SAGE-217: A 2nd Generation Neuroactive · PDF fileSAGE-217: A 2nd Generation Neuroactive...
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SAGE-217: A 2 nd Generation Neuroactive Steroid Albert J. Robichaud, James J. Doherty, Francesco G. Salituro, Gabriel Martinez-Botella, Ethan Hoffmann, Rebecca S. Hammond, Gabriel M. Belfort, Mike A. Ackley SAGE Therapeutics, Cambridge, MA • Seizure disorders that remain resistant to current therapies represent a significant unmet medical need • γ-Containing receptors are present predominantly at synaptic sites, whereas δ-containing receptors populate extra-synaptic sites • Benzodiazepines bind to the interface of the α and γ subunits and so do not modulate δ-containing receptors. In contrast neuroactive steroids (NASs) bind to the α subunit and so can potentiate a broader range of GABA A receptors • First generation NASs, e.g. ganaxolone and allopregnanolone, are limited with regard to the route of administration due to their DMPK and physical properties. • Second generation NASs, like SAGE-217, are designed to modulate GABA A receptors while achieving the right balance of physical properties and DMPK suitable for oral and i.v. dosing. • Here we describe the properties of our 2 nd generation NAS, SAGE-217 in comparison to 1 st generation NASs allopregnanolone and ganaxolone Overview • We have developed a second generation series of novel neuroactive steroid compounds with a range of pharmacologies and pharmacokinetic properties suitable for oral administration. • SAGE-217 is a potent and highly selective GABA A receptor PAM. It has a formulation and pharmacokinetic profile differentiated from 1 st Gen NAS; the compound is predicted to be suitable for either oral or parenteral dosing • SAGE-217 produces 1) dose-dependent anticonvulsant activity and 2) arrest of pharmaco-resistant SE in preclinical models • SAGE-217 is an NCE with patent applications filed for composition of matter, formulation and utilities claims Conclusions SAGE-217 is potent and efficacious at both synaptic and extrasynaptiuc GABAA receptors Superior selectivity vs 1 st generation NASs Key properties Comparison Acknowledgments: The authors would like to extend their thanks to Carla Maciag, Scott J. Grossman and Boyd L. Harrison, Shanghai Chempartners, and Wuxi Synaptic Extrasynaptic 5 -5 0 EEG (mV) SAGE-217 (5 mpk iv.) SAGE-217 Aborts SE (60 min post-onset) Diazepam Fails to Abort SE (60 min post-onset) Pilocarpine SE Onset 1 2 3 4 5 -1 0 1 2 Relative EEG Power (30-50 Hz) Vehicle 1 mg/kg 3 mg/kg 5 mg/kg SAGE-217 ** ** ** ** ** * DZ (10 mpk iv.) 5 -5 0 Time (h) 0 1 2 3 4 5 Time (h) 0 1 2 3 4 5 DZ Pilocarpine SE Onset 1 2 3 4 5 -1 0 1 2 Relative EEG Power (30-50 Hz) Vehicle 10 mg/kg EEG (mV) Vehicle SAGE-547 SAGE-217 Ganaxolone SE onset Dose SE onset Dose SE onset Dose SE onset Dose SE onset Dose SE onset Dose 5854±448 ng/ml 5657±2482 ng/ml SE onset Dose SE onset Dose 2088±132 ng/ml 1.0 10.0 100.0 1000.0 10000.0 0 2 4 6 8 10 12 14 [Conc], ng/mL Time (hr) Ganaxolone, 20 mg/kg PO SAGE-547, 20 mg/kg PO SAGE-217, 10 mg/kg PO PK parameters Unit Ganaxolone SAGE-547 SAGE-217 T max hr 1.00 0.500 0.500 C max ng/mL 60.1 13.0 1335 Terminal t 1/2 hr 3.65 NA 1.98 AUC last-plasma hr*ng/mL 111 9.16 4055 AUC INF-plasma hr*ng/mL 127 NA 4096 F % 4.31 0.563 62.4 SAGE-217 SAGE-547 Ganaxolone a1 EC 50 (nM)/Emax 652/641 149/343 440/397 a4 EC 50 (nM)/Emax 317/531 80/418 100/219 LogD/Aq Sol. (µM) 4.6/2 4.9/3.3 5.3/0.7 Microsomes M/R/D/H Clint (µl/min/mg) 77/44/9/6 415/992/38/16 251/85/31/12 B/P (mouse, rat) 1.5, 3.2 1.9, 1.8 2.5, 4.1 Mouse PO F% / t1/2 (h) 62/2.0 0.5/ND 4/3.6 Rat PO F% / t1/2 (h) 53/2.0 2.3/2.5 10/2.1 Dog PO F% / t1/2 (h) 68/12.9 ND ND PTZ at MED Tonic+%Death (mpk/nM) (dose/ plasma/brain) 0.3 (IP)/186/204 10 (IP)/453/ND 10 (IP)/1327/ND Li-Pilo SE model (50% seizure termination 60 mins post onset) mpk/nM 3-4 mpk iv 10 mpk iv No effect (>12 mpk iv) Nuclear Hormone Receptor Affinity All >10 UM AR, PPAR, PROG, ERb FXR, AR, RORg, PROG(ant) Ahr AR CAR3 ERa ERß FXR GR LXRa LXRß PPARa PPARd PPARg PR PXR RARa RARb RARg RXRa TRa TRß 0 20 40 60 80 100 fNHR agonist Fold Activation 400nM 2uM 10uM Ahr AR CAR3 ERa ERß FXR GR LXRa LXRß PPARa PPARd PPARg PR PXR RARa RARb RARg RXRa TRa TRß 0 20 40 60 80 100 %inhibition 400nM 2uM 10uM Ahr AR CAR3 ERa ERß FXR GR LXRa LXRß PPARa PPARd PPARg PR PXR RARa RARb RARg RXRa TRa TRß 0 20 40 60 80 100 Fold Activation 400nM 2uM 10uM Ahr AR CAR3 ERa ERß FXR GR LXRa LXRß PPARa PPARd PPARg PR PXR RARa RARb RARg RXRa TRa TRß 0 20 40 60 80 100 %inhibition 400nM 2uM 10uM Ahr AR CAR3 ERa ERß FXR GR LXRa LXRß PPARa PPARd PPARg PR PXR RARa RARb RARg RXRa TRa TRß 0 20 40 60 80 100 Fold Activation 400nM 2uM 10uM Ahr AR CAR3 ERa ERß FXR GR LXRa LXRß PPARa PPARd PPARg PR PXR RARa RARb RARg RXRa TRa TRß 0 20 40 60 80 100 %inhibition 400nM 2uM 10uM fNHR agonist SAGE-217 fNHR antagonist SAGE-217 fNHR agonist SAGE-547 fNHR agonist GANAXOLONE fNHR antagonist SAGE-547 fNHR antagonist GANAXOLONE SAGE-217: Dose dependent termination of pharmacoresistant SE SAGE-217 SAGE-547 Ganaxolone EC 50 (nM) SAGE-217 188 SAGE-547 452 Ganaxolone 1270 Active in PTZ model with optimal sedation profile http://www.sagerx.com/posters/poster5.pdf α1 Synaptic α4 Extrasynaptic EC 50 (nM) Emax (%) EC 50 (nM) Emax (%) SAGE-217 652 641 317 531 SAGE-547 149 342 80 418 Ganaxolone 440 397 100 219
Transcript of SAGE-217: A 2nd Generation Neuroactive · PDF fileSAGE-217: A 2nd Generation Neuroactive...
SAGE-217: A 2nd Generation Neuroactive Steroid Albert J. Robichaud, James J. Doherty, Francesco G. Salituro, Gabriel Martinez-Botella, Ethan Hoffmann,
Rebecca S. Hammond, Gabriel M. Belfort, Mike A. Ackley SAGE Therapeutics, Cambridge, MA
• Seizure disorders that remain resistant to current therapies represent a significant unmet medical need
• γ-Containing receptors are present predominantly at synaptic sites, whereas δ-containing receptors populate extra-synaptic sites
• Benzodiazepines bind to the interface of the α and γ subunits and so do not modulate δ-containing receptors. In contrast neuroactive steroids (NASs) bind to the α subunit and so can potentiate a broader range of GABAA receptors
• First generation NASs, e.g. ganaxolone and allopregnanolone, are limited with regard to the route of administration due to their DMPK and physical properties.
• Second generation NASs, like SAGE-217, are designed to modulate GABAA receptors while achieving the right balance of physical properties and DMPK suitable for oral and i.v. dosing.
• Here we describe the properties of our 2nd generation NAS, SAGE-217 in comparison to 1st generation NASs allopregnanolone and ganaxolone
Overview
• We have developed a second generation series of novel neuroactive steroid compounds with a range of pharmacologies and pharmacokinetic properties suitable for oral administration.
• SAGE-217 is a potent and highly selective GABAA receptor PAM. It has a formulation and pharmacokinetic profile differentiated from 1st Gen NAS; the compound is predicted to be suitable for either oral or parenteral dosing
• SAGE-217 produces 1) dose-dependent anticonvulsant activity and 2) arrest of pharmaco-resistant SE in preclinical models
• SAGE-217 is an NCE with patent applications filed for composition of matter, formulation and utilities claims
Conclusions
SAGE-217 is potent and efficacious at both synaptic and extrasynaptiuc GABAA receptors
Superior selectivity vs 1st generation NASs
Key properties Comparison
Acknowledgments: The authors would like to extend their thanks to Carla Maciag, Scott J. Grossman and Boyd L. Harrison, Shanghai Chempartners, and Wuxi
Synaptic Extrasynaptic
5
-5
0 EE
G (m
V)
SAGE-217 (5 mpk iv.)
SAGE-217 Aborts SE (60 min post-onset) Diazepam Fails to Abort SE (60 min post-onset)
Piloca
rpine
SE Onse
t 1 2 3 4 5
-1
0
1
2
Rela
tive
EEG
Pow
er (3
0-50
Hz)
Vehicle 1 mg/kg 3 mg/kg 5 mg/kg
SAGE-217
**
** **
**
**
*
DZ (10 mpk iv.)
5
-5
0
Time (h)
0 1 2 3 4 5
Time (h)
0 1 2 3 4 5
DZ
Piloca
rpine
SE Onse
t 1 2 3 4 5
-1
0
1
2
Rela
tive
EEG
Pow
er (3
0-50
Hz)
Vehicle 10 mg/kg
EEG
(mV)
Vehicle SAGE-547 SAGE-217 Ganaxolone
SE onset
Dose SE onset Dose SE onset Dose
SE onset Dose
SE onset Dose
SE onset Dose
5854±448 ng/ml 5657±2482 ng/ml
SE onset
Dose SE onset Dose
2088±132 ng/ml
1.0
10.0
100.0
1000.0
10000.0
0 2 4 6 8 10 12 14
[Con
c], n
g/m
L
Time (hr)
Ganaxolone, 20 mg/kg PO
SAGE-547, 20 mg/kg PO
SAGE-217, 10 mg/kg PO
PK parameters Unit Ganaxolone SAGE-547 SAGE-217
Tmax hr 1.00 0.500 0.500
Cmax ng/mL 60.1 13.0 1335
Terminal t1/2 hr 3.65 NA 1.98
AUClast-plasma hr*ng/mL 111 9.16 4055
AUCINF-plasma hr*ng/mL 127 NA 4096
F % 4.31 0.563 62.4
SAGE-217 SAGE-547 Ganaxolone
a1 EC50 (nM)/Emax 652/641 149/343 440/397
a4 EC50 (nM)/Emax 317/531 80/418 100/219
LogD/Aq Sol. (µM) 4.6/2 4.9/3.3 5.3/0.7
Microsomes M/R/D/H Clint (µl/min/mg) 77/44/9/6 415/992/38/16 251/85/31/12
B/P (mouse, rat) 1.5, 3.2 1.9, 1.8 2.5, 4.1
Mouse PO F% / t1/2 (h) 62/2.0 0.5/ND 4/3.6
Rat PO F% / t1/2 (h) 53/2.0 2.3/2.5 10/2.1
Dog PO F% / t1/2 (h) 68/12.9 ND ND
PTZ at MED Tonic+%Death (mpk/nM) (dose/ plasma/brain) 0.3 (IP)/186/204 10 (IP)/453/ND 10 (IP)/1327/ND
Li-Pilo SE model (50% seizure termination 60 mins post onset)
mpk/nM 3-4 mpk iv 10 mpk iv No effect (>12 mpk iv)
Nuclear Hormone Receptor Affinity All >10 UM AR, PPAR, PROG, ERb FXR, AR, RORg, PROG(ant)
A h rA RC A R 3
E R aE R ß
F X R G RL X R a
L X R ß
P P A R a
P P A R d
P P A R g P RP X R
R A R aR A R b
R A R gR X R a
T R aT R ß
0
2 0
4 0
6 0
8 0
1 0 0
fN H R a g o n is tS A G E -2 1 7
Fold
Act
ivatio
n
4 0 0 nM
2uM
1 0uM
A h rA RC A R 3
E R aE R ß
F X R G RL X R a
L X R ß
P P A R a
P P A R d
P P A R g P RP X R
R A R aR A R b
R A R gR X R a
T R aT R ß
0
2 0
4 0
6 0
8 0
1 0 0
fN H R a n ta g o n is tS A G E -2 1 7
%in
hibi
tion
4 0 0 nM
2uM
1 0uM
A h rA RC A R 3
E R aE R ß
F X RG RL X R a
L X R ßP P A R a
P P A R d
P P A R g P RP X R
R A R aR A R b
R A R gR X R a
T R aT R ß
0
2 0
4 0
6 0
8 0
1 0 0
fN H R a g o n is tG a n a x o lo n e
Fold
Activ
ation
4 0 0 nM
2uM
1 0uM
A h r A RC A R 3
E R aE R ß
F X R G RL X R a
L X R ßP P A R a
P P A R d
P P A R g P RP X R
R A R aR A R b
R A R gR X R a
T R aT R ß
0
2 0
4 0
6 0
8 0
1 0 0
fN H R a n ta g o n is tG a n a x o lo n e
%inh
ibitio
n
4 0 0 nM
2uM
1 0uM
A h rA RC A R 3
E R aE R ß
F X R G RL X R a
L X R ß
P P A R a
P P A R d
P P A R g P RP X R
R A R aR A R b
R A R gR X R a
T R aT R ß
0
2 0
4 0
6 0
8 0
1 0 0
fN H R a g o n is tS A G E -5 4 7
Fold
Activ
ation
4 0 0 nM
2uM
1 0uM
A h rA RC A R 3
E R aE R ß
F X R G RL X R a
L X R ß
P P A R a
P P A R d
P P A R g P RP X R
R A R aR A R b
R A R gR X R a
T R aT R ß
0
2 0
4 0
6 0
8 0
1 0 0
fN H R a n ta g o n is tS A G E -5 4 7
%inh
ibitio
n
4 0 0 nM
2uM
1 0uM
fNHR agonist SAGE-217
fNHR antagonist SAGE-217
fNHR agonist SAGE-547
fNHR agonist GANAXOLONE
fNHR antagonist SAGE-547
fNHR antagonist GANAXOLONE
SAGE-217: Dose dependent termination of pharmacoresistant SE
SAGE-217 SAGE-547 Ganaxolone
EC50 (nM)
SAGE-217 188
SAGE-547 452
Ganaxolone 1270
Active in PTZ model with optimal sedation profile
http://www.sagerx.com/posters/poster5.pdf
α1 Synaptic
α4 Extrasynaptic
EC50 (nM) Emax (%)
EC50 (nM)
Emax (%)
SAGE-217 652 641 317 531
SAGE-547 149 342 80 418
Ganaxolone 440 397 100 219
