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