Targeting HIF-2α: Myth or Reality?

Transcription

Targeting HIF-2α: Myth or Reality?
A First-In-Class HIF-2α Antagonist for the Treatment of
clear cell Renal Cell Carcinoma: PT2385
John A. Josey, Ph.D.
Chief Executive Officer
Peloton Therapeutics, Inc.
Fourteenth International Kidney Cancer Symposium
Miami, Florida, USA—November 6-7, 2015
www.kidneycancersymposium.com
Disclosure Information
John A. Josey, Ph.D.
I have the following financial relationships to disclose:
I am a shareholder and employee of Peloton Therapeutics, Inc.
- and I will not discuss off label use in my presentation
- and I will discuss investigational use in my presentation
Acknowledgements
UT Southwestern Medical Center
Mick Bakes
Guangzhou Han
Peter Stengel
Richard Bruick
Zhaodan Cao
Heli Huang
Huiling Tan
James Brugarolas
Tzuling Cheng
John Josey
Bin Wang
Kevin Gardner
Robert Czerwinski
Richard Kelly
Keshi Wang
Steven McKnight
Darryl Dixon
Steve Madden
Paul Wehn
Xinlin Du
Melissa Maddie
Shanhai Xie
Barry Goggin
Sarah Olive
Rui Xu
Jonas Grina
James Rizzi
Hanbiao Yang
Megan Halfmann
Stephen Schlachter
Naseem Zojwalla
HIF-2α:
Loss of the Tumor Suppressor VHL Complex in clear cell Renal Cell Carcinoma (ccRCC)
Paired tumor-normal DNA
from 240 ccRCC cases
226 of 240 (94%):
LOH at 3p chromosome
(loss of one VHL allele)
“TCEBP1 mutations and
VHL lesions are completely
mutually exclusive”
8 of 240 (3%): mutated TCEB1
with concomitant loss of one
copy of 8q
3% of ccRCC
221 of 226 (98%):
remaining VHL allele
inactivated
92% of ccRCC
197 of 221 (89%):
somatic mutation
24 of 221 (11%):
promoter methylation
95% of patients with ccRCC:
inactive or aberrant VHL tumor
suppressor
Sato et al. Nature Genetics 2013, 45, 860
(TCGA Nature 2013, 499, 43)
HIF-2α
HIF-2α:
Key Driver of clear cell Renal Cell Carcinoma (ccRCC)
Normoxia
O2
• Loss of the tumor suppressor VHL results
in constitutive activation of HIF-α
Hypoxia
O2

Nucleus
Defective VHL

pVHL
ARNT
OH
OH
HIF-2α
HIF-2α
pVHL
ARNT
OH
OH
HIF-2α
HIF-2α
Prolyl
hydroxylases
• In preclinical models, HIF-2α knock-out
inhibits tumor growth1,2
• Stabilization of HIF-2α overrides tumor
suppressor function of pVHL3
• Hypothesis:
Inhibiting HIF-2α will provide therapeutic
benefit in the treatment of ccRCC
Angiogenesis
Cell Proliferation
& Survival
Proteasomal Degradation
1Kondo
et al. PLoS Biology 2003, 1, 439
2Zimmer
3Kondo
et al. Mol. Cancer Res. 2004, 2, 89
et al. Cancer Cell 2002, 1, 237
PT2385:
A Small Molecule HIF-2α Antagonist
Novel HIF-2α structural insight from Kevin Gardner & Rick Bruick (UT
Southwestern Medical Center) enabled the design of small molecules that bind
to PAS-B domain and disrupt heterodimerization of the HIF-2α/ARNT complex
PT2385 bound to HIF-2α PAS-B Domain (1.9 Å)
PT2385 bound to HIF-2a PAS-B Domain ( 1.9 Å)
PT2385
• Generated >130 protein/inhibitor co-crystal structures
• Discovered essential protein interactions for antagonism
HIF-2a
ARNT
• Evaluated several selective, potent, orally bioavailable antagonists
• PT2385 selected as clinical candidate
Scheuermann et al. Nature Chem. Biol. 2013, 9, 271
Rogers et al. J. Med. Chem. 2013, 56, 1739
PT2385:
A Small Molecule HIF-2α Antagonist
Hep3B cells (Hepatoma, VHL+/+, HIF-1α+/+, HIF-2α+/+)
• Cells treated for 24 h with PT2385 under 21% O2 (normoxia) or 1% O2 (hypoxia)
HIF-1α specific gene
EPO
30
20
10
0
0
0
0.1
1
10
PT2385 (μM)
1% O2
1% O2
0
0
50
Relative mRNA levels
40
21% O2
PDK1
1% O2
21% O2
HIF-2α specific gene
1% O2
40
30
20
10
0
0.1
1
10
PT2385 (μM)
• PT2385 inhibits expression of HIF-2α target genes with no effect on HIF-1α target genes
HIF-2α:
Tumor Growth Inhibition Compared to Standard of Care Agents
786-O subcutaneous xenograft model of ccRCC (VHL-/-, HIF-1α-/-, HIF-2α+/+)
N = 8 each group
All dose groups well tolerated
Beige SCID mice
• HIF-2α inhibition provides superior efficacy in this model
HIF-2α:
Inhibition of HIF-2α Regulated Genes in vivo
• Six doses of PT2385 p.o., b.i.d.; tumor mRNA measured 12 h post final dose
0.5
1.0
0.5
kg
m
g/
kg
g/
10
85
23
PT
PT
23
85
-3
m
g/
m
-1
23
85
kg
-1
0
23
85
PT
PT
23
8
53
m
m
g/
kg
g/
kg
g/
m
51
• Dose-dependent inhibition of HIF-2α regulated genes in vivo
kg
0.0
23
8
kg
-1
0
23
85
PT
23
8
53
m
m
g/
kg
g/
kg
g/
m
51
PT
PT
23
8
Ve
hi
cl
e
kg
-1
0
23
85
PT
PT
23
8
53
m
m
g/
kg
g/
kg
g/
m
51
23
8
Ve
hi
cl
e
1.0
0.0
0.0
PT
0.5
GLUT1
1.5
1.5
PT
0.0
1.0
Ve
hi
cl
e
0.5
2.0
1.0
PAI-1
PT
Cyclin D1
1.5
1.5
GLUT1
PAI-1
Cyclin D1
VEGFA
Ve
hi
cl
e
VEGFA
Beige SCID mice
HIF-2α:
Diminution of Tumor-Derived VEGF-A Protein Levels
• Six doses of PT2385 p.o., b.i.d.; tumor mRNA measured 12 h post final dose
hVEGFA (pg/mL)
mean +/- SEM
300
200
100
0
Vehicle
1 mg/kg
PT2385
3 mg/kg
PT2385
10 mg/kg
PT2385
Treatment Group
• HIF-2α antagonism inhibits tumor-derived VEGF-A protein levels in plasma
• PT2385 has no effect on mouse VEGFA levels (data not shown)
• PT2385 inhibits mouse kidney EPO gene expression (data not shown)
Beige SCID mice
HIF-2α:
Improved Cardiovascular Safety
VEGFR TKIs and VEGFA mAb are associated with hypertension in patients
• The effect of sunitinib treatment on blood pressure and heart rate can be recapitulated in rats
Mean Arterial Pressure (mm Hg)
150
Vehicle p.o., b.i.d. (n=3)
Sunitinib 40 mg/kg p.o., q.d. (n=3)
PT2385 30 mg/kg p.o., b.i.d. (n=3)
PT2385 100 mg/kg p.o., b.i.d. (n=3)
125
100
75
0
25
50
75
100
125
Time (hours)
• Sunitinib significantly increases blood pressure at its maximally efficacious dose
• HIF-2α antagonism has no impact on blood pressure at 5x the maximally efficacious dose
telemeterized SD rats
HIF-2α:
PDX Model of ccRCC
James Brugarolas, M.D., Ph.D. – UT Southwestern Medical Center
• Patient-derived subcutaneous xenograft model ccRCC (XP164)
• Sarcomatoid features; VHL wild-type; expression of HIF-2α evident by Western blot
4500
1500
Tumor Volume (mm3)
Tumor Volume (mm3)
mean +/- SEM
mean +/- SEM
4000
1200
3500
3000
900
2500
Vehiclep.o.,
p.o.,b.i.d.
b.i.d.
Vehicle
Sunitinib
mg/kg
p.o.,
b.i.d.
Sutitinib
1010
mg/kg
p.o.,
b.i.d.
Sirolimus0.5
0.5mg/kg
mg/kgi.p.,
i.p.,q2d
q2d
Sirolimus
PT2399
100
mg/kg
p.o.,
b.i.d.
PT2399 100 mg/kg p.o., b.i.d.
2000
600
1500
1000
300
500
00
00
5 5 10
10 15
15 20
20 25
25 30
Day after treatment initiation
35
40
45
50
55
60
65
70
75
80
85
90
95 100 105 110
Day after treatment initiation
NOD SCID mice
PT2385-101:
Clinical Trial
A Phase I, Dose-Escalation Trial of PT2385 Tablets in Patients with Advance clear cell Renal Cell Carcinoma
Primary Objective:
• To identify the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose of PT2385 tablets in patients
Clinical
Site
Investigator
with advanced clear cell renal cell carcinoma
(ccRCC)
Dr. Robert Figlin
Secondary Objectives: Cedars-Sinai Medical Center
• To evaluate the safetyCleveland
profile ofClinic
PT2385
Dr. Brian Rini
• To determine the pharmacokinetic (PK) profile of PT2385
Dana-Farber Cancer Institute
Dr. Tony Choueiri
• To assess the pharmacodynamic (PD) effects of treatment with PT2385
Tennessee
Dr. Jeff Infante
• To assess the anti-tumor
activityOncology
of PT2385
University of Colorado Health Sciences Center
Dr. Elaine Lam
3+3 Design
• Increase in dose levelUniversity
by 100% until
first Southwestern
drug-related GrMedical
2 or greater
Increase in dose by 50%
of Texas
Centerseverity
Dr. toxicity;
Kevin Courtney
thereafter
University of Oklahoma Health Sciences Center
Dr. Shubham Pant
• If 2 of 6 patients experience a DLT at a dose level after an expansion from 3 patients, this dose will be declared the MTD
• Expansion to 25 additional patients at MTD or RP2D
NCT02293980
PT2385-101:
Pharmacodynamic Response to HIF-2α Antagonism
Erythropoeitin expression is regulated by HIF-2α
EPO (day 8) vs. AUClast (day 1)
75
25
50
% Change in Eryhthropoietin
%Change in Erythropoietin
Erythropoietin
All subjects:
25
0
-25
-50
-75
-100
0
5
10
15
20
25
30
35
40
45
0
-25
-50
-75
-100
0.0
0.5
8
1.0
AUClast (h*ug/mL)
Days
• Target engagement, as measured by diminution of erythropoietin expression, is rapid and pronounced
PT2385:
Novel Therapy for ccRCC
Potent, Selective, Orally Bioavailable, First-In-Class HIF-2α Antagonist
• In preclinical studies:
• PT2385 binds directly and specifically to HIF-2α – selectively antagonizes HIF-2α over HIF-1α
• PT2385 inhibits expression of HIF-2α regulated genes in a dose dependent manner in vivo
• PT2385 inhibits tumor growth and angiogenesis – selectively inhibits tumor derived VEGFA
• Favorable preclinical safety profile – modest and reversible effect on RBC compartment with no hypertension
• Additive to synergistic efficacy in combination with checkpoint inhibitors can be achieved (data not shown)
• Currently in Phase 1 clinical trial in patients with advanced or metastatic ccRCC
• Dose escalation stage complete: recommended Phase 2 dose determined
• Expansion arm of study currently recruiting
• PT2385 has the potential to be transformative in the treatment of clear cell renal cell carcinoma

Targeting HIF-2α: Myth or Reality?

Transcription

Similar documents