dalazatide, first-in-class kv1.3 channel blocker, an
TRANSCRIPT
Dalazatide, first-in-class Kv1.3 channel blocker, an immunomodulators journey
from sea to clinic
Aurora Biomed Ion Channels Retreat 2015 Shawn Iadonato
Immune regulating therapy
First in Class
Novel Kv1.3 inhibitor
Broad autoimmune indications
Immune sparing
No target organs of toxicity
Well tolerated in clinical studies
Expansive commercial opportunities
Strong global patent estate
Dalazatide: Potential Autoimmune Blockbuster
Phase 2 Ready
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DALAZATIDE: FIRST IN CLASS KV1.3 INHIBITOR
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Kv1.3: A Novel Target for Autoimmune Disease
• Effector Memory T cells (TEM) cause autoimmune disease
• TEM cells depend on the Kv1.3 channel for activation
• Blockade of Kv1.3 suppresses inflammation from TEM cells
• Kv1.3HIGH autoreactive TEM cells identified in multiple autoimmune diseases
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Kv1.3HIGH T cells Are Abundant in Atopic Dermatitis Lesional Skin
Confidential 8
AD (20x)
AD (40x)
CD3 Kv1.3 CD3 Kv1.3
Most autoreactive, infiltrating Th1/2 cells in AD are Kv1.3HIGH
Kv1.3: T Cells in Inflamed Mucosa of Ulcerative Colitis
23% of CD8+ and 54% of CD4+ T cells in UC biopsies are Kv1.3HIGH
From Koch et al. J Crohns Colitis. 2014 Nov 1;8(11):1378-91. 9
Large Number of Kv1.3 Channels Found Across Autoimmune T Cell Populations
Number of Kv1.3 channels on disease T cells 2 – 3 fold higher than control cells
Kv
1.3
ch
an
ne
ls /
ce
ll
0
500
1000
1500
2000
2500
RA
Syn
oviu
m
OA
Syn
oviu
m
Typ
e 1
Dia
bete
s
Typ
e 2
Dia
bete
s
MS
Myelin
Ctr
l
Myelin
Asth
ma
Sp
utu
m
Ctr
l
Sp
utu
m
From Koshy et al. J Biol Chem. 2014 May 2;289(18):12623-32 and Beeton et al. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17414-9. 10
Kv1.3 Expression Well-Established Across Autoimmune Space
Rheumatology Lupus (SLE)
Lupus Nephritis Vasculitis
PsA RA
GI Crohn’s Disease
Ulcerative Colitis
Other Type 1 Diabetes
Asthma GVHD
Opthalmology Uveitis / Dry Eye
CNS Multiple Sclerosis
Dermatology Psoriasis
Atopic Dermatitis Kv1.3HIGH
Autoreactive TEM cells
identified in:
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Dalazatide: Novel MOA Through Kv1.3 Blockade
• Highly specific and potent antagonist of Kv1.3 channel
• Blocks activation of autoreactive, Kv1.3HIGH, effector memory T cells (TEM)
• Does not block Naïve, Central Memory or Regulatory T cells
• Targeting of autoreactive TEM reduces number of disease causing cells and proinflammatory mediators
• Blockade of Kv1.3 may lead to a remission by immuno-modulation or induction of tolerance
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Dalazatide is a first in class Kv1.3 inhibitor that targets a differentiated pathway
Integrin, S1PR
Th1/ Th17
Au
toim
mu
nit
y
Dalazatide is Targeted and Immune Sparing CD3 CTLA4 JAK PDE4
Calcineurin
IL-12/23 integrin, S1PR
IL-1 TNFα IL-6 IL17
dalazatide
Resting
Inflamma-tory
Mediators
Kv1.3 Channel KCa3.1 Channel
Th1/Th17
K+
K+
Activated
KCa3.1↑
KCa3.1↑
Kv1.3↑
K+
K+
K+
Naï
ve
CD
4+
or
CD
8+
T C
ells
Effe
cto
r M
emo
ry
CD
4+
or
CD
8+
T C
ells
Ce
ntr
al M
emo
ry
CD
4+
or
CD
8+
T C
ells
MoA Pathway
Inflamma-tory
Mediators
Inflamma-tory
Mediators
K+
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Dalazatide: Novel Kv1.3 Inhibitor
• 37 amino acid synthetic cyclic peptide
• Derived from the stichodactyla sea anemone
• Phase 1 clinical formulation: twice weekly subcutaneous injection to abdominal fat pad
• Phase 2: ready-to-use, pre-filled single use syringe
• Developmental formulations:
– 8 – 12 week subcutaneous sustained release formulation
– Eye drop
– Topical cream
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Dalazatide is a first in class Kv1.3 inhibitor that targets a differentiated pathway
DALAZATIDE: NON-CLINICAL PD, EFFICACY & TOXICOLOGY
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Animal Models: Dalazatide Effective in Multiple Sclerosis
Dalazatide effective in animal model of relapsing MS over broad range of doses and dose frequencies
0 5 10 15 20 25 300.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Daily Placebo (P6N) Daily (100 g/kg) Every 3 Days (100 g/kg)
day post onset
Clin
ica
l S
co
re
From Tarcha et al. J Pharmacol Exp Ther. 2012 Sep;342(3):642-53.
Cum Clin Score D34
Placebog/kg1
g/kg3
g/kg
10
0
20
40
60
80
Cu
m C
lin
Sc
ore
P=0.05
P<0.001
Cu
mu
lati
ve
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Animal Models: Dalazatide Effective in Arthritis Model
Dalazatide demonstrated efficacy in pristane-induced arthritis model
DAL
Days Post-Onset
Clin
ica
l S
co
re
0 5 10 15 200
2
4
6
8
10
Controls DAL 10 g/kg
DAL 100 g/kg
Beeton et al. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17414-9.
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Animal Models: Dalazatide Effective in Autoimmune Glomerulonephritis
Dalazatide effective in glomerulonephritis model of SLE and preserved kidney function
Placebo
1 µg/kg
KIN2012-32 PCL
Protein/Creatinine
0 7 14 21 28 35 42 49 560
10
20
30
Placebo
1 g/Kg ShK-186
10 g/Kg ShK-186
100 g/Kg ShK186
Study Day
Pro
tein
/Cre
ati
nin
eKIN2012-32 PCL
Urine Protein
0 7 14 21 28 35 42 49 560
250
500
750
1000
1250
1500
1750
Study Day
Pro
tein
(m
g/d
L)
Placebo
1 g/Kg DAL
10 g/Kg DAL
100 g/Kg DAL
RBC in urine
Study Day
RB
C /
HP
F
0 7 21 28 35 42 49 560
20
40
60
80
Placebo
1ug/Kg ShK
10ug/Kg ShK
100ug/Kg ShK
WBC in urine
Study Day
WB
C /
HP
F
0 7 21 28 35 42 49 560
20
40
60
80
100
Placebo
1ug/Kg ShK
10ug/Kg ShK
100ug/Kg ShK
KIN
20
12
-32
PC
L
Uri
ne
Pro
tein
07
14
21
28
35
42
49
56
0
25
0
50
0
75
0
10
00
12
50
15
00
17
50
Stu
dy
Da
y
Protein (mg/dL)
Pla
ceb
o
1
g/K
g D
AL
10
g/K
g D
AL
100
g/K
g D
AL
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Safety Established in Pre-clinical Toxicology Program
Evaluation Toxicity
Histopathology No Clinical Chemistry/Hematology/Urinalysis
No
Safety Pharmacology
Cardiovascular No
Respiratory No
Neurological No
• Toxicology studies conducted in rat and cyno monkey
• Following ICH S6 guidance
• Six month chronic toxicology conducted in both species – Established safety margins range 17-25X
– No target organs of toxicity identified
– NOAEL was highest dose tested
No safety pharm concerns or target organs of toxicity identified
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DALAZATIDE: CLINICAL PROGRAM
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Dalazatide Clinical Development Status
1A
• Single Ascending Dose Safety Study
• 32 Healthy Volunteers
• One Dose
• One site in Netherlands
1B
• Multiple Ascending Dose Safety Study
• 32 Healthy Volunteers
• Twice-weekly dosing for 4 weeks
• One site in the U.S.
1B
• Safety and Biomarker Study in Psoriasis
• 24 Mild-moderate active plaque psoriasis
• Twice-weekly dosing for 4 weeks
• Two sites in Canada
Phase 2 Ready Asset
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Initial Phase 1 Studies Demonstrate Dalazatide Safety in Healthy Volunteers
• Open IND in Rheumatology Division of FDA
• 186-01 Single Ascending Dose Study (NL)
• 186-02 Multiple Ascending Dose 28-Day Study (USA)
• Subcutaneous administration to abdominal fat pad
Results
– Drug well tolerated in both studies
– No significant findings in labs, vitals, ECGs, physical exams, neurological exams
– AE’s were considered to be mild
– Maximum tolerated dose not determined
– No subject developed anti-drug antibody
Dalazatide is well tolerated in clinical studies
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Dalazatide Demonstrates Clinical Proof-of-Concept in Phase 1b Psoriasis Trial
• 186-03 study of the safety, tolerability and pharmacodynamics of dalazatide in active plaque psoriasis.
• Active plaque psoriasis with 3% BSA and multiple target lesions
• Received twice-weekly injections at 2 dose levels (30 mcg or 60 mcg) for 4 weeks followed by 4-week follow-up
Safety & Tolerability
– Drug well tolerated; all subjects completed all scheduled doses
– Most AEs judged to be mild, consistent with previous trials
– No subjects withdrew, reduced dose or missed a dose
Dalazatide is well tolerated in active plaque psoriasis population
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Dalazatide Demonstrates Clinical Proof-of-Concept in Phase 1b Psoriasis Trial
Clinical Activity
– Study not powered to evaluate clinical efficacy
– 50% of subjects in 60 mcg group achieved clinical improvement in target lesion
– Improvements observed as early as day 15 and for up to 4 weeks following last dose (end-of-study)
– 90% of subjects in 60 mcg group had reduction in PASI score
– Mean PASI score reduction reached statistical significance (p=.004) in 60 mcg group
Biomarker Studies
– Ongoing with James Krueger (Rockefeller U.)
– Gene expression and immunohistochemistry of biopsies
– Inflammatory mediators concentration in blood plasma
– T cell subsets/PD marker evaluation by flow cytometry
Dalazatide treatment results in improvements in validated psoriasis endpoints in up to 90% of subjects
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Dalazatide Clinical Activity - 30µg Dose
Significant improvement in target lesions following 4 weeks of treatment.
Baseline Day 32
BL
D32
Why Dalazatide?
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CD3 CTLA4 JAK PDE4
Calcineurin
IL-12/23 integrin, S1PR
IL-1 TNFα IL-6 IL17
dalazatide
Broad Autoimmune Indications
Immune sparing
Potential for Durable Remission Post Therapy
Patient Safety
Tolerability in Clinical Trials
Dalazatide offers differentiation in indications and safety from competing therapies
Dalazatide Collaborators
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UC Irvine • George Chandy • Michael Cahalan • Many others
Baylor College of Medicine • Christine Beeton
Peptides International • Mike Pennington
Monash University • Ray Norton
UC Davis • Heike Wulff
Kineta • Eric Tarcha • Ernesto Munoz • Kayla Norton • David Peckham • John Grigg • Jose Mercado • Many others
Thank You & Questions
For more information, please contact: Shawn Iadonato, PhD
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