Revolutionizing the Treatment of Autoimmune Disorders and Malignancies - John Fowler, Co-Founder and CEO Jefferies London Health Care Conference
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Revolutionizing the Treatment of Autoimmune Disorders and Malignancies John Fowler, Co-Founder and CEO Jefferies London Health Care Conference November 2018
Forward-Looking Statements Disclaimer This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "plan," "anticipate" and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. These forward-looking statements reflect Kezar's current beliefs and expectations. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ from these forward-looking statements. Forward-looking statements contained in this presentation include statements about (i) the timing of initiation, progress and scope of clinical trials for our product candidates; (ii) the potential use of our product candidates to treat patients; (iii) the timing of the filing of INDs; and (iv) the timing of program updates and data disclosures. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during preclinical or clinical studies, clinical site activation rates or clinical trial enrollment rates that are lower than expected, changes in expected or existing competition, and unexpected litigation or other disputes. Other factors that may cause our actual results to differ from current expectations are discussed in Kezar’s Prospectus and Form S-1 Registration Statement relating to its initial public offering and its other filings with the U.S. Securities and Exchange Commission, including the "Risk Factors" sections contained therein. Except as required by law, we assume no obligation to update any forward- looking statements contained herein to reflect any change in expectations, even as new information becomes available.
The Kezar Opportunity
KZR-616: A Novel,
• Potential to be a first-in-class selective immunoproteasome inhibitor
Differentiated • Promising safety profile; potential to avoid immunosuppression
Approach
• KZR-616 is a pipeline in a drug, targeting a wide range of unmet needs in
Rich Platforms & autoimmunity
Growing Pipeline
• Protein secretion platform offers significant potential to generate novel drugs
Clinical Proof of • VELCADE®, a non-selective immunoproteasome inhibitor, is active in severe
Principle autoimmune disorders, including lupus nephritis
Strong Clinical and • Phase 1 KZR-616 trial achieved desired PK, PD and safety objectives, and
Safety Data demonstrated biologic activity via reduced production of inflammatory cytokines
• Enrollment underway in Phase 1b/2 trial, with initial top-line results from Phase 1b SLE
Value Drivers in & LN patients expected 1H 2019
Multiple • Focused initial strategy in lupus nephritis, which features quantitative endpoints, with
Indications enrollment beginning in 2019
• Enrollment in up to four additional autoimmune diseases beginning in 2019
2
Kezar’s novel, complementary drug discovery and development
programs target protein homeostasis
Protein Degradation: Protein Secretion:
The Immunoproteasome The Sec61 Translocon
The target of selective
immunoproteasome
inhibitor KZR-616
• Builds on 10+ years of R&D work led by Chris • Potential orally bioavailable small molecule
Kirk replacements for biologic therapies
• Restores normal immune responses in • Potential applications in oncology and immuno-
autoimmune disorders, while avoiding oncology
immunosuppression
• Active in broad array of autoimmune disease
models
3
KZR-616 is the product of a long term R&D effort
Kezar Life Sciences
Multiple published reports formed, KZR-616
Proteolix initiates demonstrate ONX 0914 is nominated
Proteolix closes program for selective active in animal models of
Series A, immunoproteasome RA, IBD, T1D, MS, and SLE VELCADE shown to
carfilzomib inhibitors leading to be active in
discovered ONX 0914 patients with SLE
and LN
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Kyprolis
Carfilzomib (carfilzomib) FDA
Phase 1 begins Onyx acquires
approval in Amgen acquires
in multiple Proteolix for
multiple myeloma Onyx for $10.4
myeloma ~$650M
billion
4
Kezar will pursue a diverse pipeline of indications with KZR-616
Prevalence: 100K US patients
Prevalence: 70K US patients
Protein secretion program in lead optimization for oncology indications
5
The Immunoproteasome is a unique type of proteasome expressed
only in the immune system and at sites of inflammation
Constitutive proteasome Immunoproteasome
Primary targets of
approved drugs
VELCADE® & KYPROLIS®
Primary targets of KZR-616
Ubiquitous Expression Expressed in Immune System
(e.g. Heart & Liver) (e.g. T-cells)
Groettrup, Kirk, and Basler Nat Rev. Immunol. 2010
*Active sites inducing protein degradation are highlighted 6
Selective inhibition of the immunoproteasome is not cytotoxic and
results in broad immunomodulatory activity
Dual-Targeting Selective Immunoproteasome
Proteasome Inhibitors Inhibitors
Macrophage
Myeloma Cell
TNF-α
VELCADE
(bortezomib) IL-23
KYPROLIS
(carfilzomib) T-cell
• Dual Inhibition required for Th1 Th17
KZR-616
cell death (Parlati et al. 2009)
• Death induced by protein Treg
buildup (UPR)
B-cell
auto-
Ab
Apoptosis
7
VELCADE data in patients with severe SLE and Lupus Nephritis
highlights the potential for immunoproteasome inhibition
• Median SLEDAI • Median proteinuria Alexander Ann Rheum. Dis. 2015
• Baseline: 14 • Baseline: 2.2 g/day
• Post-treatment: 4 • Post treatment: 0.87 g/day
• Durable reduction in SLEDAI • Continued reduction in proteinuria seen
improvements post treatment
• Rapid resolution of disease symptoms across all organ systems despite a short duration of therapy
• 100% response rate with prolonged remission after end of treatment
• Multiple published reports of efficacy in SLE & LN (Zhang Lupus 2017; de Groot Lup Sci Med 2015)
• Chronic therapy is precluded by toxicities driven by dual proteasome inhibition and off-target
activity
8
Immunoproteasome inhibition replicates the activity of VELCADE
in mouse models of SLE and LN
R e n a l D is e a s e (M R L /lp r )
F r e q u e n c y o f m ic e w ith
> 1 0 0 m g /d L p r o te in u r ia
100
80
60 V e h ic le
O N X 0 9 1 4 (1 /3 M T D )
40 K Y P R O L IS (M T D )
V E L C A D E (M T D )
20
0
10 15 20 25
W eek
• Selective immunoproteasome inhibition resulted in equivalent efficacy as dual inhibitors – but
at much better tolerated doses
• Selective immunoproteasome inhibition induced similar improvements in autoantibody
reduction, blockade of IFN-α production and reduced plasma cell formation as dual inhibitors
Ichikawa et al. Arthritis and Rheumatism 2011
9KZR-616 is active as a single agent and in combination with
MMF (CellCept) in mouse SLE/LN models
M e a n P r o te in u r ia
4
3
V e h ic le
• KZR-616 outperformed CellCept
C e llC e p t Q D
2
K Z R -6 1 6 Q W • Prolonged response for up to 8 weeks
1
after end of dosing
0
25 30 35 40 45
T re a tm e n t F o llo w - u p
A g e o f M ic e (w e e k s )
M e a n P r o te in u r ia
4
3 V e h ic le
• Combination of KZR-616 + CellCept
K Z R - 6 1 6 ( lo w d o s e ) Q W better than CellCept or KZR-616 alone
2
• Ph 2 study will test KZR-616 + CellCept
C e llC e p t Q D
K Z R - 6 1 6 + C e llC e p t
1 vs. CellCept in LN
0
25 30 35
T re a tm e n t
A g e o f M ic e (w e e k s )
Muchamuel et al. ACR 2017
10KZR-616 is well positioned in Lupus Nephritis and beyond
• LN enjoys a quantitative measurement of therapeutic benefit
• Ongoing and planned Phase 3 trials are using renal response (total and/or
complete response) as primary endpoints
• VELCADE induces a rapid improvement in renal function in LN patients
• Improvements in proteinuria seen within 3 months
• Current LN candidates are focused on B-cell targeted therapies and
immunosuppressive small molecules
• Likely challenges will include response rate (biologics) and / or risk/benefit profile
(immunosuppressive agents)
• Diseases involving dysfunction of multiple immune system components or cytokines
are well suited to the broad activity of KZR-616
• Biologic therapies targeting an individual cell type or cytokine (e.g. ENBREL or
RITUXAN) do not induce a sufficient depth of response to provide clinical benefit
11There are many published accounts of clinical activity with VELCADE in
autoimmune indications and in animal models with Kezar compounds
Clinical Data Preclinical Data with Kezar
Indication
with VELCADE Compounds
Lupus Nephritis & SLE
Graft vs Host Disease
Myasthenia Gravis
Idiopathic Thrombocytopenic Purpura
Autoimmune Hemolytic Anemia
IgA nephropathy
IgG4 related disease
Neuromyelitis Optica
Pemphigoid
Chronic Inflammatory Demyelinating
Polyneuropathy
anti-NMDA encephalitis
ANCA-associated Vasculitis
Multiple Sclerosis
Rheumatoid Arthritis
Crohn's Disease
12A single dose of an immunoproteasome inhibitor ameliorates
inflammation in a mouse model of rheumatoid arthritis
Muchamuel et al. Nat Med. 2009
13Immunoproteasome inhibition is superior to TNF inhibitor
therapy in mouse models of RA
Anti-Collagen Ab Model (CAIA) Collagen Immunization Model (CIA)
• T/B-cell independent • T/B-cell Dependent
Muchamuel et al. Nat Med. 2009
14The data from Kezar’s Phase 1a trial supports development in
autoimmune diseases
• Phase 1a safety data suggest a favorable safety profile relative to published data for non-
selective proteasome inhibitors
• No hematologic adverse events (AEs) (thrombocytopenia, neutropenia, anemia)
• No electrocardiographic changes
• No peripheral neuropathy (off-target effect of Velcade)
• Most common AEs (>80%) related to injection site reactions (erythema, induration, pain)
• Most (>75%) mild (Multiple doses in our Phase 1a study achieved our desired
proteasome subunit inhibition profile
Target Subunit Inhibition Profile
Beta5 LMP7 LMP2
80% >40%
B e ta 5 L M P 7 L M P 2
A c tiv ity (v s . D a y 1 P r e d o s e )
100 100 100
80 80 D e s ir e d 80
30 m g
In h ib itio n
60 60 60 45 m g
L e v e ls
60 m g
40 40 40
20 20 20
0 0 0
A v o id
E x c e s s iv e
%
In h ib itio n
16The 45 mg dose delivered our desired inhibition profile in all 18
treated MAD subjects and showed bioactivity in ex vivo assays
Ex Vivo Cytokine Release
IL -2 3
( p 4 0 s u b u n it)
(v s . D a y 2 2 P re d o s e )
120
45 mg
% A c tiv ity
100
Im m u n o p r o te a s o m e S u b u n it
QW for
80
60
In h ib itio n 4 weeks 40
P < 0 .0 0 0 1
20
100 0
(v s . D a y 1 P re -d o s e )
P la c e b o 45 m g
D e s ir e d L M P 2 In h ib itio n
80 IL -6
A c tiv ity
(v s . D a y 2 2 P re d o s e )
60 Whole Blood 120
% A c tiv ity
100
40
D e s ir e d L M P 7 In h ib itio n
(Pre-dose & 80
60 P < 0 .0 0 0 1
4 hr post-dose)
40
%
20
20 0
P la c e b o 45 m g
0 IL -1 7 A
(v s . D a y 2 2 P re d o s e )
P B M C C T -L LM P 7 LM P 2
( L M P 7 A c t iv it y )
PHA stimulation 120
% A c tiv ity
100
D a y 1 4 5 m g (N = 6 ) D a y 8 4 5 m g (N = 1 2 ) (20 – 24 hr) 80
60
P < 0 .0 0 0 1
40
20
0
P la c e b o 45 m g
T N F -
(v s . D a y 2 2 P re d o s e )
Measure 120
% A c tiv ity
100
Cytokines 80
60
P = 0 .0 0 7
40
20
0
P la c e b o 45 m g
17Kezar has launched a Phase 1b/2 trial in LN/SLE and plans to
begin testing KZR-616 in up to four additional indications in 2019
2018 2019
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Phase 1b dose escalation Further Dosing & Expansion
SLE and LN
Cohorts
13 weeks treatment (weekly SC)
Phase 2 Lupus Nephritis, (n=48)
MMF & Prednisone +/- KZR-616 (2 dose levels)
13 weeks treatment with follow-up
Phase 2
Polymyositis/Dermatomyositis
Phase 1b/2 orphan/unmet need
autoimmune indication
Phase 1b/2 orphan/unmet need
autoimmune indication
Phase 1b/2 orphan/unmet need
autoimmune indication
18Kezar has two distinct small molecule approaches to modulating
protein secretion at the Sec61 Translocon: Cotransins and SPSIs
Specific Protein Secretion
Cotransins Inhibitors (SPSIs)
Signal
• Multiple chemical sequence • Target selective
scaffolds binding site
approach
• Tunable selectivity SRP
• High value/validated
• Rapid advancement to Cytosol SR
targets (e.g., TNF-a)
Go / No-Go decisions
• Chemically tractable
on clinical ER membrane
targets
development
• Applications in
• Applications in Lumen immuno-oncology and
oncology and
Sec61 translocation autoimmunity
autoimmunity
channel
19Strong Cash Position
Key Cash Metrics
$112.8 million
Cash, cash equivalents & marketable securities as of September 30,
2018
Debt $0
19.1 million
Shares outstanding as of November 8,
2018
20The Kezar Opportunity: Pioneering immunoproteasome
inhibition, a new approach in autoimmunity
KZR-616: A Novel,
• Potential to be a first-in-class selective immunoproteasome inhibitor
Differentiated • Promising safety profile; potential to avoid immunosuppression
Approach
• KZR-616 is a pipeline in a drug, targeting a wide range of unmet needs in both rare &
Rich Platforms & large market autoimmune indications
Growing Pipeline
• Protein secretion platform offers significant potential to generate novel drugs
Clinical Proof of • VELCADE®, a non-selective immunoproteasome inhibitor, is active in severe
Principle autoimmune disorders, including lupus nephritis
Strong Clinical and • Phase 1 KZR-616 trial achieved desired PK, PD and safety objectives, and
Safety Data demonstrated biologic activity via reduced production of inflammatory cytokines
• Enrollment underway in Phase 1b/2 trial, with initial top-line results from Phase 1b SLE
Value Drivers in & LN patients expected 1H 2019
Multiple • Focused initial strategy in lupus nephritis, which features quantitative endpoints, with
Indications enrollment beginning in 2019
• Enrollment in up to four additional autoimmune diseases beginning in 2019
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