SCYNEXIS Proprietary and Confidential Information The Discovery and Clinical Evaluation of the Cyclophilin Inhibitor SCY-635 in HCV Infected Subjects Michael Peel 1 , Richard Harris 1 , Zhuhui Huang 2 , Sam Hopkins 1 , Keqiang Li 1 , Thomas E. Richardson 1 , Bernard Scorneaux 1 , Andrew Scribner 1 , Steve Wring 1 . 1 SCYNEXIS INC. and 2 Southern Research Institute. HCV2009.
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SCYNEXIS Proprietary and Confidential Information The Discovery and Clinical Evaluation of the Cyclophilin Inhibitor SCY-635 in HCV Infected Subjects Michael.
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SCYNEXIS Proprietary and Confidential Information
The Discovery and Clinical Evaluation of the Cyclophilin Inhibitor SCY-635 in HCV Infected Subjects
Michael Peel1, Richard Harris1, Zhuhui Huang2, Sam Hopkins1, Keqiang Li1, Thomas E. Richardson1, Bernard Scorneaux1, Andrew Scribner1, Steve Wring1.1SCYNEXIS INC. and 2Southern Research Institute.HCV2009.
Non-immunosuppressive 4-(-OH-Leu)-3-Sar-Thioethers with Potent HCV Activity
N
N
O
N
NNNN
OHH
NO
N N N
OOOO
O O O
O
O
OH
X
X Cyp A (IC50, ng/mL)
CypB (IC50, ng/mL)
HCV (EC50, uM)
IL-2 (EC50, uM)
CsA 9 12 0.35 0.005 H 14 20 0.35 0.15
SCH3 8 4 0.06 0.06
S
37 29 0.2 0.18
S
12 28 0.15 >10
S
N
12 11 0.06 >10
SN
14 16 0.07 >25
S
N
N
17 18 0.1 >25
S
S
N
16 15 0.1 24
S
N
NNH
147 121 0.58 8
S OMe 6 24 0.06 (MLR 2.3 uM) S NMe2 6 11 0.1 >10
S N(Et)t-Bu 12 6 0.06 >25 S N(Me)t-Bu 17 15 0.07 >25
S NHt-Bu 16 14 0.2 >25
SCY-635
SCYNEXIS Proprietary and Confidential Information
SCY-635 Inhibits Cyclophilin A PPIase Catalytic Activity
[SCY-635] (nM)
0.0001 0.001 0.01 0.1 1 10 100 1000
Res
idua
l act
ivity
(%
)
0
20
40
60
80
100
[CsA] (nM)
0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000
Res
idua
l act
ivity
(%
)
0
20
40
60
80
100
SCY-635 Cyclosporin A
Ki = 1.84 ± 0.33 nM Ki = 2.64 ± 0.56 nM
Cyclophilin:Protease coupled assay using N-Suc-Ala-Ala-Pro-Phe-p-nitroanilide.G. Fischer, Max-Planck
SCYNEXIS Proprietary and Confidential Information
SCY-635 Binds to the Cyclophilin Active Site
Key residues required for PPiase activity are blocked by ligand
SCYNEXIS Proprietary and Confidential Information
Effect of Serum on Anti-Viral Activity in the Replicon Assay
0
20
40
60
80
100
120
0 0.05 0.16 0.50 1.58 5.00
SCY-635 Concentration (mM)
Vira
l Re
plic
atio
n
(% L
uci
fera
se C
on
tro
l)
0% Added Serum
10% Added Serum
20% Added Serum
40% Added Serum
Human serum added to subgenomic replicon system. EC50s determined at 0%10%, 20%, 40% are 0.08 uM, 0.09 uM, 0.11 uM and 0.12 uM respectively.
SCY-635 is ca. 77% protein bound (cf. >99% for CsA)
SCYNEXIS Proprietary and Confidential Information
Synthesis of Cyclosporin Derivatives
● Biotransformation of Cyclosporin
N
N
O
N
NNNN
OHH
NO
N N N
OOOO
O O O
O
O OH
N
N
O
N
NNNN
OHH
NO
N N N
OOOO
O O O
O
O
Sebekia benihana
● Chemical modification of Cyclosporins
N
N
O
N
NNNN
OHH
NO
N N N
OOOO
O O O
O
O X
RN
N
O
N
NNNN
OHH
NO
N N N
OOOO
O O O
O
O X
1) LDA/nBuLi2) Electrophile
X = H or OH
SCYNEXIS Proprietary and Confidential Information
SCY-635 Profile
SCY-635N
N
O
OH
N
NNNN
OHH
NO
N N N
OOOO
O O O
O
O
SNMe2
● Potent inhibitor of HCV RNA replication in con 1b derived replicons; EC50 = 0.1 uM (subgenomic); EC50 = 0.17 uM (full length)
● Additive or synergistic activity with IFN, ribavirin, protease, polymerase. (Data to be presented at AASLD 2009, S. Hopkins)
● No inhibition (IC50 >10 uM) of Cyp450 3A4, 2D6, 2C9, 2C19.
● No induction of Cyps in primary human hepatocytes.
● Weak interaction with Pgp transporter (cf. CsA)
● Low intrinsic clearance rates in microsomal preparations.
SCYNEXIS Proprietary and Confidential Information
0
0.5
1
1.5
2
2.5
3
0 5 10 15 20 25
Time Post Dosing (hr)
Con
cent
ratio
n (µ
g/m
L)
Debio-025
Cyclosporin A
SCY-635
Mouse blood concentrations: Oral delivery (8 mpk) of CsA, Debio-025 and SCY-635
SCY-635 Profile ● Orally bioavailable in multiple animal species.
● Rat: Cl = 110 mL/h/kg; t0.5 = 24 h; F = 22%.
● Monkey: Cl = 45 mL/h/kg; t0.5 = 32 h; F = 13%.
● Improved oral exposure compared to CsA, Debio-025 from simple vehicle.
SCYNEXIS Proprietary and Confidential Information
Clinical Studies
SCYNEXIS Proprietary and Confidential Information
Clinical Proof of Principle Study Design
● 15-day randomized, double blind assessment of safety, pharmacokinetics, and effect of treatment on plasma viremia.
● Entry criteria
● Proof of Principle Study was conducted in two parts:
● Subjects remained in the CRU on Study Days 1, 2, 3, 4, and 14 for intensive PK and viral load sampling.
Cohorts 1-3
(9 active: 3 placebo)
Cohorts 4-6
(6 active: 1 placebo)
Cohort 1: 30 mg q.d. Cohort 4: 100 mg t.i.d.
Cohort 2:100 mg q.d. Cohort 5: 200 mg t.i.d.
Cohort 3: 300 mg q.d. Cohort 6: 300 mg t.i.d.
Adults aged 18 to 65 No co-infections
Genotype 1 infection Plasma viral > 100,000 IU/mL
Enrollment in Cohort 6 restricted to treatment naïve subjects
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Safety Summary
●No deaths or serious adverse events occurred.
●No subjects discontinued treatment.
●One Grade 4 laboratory event (elevated triglycerides following consumption of a high fat meal); resolved without interrupting treatment.
●One subject missed one dose of study medication due to transient nausea on Day 3.
●All other treatment-related adverse events resolved without interruption of study medication.
SCYNEXIS Proprietary and Confidential Information
SCY-635-104: Mean and Median HCV RNA Profiles for Cohort 6 vs. Pooled Placebo
-2.50
-2.00
-1.50
-1.00
-0.50
0.00
0.50
1.00
0 2 4 6 8 10 12 14
Study Day
Lo
g10
Ch
an
ge
in H
CV
RN
A f
rom
Ba
se
line
Mean Cohort 6 Response Median Cohort 6 Response
Mean Placebo Response* Median Placebo Response*
* Mean and median placebo responses determined from placebo subjects in Cohorts 4, 5, and 6 (n=3)
Change in HCV RNA for subjects treated with SCY-635 was significant (p<0.05) from Study Days 2 through 15 (Student’s t-test; one-tailed, unequal variance)
SCYNEXIS Proprietary and Confidential Information
Summary● Thioether derivatives of [4-hydroxy-Leu]4-cyclosporin A have potent
activity in the HCV replicon assay and have low immunosuppressive potential.
● SCY-635 is a potent inhibitor of the enzymatic activity of Cyclophilin A.
● The potency of SCY-635 in the replicon system is unaffected by the addition of added serum.
● SCY-635 achieved a mean 2.3 Log(10) reduction of plasma viral RNA when delivered to treatment naïve HCV patients at a dose of 300 mg t.i.d.
● No clinical or laboratory evidence of dose limiting toxicities was observed.
● SCY-635 is a new cyclophilin inhibitor that has robust anti-HCV activity as a single agent and further, dose escalating, clinical studies are planned.