Late-breaking oral presentation at ERS 2018:
“RPL554, a first-in-class dual PDE3/4 inhibitor,
causes significant bronchodilation and symptom
relief; a Phase 2b COPD study,”D Singh, M.D., Professor, MEU, University of Manchester
September 18, 2018
2
Study Design
• Description:
– Phase 2b randomized, double blind, placebo controlled, dose ranging study
• Patient Population:
– 403 patients with moderate-to-severe COPD, diagnosed >12 months previously
– males and females, age 40-75
• Location:
– approx. 45 out-patient centers in Western & Eastern Europe
• Background therapy:
– no background bronchodilator therapy
– stable ICS regimen could be maintained
3
Study Design
Screening/
run-inTreatment (4 weeks) Follow-up
RPL554 0.75 mg BID
RPL554 1.5 mg BID
RPL554 3.0 mg BID
RPL554 6.0 mg BID
Placebo BID
Randomisation
4
Demographics
Parameter Patients (N=403)
Age 63.2 years
Gender, male 60.5%
Race, Caucasian 100%
Disease characteristics
COPD duration 7.8 years
Chronic bronchitis 62%
MRC ≥2 93.6%
Smoking, current smoker 54.8%
Pack-years 42.1
Screening spirometry
FEV1, post-salbutamol 55.8% predicted normal
FEV1, post-salbutamol 1.64 L
FEV1 reversibility 11.7%
5
Lung function: Highly reproducible peak FEV1
over 4 weeks
0
50
100
150
200
250
300
350
Week 1 Week 2 Week 3 Week 4
Peak F
EV
1fr
om
0–3 h
tr
eatm
ent-
pla
cebo d
iffe
rence,
mL
RPL554 0.75 mg (N=81) RPL554 1.5 mg (N=81)
RPL554 3 mg (N=82) RPL554 6 mg (N=80)
FEV1, forced expiratory volume in 1 second.
All treatment–placebo differences p<0.001. Data are LS mean and 95% confidence intervals.
6
Lung function: Average FEV1 from 0–12 hours after 4 weeks
0
25
50
75
100
125
150
175
200
225
Avera
ge F
EV
1fr
om
0–12 h
tr
eatm
ent-
pla
cebo d
iffe
rence,
mL
RPL554 0.75 mg (N=81) RPL554 1.5 mg (N=81)
RPL554 3 mg (N=82) RPL554 6 mg (N=80)
FEV1, forced expiratory volume in 1 second. Treatment–placebo difference: *p<0.05; †p<0.01; ‡p<0.001. Data are LS mean and 95% confidence intervals
**
†
‡
7
Lung function: Trough FEV1 after 4 weeks
FEV1, forced expiratory volume in 1 second. Reversible defined as FEV1 change from pre- to post-salbutamol
≥12% and ≥200 mL; not reversible <12% or <200 mL. Treatment–placebo difference: *p<0.05; †p<0.01. Data
are LS mean and 95% confidence intervals.
-200
-100
0
100
200
300
400
Total Reversible Not reversible
Tro
ugh F
EV
1
treatm
ent-
pla
cebo d
iffe
rence,
mL
RPL554 0.75 mg RPL554 1.5 mg
RPL554 3 mg RPL554 6 mg
*
*
† †
8
Respiratory symptoms (E-RS): Progressive improvement over 4 weeks
MCID, minimum clinically important difference; E-RS, EXAcerbations of Chronic Pulmonary Disease Tool-
Respiratory Symptoms. Treatment–placebo difference: *p<0.05; †p<0.01; ‡p≤0.001. Data are LS mean and
95% confidence intervals.
-4
-3
-2
-1
0
Week 1 Week 2 Week 3 Week 4
E-R
S tota
l score
treatm
ent-
pla
cebo d
iffe
rence
RPL554 0.75 mg (N=81) RPL554 1.5 mg (N=81)
RPL554 3 mg (N=82) RPL554 6 mg (N=80)
* * ** *
† † †
† †
‡ ‡ ‡
‡ ‡
‡ MCID
9
Health status (SGRQ-C) at Week 4
SGRQ-C, St George’s Respiratory
Questionnaire – COPD. Treatment–placebo difference: †p<0.01.
51
42
32
42
26
0
10
20
30
40
50
60
70
Pa
tie
nts
with
SG
RQ
-C im
pro
ve
me
nt
≥4
un
its fro
m b
ase
line
, %
RPL554 0.75 mg (N=81) RPL554 1.5 mg (N=81) RPL554 3 mg (N=82)
RPL554 6 mg (N=80) Placebo (N=79)
-4
-3
-2
-1
0
1
SG
RQ
-C to
tal sco
rem
ea
n c
ha
ng
e fro
m b
ase
line
†
10
Adverse events
Patients, n (%)
RPL554
Placebo(N=79)
0.75 mg(N=81)
1.5 mg(N=81)
3 mg(N=82)
6 mg(N=80)
Any AE 27 (33.3) 36 (44.4) 29 (35.4) 29 (36.3) 31 (39.2)
Drug-related
8 (9.9) 11 (13.6) 12 (14.6) 8 (10.0) 10 (12.7)
Severe AE 4 (4.9) 1 (1.2) 2 (2.4) 1 (1.3) 2 (2.5)
Serious AE 2 (2.5) 2 (2.5) 1 (1.2) 1 (1.3) 1 (1.3)
Drug-related
1 (1.2) 1 (1.2) 0 0 0
AE leading to death
0 1 (1.2) 0 1 (1.3) 0
11
Conclusions
• RPL554 – first-in-class, dual PDE3/4 inhibitor
• In patients with COPD, 4 weeks treatment with RPL554:
– improved lung function
– reduced symptoms
• The improvement in symptoms was progressive and clinically meaningful
– Probably due to an anti-inflammatory effect
• RPL554 was well tolerated, all doses having a placebo-like adverse event profile
• RPL554 demonstrates benefit as standalone and add-on treatment