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HX4 as a PET Companion Diagnostic for Hypoxia-Targeted Drugs
Katrin Szardenings
NN
NO2
N NN
OH
18F
P
HN
ONH
ON
NO2N
Br
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Rx
Dx
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Introduction: Threshold Pharmaceuticals
• Building a broad therapeutic platform in cancer – Based upon selectively targeting tumor hypoxia
• A fundamental property of solid tumors as well as some hematologic cancers • A significant unmet medical need
– And including the HX4 hypoxia PET imaging agent acquired from Siemens in 2013
• Discovered and developing TH-302 – Industry’s most advanced hypoxia targeted anti-cancer compound in active
development • Partnered with Merck KGaA
• Pivotal studies underway in 2 indications – Phase 3 in soft tissue sarcoma – Phase 3 in pancreatic cancer
• Earlier stage studies underway in a variety of indications
3
Tumor Hypoxia Overview – Hypoxia is a feature of all solid
tumors – Hypoxic conditions are created by
rapid cell proliferation and development of a disordered vascular network
– Hypoxic cells are resistant to traditional chemotherapy and radiation
– Tumor hypoxia is associated with a poor prognosis, aggressive phenotype, metastasis and relapse
150µm
Blood Vessels
Hypoxic region Necrosis
Minchinton, AI & Tannock , IF. Nat Rev Cancer. 2006; 6:583-92.
Blood vessels (CD31)
Hypoxic regions (Pimonidazole)
HCT-116 CRC model
Oxic region
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The More Hypoxic, the Worse the Prognosis Three examples from many published studies
Reviewed in Vaupel, P. & Mayer, A. Cancer Metastases Rev 26 225, 2007
pO 2 ? 10 mmHg (n = 41)
pO 2 ? 10 mmHg
Head and Neck Cancer (n = 63 pts)
Cervical Cancer (n = 89 pts)
Soft Tissue Sarcoma (n = 28 pts)
pO 2 < 10 mmHg pO 2 < 10 mmHg
(n = 48)
pO 2 ? 19 mmHg (n = 14)
pO 2 < 19 mmHg (n = 14)
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
Sur
viva
l (%
)
Sur
viva
l (%
)
Sur
viva
l (%
)
Time (months) 12 24 36 48 0 10 20 30 40 0 50 60 70 80
Time (months) Time (months) 12 24 36 48 0 60
Brizel , D.M. et al. Radiother . Oncol . 53 : 113 - 117, 1999
Hockel,M . et al. Cancer Res . 56 : 4509 - 4515, 1996
Nordsmark,M . et al. Brit. J. Cancer 84 : 1070 - 1075, 2001
pO 2 ? 10 mmHg (n = 41)
Head and Neck Cancer (n = 63 pts)
Cervical Cancer (n = 89 pts)
Soft Tissue Sarcoma (n = 28 pts)
(n = 14)
pO 2 < 19 mmHg (n = 14)
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
Sur
viva
l (%
)
Sur
viva
l (%
)
Sur
viva
l (%
)
Time (months) 12 24 36 48 0 10 20 30 40 0 50 60 70 80
Time (months) Time (months) 12 24 36 48 0 60
Brizel , D.M. et al. Radiother . Oncol . 53 : 113 - 117, 1999
Hockel,M . et al. Cancer Res . 56 : 4509 - 4515, 1996
Nordsmark,M . et al. Brit. J. Cancer 84 : 1070 - 1075, 2001
pO 2 < 10 mmHg (n = 48)
pO 2 > 10 mmHg _
pO 2 > 10 mmHg _ pO 2 > 19 mmHg _
(n = 19)
(n = 41)
pO 2 < 10 mmHg (n = 44)
5 Tumor Hypoxia and Poor Clinical Prognosis Treatment failure and metastatic progression
• Hypoxia is associated with treatment failure – Both radiotherapy and chemotherapy resistance
– Quiescent hypoxic cells resist anti-proliferative therapy
• Hypoxia yields a more aggressive, invasive, metastatic phenotype – Upregulates survival factors; inhibits apoptosis
– Stimulates production of enzymes mediating invasiveness
– Induces angiogenic signals
– Promotes genetic and epigenetic changes
– Promotes the epithelial to mesenchymal transition (EMT)
– Cancer stem cells (CSCs) can reside in the hypoxic compartments
Tumor hypoxia can also be the basis for selective targeting by HAPs (hypoxia-activated prodrugs)
5
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TH-302 Overview, the “cart”
• TH-302 is a small molecule prodrug that releases the potent DNA-alkylating agent, Br-IPM, via reductases under hypoxic conditions.
• 1,000 patients have been treated with TH-302 in clinical trials to date demonstrating antitumor activity: – across multiple tumor types (solid tumors and hematological malignancies) – as a single agent and in combination with chemotherapy/antiangiogenics – with a consistent safety profile and manageable toxicity
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Hypoxia Trigger
TH-302 (inert prodrug)
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Br-IPM (active cytotoxin)
Normoxia Hypoxia
Oxygen Gradient
5% O2 0.5% O2
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TH-302: Current Clinical Trials
Study Name Indication Combination Therapy Target # Pts. Phase 1 Phase
1/2 Phase 2 Phase 3
TH-CR-406 Soft Tissue Sarcoma doxorubicin 620
MAESTRO Pancreatic Cancer gemcitabine 660
TH-CR-413 Advanced Melanoma single agent 40
TH-CR-408 Multiple Myeloma bortezomib 60
IST-4003 Glioblastoma bevacizumab 28
TH-CR-410 RCC, GIST, PNET sunitinib 58
IST-4004 RCC, HCC sorafenib 48
TH-CR-407 Advanced Leukemias single agent 49
EMR200592-002 Pancreatic Cancer (Japan) gemcitabine 30
IST-4001 Various solid tumors pazopanib 50
EMR200592-006 Pancreatic Cancer Gemcitabine + nab paclitaxel 48
∗ ∗
∗ Registration trial being conducted under a Special Protocol Agreement (SPA) with the FDA Antiangiogenic agents Threshold-sponsored trial
Merck KGaA-sponsored trial Investigator-sponsored trial Planning: Ph 2 NSCLC 2nd line + pemetrexed, 440 Pts.
8
TH-302, pimonidazole, and [18F]-HX4 … • Have the same ‘trigger’ for hypoxia: 2-nitroimidazole • Require the same reductases for one-electron reduction • Have similar oxygen concentration dependence for activation HX4 and TH-302 will “see” the same hypoxic areas as pimonidazole
does
Introduction: Dx [18F]-HX4, the horse
[18F]-HX4 autoradiography
Pimonidazole stain
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H460 Tumor 786-O Tumor
High HX4 signal Low HX4 signal
Highly Hypoxic Tumor Low hypoxia Tumor
High Pimonidazole
signal
Low Pimonidazole
signal
Siemens Collaboration: [18F]HX4 in Xenograft Models [18F]HX4 signal correlates with pimonidazole staining
10
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Day 0 Day 4
T/M
(Upt
ake
of H
X4) *
(n=17) (n=17)
[18F]-HX4 as a ‘Response Biomarker’: Reduced [18F]HX4 signal after TH-302 in H460 xenograft model
0.00.51.01.52.02.53.03.54.04.5
Day 0 Day 4
T/M
(Upt
ake
of H
X4 )
2-12-22-32-42-52-62-72-82-92-102-112-123-33-73-93-143-18
TH-302 150mg/kg
[18F]-HX4 [18F]-HX4
72hr 24hr
11
Siemens: stand-alone hypoxia PET tracer prognostic imaging agent regulatory hurdles:
Proof of concept trials: does HX4 measure hypoxia? What is the gold standard of measuring hypoxia? (Eppendorf probe
is the only approved device, but no longer available; pimonidazole doesn’t count; areas of hypoxia are in-homogenous and biopsies therefore flawed..)
How would HX4 (or knowing about hypoxia) benefit the patient? How would clinical management change, since there is no hypoxia
specific drug?
Threshold: companion Dx to TH-302 predictive imaging agent TH-302 and HX4 have the same molecular target TH-302 provides treatment for patients selected with HX4
The future for HX4 has changed
12
Past HX4 Clinical Experience (Siemens, P. Lambin/Maastro)
Lung H&N Cervical CRC Thymus 40 29 6 11 2
US EU Asia Fox Chase Cancer Center (PA)
USC (CA) Holy Name (NJ) UC Irvine (CA)
Cedars Sinai Medical Center (CA) UMDNJ (NJ) U Iowa (IA)
Cleveland Clinic (OH) Lakenau Institute for Medical research(PA)
Eastern Regional Medical Center (PA) Boston Medical Center (MA)
The Angeles Clinic and Research Institute (CA)
Maastro (Netherlands) Fudan University (Shanghai, CN) Samsung (Korea)
Asan (Korea)
[18F]HX4 Imaged Patients
[18F]HX4 Clinical Sites
13
A total of 39 patients had two interpretable pre-treatment [F-18]HX4 PET/CT scans and were included in the reproducibility of [F-18]HX4 uptake: • 12 head/neck • 12 lung • 9 rectal • 6 cervical
First and second pre-treatment uptake parameters (SUVMax, SUVMean
and T/B ratio) were highly correlated and statistically significant (P<0.001).
Going forward: • There is a sufficient range of hypoxia in these types of cancers providing a
base for selecting a hypoxia threshold • Method to analyze hypoxia and selecting the appropriate cut-off is important
HX4 200 Study: A pilot, Phase 2, multi-center, open-label, non-randomized, study in patients with confirmed cancer (Siemens)
14
Results Summary for HX4-200 by cancer type
Head & Neck
1.00
1.50
2.00
2.50
3.00
3.50
4.00
0302 0303 0305 0306 0308 0309 0803 0804 0908 1001
T/B
max
/mea
n/pe
ak
Patient ID
1.00
1.50
2.00
2.50
3.00
3.50
4.00
0101 0102 0301 0304 0310 0506 0507 0601 0801 0902 0906 0907
T/B
max
/mea
n/pe
ak
Patient ID
1.00
1.50
2.00
2.50
3.00
3.50
4.00
0403 0405 0406 0501 0508 0903 0904 0905 1002
T/B
max
/mea
n/pe
ak
Patient ID
Cervical
1.00
1.50
2.00
2.50
3.00
3.50
4.00
0204 0307 0505 0509 1004
T/B
max
/mea
n/pe
ak
Patient ID
Lung
Rectal
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[18F]HX4 can measure hypoxia in lung cancer (Siemens)
Significant Hypoxia
Minimal/No Hypoxia
Low-Hypoxic Lung Cancer (Right lung mass)
Hypoxic Lung Cancer (Left lung mass)
16
[18F]HX4 can measure hypoxia in SCCHN (Siemens)
Significant Hypoxia
Minimal/No Hypoxia
Hypoxic H&N Cancer (Right Maxillary Mass)
Low-Hypoxic H&N Cancer (Palate mass)
17
Companion Dx Clinical research tool Stand-alone Dx
Label: “For use in identifying hypoxic tumors in patients being considered for treatment with TH-302”
Label: “For the identification of hypoxic tumors”
TH-302 HX4 PET
Therapy
HX4 PET HX4 PET
HX4 PET
Development options for HX4:
Elucidates presence of hypoxia in patients; Supports mechanism for TH-302 “For use in identifying hypoxic tumors in patients being considered for treatment with TH-302”
18
Clinical phase: proof of concept studies (generate data!) are now beginning
Can HX4 select patients that will respond better to TH-302
treatment? Make HX4 available as THE hypoxia imaging agent to
investigators (with or without TH-302) Increase awareness of hypoxia and learn more about HX4 Find possible new patient populations for TH-302
Need data to start discussions with the FDA with a clear vision of clinical utility & label
Decide on commercialization path or keep as clinical research tool
HX4 as a companion Dx: one step at the time
19
Lesson: Setting up HX4 production is costly! • IND research uses only needs few clinical and manufacturing sites to
help understand value • Currently setting up clinical sites which can participate in TH-302 clinical
development AND have PET manufacturing capabilities • Continue chemistry improvements for HX4 with commercial
manufacturer (PETNET?) to optimize commercial build-out only if needed
Manufacturing/supply chain
20 Current sites for HX4 clinical production: North America
• Toronto (CPDC) ready in March • NCM (New York): currently being set up • Philadelphia: PETNET ready • Los Angeles (Culver City): PETNET ready
21
Current sites for HX4 clinical production: Europe/UK
21
• Nottingham/UK: PETNET ready • Amsterdam/Netherlands, VU University Medical Center ready
22
What is the most clinically valuable imaging information: • Binary result (hypoxic, yes or no?)? • Quantitation (how much hypoxia, hypoxic fraction)? • When should the patient be scanned: baseline? After one cycle of
treatment (response biomarker)?
If an imaging outcome is rare (e.g. mostly positive/negative)
how is it valuable to TH-302?
Value claims and price driven by • Relative cost of HX4 to TH-302 • How HX4 intervention improves patient outcome
The value of HX4 imaging information
23
Preclinical studies with HX4 and TH-302 look very promising
Clinical experience with HX4 (no TH-302) indicates that HX4 is a superior hypoxia PET tracer
Proof of concept studies with TH-302 in the clinic (currently ongoing): does it work? Does patient selection by HX4 significantly improve TH-302 response rates? • HX4 predicts outcome for TH-302 • In what patient group?
Key milestones for HX4