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

manageable

20

Preliminary Clinical Activity – QD schedule

21

# Prior anti-PD-1 and/or anti-CTLA-4 treated patients

* Patients ongoing as of the data cut-off date

Data cut-off date 15 Aug 2017

100

50

0

-50

-100

N=38

PD

PD

#

PD

# PD

PD

PD

PD

# SD

# SD

SD

# SD SD

SD

# SD

# SD SD

PD

#

SD

# SD

#

SD

#

SD SD

*# SD

# SD

#

SD

#

SD

#

SD

SD

#

PD

SD SD SD SD

SD

# SD

#

PR

#

PR

#

SD

#

Bes

t %

ch

an

ge

fro

m b

as

eli

ne

Treatment group

LXS196 100 mg QD LXS196 200 mg QD LXS196 300 mg QD LXS196 500 mg QD LXS196 800 mg LXS196 1000 mg QD

QD regimen

SD, stable disease; PD, progressive disease; PR, confirmed partial response; QD, once daily;

Preliminary Clinical Activity – BID schedule

22

# Prior anti-PD-1 and/or anti-CTLA-4 treated patients

* Patients ongoing as of the data cut-off date

Data cut-off date 15 Aug 2017

100

50

0

-50

-100

Bes

t %

ch

an

ge

fro

m b

as

eli

ne

Treatment group LXS196 200 mg BID LXS196 300 mg BID LXS196 400 mg BID

N=17 BID regimen PD

SD

#

PR*

#

PD

PD

#

SD* SD

#

SD

#

SD SD*

# SD*

# SD*

#

SD* SD*

# SD* uPR*

uPR*

SD, stable disease; PR, confirmed partial response; PD, progressive disease; uPR, unconfirmed partial

response;

History of primary uveal

melanoma resected 2009

Developed metastatic

disease involving liver,

lung, adrenal and bone

Apr-2016

Progressive disease after

treatment with

Pembrolizumab (May to

Jun-2016)

Commenced 300 mg QD

LXS196 (Jul-2016)

PR (-41% reduction) after

2 cycles, subsequently

confirmed after 4 cycles

Baseline

C5D1

Confirmed PR in a 72 y/o male patient with metastatic uveal melanoma on LXS196

Summary

24

We have optimized the aminopyrazine series to afford a selective inhibitor of Protein Kinase C

Improved selectivity afforded increased tolerability in preclinical species

Full regression of tumors achieved in mouse xenograft studies

SBDD leveraged to rapidly move away from unwanted 5-HT2B agonist activity

Dose dependent exposure observed across multiple preclinical species

LXS196 has been advanced to the clinic for the treatment of metastatic uveal melanoma (NCT02601378)

LXS196

Acknowledgements

Oncology Biology Andy Wylie (PTL)

Rosie Barrett

Tony Vattay

Ribo Guo

Alice Loo

Vesi Cooke

Jing Yuan

Anka Bric

Pascal Fortin

Ping Wang

Mike Acker

Mike Jones

Mike Schlabach

Tami Hood

Ali Farsidjani

Suzanne Zhu

Tara Naylor

Dhiren Belur

Frank Stegmeier

Franklin Chung

Nick Keen

CPP Christopher Campbell

Faraj Atassi

Chemistry Mike Visser (PTL)

Christine Chen

Matt LaMarche

Mike Shultz

Mitsunori Kato

Julien Papillon

Jianmei Fan

Mike Luzzio

Walter Michael

David Wang

Tim Ramsey

Alan Zhang

Troy Smith

Chris Straub

Simon Mathieu

Carol Joud

Mark Palermo

MAP Guiqing Liang

Jamie Spear

Myrtha Durena

Suzie Ferreira

Shari Bickford

Giuliano Berellini

Franco Lombardo

Ty Gould

OTM/OTR Lilli Petruzzelli

Scott Cameron

Padmaja Yerramilli-Rao

Carrie Emery

Lujian Tan

Somesh Choudhury

Dale Porter

Ron Meyer

Meg McLaughlin

Ramu Thiruvamoor

Xin Li

ATI Walter Schuler

Hans-Guenther Zerwes

Peter von Matt

Maurice van Eis

Guido Koch

Bruno Cenni

Nigel Cooke

CPC Travis Stams

Sandra Jacob

Ian Hunt

Michael Romanowski

PM

Xia Yang

LeAnne Skordos

PCS Sanjeev Thohan

TRD Bernhard Erb

Raman Iyer

25

ASI Upendra Argikar

Jennifer Bushee

Adam Amaral

Xiaohui Chen

Jakal Amin

Chitra Saran

Hongjuan Zhao

Johannes Voshol

Debora Bonenfant

CHAD Jiang Lu

Jibin Zhao

Chiming Cheung

Jianliang Zhou

Larry Gu

Donghui Gou

Yunwei Zhu

Jialiang Li

Pengfei Guo

Jianguang Zhou