HIF 2 HIF 2 knock out inhibits tumor growth 1,2 ARNT pVHL [PDF]

SLIDE 1

5/4/2016 1 PT2385: HIF‐2α Antagonist for the Treatment of VHL Mutant ccRCC

12th International VHL Medical Symposium April 8, 2016 Eli Wallace, Ph.D. Vice President of Chemistry

Peloton Therapeutics, Inc.

1 April 8, 2016

Disclosure Information

I have the following financial relationships to disclose:

I am a stockholder and employee of Peloton Therapeutics, Inc.

and -

I will not discuss off label use or investigational use in my presentation.

2

Eli Wallace

April 8, 2016

HIF‐2

Normoxia O2

Prolyl hydroxylases

OH OH OH

HIF‐2

pVHL OH OH

HIF‐2

pVHL

Proteasomal Degradation

Nucleus

HIF‐2  Regulated by O2 in Concert with pVHL

ARNT

Hypoxia O2



HIF‐2

Cell Proliferation Angiogenesis & Survival

HIF‐2 ARNT

3



Defective VHL

70% of VHL disease patients develop ccRCC
ccRCC is the leading cause of mortality in VHL

patients

95% of patients with sporadic ccRCC have

defective pVHL

Loss of VHL results in constitutive activation of

HIF‐2

April 8, 2016

OH OH

HIF‐2

pVHL

Nucleus ARNT HIF‐2

Angiogenesis Cell Prolifera on & Survival

HIF‐2 ARNT Defec ve VHL

H y p

x

i a ‐ R e s p

n

s e E l e m e n t

All pVHL defective ccRCC patients express

HIF‐2

Loss of VHL results in constitutive

activation of HIF‐

HIF‐2 knock‐out inhibits tumor growth1,2
Stabilization of HIF‐2 overrides tumor

suppressor function of pVHL3

4

HIF‐2  Driver of VHL‐Associated ccRCC

Hypothesis: Inhibiting HIF‐2α will provide therapeutic benefit in the

treatment of ccRCC

1Kondo et al. PLoS Biology 2003, 1, 439 2Zimmer et al. Mol Cancer Res 2004, 2, 89 3Kondo et al. Cancer Cell 2002, 1, 237

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5/4/2016 2

April 8, 2016

HIF‐2α Nucleus ARNT HIF‐2α

Cell Proliferation Angiogenesis & Survival

HIF‐2α ARNT

PT2385: A Potent and Selective HIF‐2 Antagonist PT2385

ITC Binding Affinity (Kd) HIF‐2α < 50 nM HIF‐1α Inactive 786‐O VEGFa ELISA (IC50) 44 nM Rat Brain:Plasma Ratio 0.9

PT2385 binds to PAS‐B domain of HIF‐2
Binding blocks HIF‐2:ARNT heterodimerization

5 April 8, 2016

Hypoxia‐Inducible Factor‐2 and Cancer

VEGFA Angiogenesis Cyclin D1 Cell Cycle Progression GLUT1 Cell Metabolism Arginase 1 Inflammatory Response CXCR4 Metastasis CD74 Immune Response

HIF‐2 regulates the expression of multiple genes impacting

proliferation
angiogenesis
metastasis
immune evasion

HIF‐2 ARNT

Hypoxia‐Response Element

Plasminogen activator inhibitor‐1 Angiogenesis / Survival TGF Growth Factor Signaling

Gene

HIF‐drives the expression of several genes involved in cancer

6 April 8, 2016

0.1 1 10 10 20 30 40 Relative mRNA levels 0.1 1 10 10 20 30 40 50 Relative mRNA levels

7

PT2385: Selective Antagonism of HIF‐2 Over HIF‐1

PT2385 inhibits expression of HIF‐2target genes with no effect on HIF‐1target genes

Hep3B cells (Hepatoma, VHL+/+, HIF‐1+/+, HIF‐2+/+)

Cells treated for 24 h with PT2385 at 21% O2 (normoxia) or 1% O2 (hypoxia)

PDK1 HIF‐1 specific genes HIF‐2 specific genes EPO

PT2385 (M) 21% O2 21% O2 PT2385 (M) 1% O2 1% O2 1% O2 1% O2

April 8, 2016

PT2385: Efficacious in 786‐O Xenograft

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786‐O subcutaneous xenograft model of ccRCC (VHL‐/‐, HIF‐1‐/‐, HIF‐2+/+)

Tumor regressions with 3 and 10 mg/kg, p.o., b.i.d. dose
Similar efficacy in A498 ccRCC xenograft (VHL‐/‐, HIF‐1‐/‐, HIF‐2+/+)

5 10 15 20 25 100 200 300 400 500 600 700 800 900 Time After Treatment Initiation (d) Tumor Volume (mm3) mean +/- SEM Vehicle p.o., b.i.d. (n=8) Sunitinib 40 mg/kg p.o., q.d. (n=8) PT2385 3 mg/kg p.o., b.i.d. (n=8) PT2385 10 mg/kg p.o., b.i.d. (n=8)

All dose groups well tolerated

Beige SCID mice

SLIDE 3

5/4/2016 3

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786‐O subcutaneous xenograft model of ccRCC (VHL‐/‐, HIF‐1‐/‐, HIF‐2+/+) Six doses of PT2385 p.o., b.i.d.; plasma protein VEGFA measured 12 h post final dose

PT2385: Inhibits Tumor‐Derived VEGFA Protein Levels

PT2385 has no effect on mouse VEGFA levels (data not shown)
PT2385 inhibits mouse kidney EPO gene expression (data not shown)

Vehicle 1 mg/kg PT2385 3 mg/kg PT2385 10 mg/kg PT2385 100 200 300 Treatment Group hVEGFA (pg/mL) mean +/- SEM

Beige SCID mice 9 April 8, 2016

PT2385: Inhibition of the Expression of Multiple Genes

Dose‐dependent Inhibition of HIF‐2 regulated genes

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786‐O subcutaneous xenograft model of ccRCC (VHL‐/‐, HIF‐1‐/‐, HIF‐2+/+) Six doses of PT2385 p.o., b.i.d.; tumor mRNA measured 12 h post final dose

Beige SCID mice

VEGFA 1 3 10 0.0 0.5 1.0 1.5 Relative mRNA levels

PT2385 (mg/kg)

PAI-1 1 3 10 0.0 0.5 1.0 1.5 2.0 Relative mRNA levels

PT2385 (mg/kg)

Cyclin D1 Relative mRNA levels 1 3 10 0.0 0.5 1.0 1.5

PT2385 (mg/kg)

GLUT1 1 3 10 0.0 0.5 1.0 1.5 Relative mRNA levels

PT2385 (mg/kg) April 8, 2016

786‐O subcutaneous xenograft model of ccRCC (VHL‐/‐, HIF‐1‐/‐, HIF‐2+/+) Six doses of PT2385 10 mg/kg p.o., b.i.d.; tumor tissue collected 12 h post final dose

PT2385: Inhibits Proliferation and Angiogenesis

PT2385 treatment reduces proliferation (Ki67) and angiogenesis (CD‐31)

Vehicle PT2385 Ki67 CD‐31

11 April 8, 2016 5 10 15 20 25 200 400 600 800 1000 Time After Treatment Initiation (d) Tumor Volume (mm3) mean +/- SEM Vehicle p.o., b.i.d. Sunitinib 40 mg/kg, p.o., q.d. PT2385 30 mg/kg, p.o., b.i.d.

PT2385: Efficacious in Sunitinib Refractory PDX Model

PDX subcutaneous xenograft model of ccRCC (VHL‐/‐, HIF‐1+/+, HIF‐2+/+)

Model derived from a patient refractory to both sunitinib and everolimus
PT2385 efficacious in sunitinib refractory model
Tumor expresses both HIF‐1 and HIF‐2

All dose groups well tolerated

CRO: Champions Oncology 12

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5/4/2016 4

April 8, 2016

Sunitinib significantly increased blood pressure at its maximally efficacious dose
Sunitinib also significantly reduced (10‐20%) heart rate

CRO: CorDynamics

VEGFR TKIs and VEGFA mAb are associated with hypertension in patients The effect of sunitinib on blood pressure and heart rate are recapitulated in rats

25 50 75 100 125 75 100 125 150 Time (hours) Mean Arterial Pressure (mm Hg) Sunitinib 40 mg/kg p.o., q.d. (n=3) Vehicle p.o., b.i.d. (n=3)

Effect of PT2385 and Sunitinib on Blood Pressure

telemeterized SD rats 13 April 8, 2016

PT2385 had no effect on blood pressure at 5x the maximal efficacious exposure
PT2385 had no effect on heart rate or any other ECG parameter
PT2385 has a favorable preclinical safety profile

CRO: CorDynamics

Effect of PT2385 and Sunitinib on Blood Pressure

VEGFR TKIs and VEGFA mAb are associated with hypertension in patients The effect of sunitinib on blood pressure and heart rate are recapitulated in rats

25 50 75 100 125 75 100 125 150 Time (hours) Mean Arterial Pressure (mm Hg) Sunitinib 40 mg/kg p.o., q.d. (n=3) Vehicle p.o., b.i.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) telemeterized SD rats 14 April 8, 2016 15

PT2385 – 101

Objectives & Design

Primary Objective:

To identify the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose
f PT2385 tablets in patients with advanced clear cell renal cell carcinoma (ccRCC)

Secondary Objectives:

To evaluate the safety profile of PT2385
To determine the pharmacokinetic (PK) profile of PT2385
To assess the pharmacodynamic (PD) effects of treatment with PT2385
To assess the anti‐tumor activity of PT2385

Design:

3+3 Design
Dose limiting toxicity (DLT) observation period 3 weeks
Expansion to 25 additional patients at MTD or RP2D

April 8, 2016

Erythropoietin expression is regulated by HIF‐2α

In patients, target engagement, as measured by diminution of erythropoietin expression,

is exposure related, rapid and pronounced

PT2385‐101: Pharmacodynamic Response in Patients

0.0 0.5 1 8

100
80
60
40
20

20 40

% Change in Erythropoietin (Average +/- SD)

dose level 1 (n=3) dose level 2 (n=3) dose level 3 (n=4) dose level 4 (n=7) dose level 5 (n=6) dose level 6 (n=3)

Day

Average %Change in Erythropoietin

16

SLIDE 5

5/4/2016 5

April 8, 2016

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

Currently in Phase 1 clinical trial in patients with advanced or metastatic ccRCC
Dose escalation stage complete: recommended Phase 2 dose determined
Expansion arm recruitment complete

PT2385: Novel Therapy for ccRCC

17 April 8, 2016

Acknowledgments Peloton Therapeutics, Inc.

Mick Bakes Zhaodan Cao Tzuling Cheng Robert Czerwinski Darryl Dixon Xinlin Du Barry Goggin Jonas Grina Megan Halfmann Michael Haller Guangzhou Han Heli Huang John Josey Rick Kelley Steve Madden Melissa Maddie Sarah Olive James Rizzi Stephen Schlachter Pete Stengel Huiling Tan Bin Wang Keshi Wang Paul Wehn Tai Wong Shanhai Xie Rui Xu Hanbiao Yang Naseem Zojwalla

Dana‐Farber

Tony Choueiri William Kaelin

Cedars‐Sinai

Robert Figlin

Tenn. Oncology

Jeff Infante

Cleveland Clinic

Brian Rini

U. of Colorado

Elaine Lam

Patients and their families

www.clinicaltrials.gov: NCT02293980

UT Southwestern

Kevin Courtney James Brugarolas

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