LXS196, a novel PKC inhibitor for the treatment of uveal melanoma Julien Papillon, Novartis Institutes for BioMedical Research 8 th RSC / SCI symposium on kinase inhibitor design Babraham Research Campus, Cambridge, UK May 14 th 2018 Novartis Institute of Biomedical Research
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LXS196, a novel PKC inhibitor for the treatment of uveal melanoma · 2019-02-22 · LXS196, a novel PKC inhibitor for the treatment of uveal melanoma Julien Papillon, Novartis Institutes
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LXS196, a novel PKC
inhibitor for the treatment of
uveal melanoma
Julien Papillon, Novartis Institutes for BioMedical Research
8th RSC / SCI symposium on kinase inhibitor design
Babraham Research Campus, Cambridge, UK
May 14th 2018
Novartis Institute of Biomedical Research
Most common intraocular malignant tumor
• Estimated 2000 newly diagnosed patients in the USA per year
• Primary tumor treated by radio plaque therapy or surgical removal of the eye
Metastatic Uveal Melanoma (~50% patients)
• >90% metastases found in the liver
• No approved therapy, median survival <12 months
Characterized by GNAQ/11 activating mutations leading to constitutive signaling through Protein Kinase C (PKC)
PKC, target for metastatic uveal melanoma
2
Protein Kinase C family
The PKC Family
• 12 isoforms, not including splice variants
• 3 sub families: Classical, Novel, and Atypical differentiated by
regulatory domains
3
AEB071
Protein Kinase C Project
From Autoimmunity to Oncology
Autoimmunity and Transplantation
Oncology
AEB071 is a pan-PKC inhibitor designed to modulate T-cell
activation
Targeted indications
• Graft v. host disease
• Psoriasis
Demonstrated efficacy in phase 2 clinical trials
Targeted Indications
• Metastatic Uveal Melanoma harboring an activating mutation in GNAQ/11
4
Boris Bastian, AACR 2011
AEB071 is clinically active in uveal melanoma
Clinical potential may be limited:
Responses generally limited to stable disease
Dose escalation did not lead to a proportional increase in exposure
Higher doses associated with increased frequency of dose limiting GI toxicities
Goal:
Design a compound optimized for a uveal melanoma indication with improved selectivity and pharmaceutical properties
AEB071 Phase I Uveal Melanoma trial data • 70 patients (50%) with stable disease
• PFS of 15 weeks
5
Aminopyrazines as an alternative lead
scaffold
hinge a IC50 = 0.2 nM
IC50 = 2 nM
92.1 AC50 = 140 nM
6
1
Cmpd 1 crystal structure with PKCa (2.48 Å)
hinge a IC50 = 0.2 nM
IC50 = 2 nM
92.1 AC50 = 140 nM
7
1
MTD
MTD
Vehicle po BID
Cmpd 1 3 mpk BID
Cmpd 1 10 mpk BID
Cmpd 1 30 mpk BID
Cmpd 1 60 mpk QD
AEB071 120 mpk BID
92.1 mutant GNAQ Xenograft
Cmpd 1 affords equivalent efficacy to AEB071
at a lower dose
Is GI irritation mediated by PKC inhibition?
Compound DOSE
(8d QD) Route
Exposure
(µM.h)
Observed
GI irritation
Histopathology
results
2 50 mg/kg PO 8 ++ Stomach ulceration
2 10 mg/kg SC 20 negative negative
Compound DOSE
(8d QD) Route
92.1 IC50
(µM)
Observed
GI irritation
Histopathology
results
1 120mg/kg PO 0.14 ++++ Stomach ulceration
AEB071 240 mg/kg PO 0.25 mild negative
3 100 mg/kg PO 4 negative negative
GI irritation is
not linked to
PKC inhibition
GI irritation is
locally
mediated
8
2 1 AEB071 3
Can selectivity be improved while retaining
anti-proliferative activity?
hinge a IC50 = 0.2 nM
IC50 = 2 nM
92.1 AC50 = 140 nM
9
1
Cmpd 1 crystal structure with PKCa (2.48 Å)
10
Compound
PKC IC50 (nM)
92.1 (nM)
FLT3 (nM)
GSK3b (nM) a
2 <0.1 0.6 34 230 10
4 0.4 1.3 230 30 530
5 43 69 3680 3000 6900
6 0.3 2 180 8460 3350
Moving away from the 4-amino pyridine
improves selectivity
Improved kinase selectivity of Cmpd 6
11
PKC
Cmpd 6 @ 1 mM Cmpd 1 @ 1 mM
a IC50 = 0.2 nM
IC50 = 2 nM
92.1 AC50 = 140 nM
12
1
a IC50 = 0.3 nM
IC50 = 2 nM
92.1 AC50 = 180 nM
3-Pyridyl series
6
2 0 3 0 4 0 5 0
0
5 0 0
1 0 0 0
1 5 0 0
D a y s p o s t tre a tm e n t
Tu
mo
r v
olu
me
(m
m3
)
me
an
S
EM
V e h ic le p o b id
L Q V 2 1 8 3 0 m g /k g b id
L Q V 2 1 8 7 5 m g /k g b id
L Q V 2 1 8 1 5 0 m g /k g b id
A E B 0 7 1 1 2 0 m g /k g b id
2 0 3 0 4 0 5 0
0
5 0 0
1 0 0 0
1 5 0 0
D a y s p o s t tre a tm e n t
Tu
mo
r v
olu
me
(m
m3
)
me
an
S
EM
V e h ic le p o b id
L Q V 2 1 8 3 0 m g /k g b id
L Q V 2 1 8 7 5 m g /k g b id
L Q V 2 1 8 1 5 0 m g /k g b id
A E B 0 7 1 1 2 0 m g /k g b id
Vehicle po BID
Cmpd 6 30 mpk BID
Cmpd 6 75 mpk BID
Cmpd 6 150 mpk BID
AEB071 120 mpk BID
Vehicle po BID
Cmpd 1 3 mpk BID
Cmpd 1 10 mpk BID
Cmpd 1 30 mpk BID
Cmpd 1 60 mpk QD
AEB071 120 mpk BID
Moving away from the 4-amino pyridine
improves tolerability
Is there a potential for off-target toxicity?
Cmpd 6 has potent 5-HT2B agonist activity
13
Cmpd 6 AEB071
Cmpd 6 has an improved profile to limit potential for off-target toxicity
5-HT2B agonist activity strongly implicated in valvular heart disease
14
Modifications to mitigate 5HT2B
agonism
6
Docking model of cmpd 6 in
5-HT2B structure
Closed side of the pocket
Open side of the pocket
ergotamine
Sterically tight
region in this
docking model
Substitution of the piperidine ring should mitigate 5-HT2B activity
5-HT2B crystal
structure with
ergotamine
Stevens, R. C. Science, 2013, 615
Overlay of ergotamine X-ray
structure and cmpd 6 model
Basic
amine
Phenyl,
indole,
etc.
15
Substitution of the piperidine ring does mitigate 5-HT2B activity
5-HT2B
SAR for the aminopyrazine series
5-HT2B <1 mM
5-HT2B 1-10 mM
5-HT2B >30 mM
6
5-HT2B 0.2 mM
a IC50 = 2 nM
IC50 = 0.4 nM
92.1 AC50 = 170 nM
5-HT2B >30 mM
Addition of a geminal methyl removes 5-HT2B
agonist activity
a IC50 = 0.2 nM
IC50 = 2 nM
92.1 AC50 = 140 nM
16
LXS196
1
a IC50 = 0.3 nM
IC50 = 2 nM
92.1 AC50 = 180 nM
5-HT2B = 0.2 mM
3-Pyridyl series
6
LXS196 crystal structure with PKCα (2.82 Å)
LXS196 maintains improved efficacy over AEB071
• Regression achieved with LXS196 at multiple doses, in contrast to AEB071 where
maximum efficacy at MTD is stasis
17
1 5 2 0 2 5 3 0 3 5
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
D a y s p o s t im p la n t
Tu
mo
r v
olu
me
(m
m3
)
me
an
+/-
SE
M
V e h ic le p o b id
L X S 1 9 6 1 5 m g /k g b id
L X S 1 9 6 3 0 m g /k g b id
L X S 1 9 6 7 5 m g /k g b id
L X S 1 9 6 1 5 0 m g /k g b id
A E B 0 7 1 1 2 0 m g /k g b id
92.1 mutant GNAQ Xenograft
2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
D a y s p o s t tu m o r im p la n ta t io n
Tu
mo
r v
olu
me
(m
m3
)
me
an
S
EM
s to p d o s in g
re -d o s e 1 5 0 m p k b id
V e h ic le
L X S 1 9 6 1 5 0 m g /k g B ID
2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0
0
4 0 0
8 0 0
1 2 0 0
1 6 0 0
2 0 0 0
D a y s p o s t tu m o r im p la n ta t io n
Tu
mo
r v
olu
me
(m
m3
)
me
an
+/-
SE
M
V e h ic le p o B ID
A E B 0 7 1 1 2 0 m p k B ID
s top
d o s in g
re -d o s e w ith
L X S 1 9 6
1 5 0 m p k B ID
s to p L X S
d o s in g
Can we predict human clearance?
Dose dependent exposure across species and good ivivc
LXS196 PK in Dog
(male Beagle)
LXS196 PK in Mice
(male C57BL/6)
LXS196 PK in Rat
(male Wistar Han rat)
18
Activity Mouse Rat Dog Monkey Human
Hepatocyte clearance
CLint (mL/min/kg) 33 22 8.4 16 6.9
In vivo clearance
(mL/min/kg) 26 17 5 NA NA
Plasma protein binding 92.5% 85.4% 90.4% 83.5% 70.6%
Human Pharmacokinetics
19
Moderate PK variability for Cmax and AUCtau
Rapid absorption (Tmax ~ 1 hr post dose)
Consistent terminal half-life across different doses (8 - 13 hr, median ~ 11 hr)
No or minimal accumulation with repeated administration
LXS196 total plasma concentration profiles on Cycle 1 Day 1 and Day 15
following multiple oral doses of 100 to 1000 mg QD and 200 to 400 mg BID
Preliminary clinical activity and safety
As of the data cut-off date (15-Aug-2017), 55 patients had
completed at least 1 post-baseline assessment
Of these, 5 patients achieved partial responses (PR)
A further 38 patients have achieved stable disease (SD)
The most common LXS196 related AEs (all grades, all
doses) were nausea (57%), diarrhea (35%), vomiting (25%)
and hypotension (22%)
GI toxicities are generally low grade (Grade 1 or 2) and