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“Discovering Vismodegib in the Fight Against Skin Cancer” Session 7 of the 2017 Industry Science Series
Dan Sutherlin
Mark Jones
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Executive External Strategy and Communications Fellow, Dow Chemical
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Discovering Vismodegib in the Fight Against Skin Cancer: The First Approved Inhibitor of the Hedgehog Pathway
Dan Sutherlin, PhD Department of Discovery Chemistry Genentech
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Outline • Introduction to the Hedgehog (Hh) pathway and the biological detective story leading to it’s identification as a drug target • Discovery of Vismodegib (Erivedge) and its properties • Overview of the Clinical Results • Final thoughts on the pathway as a drug target
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Hedgehog Pathway Intro: Signaling Through PATCHED (PTCH) and SMOOTHENED (SMO)
Inactive Receptor
Ligand-dependent Activation Hh
PTCH
SMO
No Signal -
OFF
Signal Gli1
Gli2,3
Growth Differentiation Survival
DNA
17
Audience Challenge Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
The Hedgehog protein got it’s name… • From the number of lysine amino acids on the protein giving it a “spiky” appearance • Because the Hh protein burrows into the protein patched like the animal burrows into the ground • From the way a fly embryo looked in a genetic screen • Because cells “roll-up” into a ball like shape resembling a hedgehog when treated with the protein 18
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The hedgehog pathway regulates proliferation and differentiation during development fly
mouse
Polydactyly
• •
Developmental defects result from pathway inactiviation Mainly quiescent in adult - roles in tissue maintenance and repair Nusslein-Volhard & Weischaus, Nature, 1980 Hui and Angers, Annu Rev Cell Dev Biol, 2011
19
Inappropriate regulation associated with developmental disorders in humans Holoprosencephaly (SHH)
Pallister-Hall Syndrome (GLI3)
• Loss of signaling in utero leads to cyclopia in offspring.
• Polydactyly • Hypothalamic Harmatomas
Gorlin Syndrome (PTCH1) Basal Cell Nevus Syndrome
Polydactyly - PHS
reduced pathway activity in fetal development
increased pathway activity in the adult
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Activating pathway mutations are implicated in most BCCs and up to a third of medulloblastomas Mutations in the Hedgehog (Hh) pathway drive unregulated growth in BCC BCC – Basal Cell Carcinoma (the most common form of skin cancer)
90%
10%
•Incidence of over a million cases in the US every year (wear sunscreen and a hat!) •Most are removed by surgery •The unmet need: progression to unresectable locally advanced or metastatic tumors (small percentage of BCCs)
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Cyclopamine causes similar birth defects in sheep •
Sheep grazing in mountain ranges of central Idaho produced offspring with cyclopia
•
Birth defect traced to a specific plant – the corn lily, Veratrum Californicum
•
Natural product cyclopamine produced in the corn lily was found to be the cause
•
Appears to have no effect on adult sheep
cyclopamine 22
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Cyclopamine identified as a inhibitor of the Hh signaling pathway – binds to SMO
Inactive Receptor
Ligand-dependent Activation Hh
Hh
PTCH
Cyclopamine
SMO
No Signal
Signal
X
No Signal Gli2,3 Cyclopamine • small molecules can inhibit the pathway • not a very good starting point for a drug discovery effort based on poor solubility, pharmacokinetics (PK), synthetically challenging
23
Cooper, M. K., Porter, J. A., Young, K. E. & Beachy, P. A. (1998) Science
If Cyclopamine is not suitable what are we looking for in a drug? Compounds need to be… •Potent (low dose) •Selective the target (safe – minimize side effects) •Metabolically stable (dosing schedule) •Orally available (convenient) •Soluble (suitable for dosing strategy) •Eventually scalable to multi-kilograms
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Curis Systemic Hedgehog Antagonist Program Proof of Concept Molecules developed prior to Genentech Collaboration:* • HTS with a 79,000 compound library • Cell based assay using Gli-Luciferase reporter (S12 mouse) • Follow up with human cell based assay (HEPM human) Lead Discovery and Optimization
Luciferase
topical Hh antagonist
Lead Discovery
Orally available Hh antagonists
Luciferase gene
Phase I in BCC
CUR-2 S12 = 12 nM HEPM = 3 nM
JACS 2008
*
Under the Genentech-Curis collaboration agreement, Curis provided broad intellectual property rights relating to the Hedgehog pathway, including several classes of proprietary small molecule inhibitors.
Curis/Evotec
Demonstrated Efficacy in a Medulloblastoma Allograft Efficacy Model Ptch (+/-) Passage in vivo
% Tumor Growth
Dose response w/ Curis leads
(mg/kg QID)
300
CUR-1 100 100 CUR-0199691
275
CUR-0200929 CUR-2 100 100
250
CUR-0199691 CUR-1 25 25
225
CUR-0200929 CUR-2 25 25
200
Vehicle
175 150
CUR-1
125 100 75 50 0
1
2
3
4
5
6
7
-fresh suspension made daily 26
8
9 10 11 12 13
Days
CUR-2
Tumors regress at maximum efficacious dose
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A Lead but not a drug: concerns with metabolic stability and solubility Potency HEPM 3 nM S12 12 nM CUR-2
Solubility
(pH 6.5) 0.3 ug/ml In vitro
Some PK parameters
Microsomal CLhep
Measured CLp
Mouse
2
16
Rat
17
3
Dog
22
145
Cyno
41
25
Human
9
???
Species
ml/min/kg
dose
Clearance = AUC (Cl)
V * 0.693 T1/2 = Cl
Color code
In vivo
ml/min/kg
27
Medicinal Chemistry Program Goals 1. Improve predicted PK in human measured by… • in vitro (predicted) and in vivo (actual) stability in higher species • in vitro stability in human
2. Increase Solubility measured by… • Thermodynamic solubility at pH 6.5 (crystalline material) • Oral PK as a solution and suspension Chemistry Plans: A. Explore SAR of the the heterocycle (benzimidazole)
A.
B.
B. Then focus on the amide 28
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General Synthetic Scheme
Benzimidazoles Imidazoles Amides benzothiazoles
Indazoles Pyrazoles
Pyridines Pyrimidines Qunoxalines Pyridazines Indolizines Imidazolethiazoles Pyrazines
Pyrazolopyridine
29
Summary of A ring SAR (Structure Activity Relationship)
1 (CUR2)
30
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H-bond acceptor is important for potency
1 (CUR2)
✔ H-bond acceptor
✗H-bond donor
31
H-bond acceptor preferred in the 2-position of the heterocycle
1 (CUR2)
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2-pyridiyl biphenyl docked into a public structure of SMO helps to explain SAR
Trp
Tyr
2-pyridyl biphenyl docked into the Smoothened structure Arg
33
New Heterocycles have Improved Stability Relative to Benzimidazole
R group
Predicted Microsomal Clearance mL/min/kg
Measured Cl mL/min/kg
Gli S12 IC50 (mouse)
rat
dog
human
rat
dog
12 nM
19
22
9
3
120
80 nM
32
17
8
99
-
52 nM
9
16
7
11
7
42 nM
6
10
1
5
2 34
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Pyridine has Improved Stability and Solubility Relative to Benzimidazole and Quinoxaline
R group
Measured Cl mL/min/kg
Predicted Microsomal Clearance mL/min/kg
Solubility ug/mL
Gli S12 IC50 (mouse)
rat
dog
human
rat
dog
pH 1
pH 6.5
12 nM
19
22
9
3
120
300
0.3
80 nM
32
17
8
99
-
-
-
52 nM
9
16
7
11
7
0.1
0.1
42 nM
6
10
1
5
2
1000
2 35
SAR Summary for C Ring Aryls Cl
O N H
N
R
36
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Further Improvement in Potency Following SAR Trends Cl
O N H
N
R
S(12) = 20 nM HEPM = 3 nM
37
In Vivo Clearance Predicted Well by Microsomes Suggests Low Clearance in Humans
Species
Predicted Clearance
Measured Clearance
Vss
Rat
2
5
0.5
Cyno
26
19
1.0
Dog
0.7
0.3
1.0
Human
4.6
predict low
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What about solubility? Addition of chlorine increases cLogP Improved solubility at both pH’s S(12) = 20 nM HEPM = 3 nM
R
cLogP
H
3.3
Cl
3.9
39
Audience Challenge Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
Increasing LogP is expected to correlate with… • a decrease in solubility • an increase in solubility • other properties but solubility is not one of them
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Orthochloro - Improves Solubility Despite Higher cLogP Improved solubility at both pH’s S(12) = 20 nM HEPM = 3 nM
R
cLogP
H Cl
Solubility ug/mL pH 1
pH 6.5
3.3
420
0.5
3.9
>3800
~25
cLogP vs. solubility
Hill and Young, Drug Discovery Today 2010, Vol 15, p. 648
41
41
Orthochloro - Improves Solubility Despite Higher cLogP Improved solubility at both pH’s S(12) = 20 nM HEPM = 3 nM
H
R
cLogP
H Cl
Solubility ug/mL pH 1
pH 6.5
3.3
420
0.5
3.9
>3800
~25
Cl
42
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High Exposure Contributes to Good PD Response Calu-6 tumor PK/PD
Vismodegib
• 200-400 mm3 • bid, 2.5 days, 75 mg/kg • sample plasma 4 hrs. • harvest tumor 6 hrs.
% Gli Suppression (SD) vs. Control
100
Gli expression
80 60 40 20 0
Plasma Conc. 0.86 0.21 uM
14 6.6 uM
23 7.9 uM
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Solubility Affects Oral Bioavailability When Dosed as a Suspension in Dog G-025897 Dog IV 1mg/kg and PO 2 mg/kg (Soln and Susp)
G-025638 Dog PK - Average (N=3) 100
Average- G-025638 Dog IV 1 mg/kg (N=3) Average- G-025638 Dog PO 2 mg/kg Soln (N=3) Average- G-025638 Dog PO 2 mg/kg Susp (N=3)
100
GDC-0449 Vismodegib
10
Plasma Conc (uM)
Plasma Conc. (uM)
10
1
0.1
PO 2mg/kg solution PO 2mg/kg suspension IV dose
0.01
1
G-025897 IV 1 mg/kg Dog TKR PO solution and suspension G-025897 IV 1 mg/kg Dog CXV G-025897 IV 1 mg/kg Dog IGT G-025897 PO 2to mg/kg Soln curves are equivalent IVDog TKR G-025897 PO 2 mg/kg Soln Dog CXV
0.1
G-025897 PO 2 mg/kg Soln Dog IGT G-025897 PO 2 mg/kg Susp Dog TKR G-025897 PO 2 mg/kg Susp Dog CXV G-025897 PO 2 mg/kg Susp Dog IGT
0.01
0.001 0
120 240 360 480 600 720 840 960 1080 1200 1320 1440 Time (min)
0.001 0
120
240
360
480
600
720
840
960
1080
1200
1320
1440
Time (min)
44
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Vismodegib is Efficacious in Medulloblastoma Allograft Model 3500
tumor volume (mm3)
3000 2500 Vehicle (MCT) 50 25 12.5 6.25
2000 1500
BID
1000 500 0 0
1
2
3
4
5
6
7
8
time (days)
45
Favorable In Vitro ADME Properties Potency IC50 (HEPM) = 3 nM IC50 (S12) = 20 nM MW = 412 g/mol cLogP = 3.0
Permeability (Caco) Papp A to B (cm/s) = 39.5 E-06
GDC-0449 (Vismodegib) 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)
Papp B to A (cm/s) = 39.1 E-06 (B to A)/(A to B) ratio = 0.99 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%
46
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Medchem Synthesis of Vismodegib
47
Robarge, K. D.; et al. Bioorg. Med. Chem. Lett. 2009, 19, 5576.
Vismodegib Phase I Trial 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
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GDC-0449 is being developed under collaboration agreements between Genentech, Curis, and Roche.
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Vismodegib Total Plasma Concentration (uM)
Mean ± SD Concentration - Time Profiles After a Single Dose of GDC-0449
10 8 150mg (N=7) 270mg (N=9) 540mg (N=4)
6 4 2 0 0
1
2 Day 3 of Study 4 5 Time (Day)
6
7
49
Median Concentration: Time Profiles of Stage 1 Patients (multi-dose) 150 mg (N=7) 270 mg (N=9) 540 mg (N=4)
Stage 1- Median Plot
Vismodegib Concentration (μM)
60
GDC-0449 Concentration (µM)
50
50 40 30 20 10 0 0
7
14
21
28
35
42
49
56
63
Time (Day)
(Error bars represent 25th and 75th percentiles)
50
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Vismodegib Adverse Events from Phase I
•
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)
51
Rudin et al., EORTC-NCI-AACR 2008 Data cutoff 6/1/08
As reported by 01 April 2008
51
49 year old with Multiple Large, Invasive Lesions of Skin Baseline
52
After 3 months
52
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Vismodegib in locally advanced BCC Baseline
Week 24
Week 24: no residual BCC on biopsy 53
67 year old with BCC Metastatic to Lung, Liver, and Bone Baseline
54
At 8 months (confirmed PR)
54
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Pivotal Phase 2 Study of Metastatic and Locally Advanced BCC Patients Metastatic BCC
Locally Advanced BCC
mBCC (n=33)
laBCC (n=63)
ORR by Indep Rev
30.3%
42.3%
ORR by Investigator
45.5%
60.3%
PFS by Investigator
9.2 m
11.3 m
Sekulic et al. NEJM. 2012
55
55
Vismodegib efficacy in Gorlin patients • Investigator-initiated, randomized, placebo controlled trial • 41 patients with Basal cell nevus syndrome randomized 2:1 (active:placebo) • Vismodegib at 150mg per day for 18 months
Baseline Reduction in Existing BCC size
GDC-0449 prevents BCCs
P
