Safety, Pharmacokinetics and Proof-of-Mechanism of an Oral Bruton’s Tyrosine Kinase Inhibitor HM71224 in Healthy Adult Volunteers Jimin Lee1, Jeewoong Son2, Hui Jung Sin1, Jongsoo Woo2, Salah Hadi3, Khee Hyun Suh4, Young-Mi Lee4, Sunyoung Jang4, Jin-A Jung1
1Clinical Research Team, Hanmi Pharm. Co., Ltd., 2Hanmi Pharm. Co., Ltd., Seoul, Korea, Republic Of, 3PRA HealthSciences, Zuidlaren, Netherlands, 4Hanmi Research Center, Seoul, Korea, Republic Of
Introduction
Conclusions • HM71224 demonstrated well-tolerated safety profile in healthy volunteers and
desirable PK and PD properties
• The data support the potential for HM71224 to be evaluated for treatment of
autoimmune diseases such as rheumatoid arthritis
THU0185
• Bruton’s Tyrosine Kinase (BTK) plays key roles in B-cell receptor (BCR) and Fc
receptor (FcR) signaling cascades and B cell development and activation1-8
• HM71224 is an orally available, irreversible and highly selective small molecule
inhibiting BTK protein
• HM71224 may provide therapeutic opportunities in autoimmune diseases
• Primary Objective: To evaluate the safety and tolerability and if possible to
determine the maximum tolerated dose of HM71224 after single and multiple
ascending dose administration in healthy subjects
• Secondary Objective:
a. To determine the pharmacokinetics(PK) of HM71224 and selected metabolites
(M1 and M2) following single and multiple oral dose administration of HM71224
b. To assess whether the PK of HM71224 is affected by food
c. To assess the occupancy by HM71224 after multiple oral administration of
HM71224 (Multiple Ascending Dose Part only)
Methods • Phase 1 study is consisted of 3 parts; a single ascending dose (SAD) part, a single
food effect (FE) part and a multiple ascending dose (MAD) part
• The SAD, FE and a part of MAD part results were revealed previously
• In the MAD part, once daily dosing and twice daily dosing were evaluated in placebo
controlled manner under fasted conditions
Results
• Total 90 subjects were included in the Phase 1 study
• 2 subjects were withdrawn due to adverse events in the MAD part; 88 subjects
completed the study per protocol
• No serious adverse events were reported in the Phase 1 study
• No clinically relevant changes in vital signs, ECGs and clinical laboratory tests
• All treatment emergent adverse events (TEAEs) were transient and resolved without
sequelae by follow-up
• Most common TEAEs were reported in Gastrointestinal system classified by system
organ
Reference 1. Bioessays. 2001 May; 23(5):436-46.
2. Nat Rev Immunol. 2002 Dec; 2(12):945-56.
3. Nat Rev Drug Discov. 2003 Jun; 2(6):473-88.
4. Immunol Rev. 2007 Aug; 218:45-64.
5. Immunol Rev. 2009 Mar; 228(1):58-73.
6. Nat Rev Rheumatol. 2009 Jun; 5(6):317-24.
7. Int Rev Immunol. 2012 Apr; 31(2):119-32.
8. Clin Immunol. 2013 Jul; 148(1):66-78.
Acknowledgement We would like to thank all of the participating patients and their families, as well as study
coordinators of the all study sites
This study was sponsored by Hanmi Pharmaceutical Co., Ltd. ClinicalTrial.gov identifier :
NCT01765478
• BTK occupancy was evaluated with BID dosing cohorts in MAD part
• More than 80% of BTK occupancy was maintained until 48 hours after the single
dose (Day 3, pre-dose)
• At steady state, more than 90% of BTK occupancy was achieved above 20mg BID
dosing
• BTK occupation lasted more than 7 days after completion of dosing (data not shown)
% BTK occupancy after 2 weeks
Dose (mg)
% B
TK
occu
pa
ncy a
t C
tro
ug
h
02
04
06
08
01
00
1 5 10 15 20 25 30 40
90
%
QD dose
BID dose
• A PK-PD model for HM71224 showed a steep dose response relationship with
BTK occupancy
• According to the PK-PD model above 10mg BID dosing or 20mg QD dosing shows
90% of BTK occupancy with HM71224
B-Cell Receptor Fcγ Receptor
B-cell Myeloid cell
- Proliferation - Cytokine production - Antibody Secretion
- Phagocytosis - Cytokine production
Bruton’s Tyrosine Kinase
Bruton’s Tyrosine Kinase
HM71224
Objectives
The 16th European League Against Rheumatism (EULAR) Annual European Congress, Rome, Italy; June 10-13, 2015
Sing Ascending Dose (n=18)
Food Effect (n=8)
Multiple Ascending Dose QD, 14-day (n=40)
Multiple Ascending Dose BID, 14-day (n=24)
10mg
20mg
40mg
80mg
140mg
60mg 10mg
20mg
40mg
80mg
200mg
120mg
40mg
5, 20mg
60mg
1. Subject Demography
Characteristics SAD Part
(n=18)
FE Part
(n=8)
MAD Part
QD
(n=40)
BID
(n=24)
Race (N, %)
Caucasian 17 (94.4%) 6 (12.5%) 32 (80.0%) 22 (91.7%)
Black - 1 (12.5%) 3 (7.5%) 1 (4.2%)
Asian, American
Indian or Alaska naïve 1 (5.6%) 1 (75.0%) 3 (7.5%) 1 (4.2%)
Others - - 2 (5.0%) -
Age, median (yr) 52.5 (±10.0) 28.5 (±19.8) 33.5 (±15.0) 33.0 (±12.6)
Height (cm) 182.4 (±7.8) 179.3 (±8.6) 179.6 (±9.7) 180.5 (±5.2)
Weight (kg) 81.7 (±11.5) 75.6 (±10.7) 79.3 (±11.8) 78.4 (±10.0)
BMI (kg/m2) 24.5 (±2.4) 23.5 (±3.0) 24.5 (±2.5) 24.1 (±2.9)
2. Adverse Events in Multiple Ascending Dose Part QD dosing BID dosing
Placebo
N=10
n (%)
[#AEs]
10 mg
N=6
n (%)
[#AEs]
20 mg
N=6
n (%)
[#AEs]
40 mg
N=6
n (%)
[#AEs]
80 mg
N=6
n (%)
[#AEs]
120 mg
N=6
n (%)
[#AEs]
Placebo
N=6
n (%)
[#AEs]
5 mg
N=3
n (%)
[#AEs]
20 mg
N=3
n (%)
[#AEs]
40 mg
N=6
n (%)
[#AEs]
60 mg
N=6
n (%)
[#AEs]
TEAEs
6
(60%)
[13]
3
(50%)
[3]
5
(83.3%)
[7]
3
(50%)
[3]
5
(83.3%)
[20]
5
(83.3%)
[18]
3
(50%)
[5]
2
(66.7%)
[3]
2
(66.7%)
[3]
4
(66.7%)
[7]
5
(83.3%)
[16]
Any ADRs - - - -
1
(16.7%)
[1]
4
(66.7%)
[12]
- - -
1
(16.7%)
[2]
-
Severity
Mild - - - - -
3
(50%)
[7]
- - -
1
(16.7%)
[1]
-
Moderate - - - - -
1
(16.7%)
[1]
- - -
1
(16.7%)
[1]
-
Severe - - - -
1
(16.7%)
[1]
3
(50%)
[4]
- - - - -
By System Organ
Class (SOC)
Skin/Subcutaneous
tissue disorders - - - - -
4
(66.7%)
[6]
- - -
1
(16.7%)
[1]
-
Nervous system
disorders - - - - -
1
(16.7%)
[2]
- - -
1
(16.7%)
[1]
-
Gastrointestinal
disorders - - - - -
1
(16.7%)
[1]
- - -
1
(16.7%)
[1]
-
General disorders/
Administration site
conditions
- - - - -
1
(16.7%)
[1]
- - - - -
Immune system
disorders - - - -
1
(16.7%)
[1]
- - - - - -
Musculoskeletal
/Connective tissue
disorders
- - - - -
1
(16.7%)
[1]
- - - - -
Vascular disorders - - - - -
1
(16.7%)
[1]
- - - - -
3. Pharmacokinetic Profiles
4. BTK Occupancy
• HM71224 showed increasing PK profiles as ascending dose levels in QD dosing
• HM71224 indicated slight accumulation after multiple dosing for 14 days
• Inter subject variability in exposure was relatively large
• Excretion of HM71224 and metabolites in urine was limited (data not shown)
* Only active data is included above.
Study Drug Administration
Day Morning
dose
Evening
dose
1 O X
2 X X
3-13 O O
14 O X
5. PK-PD Modeling
D1 P
red
ose
D1 4
hr
D1 1
2 hr
D3 P
red
ose
D3 2
hr
D6 P
red
ose
D1 7
D1 P
red
ose
D1 4
hr
D1 1
2 hr
D3 P
red
ose
D3 2
hr
D6 P
red
ose
D1 7
D1 P
red
ose
D1 4
hr
D1 1
2 hr
D3 P
red
ose
D3 2
hr
D6 P
red
ose
D1 7
D1 P
red
ose
D1 4
hr
D1 1
2 hr
D3 P
red
ose
D3 2
hr
D6 P
red
ose
D1 7
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
BT
K O
cc
up
an
cy
(%
)
0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 0 4 4 4 8
0 .1
1
1 0
1 0 0
1 0 0 0
1 0 m g , M A D , D 1
1 0 m g , M A D , D 14
2 0 m g , M A D , D 1
2 0 m g , M A D , D 14
4 0 m g , M A D , D 1
4 0 m g , M A D , D 14
8 0 m g , M A D , D 1
8 0 m g , M A D , D 14
1 2 0 m g , M A D , D 1
1 2 0 m g , M A D , D 14
T im e (h r)
Pla
sm
a c
on
ce
ntr
ati
on
(n
g/m
L)
0
2 0 0
4 0 0
6 0 0
8 0 0
1 ,0 0 0
Cm
ax
(n
g/m
L)
D1
D1
4
D1
D1
4
D1
D1
4
D1
D1
4
D1
D1
4
1 0 m g 2 0 m g 4 0 m g 8 0 m g 1 2 0 m g
0
1 ,0 0 0
2 ,0 0 0
3 ,0 0 0
4 ,0 0 0
5 ,0 0 0
6 ,0 0 0
7 ,0 0 0
AU
C0
-t (
ng
*h
/mL
)
D1
D1
4
D1
D1
4
D1
D1
4
D1
D1
4
D1
D1
4
1 0 m g 2 0 m g 4 0 m g 8 0 m g 1 2 0 m g
HM71224, a Selective BTK Inhibitor, Ameliorates Murine Lupus Development
Yu -Yon Kim1, Ki Tae Park1, Kyu Hang Lee1, Sun Young Jang1, Tae Hun Song1, Young-Mi Lee1, Young Hoon Kim1, Kwee Hyun Suh1 1Hanmi Research Center, Hanmi Pharmaceutical Co. Ltd., Korea, Republic Of
Introduction
FRI0380
Methods
Results
The 16th European League Against Rheumatism (EULAR) Annual European Congress, Rome, Italy; June 10-13, 2015
• Systemic lupus erythematosus (SLE) is known to be associated with the
formation of autoantibodies by B cell hyperactivity.
• Bruton’s tyrosine kinase(BTK) is a member of TEC family tyrosine kinases
important in B cell activation, proliferation, survival and differentiation.
• HM71224 is an orally irreversible BTK inhibitor with IC50 of 2.6 nM in kinase
inhibition assay and IC50 of 1 nM in phosphorylation inhibition assay.
• Commonly used model for SLE drug discovery is the spontaneous lupus mice
model, MRL/lpr with the lymphoproliferation mutation(Faslpr) and New Zealand
Black and White F1 hybrid (NZB/W F1) strain with co-expression of several sle
susceptibility genetic loci.
• The aim of this study is to evaluate the impacts of therapeutic intervention
on the development of SLE like disease features by HM71224 in MRL/lpr
and NZB/W F1 mice lupus models.
Clin Pharmacol Ther. 2012 91(1) 143-9
1. Animals and Administration
8
18
Dosing start
18
28~32
28 weeks old
40 weeks old
Disease onset End of the study
Mice
Female MRL/lpr
NZB/W F1
N=12/group once a day
• The measurements of urine protein with urine strip, blood urea
nitrogen and creatinine with chemical analyzer and anti-dsDNA IgG
with ELISA were conducted.
• Relative organ weights of spleen, cervical lymph node and kidney
were measured.
• Phenotyping of splenic B cells were performed by flowcytometry.
• Renal histopathology was scored in H&E and PAS stain.
• Survival rates were calculated with the Kaplan-Meier method.
• Statistical significance between groups was evaluated by one-way
ANOVA with Dunnett’s test or Kruskal-Wallis with Dunn’s test.
2. Results in MRL/lpr Mice
1. In vitro Cellular Activity
Cell Inhibition of phospho-kinase (IC50, nM)
Stimulant p-Kinase HM71224
Ramos 1) anti-IgM
p-BTKY223 1.0
p-PLCγ2 1.0
IL-4 p-STAT6 445
CTLL-2 2) IL-2 p-STAT5 >1,000
A431 3) EGF p-EGFR 800
1) Human Burkitt's lymphoma B-cell line, 2) murine cytotoxic T-cell line, 3) human epidermoid carcinoma cell line
• HM71224 is a potent and selective BTK inhibitor
• HM71224 prevents the development of skin lesions
V e h ic le 5 0 3 1 0 3 0
0 .0
0 .5
1 .0
1 .5
2 .0
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
* * * * * * * * * * * *Cli
nic
al
Sc
ore
at
28
we
ek
s * * * p < 0 .0 0 1 v s . v e h ic le Vehicle HM71224 (10mg/kg, QD)
2. Observations V e h ic le 5 0 3 1 0 3 0
0
1 0
2 0
3 0
4 0
* * *
* *
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
B2
20
+C
D6
9+ (
x1
02 c
ell
s /
10
4c
ell
s)
* * p < 0 .0 1
* * * p < 0 .0 0 1
v s . v e h ic le
V e h ic le 5 0 3 1 0 3 0
0
2 0 0
4 0 0
6 0 0
* * *
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
An
ti-d
sD
NA
Ig
G (
un
it/u
l)
* * * p < 0 .0 0 1
v s . v e h ic le
V e h ic le 5 0 3 1 0 3 0
0
1 0
2 0
3 0
* * *
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
B2
20
+G
L7
+ (
x1
02c
ell
s/1
04c
ell
s)
* * * p < 0 .0 0 1
v s . v e h ic le
Spleen Cervical LN Kidney
0.0
0.5
1.0
1.5
2.0 Vehicle control
Cyclophosphamide, 50 mg/kg, ip, QW
HM71224, 3 mg/kg, po, QD
HM71224, 10 mg/kg, po, QD
HM71224, 30 mg/kg, po, QD
***
***
*
***
**
* ** ****
Weig
ht
(g)
* p<0.05, ** p<0.01, *** p<0.001 vs. vehicle
a. Splenic Activated B cells b. Splenic Germinal Center B cells
d. Organ weights c. Autoantibody
• HM71224 inhibits the B cell activation, autoantibody production
and enlargement of lymphatic organs
a. Serum BUN
V e h ic le 5 0 3 1 0 3 0
0
1 0
2 0
3 0
4 0
* * * *
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
Se
ru
m B
UN
(m
g/d
l)
* p < 0 .0 5
* * * p < 0 .0 0 1
v s . v e h ic le
V e h ic le 5 0 3 1 0 3 0
0
1
2
3
4
* * *
** *
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
Glo
me
ru
lon
ep
hrit
is S
co
re * p < 0 .0 5
* * p < 0 .0 1
* * * p < 0 .0 0 1
v s . v e h ic le
V e h ic le 5 0 3 1 0 3 0
0
1
2
3
4
* * *
H M 7 1 2 2 4C y c lo p h o s p h a m id e
(m g /k g )
Inte
rs
tit
ial
Infla
mm
atio
n
&F
ibro
sis
Sc
ore
* * * p < 0 .0 0 1
v s . v e h ic le
• HM71224 ameliorates the renal injury and inflammation from SLE
b. GN score c. IN score
3. Results in NZB/W F1 Mice
• HM71224 inhibits the activation of B lymphocytes
d. Survival Rates c. Urine Protein
0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2
5 0
6 0
7 0
8 0
9 0
1 0 0
1 1 0
V e h ic le c o n t r o l
M y c o p h e n o la t e
m o fe t i l , 3 0 m g /k g
H M 7 1 2 2 4 , 3 m g /k g
H M 7 1 2 2 4 , 1 0 m g /k g
H M 7 1 2 2 4 , 3 0 m g /k g
W e e k s a fte r A d m in is tra tio n
% S
urv
iva
l Survival rate Vehicle 66.7% MMF (30mpk) 91.7% HM (3mpk) 75.0% HM (10mpk) 100% HM (30mpk) 100%
1 1 1 1 1
0
5
1 0
1 5
M y c o p h e n o la te
m o fe til
H M 7 1 2 2 4
V e h ic le 30 3 10 30
* *
*
B2
20
+C
D6
9+ (
x1
02 c
ell
s /
10
4c
ell
s)
* p < 0 .0 5
* * p < 0 .0 1
v s . v e h ic le
1 1 1 1 1
0
2
4
6
M y c o p h e n o la te
m o fe til
H M 7 1 2 2 4
V e h ic le 30 3 10 30
* * *
*
B2
20
+/C
D1
38
+ (
x1
02c
ell
s/1
04c
ell
s)
* p < 0 .0 5
* * * p < 0 .0 0 1
v s . v e h ic le
a. Splenic Activated B cells b. Splenic Plasma B cells
V e h ic le 3 0 3 1 0 3 0
0
1
2
3
4
H M 7 1 2 2 4M y c o p e n o la te
m o fe til
(m g /k g )
Urin
e p
ro
te
in s
co
re
(4
0 w
ee
ks
of
an
ima
l a
ge
)
* *
** p < 0 .01
v s . v e h ic le
* *
G N1 )
s c o re IN2 )
s c o re V I3 )
s c o re
0
1
2
3
4V e h ic le c o n tro l
H M 7 1 2 2 4 , 3 0 m g /k g , p o , Q D
M y c o p h e n o la te m o fe til,
3 0 m g /k g , ip , Q D
H M 7 1 2 2 4 , 1 0 m g /k g , p o , Q D
H M 7 1 2 2 4 , 3 m g /k g , p o , Q D
*
*
* * * ** * *
His
top
ath
olo
gic
al
Sc
ore
(Me
an
± S
D)
1 ) G lo m e r u lo n e p h r i t i s
2 ) In te r s t i t ia l N e p h r it is
3 ) V a s c u l it is
* p < 0 .0 5 , * * p < 0 .0 1 , * * * p < 0 .0 0 1 v s . v e h ic le
Vehicle
HM71224 3 mg/kg HM71224 10 mg/kg HM71224 30 mg/kg
Mycophenolate mofetil
30 mg/kg
a. Renal Histopathology
• HM71224 reduces renal damages and lymphocyte infiltration
The thickening of basement membrane(arrow) and tubule distended with proteinaceous fluid(asterisk) were ameliorated in HM71224 treated groups.
- Effectively dampened splenic B cells and autoantibody.
- Significantly decreased the development of SLE like
manifestations such as skin lesions, enlargement of
lymph node, splenomegaly, urine protein and renal injury.
- Markedly decreased mortality from SLE in NZB/W F1 mice
model.
• BTK inhibition by HM71224 in MRL/lpr and NZB/W F1 mice
• HM71224 can efficaciously ameliorate lupus developments
in murine disease model that resembles human SLE.
Conclusion
References • Current Protocol in Pharmacology 2011; 5 : 5.60.1-5.60.40.
• BioDrugs 2013; 27(2), 85-95.
• Arthritis Research & Therapy 2012; 14, R243.