical & Engineering News (C&EN) The preeminent weekly news source.
NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.
NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.
8/2/2017
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ACS Webinars does not endorse any products or services. The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the American Chemical Society.
Spinal Muscular Atrophy: Novel Approaches for Treatment Co-produced with the ACS Medicinal Chemistry Division and AAPS
Kevin Hodgetts, Director of LDDN and Head of Medicinal Chemistry, Assistant Professor of Neurology at Brigham and Women's Hospital and Harvard Medical School