1
http://www.utsouthwestern.edu/kidneycancer
COI: Patent HIF-2 biomarkerResearch funding – Peloton Therapeutics
Scheuermann et al. PNAS 2009
B
A
B
A
HRE (DNA)
HIF-2 HIF-1
HRE (DNA)
HIF-1HIF-2
Scheuermann et al. Nat Chem Biol 2013
High-Throughput Screen
HIF2-I
Development of a HIF-2 inhibitor (HIF2-I)
PT2399
Validating HIF-2 as a target for ccRCC
Pavia-Jimenez et al., Nat Protoc 2014
>100 lines
2
Validating HIF-2 as a target
Human tumors in mice - do they reproduce: Histological appearance? Gene expression? Mutations? DNA copy number alterations? Treatment responsiveness?
Sivanand et al., Sci Transl Med 2012Adapted from Sivanand et al., Sci Transl Med 2012
Unsupervised hierarchical clustering of gene expression shows similarities between tumors and corresponding tumorgrafts
HIF2-I (PT2399) is active against human ccRCC transplants in mice
Days
Tum
or v
olum
e (m
m3 )
Vehicle
Sunitinib
HIF2-I
HIF2-I is active in 50% of ccRCC
Inte
rmed
.Se
nsiti
veR
esis
tant
VehicleSunitinibHIF2-I
267 mice from 22 independently derived TG lines (18 ccRCC)
Chen et al., Nature 2016
HIF2-I (PT2399) has greater activity than sunitinib and is better tolerated
Chen et al., Nature 2016
3
HIF2-I (PT2399) inhibits proliferation & angiogenesis in sensitive ccRCC
HIF2-Iveh
XP37
3XP
144
CD
31H
&E
XP37
3Ki67
veh HIF2-I
XP16
4XP
490
XP16
9XP
373
vehicle HIF2‐I
V4237
V5239 V5229 P5231 P5240
V4236 V4241V4234
V3290 V3294 V3287 V3281
V3212 V3224 V3210 V3214
Chen et al., Nature 2016
HIF2-I (PT2399) suppresses VEGF only in the tumor
Circulating Human VEGF (tumor) Circulating Mouse VEGF (host)
Chen et al., Nature 2016
HIF2-I (PT2399) dissociates HIF-2 in both sensitive & resistant tumors
RES
ISTA
NT
SEN
SITI
VE
Chen et al., Nature 2016
HIF2-I (PT2399) is a highly specific inhibitor
Veh HIF2-I Veh HIF2-I
Sensitive Resistant
VehicleHIF2-ISunitinib
Up 195 0
Down 297 0
Total 492 0
Differential Gene Expression
Sensitive ResistantVeh v HIF2-I Veh v HIF2-I
Rel
ativ
em
RN
Aex
pres
sion
Rel
ativ
em
RN
Aex
pres
sion
CCND1 TGFA
hVEGF SERPINE1 IGFBP3
SLC2A1
Chen et al., Nature 2016
4
Higher HIF-2in sensitive tumors
HIF-2α HIF-1αHIF-2αHIF-1α
XP46
9XP
374
XP16
4
XP49
0XP
530
XP46
2HIF2-
Perc
enta
ge p
ositi
ve c
ells
Chen et al., Nature 2016
Identification of biomarkers of HIF-2-dependency
RNAseq
Chen et al., Nature 2016
Acquired resistance?P3283V3286
Forw
ard
Rev
erse
G323E(HIF-2)
V1849 P5123
Forw
ard
Rev
erse
F446L(HIF-1)
HIF-1 HIF-2
0500
100015002000250030003500400045005000
‐20 0 20 40 60 80 100 120 140 160 180 200
Tum
or V
olum
e (m
m3 )
XP164
3283
3288
3296
3295
3299
3286 Veh
Sunitinib
HIF2-I
Input
IP HIF-1
V3290
V3294
V3298
P3283
P3288
P3297
V3290
V3294
V3298
P3283
P3297
Tubulin
post-resistance
HIF‐2
HIF‐1
P3288
pre-resistance
vehicle HIF2-I
HIF-2and HIF-1mutants preserve HIF complexes despite HIF2-I (PT2399)
FLAG-HIF-1
Input IP FLAG
Vehicle Vehicle PT2399PT2399
+-+
+-
--
--+
+ +
++
- -
Tubulin
HA
FLAG
FLAG-HIF-1(F466L)HA-HIF-2
HA-HIF-2 (G323E)
+-+
+-
--
--+
+ +
++
- - +-+
+-
--
--+
+ +
++
- - +-+
+-
--
--+
+ +
++
- -
Chen et al., Nature 2016
5
Baseline Characteristics
Pharmacokinetics & Pharmacodynamics
• Targeted Cmin of 280 ng/mL exceeded at ≥ 400 mg b.i.d.
• Increased exposure up to 800 mg b.i.d. (no further increase beyond 800 mg b.i.d.)
Toxicity
6
Duration of Treatment Prolonged stable disease in heavily pretreated patient (7 prior lines)
Kidney
-12 37 100 225 350 Days
Pelvis
Liver
PT2385
Chen et al., Nature 2016
Higher exposure correlates with anti-tumor activity
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
7
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
Second generation inhibitor, PT2977 –greater potency in preclinical models
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
PT2977 Phase I
Slide 13
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
PT2977 Phase I Pharmacokinetics
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
PT2977 - Pharmacodynamics
PT2385
8
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
Response Duration
Presented By Kyriakos Papadopoulos at 2018 ASCO Annual Meeting
Responses in ccRCC
PT2977 – VHL pts RCC
Inclusion Criteria:• von Hippel Lindau disease with a germline VHL
mut.• At least 1 measurable solid RCC tumor
(diagnosis of RCC can be radiologic). • VHL disease-associated tumors in other organ
systems.Exclusion Criteria:• Prior systemic anti-cancer therapy (includes anti-
VEGF therapy and investigational agents).• Immediate need for surgical intervention for tumor
treatment.• Metastatic disease.
University of Colorado Cancer Center Not yet recruitingAurora, Colorado, United States, 80045Yale Cancer Center Not yet recruitingNew Haven, Connecticut, United States, 06519National Institutes of Health Clinical Center RecruitingBethesda, Maryland, United States, 20892Massachusetts General Hospital RecruitingBoston, Massachusetts, United States, 02114University of Michigan RecruitingAnn Arbor, Michigan, United States, 48109Memorial Sloan Kettering Cancer Center Not yet recruitingNew York, New York, United States, 10065Wake Forest Not yet recruitingWinston‐Salem, North Carolina, United States, 27103University of Pennsylvania Medical Center Not yet recruitingPhiladelphia, Pennsylvania, United States, 19104University of Pittsburgh Medical Center Not yet recruitingPittsburgh, Pennsylvania, United States, 15232Vanderbilt Medical Center RecruitingNashville, Tennessee, United States, 37232UT Southwestern Medical Center Not yet recruitingDallas, Texas, United States, 75239MD Anderson Cancer Center RecruitingHouston, Texas, United States, 77030Huntsman Cancer Institute RecruitingSalt Lake City, Utah, United States, 84112Aarhus University Hospital Not yet recruitingAarhus, DenmarkHospital Georges Pompidou Not yet recruitingParis, FranceUniversity Medical Center Utrecht Not yet recruitingUtrecht, NetherlandsCambridge University Hospitals Not yet recruitingCambridge, United KingdomGuy's and St. Thomas' Hospitals Not yet recruitingLondon, United KingdomChristie NHS Foundation Trust Not yet recruitingManchester, United Kingdom
June 6, 2018
Photo, courtesy of Brian Coats
Conclusions HIF-2 is a valid target in ccRCC. Inhibition of the HIF-2 transcription factor abrogates tumor growth in >50% of human
ccRCC tumors implanted in mice, including tumors resistant to sunitinib. HIF2-I effectively (and specifically) dissociates HIF-2 from HIF-1 in human ccRCC
implanted in mice. HIF-2 inhibition results in the downregulation of HIF-2 target genes and decreased
circulating levels of tumor-produced VEGF. HIF-2 inhibitors are more effective and better tolerated than sunitinib in TG models. Primary resistance occurs despite dissociation of the HIF-2 complex in tumors. Sensitive and resistant tumors can be distinguished by HIF-2 levels and gene
expression. Resistance develops in sensitive tumors due to binding site and “second-site
suppressor mutations.” A Phase I clinical trial of PT2385 showed that HIF-2 inhibitors are safe and may benefit
a subset of patients, but resistance develops. Second generation inhibitors (PT2799) have greater potency. HIF-2 inhibitors are well tolerated and associated with anemia. Close monitoring for
hypoxia is needed (which can be severe).
9
Brugarolas LabAlana Christie
Roy EliasAdrien Jump
Eric MaRenee McKay
Tiffani McKenzieOreoluwa OnaboluGopinath Prakasam
Nirmish Singla Christina Stevens Vanina Toffessi Layton Woolford
Juan YangHui Ye
Xiaolin Zhu
Wenfang ChenShannon Cohn
Yifeng GuHaley Hill
Allison JoyceBlanka Kucejova
Andrea Pavia-JimenezSamuel Peña-LlopisSharanya Sivanand
Tram Anh TranSilvia Vega-Rubin de Celis
Shanshan WangNick Wolff
Toshinari YamasakiAnum Yousuf
Avery Anderson Megan Dougherty
Debbie HarveyMarieshia HicksChey Reynolds
FundingVirginia Murchison Linthicum Endowment
Cancer Prevention and Research Institute of TexasNIH, National Cancer Institute
Peloton Therapeutics, Inc
Kidney Cancer ProgramUrology
Aditya Bagrodia Jeff CadedduJeff GahanYair Lotan
Vitaly MargulisGanesh Raj
Arthur Sagalowsky
Medical OncologyYull Arriaga
Alex BowmanKevin CourtneyEugene FrenkelHans Hammers
Radiation OncologyNeil Desai
Michael FolkertRaquibul Hannan
Robert TimmermanZabi Wardak
PathologyPayal Kapur
Dinesh Rakheja
RadiologyAlberto Diaz de Leon
Ananth Madhuranthakam Ivan PedrosaXiankai Sun
Lori Watumull
Illumina Inc. Mark Ross
David Bentley
Mayo ClinicRichard W. Joseph
Daniel J. SerieJeanette Eckel-Passow
Thai HoJohn C. ChevilleAlexander Parker
GenentechAnwesha Dey
Steffen DurinckEric W. StawiskiZora ModrusanSekar Seshagiri
NCILaura Schmidt
Marston Linehan
Other CollaboratorsKevin Jones
Brian Rini
UTSW CollaboratorsLaura Banaszynski
Tom CarrollRalph DeBerardinis
Bob HammerLisa KinchSri Malladi
Josh MendellBruce Posner
Noelle WilliamsJin Ye
Yonghao Yu
Phase 1 Trial (PT2385)Kevin CourtneyJeffrey Infante
Elaine LamRobert Figlin
Brian RiniNaseem Zojwalla
Keshi WangEli WallaceJohn Josey
Toni Choueiri
BioinformaticsMin Kim
Satwik Rajaram Phillip Reeder
Tao WangJason Xie
Guanghua Xiao Yang XieHe Zhang
Clinical CoordinatorsJenny Chang
Dendra Von Merveldt