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Confidential and Proprietary
Targeting Viruses
to Improve
Human Health
Single- and multiple-
ascending doses (SAD/MAD)
and food effect of orally
administered JNJ-64155806
in healthy volunteers
Thomas N. Kakuda1, Jeysen Yogaratnam1, Jennifer Rito1,
Omair Sahgal2, Malcolm Boyce2, Toni Mitchell2, Kusum
Gupta1, Sushmita Chanda1, John Fry1, Pieter van
Remoortere3
1Alios BioPharma, Inc., South San Francisco, CA, USA2Hammersmith Medicines Research, London, UK
3Janssen Research & Development, Titusville, NJ, USA
18th International Workshop on Clinical
Pharmacology of Antiviral Therapy
6/19/2017Confidential and Proprietary 2
» Despite the availability of vaccines and antivirals, influenza remains a
significant global healthcare challenge that results in significant
morbidity and mortality, particularly in the event of a pandemic
– No approved treatment for hospitalized patients with influenza
» JNJ-64155806 (AL-794) is an ester prodrug of ALS-033719, a novel
potent endonuclease inhibitor of influenza A and B including strains
resistant to neuraminidase inhibitors
– Rapid and complete conversion from JNJ-64155806 to ALS-033719 via esterases
– Protein-binding adjusted EC90: 41 ng/mL
– Metabolism and transport characteristics
• UGT substrate → major inactive metabolite (glucuronide): ALS-033927
• (moderate) CYP inducer in vitro
• P-glycoprotein substrate and (weak) inhibitor in vitro
• OATP1B1 (weak) inhibitor in vitro
Background
6/19/2017Confidential and Proprietary 3
150mg
» Dose escalation based on safety and PK of prior cohort
– Dose increase ≤ 3 x
First-in-Human study design in healthy volunteers:
SAD, food effect, MAD, and challenge (Parts 1-4)
SAD (fasted)
N = 8/cohort
3:1 AL-794:placebo
450 mg
Food effect
N = 8/cohort
3:1 AL-794:placebo50 mg
450 mg
1000 mg
2000 mg
MAD x 7 days
N = 10/cohort
4:1 AL-794:placebo
600mg BID fasted
200 mg BID fasted
50 mg BID fed
Influenza challenge
N = 30/cohort
Cohort 1: 3:2:1 50 mg:150 mg:placebo BID fasted x 5 days
Cohort 2: 1:1 150 mg:placebo BID fasted x 5 days
6/19/2017Confidential and Proprietary 4
Mean (SD) ALS-033719 plasma concentration-time
profiles: AL-794-801 SAD and food effect (Parts 1 and 3)
6/19/2017Confidential and Proprietary 5
– Dose proportional between 50 and 150 mg but less than dose proportional
between 150 and 1000 mg
• See poster 33 for more details
– 3.6-fold ↑ Cmax and 3.0-fold ↑ AUC with high-fat meal
Summary of ALS-033719 PK parameters:
AL-794-801 SAD and food effect (Parts 1 and 3)
JNJ-64155806
Dose (mg), Condition
Mean ± SDb
Cmax
(ng/mL)
tmax
(h)
AUC∞
(ng.h/mL)
t1/2
(h)
50 Fasted 115 ± 23 1.5 (1.0-4.0) 956 ± 267 6.1 ± 1.1
150 Fasted 359 ± 88 2.0 (1.0-3.0) 3,035 ± 615 6.6 ± 0.5
450 Fasted 562 ± 93 2.0 (1.0-3.0) 5,671 ± 1,356 7.6 ± 1.6
1,000 Fasted 1,118 ± 219 2.5 (1.0-4.0) 12,289 ± 2,153 9.5 ± 2.2
2,000 Fasted 725 4.0 10,710 8.0
450 Fed 2,052 ± 428 3.0 (2.0-4.0) 16,489 ± 2,884 10.3 ± 3.0
a n=6 for all doses except for 2,000 mg, n=1b Median (range) for tmax.
6/19/2017Confidential and Proprietary 6
» AL-794 was well tolerated in single doses from 50 mg to 450 mg in a
fasted state
– There were no serious adverse events (SAEs) or fatal adverse events
– No clinically significant laboratory, ECG, vital sign or physical examination
abnormalities
– All of the treatment-emergent adverse events (TEAEs) were mild to moderate
» Adverse events of dizziness were reported at single oral doses of 450
mg (fed) and 1000 mg (fasted)
» All HV dosed with up to 1000 mg of AL-794 completed the study
– In the 2000 mg SAD cohort, only 2 HV were randomized:
• 1 HV dosed with AL-794 and another with placebo
• All other subjects were not dosed and were withdrawn from the study due to observed
dose-limiting toxicity in the 600 mg BID, multiple dosing cohort (Part 2)
Safety Summary:
AL-794-801 SAD and food effect
6/19/2017Confidential and Proprietary 7
» Target trough concentration (at steady-state)
– protein-binding adjusted EC90 = 41 ng/mL
» Future combinations
– Pimodivir (JNJ-63623872) dosed 600 mg BID
– Oseltamivir dosed 75 mg BID
» PK characteristics
– t½ from SAD (mean 6-10 hours) suggested BID dosing
– Mean C12h for 150 mg (SAD) was 81 ng/mL
– Nonparametric superpositioning of 200 mg BID suggested 3 x protein-binding
adjusted EC90 can be achieved by second dose onwards
• Loading dose considered not necessary
Considerations for MAD dose selection
6/19/2017Confidential and Proprietary 8
0
500
1000
1500
2000
2500
3000
3500
Mean (
SD
) pla
sma c
once
ntr
ati
on (
ng/m
L)
0 4 8 12 16 20 24
Time (h)
50 mg BID fed
200 mg BID fasted
600 mg BID fasted
Analyte=ALS-033719
0
500
1000
1500
2000
2500
3000
3500
Mean (
SD
) pla
sma c
once
ntr
ati
on (
ng/m
L)
144 148 152 156 160 164 168
Time (h)
50 mg BID fed
200 mg BID fasted
600 mg BID fasted
Analyte=ALS-033719
Day 1 Day 7
– Steady-state exposure ~2-3x first dose and is achieved by 2nd dose
– AM trough concentration > PM trough concentration
– 200 mg BID achieved C0h > 3 x protein-bind adjusted EC90 at steady-state
Mean (SD) ALS-033719 plasma concentration-time
profiles: AL-794-801 MAD (Part 2)
EC90 x 3 = 123 ng/mL
6/19/2017Confidential and Proprietary 9
Summary of ALS-033719 PK parameters:
AL-794-801 MAD
JNJ-64155806
Dose (mg), Conditiona
Mean ± SDb
Cmax (ng/mL) tmax (h) AUCtau (ng.h/mL)
Day 1 AM
50 bid, Fed 135 ± 16 3.5 (2.0–8.0) 947 ± 129
200 bid, Fasted 377 ± 85 2.0 (2.0–3.0) 2,338 ± 541
600 bid, Fasted 691 ± 355 2.0 (1.0–3.0) 4,441 ± 2,668
Day 1 PM
50 bid, Fed 208 ± 50 3.0 (2.0–4.0) 1,616 ± 321
200 bid, Fasted 756 ± 166 3.5 (2.0–6.0) 5,809 ± 1,055
600 bid, Fasted 2,636 ± 752 3.5 (2.0–11.8) 19,905 ± 4,432
Day 7 AM
50 bid, Fed 196 ± 51 4.0 (2.0–6.0) 1,402 ± 327
200 bid, Fasted 767 ± 147 2.0 (1.0–3.0) 4,710 ± 1,044
600 bid, Fasted – – –
Day 7 PM
50 bid, Fed 181 ± 62 3.0 (2.0–4.0) 1,469 ± 348
200 bid, Fasted 816 ± 146 4.0 (2.0–6.0) 6,426 ± 1,090
600 bid, Fasted – – –
a n=8b Median (range) for tmax
6/19/2017Confidential and Proprietary 10
Safety Summary:
AL-794 801 MAD
» No SAEs
» No clinically significant laboratory, ECG, vital sign or physical
examination abnormalities
» JNJ-64155806 was well tolerated when administered at 50 mg (fed) or
200 mg (fasted) BID for 7 days:– All subjects in the 50 mg and 200 mg multiple dosing cohorts completed the study
» JNJ-64155806 was not well tolerated when administered at 600 mg
(fasted) BID:– All of subjects in the 600 mg BID, multiple dosing cohort, were withdrawn from the study
due to a subject developing 2 severe TEAEs of vasovagal syncope after the 3rd. dose
that was considered to be related to study medication
– 75% of subjects (n=6/8) developed dizziness after the 2nd dose
» All other TEAEs were mild to moderate
6/19/2017Confidential and Proprietary 11
Dizziness more likely when ALS-033719 Cmax > 1,000 ng/mL
Lightheadedness by ALS-033719 Cmax
Presence of lightheadedness
Yes No
AL
S-0
33
71
9 C
ma
x (
ng/m
L)
0
1000
2000
3000
4000
5000
600 mg BID Day 1 PM
200 mg BID Day 1 PM
1000 mg
450 mg (fed)
450 mg
150 mg
50 mg
Presence of dizziness
6/19/2017Confidential and Proprietary 12
AL-794-801 influenza viral challenge study in healthy
volunteers: ITT-I Viral Kinetics
Time from first dose (Days)
Me
an
(+
SE
) V
ira
l L
oa
d (
Lo
g1
0T
CID
50
/mL
)
LLOD
Placebo BID (N=14)
AL-794 50 mg BID (N=10)
AL-794 150 mg BID (N=18)
Observations less than two are not represented
BID = Twice Daily
6/19/2017Confidential and Proprietary 13
» SAD
– Dose proportional to 150 mg and (slightly) less than dose proportionality at doses
above 150 mg
– t½ ~6 to 10 hours BID dosing to achieve target trough concentration
» Food effect
– High-fat meal ↑ Cmax and AUClast by 3.6- and 3.0-fold, respectively
» MAD
– Steady-state exposure ~2-3x first dose and is achieved by 2nd dose
» Safety
– JNJ-64155806 was well tolerated when given to healthy volunteers at doses that
demonstrated antiviral activity (50 and 150 mg BID) in an influenza human
challenge study
– Dizziness was observed at higher doses with exposures of ALS-033719 Cmax >
1,000 ng/mL
» Further development of JNJ-64155806 is ongoing
Conclusions
