Post on 18-Sep-2020
Lessons learned from the metastatic castration-resistant prostate cancer phase 1 trial of EPI-506, a �rst-generation androgen receptor N-terminal domain inhibitor Ronan Le Moigne1, Han-Jie Zhou1, Jon K. Obst2, C. Adriana Banuelos2, Kunzhong Jian3, David Williams3, Peter Virsik1, Raymond J. Andersen3, Marianne D. Sadar2, Frank Perabo1, Kim N. Chi4
1ESSA Pharmaceuticals Inc., Houston, TX and South San Francisco, CA, USA, 2Department of Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada, 3Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada, 4Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, V5Z 1L3, Canada
INTRODUCTIONAniten compounds bind to the N-terminal domain (NTD) of the an-drogen receptor (AR) to inhibit its transcriptional activity. EPI-506, a triacetate prodrug of EPI-002 (ralaniten), was the �rst AR NTD inhibi-tor tested in a First-in-Human phase 1 study in patients with meta-static castration-resistant prostate cancer (mCRPC) failing enzalut-amide and/or abiraterone (NCT02606123). The drug was well-toler-ated but required high doses to achieve meaningful exposures. At doses >1280 mg, EPI-506 treatment resulted in PSA declines. Howev-er, these did not achieve 50% and were of short duration, re�ecting the low potency and short half-life of EPI-002. To understand EPI-506’s metabolic vulnerabilities, patient plasma samples were an-alyzed to identify metabolites.
CONCLUSION• EPI-506 was tested in a phase 1 trial and showed PSA declines, but all declines were less than 50%• The drug was well-tolerated, but exposure was insu�cient due to signi�cant metabolism• EPI-002 and EPI-506 exhibited extensive metabolism in both human hepatocytes and clinical samples, but demonstrated dif-ferent metabolic pathways in vitro vs. in patients• Oxidation was the major metabolic pathway seen in the phase 1 clinical samples while O-glucuronidation was the major metabolic pathway seen in in vitro hepatocytes• Patient plasma samples identi�ed 19 metabolites, including the highly abundant oxidation metabolite M19, which was inactive in an AR-dependent reporter assay• More potent and stable molecules have been synthesized to ad-dress EPI-506/002’s metabolic and potency limitations. These next-generation Anitens are currently being prepared for IND �ling (see Abstract 220, poster board J21)
Results: The major metabolic pathway in human hepatocytes is via direct O-glucuronidation. Direct oxidation is also ob-served with the loss of chlorine followed by cysteine conjugation (exempli�ed by M4), but is much less common. The major metabolic pathway in human plasma samples is via oxidation (exempli�ed by M19, M18, etc). Direct O-glucuronidation is also observed (exempli�ed by M15, M12, etc.) but is less common.
14625
Time2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00
%
0
100
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00
%
0
100EPI002_RHP 1: TOF MS ES-
Sum 0.0200Da3.74e6
12.85
11.085.67 7.99
14.70
13.44 17.2915.44
EPI002_HHP 1: TOF MS ES- Sum 0.0200Da
3.82e612.84
7.18
5.92
7.96
14.68
17.29
14540
Time2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00
%
0
100EPI_002_QD_AUC 1: TOF MS ES-
Sum 0.0200Da1.60e6
17.33
12.75
5.49
4.849.88
10.84
14.70
13.46
15.43
O OOH
OH
HO
HOM3m/z 375
O OOH
OH
HO
HO OM6M/Z 389
HO OOH
Cl
M11m/z 495
O OO
Cl
HO
HO
Gluc
+Gluc
M13m/z 745
O OOH
Cl
HO
HO
+Gluc
O
M16m/z 583
O OOH
Cl
HO
HO O
M18m/z 407
O OOH
ClO
HO M19m/z 377
O OOH
OHO
HO M8m/z 359
O OOR
Cl
RO
ROR=H, EPI-002, m/z 393R=Ac, EPI-506, m/z 521
+Gluc
O OHHO
HO
+Gluc
M2m/z 477
O OO
Cl
HO
HO
M15m/z 569
Gluc
0
25
50
75
100
125
Concentration of compound [µM]
1 10 1000.1
EPI-002: IC50 ≈ 12 µM
M18: IC50 > 35µMM19: IC50 > 35µM
PSA-
luci
fera
se a
ctiv
ity ±
SEM
(% a
ndro
gen-
indu
ced)
-50
-25
0
25
5075
100
Max
% D
eclin
e in
PSA
1800
mg
(BID
)16
0 m
g32
0 m
g
640
mg
1800
mg
(BID
)36
00 m
g24
00 m
g12
80 m
g64
0 m
g80
mg
1280
mg
80 m
g36
00 m
g80
mg
2400
mg
320
mg
3600
mg
320
mg
640
mg
640
mg
160
mg
640
mg
160
mg
1280
mg
2400
mg
640
mg
640
mg
2400
mg
1280
mg
3600
mg
1280
mg
1800
mg
(BID
)
Patients receiving < 1280 mgPatients receiving > 1280 mg
320
mg
0 6 12 18 241
10
100
1000
10000
100000
EPI-002 PK - day 8
Time (hr)
EPI-0
02 [p
lasm
a] in
ng/
mL
80 mg160 mg320 mg640 mg1280 mg2400 mg3600 mg
EPI-002 cell IC50
1800 mg bid1800 mg bid simulated
EPI-002 (active drug)
EPI-506 (tri-acetate prodrug)
OO
(R)
HO(S)
Cl
OHHO
EPI-002
Figure 2: EPI-506/002 clinical activity and day 8 PK(A) Maximal PSA change at any time from start of multi-dose period. PSA declines (ranging from 8-37%) have been observed, especially in higher dose cohorts (≥ 1,280 mg). (B) Mean steady-state EPI-002 plasma concen-tration-vs-time pro�les across EPI-506 dose cohorts. EPI-002 plasma pro�les from day 8 multiple-dose samples indicate that EPI-002 plasma drug levels above cellular IC50 were not reached for long-periods. The EPI-506 prodrug was not detected in plasma at any measured time point across dose groups. (C) EPI-002 steady-state plasma pharmacokinetics following 8 days of EPI-506 administration (mean ± SD).
N-Terminal Domain(NTD)
DNA Binding Domain(DBD)
Ligand Binding Domain (LBD)
A
B Figure 1: EPI-506/002 is a �rst in class NTD inhibitor of the androgen receptor(A) Structure of the androgen receptor (AR) and mechanisms of inhibitions. The AR is organized in 3 distinct domains: the LBD, involved in binding with androgens, the DBD, and the NTD, which orchestrate the transactivation of the receptor. Inhibiting the NTD with Anitens allows the inactivation of the AR dow-stream of the LBD, and is an e�ective strategy to counteract the resistance mechanism involving the LBD (mutations, splice vari-ants). (B) EPI-506, a rapidly cleaved triacetate prodrug of EPI-002, was a �rst-in-class oral small molecule from the Aniten family of compounds.
A
C
B
EPI-506/002 showed minor PSA declines in patients with mCRPC, due to insu�cent exposure
A
C
B
Below Quanti�cation Limit (<5.00 ng/mL)ª n=3 for t1/2b n=6 for t1/2c n=4 for t1/2 and Vz/F
EPI-002 is highly metabolized via oxidation and glucuronida-tion in patient samples, suggesting a �rst pass e�ect
Figure 4: EPI-002 metabolites are inactive in LNCaP PSA-Luciferase cell line(A) A dose-dependent decrease in AR pathway activity is demonstrated by incubating LNCaP cells transiently-expressing a PSA-driven luciferase construct with di�erent Aniten compounds, in the presence of androgens (R1881).
EPI-002 metabolites are inactive on the AR path-way
AndrogenAndrogen
DeprivationCYP17
inhibitors
Antiandrogens
Reduce levelof androgen
Inhibit synthesis of androgen
Block androgen binding to LBD
Current Hormonal Therapies
Resistance to current hormonal therapy occurs predominantly in the LBD and can cause the AR to remain active
�
M2M2a
M4
M5a
M6 M8
M11M12
M12a
M15
M15aM17
EPI-002
M18M19
M2
M1
M4/M5
M3
M6
M8
M10/M11
M13
M15
M17
EPI-002
M18
M19
M7
M9 M12M14 M16
Figure 3: EPI-002 metabolite identi�ca-tionExtracted ion chromatograms from metabo-lite pro�ling of EPI-002 incubated in human hepatocytes incubation (A) and human plasma samples (B). Samples were analyzed using UPLC/MS method. (A) Samples of EPI-002 were incubated in human hepato-cytes for 4 hours. (B) Three plasma samples from patients (one 80 and two 3,600 mg doses), were pooled across timepoints and metabolites were analyzed. (C) Proposed major metabolic scheme of main metabo-lites of EPI-002.
A portion of the data presented in the poster was funded by US National Cancer In-stitute (R01 CA105304) awarded to Marianne Sadar.
PK parameter
Cohort 1EPI-506
80 mg qd
Cohort 2EPI-506
160 mg qd
Cohort 3EPI-506
320 mg qd
Cohort 4EPI-506
640 mg qd
Cohort 5EPI-506
1280 mg qd
Cohort 6EPI-506
2400 mg qd
Cohort 7EPI-506
1800 mg bid
Cohort 8EPI-506
3600 mg qdn 3 4 4a 7b 7c 4 3 2
Cmax
(ng/mL)26.3
(9.31)134
(95.2)345
(437)768
(391)1,528(806)
2,888(1,257)
3,430(118)
8,397(1,396)
tmax
(h)1.00
(0.98-4.00)0.72
(0.52-1.00)0.99
(0.50-1.97)1.93
(0.50-4.00)1.92
(1.00-4.05)1.98
(1.90-4.08)2.00
(1.95-2.00)2.5
(1.00-4.00)
AUCtau
(ng.h/mL)94.3
(8.65)257
(83.7)680
(692)2,439(678)
5,858(1,602)
13,545(5,331)
14,443(2,429)
42,988(24,841)
t1/2
(h)- -
1.6(0.4)
3.2(1.8)
5.4(1.2) - - -
Abstract Number: 257Contact info:rlemoigne@essapharma.com