Effects of the siRNA JNJ-3989 and/or the Capsid Assembly Modulator JNJ-6379 on Viral Markers of Chronic Hepatitis B: Results From the REEF-1 Study
Man-Fung Yuen,1,* Tarik Asselah,2 Ira M. Jacobson,3 Maurizia Brunetto,4 Harry L.A. Janssen,5 Tetsuo Takehara,6 Jin Lin Hou,7 Thomas N. Kakuda,8 Tom Lambrecht,9
Ronald Kalmeijer,10 Carine Guinard-Azadian,9 Cristiana Mayer,10 John Jezorwski,10 Thierry Verbinnen,9 Oliver Lenz,9 Umesh Shukla,10 Michael Biermer9
1Department of Medicine & State Key Laboratory of Liver Research, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; 2Université de Paris, INSERM UMR1149 and Hôpital Beaujon, APHP, Clichy, France; 3New York University Grossman School of Medicine, New York, NY, USA; 4University of Pisa, Pisa, Italy; 5University of Toronto, Toronto, Canada; | *Presenting author. |
6Osaka University Graduate School of Medicine, Osaka, Japan; 7Nanfang Hospital, Southern Medical University, Guangzhou, China; 8Janssen Research & Development, LLC, South San Francisco, CA, USA; 9Janssen Research & Development, Beerse, Belgium; 10Janssen Research & Development, LLC, Titusville, NJ, USA. |
Key Findings
> | Similar to HBsAg, a |
JNJ-3989dose-response | |
relationship was observed |
Introduction
- JNJ-73763989(JNJ-3989) is a liver-targetedshort-interfering RNA (siRNA) designed to target all hepatitis B virus (HBV) RNAs for degradation, thereby reducing all HBV viral proteins and pregenomic RNA1
- JNJ-56136379(JNJ-6379) is a capsid assembly modulator that interferes with HBV replication by causing the formation of structually normal capsids that are devoid of HBV DNA and RNA (CAM-N)2
- The phase 2b REEF-1 study (ClinicalTrials.gov Identifier: NCT03982186) assessed the efficacy and safety of 48 weeks of JNJ-3989 and/or JNJ-6379 in combination with nucleos(t)ide analogues (NA) in patients with chronic hepatitis B (CHB)3
- JNJ-3989treatment resulted in a dose-dependent reduction in hepatitis B surface antigen (HBsAg) through follow-up Week 24; the greatest decline was observed with the subcutaneous (SC) 200 mg dose received every 4 weeks (Q4W)
- There was no beneficial effect of coadministration with JNJ-6379 on HBsAg decline
- JNJ-3989and/or JNJ-6379 were safe and well tolerated
Objective
-
To assess JNJ-3989- and/or JNJ-6379-induced changes to viral markers in CHB patients
who were not currently treated (NCT) or virologically suppressed (VS) with NA treatment and who were hepatitis B e antigen (HBeAg)+ or HBeAg-
Methods
Study Design and Participants
• | REEF-1 is a phase 2b, multicenter, double-blind,active-controlled, randomized study; results |
through follow-up Week 24 are reported here | |
• | Eligible patients included those aged 18 to 65 years |
- Patients were randomized to 6 treatment arms (Figure 1), all of which included NA, and received study treatment for 48 weeks
- Patients who met the criteria for stopping NA treatment at Week 44 (primary endpoint; Figure 1) terminated NA treatment at the Week 48 visit and began a 48-weekNA-freefollow-up phase
- Patients could stop NA treatment and enter a 48-weekNA-freefollow-up phase at any time if NA stopping criteria were met
- Patients having met NA stopping criteria and having stopped NA treatment were monitored for HBV DNA and alanine aminotransferase (ALT); NA treatment restarted based on predefined NA retreatment criteria
Figure 1. Study design.
Inclusion criteria: | PBO (n = 45) | Analysis up to follow-up Week 24 | |
• Active CHB (NCT or VS) | JNJ-6379 250 mg PO QD (n = 48) | ||
• HBsAg >100 IU/mL at screening | |||
JNJ-3989 40 mg SC Q4W (n = 93) | NA continued when NA stopping criteria† not met | ||
• Fibrosis stage F0-F2 | |||
†ALT <3x ULN, HBV DNA HBeAg-, and HBsAg <10 IU/mL | |||
Stratification: | JNJ-3989 100 mg SC Q4W (n = 93) | ||
NA stopping criteria reassessed at every follow-up visit | |||
• HBeAg+ vs HBeAg- | |||
JNJ-3989 200 mg SC Q4W (n = 96) | |||
• Treatment history (NCT vs VS) | |||
JNJ-3989 100 mg SC Q4W + JNJ-6379 250 mg PO QD (n = 95) | |||
All patients received NA* during treatment
0 | 12 | 24 | 36 | 48 | F12 | F24 | F36 | F48 |
Weeks
Primary endpoint: Proportion of patients meeting NA stopping criteria (ALT <3x ULN, HBV DNA HBeAg-, and HBsAg <10 IU/mL) at Week 48
ETV, entecavir; F, follow-up; LLOQ, lower limit of quantitation; PBO, placebo; PO, oral; QD, daily; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal.
*NA = ETV/TDF/TAF.
Results
Participants
- A total of 470 patients with CHB were included, with a mean age of 43 years and a mean duration of CHB infection of 25.4 years; 66% were male and 40% were Asian (Table 1)
- 95% of patients enrolled completed the 48-week treatment phase, with no differences across treatment groups
Table 1. Baseline Demographics and Clinical Characteristics by Treatment History and HBeAg Status at Screening
NCT | VS | |||
HBeAg+ | HBeAg- | HBeAg+ | HBeAg- | |
Characteristic* | (n = 75) | (n = 97) | (n = 67) | (n = 231) |
Primary Endpoint
- 19.1% (18/94) and 29.8% (28/94) of patients (all of whom were VS, except for 7) met NA stopping criteria with JNJ-3989 200 mg at Week 48 and until follow-up Week 24, respectively
- For HBeAg- patients, the main reason for not meeting NA stopping criteria was not achieving HBsAg <10 IU/mL
- For HBeAg+ patients, the main reasons for not meeting stopping criteria were not achieving HBeAg seroclearance and/or HBsAg <10 IU/mL and, in those who were also NCT, not achieving HBV DNA <>
- 2 of 63 (3.2%) patients who met NA stopping criteria and stopped NA treatment subsequently met NA restarting criteria through follow-up Week 24
Changes in HBsAg
- Consistent with the overall population,3 JNJ-3989 reduced HBsAg in a dose-dependent manner in subgroups by treatment history and HBeAg status (Figure 2); the greatest mean declines were generally seen with the 200 mg dose
- The largest reductions of HBsAg were observed in NCT HBeAg+ patients (Figure 2)
Figure 2. Mean change in HBsAg (±SE) from baseline by treatment history and HBeAg status.
NCT HBeAg+ | VS HBeAg+ |
1 | Mean (SE) Mean (SE) | 1 | Mean (SE) Mean (SE) | ||||||||||||||||||||||
Follow-up | Change | Change | Follow-up | Change | Change | ||||||||||||||||||||
Week 48 | FU Week 24 | Week 48 | FU Week 24 | ||||||||||||||||||||||
0 | 0 | 0.04 (0.025) | -0.04 (0.037) | ||||||||||||||||||||||
HBsAg | IU/mL | HBsAg | IU/mL | -0.08 (0.028) | -0.14 (0.049) | ||||||||||||||||||||
-0.43 (0.306) | -0.40 (0.295) | ||||||||||||||||||||||||
-1.27 (0.114) | -0.91 (0.094) | ||||||||||||||||||||||||
(SE) change in | 10 | -1 | (SE) change in | 10 | -1 | ||||||||||||||||||||
baseline, log | -0.80 (0.795) | -1.02 (0.985) | baseline, log | ||||||||||||||||||||||
-1.77 (0.138) | -1.32 (0.198) | -1.78 (0.128) | -1.43 (0.138) | ||||||||||||||||||||||
-2.01 (0.169) | -1.39 (0.259) | ||||||||||||||||||||||||
-2 | -2.52 (0.270) | -2.04 (0.256) | -2 | ||||||||||||||||||||||
-2.55 (0.263) | -2.10 (0.365) | -2.61 (0.175) | -2.18 (0.259) | ||||||||||||||||||||||
Mean | from | -3.56 (0.355) | -2.63 (0.339) | Mean | from | ||||||||||||||||||||
-3 | -3 | ||||||||||||||||||||||||
-4 | -4 | ||||||||||||||||||||||||
0 | 4 | 8 | 12 | 16 | 20 24 | 28 | 32 | 36 40 44 48 F4 F8 F12 F16 F20 F24 | 0 | 4 | 8 | 12 | 16 | 20 24 | 28 | 32 | 36 40 44 48 F4 F8 F12 F16 F20 F24 | ||||||||
Weeks | Weeks |
NCT HBeAg- | VS HBeAg- | |||||||||||||||||||||||||
1 | Mean (SE) Mean (SE) | 1 | Mean (SE) Mean (SE) | |||||||||||||||||||||||
Follow-up | Change | Change | Follow-up | Change | Change | |||||||||||||||||||||
Week 48 | FU Week 24 | Week 48 | FU Week 24 | |||||||||||||||||||||||
0 | -0.03 (0.072) | -0.15 (0.070) | 0 | 0.01 (0.016) | -0.09 (0.015) | |||||||||||||||||||||
HBsAg | HBsAg | -0.11 (0.033) | -0.11 (0.028) | |||||||||||||||||||||||
IU/mL | -0.13 (0.110) | -0.13 (0.113) | IU/mL | |||||||||||||||||||||||
-1.40 (0.126) | -0.90 (0.107) | |||||||||||||||||||||||||
(SE) change in | 10 | -1 | (SE) change in | 10 | -1 | -1.51 (0.065) | -0.98 (0.051) | |||||||||||||||||||
baseline, log | -1.40 (0.107) | -1.08 (0.111) | baseline, log | |||||||||||||||||||||||
-1.71 (0.080) | -1.30 (0.079) | |||||||||||||||||||||||||
-2.16 (0.163) | -1.53 (0.192) | -1.93 (0.072) | -1.34 (0.079) | |||||||||||||||||||||||
-2.22 (0.141) | -1.48 (0.136) | -2.41 (0.128) | -1.62 (0.113) | |||||||||||||||||||||||
-2 | -2 | |||||||||||||||||||||||||
Mean | from | -3 | Mean | from | -3 | |||||||||||||||||||||
-4 | -4 | |||||||||||||||||||||||||
0 | 4 | 8 | 12 | 16 | 20 24 | 28 | 32 | 36 40 44 48 F4 F8 F12 F16 F20 F24 | 0 | 4 | 8 | 12 | 16 | 20 24 | 28 | 32 | 36 40 44 48 F4 F8 F12 F16 F20 F24 | |||||||||
Weeks | Weeks | |||||||||||||||||||||||||
PBO | JNJ-6379 | JNJ-3989 40 mg | JNJ-3989 100 mg | JNJ-3989 200 mg | JNJ-3989 100 mg + JNJ-6379 |
FU, follow-up; SE, standard error.
- The JNJ-3989 200 mg arm had the highest proportion of patients who achieved HBsAg reduction ≥2 log10 and ≥3 log10 at Week 48 (73.6% and 27.5%, respectively; Figure 3A) and at the time of follow-up Week 24 (37.3% and 10.8%, respectively; Figure 3B)
Figure 3. Individual changes in HBsAg from baseline at (A) Week 48 and at (B) follow-up Week 24 in individual patients by HBeAg status.
A. | ||||||||||||||||||||
PBO | JNJ-6379 | JNJ-3989 40 mg | JNJ-3989 100 mg | JNJ-3989 200 mg | JNJ-3989 100 mg | |||||||||||||||
+ JNJ-6379 | ||||||||||||||||||||
48, | 1 | |||||||||||||||||||
Week | 0 | Treatment Arm | ||||||||||||||||||
at | -1 | PBO HBeAg+ | ||||||||||||||||||
baseline | PBO HBeAg- | |||||||||||||||||||
IU/mL | -2 | JNJ-6379 HBeAg+ | ||||||||||||||||||
JNJ-6379 HBeAg- | ||||||||||||||||||||
JNJ-3989 40 mg HBeAg+ | ||||||||||||||||||||
HBsAg from | -3 | JNJ-3989 40 mg HBeAg- | ||||||||||||||||||
10 | JNJ-3989 100 mg HBeAg+ | |||||||||||||||||||
log | -4 | JNJ-3989 100 mg HBeAg- | ||||||||||||||||||
JNJ-3989 200 mg HBeAg+ | ||||||||||||||||||||
JNJ-3989 200 mg HBeAg- | ||||||||||||||||||||
-5 | JNJ-3989 100 mg + JNJ-6379 HBeAg+ | |||||||||||||||||||
in | JNJ-3989 100 mg + JNJ-6379 HBeAg- | |||||||||||||||||||
Change | -6 | |||||||||||||||||||
-7 | ||||||||||||||||||||
B. | ||||||||||||||||||||
JNJ-6379 | JNJ-3989 40 mg | JNJ-3989 100 mg | JNJ-3989 200 mg | JNJ-3989 100 mg | ||||||||||||||||
+ JNJ-6379 | ||||||||||||||||||||
Treatment Arm | ||||||||||||||||||||
72, | ||||||||||||||||||||
PBO HBeAg+ | ||||||||||||||||||||
0 | PBO HBeAg- | |||||||||||||||||||
Week | JNJ-6379 HBeAg+ | |||||||||||||||||||
JNJ-6379 HBeAg- | ||||||||||||||||||||
JNJ-3989 40 mg HBeAg+ | ||||||||||||||||||||
at | -1 | |||||||||||||||||||
JNJ-3989 40 mg HBeAg- | ||||||||||||||||||||
baseline | JNJ-3989 100 mg HBeAg+ | |||||||||||||||||||
IU/mL | -2 | JNJ-3989 100 mg HBeAg- | ||||||||||||||||||
JNJ-3989 200 mg HBeAg+ | ||||||||||||||||||||
JNJ-3989 200 mg HBeAg- | ||||||||||||||||||||
HBsAgfrom | -3 | JNJ-3989 100 mg + JNJ-6379 HBeAg+ | ||||||||||||||||||
10 | ||||||||||||||||||||
log | -4 | JNJ-3989 100 mg + JNJ-6379 HBeAg- | ||||||||||||||||||
Figure 4. Mean (±SE) change in HBeAg over time in HBeAg+ patients (A) NCT or (B) VS.
A. | B. | ||||||||||||||||||||||
HBeAg | 0 | Follow-up | HBeAg | 0 | |||||||||||||||||||
IU/mL | IU/mL | ||||||||||||||||||||||
-0.5 | -0.5 | ||||||||||||||||||||||
(SE) change in | 10 | -1.0 | (SE) change in | 10 | -1.0 | Follow-up | |||||||||||||||||
baseline, log | baseline, log | ||||||||||||||||||||||
-1.5 | -1.5 | ||||||||||||||||||||||
-2.0 | -2.0 | ||||||||||||||||||||||
Mean from | -2.5 | Mean from | -2.5 | ||||||||||||||||||||
-3.0 | 0 | 4 | 8 | 12 | 16 | 20 24 28 | 32 | 36 40 44 48 F4 F8 F12 F16F20F24 | -3.0 | 0 | 4 | 8 | 12 | 16 | 20 24 | 28 | 32 | 36 40 44 48 F4 F8 F12 F16F20F24 | |||||
Weeks | Weeks | ||||||||||||||||||||||
PBO | JNJ-6379 | JNJ-3989 40 mg | JNJ-3989 100 mg | JNJ-3989 200 mg | JNJ-3989 100 mg + JNJ-6379 |
Table 2. Baseline and Change From Baseline HBeAg Values
NCT and HBeAg+ | VS and HBeAg+ | |||||||||||||||
Change | Change | |||||||||||||||
Change | Change | from BL | Change | Change | from BL | |||||||||||
from BL | from BL | at FU | from BL | from BL | at FU | |||||||||||
BL, | at W24, | <> | at W48, | <> | W24, | BL, | at W24, | <> | at W48, | <> | W24, | |||||
N | log10 | log10 | at W24, | log10 | at W48, | log10 | FU W24, | N | log10 | log10 | at W24, | log10 | at W48, | log10 | FU W24, | |
IU/mL | IU/mL | n/N (%) IU/mL n/N (%) | IU/mL | n/N (%) | IU/mL | IU/mL | n/N (%) IU/mL n/N (%) | IU/mL | n/N (%) | |||||||
PBO | 7 | 1.92 | -0.97 | 0/7 | -1.45 | 1/7 | -1.50 | 1/7 | 6 | -0.02 | -0.15 | 0/6 | -0.39 | 1/6 | -0.35 | 1/6 |
(0.54) | (0.35) | (0.63) | (14.3) | (0.64) | (14.3) | (0.07) | (0.07) | (0.40) | (16.7) | (0.36) | (16.7) | |||||
JNJ-6379 | 8 | 1.60 | -1.27 | 1/7 | -1.49 | 1/7 | -1.56 | 1/8 | 7 | -0.11 | -0.18 | 0/6 | -0.20 | 0/7 | -0.26 | 0/7 |
(0.42) | (0.31) | (14.3) | (0.31) | (14.3) | (0.28) | (12.5) | (0.18) | (0.08) | (0.16) | (0.26) | ||||||
JNJ-3989 | 15 | 1.86 | -0.69 | 1/15 | -1.03 | 2/13 | -1.13 | 2/15 | 15 | 0.67 | -0.39 | 1/15 | -0.54 | 1/14 | -0.43 | 1/12 |
40 mg | (0.38) | (0.12) | (6.7) | (0.17) | (15.4) | (0.19) | (13.3) | (0.22) | (0.05) | (6.7) | (0.35) | (7.1) | (0.36) | (8.3) | ||
JNJ-3989 | 14 | 2.77 | -1.53 | 1/14 | -2.09 | 2/14 | -2.06 | 2/13 | 11 | 0.29 | -0.60 | 3/11 | -0.75 | 3/10 | -0.64 | 3/10 |
100 mg | (0.22) | (0.13) | (7.1) | (0.25) | (14.3) | (0.24) | (15.4) | (0.30) | (0.10) | (27.3) | (0.39) | (30.0) | (0.40) | (30.0) | ||
JNJ-3989 | 16 | 2.65 | -1.60 | 0/15 | -2.22 | 1/14 | -2.52 | 2/14 | 14 | 0.40 | -0.70 | 1/14 | -0.78 | 1/14 | -0.75 | 1/13 |
200 mg | (0.25) | (0.23) | (0.30) | (7.1) | (0.33) | (14.3) | (0.22) | (0.12) | (7.1) | (0.56) | (7.1) | (0.53) | (7.7) | |||
JNJ-3989 + | 13 | 2.52 | -1.66 | 0/15 | -2.48 | 1/12 | -2.59 | 1/12 | 14 | 0.02 | -0.39 | 2/14 | -0.52 | 4/14 | -0.49 | 1/13 |
JNJ-6379 | (0.25) | (0.20) | (0.25) | (8.3) | (0.26) | (8.3) | (0.69) | (0.12) | (14.3) | (0.48) | (28.6) | (0.50) | (7.7) | |||
BL, baseline; W, Week.
Values are mean (SE) unless otherwise noted; LLOQ = 0.11 IU/mL = -0.96 log10 IU/mL.
Changes in HBV DNA
- A numerically greater decline in HBV DNA was seen with JNJ-3989 100 and 200 mg and JNJ-6379-containing arms compared to control in NCT HBeAg+ patients (Figure 5A)
- Assessment of mean change from baseline in HBV DNA in NCT HBeAg- patients was limited by a high proportion of patients reaching HBV DNA Figure 5B and Table 3)
Figure 5. Mean (±SE) change in HBV DNA over time in patients NCT and (A) HBeAg+ or (B) HBeAg-.
A. | B. | ||||||||||||||||||||||||
DNA | 0 | Follow-up | DNA | 0 | Follow-up | ||||||||||||||||||||
IU/mL | IU/mL | ||||||||||||||||||||||||
-1 | -1 | ||||||||||||||||||||||||
-2 | -2 | ||||||||||||||||||||||||
HBV | 10 | -3 | HBV | 10 | -3 | ||||||||||||||||||||
Mean (SE) change in | from baseline, log | Mean (SE) change in | from baseline, log | ||||||||||||||||||||||
-4 | -4 | ||||||||||||||||||||||||
-5 | -5 | ||||||||||||||||||||||||
-6 | -6 | ||||||||||||||||||||||||
-7 | -7 | ||||||||||||||||||||||||
-80 | -8 | ||||||||||||||||||||||||
4 | 8 | 12 | 16 | 20 24 28 | 32 | 36 40 44 48 F4 F8 F12 F16F20F24 | 0 | 4 | 8 | 12 | 16 | 20 | 24 | 28 | 32 | 36 | 40 44 48 F4 | F8 F12 F16F20F24 | |||||||
Weeks | Weeks | ||||||||||||||||||||||||
PBO | JNJ-6379 | JNJ-3989 40 mg | JNJ-3989 100 mg | JNJ-3989 200 mg | JNJ-3989 100 mg + JNJ-6379 |
Table 3. Baseline and Change From Baseline HBV DNA Values
NCT and HBeAg+ | NCT and HBeAg- | |||||||||||||||
Change | Change | |||||||||||||||
Change | Change | from BL | Change | Change | from BL | |||||||||||
from BL | from BL | at FU | from BL | from BL | at FU | |||||||||||
BL, | at W24, | <> | at W48, | <> | W24, | BL, | at W24, | <> | at W48, | <> | W24, | |||||
N | log10 | log10 | at W24, | log10 | at W48, | log10 | FU W24, | N | log10 | log10 | at W24, | log10 | at W48, | log10 | FU W24, | |
IU/mL | IU/mL | n/N (%) | IU/mL | n/N (%) | IU/mL | n/N (%) | IU/mL | IU/mL | n/N (%) | IU/mL | n/N (%) | IU/mL | n/N (%) | |||
PBO | 7 | 7.92 | -5.03 | 2/7 | -5.46 | 4/7 | -5.72 | 5/7 | 9 | 5.20 | -3.81 | 5/9 | -4.07 | 9/9 | -4.11 | 8/9 |
(0.49) | (0.56) | (28.6) | (0.90) | (57.1) | (0.82) | (71.4) | (0.47) | (0.43) | (55.6) | (0.48) | (100) | (0.47) | (88.9) | |||
JNJ-6379 | 8 | 8.03 | -6.17 | 1/7 | -6.72 | 5/7 | -6.72 | 6/8 | 10 | 5.24 | -4.22 | 7/9 | -4.83 | 8/8 | -4.39 | 9/9 |
(0.35) | (0.38) | (14.3) | (0.43) | (71.4) | (0.42) | (75.0) | (1.74) | (0.47) | (77.8) | (0.50) | (100) | (0.55) | (100) | |||
JNJ-3989 | 7.57 | -5.28 | 2/15 | -5.89 | 8/14 | -6.12 | 8/15 | 4.87 | -3.84 | 15/16 | -3.96 | 15/16 | -4.02 | 16/16 |
Figure 6. Mean (±SE) change in HBcrAg over time by treatment history and HBeAg status in patients with HBcrAg >LLOQ at baseline who received treatment with either PBO or JNJ-3989 200 mg.
0 | Follow-up | ||||||||||||||||||
HBcrAg | |||||||||||||||||||
IU/mL | -0.5 | ||||||||||||||||||
-1.0 | |||||||||||||||||||
Mean (SE) change in | 10 | ||||||||||||||||||
from baseline, log | -1.5 | ||||||||||||||||||
-2.0 | |||||||||||||||||||
-2.5 | |||||||||||||||||||
-3.0 | |||||||||||||||||||
-3.5 | |||||||||||||||||||
0 | 4 | 8 | 12 | 16 | 20 | 24 | 28 | 32 | 36 | 40 | 44 | 48 | F4 | F8 | F12 | F16 | F20 F24 | ||
Weeks |
PBO: NCT HBeAg+ | PBO: NCT HBeAg- | PBO: VS HBeAg+ | PBO: VS HBeAg- |
JNJ-3989: NCT HBeAg+ | JNJ-3989: NCT HBeAg- | JNJ-3989: VS HBeAg+ | JNJ-3989: VS HBeAg- |
Table 4. Baseline and Change From Baseline Mean (SE) HBcrAg by Subgroup for NA and JNJ-3989 200 mg Treatment Arms in Patients With HBcrAg >LLOQ at Baseline
Change from BL | Change from BL | Change from BL | ||||||
BL, | at W24, | at W48, | at FU W24, | |||||
N* | log10 IU/mL | log10 IU/mL | n/N (%) | log10 IU/mL | n/N (%) | log10 IU/mL | FU W24, n/N (%) | |
NCT HBeAg+ | ||||||||
PBO | 7 | 7.76 (0.47) | -1.31 (0.33) | 0/7 | -1.69 (0.53) | 0/7 | -1.71 (0.59) | 0/7 |
JNJ-3989 200 mg | 16 | 8.43 (0.28) | -2.01 (0.18) | 0/15 | -2.56 (0.25) | 0/14 | -2.74 (0.30) | 0/14 |
NCT HBeAg- | ||||||||
PBO | 8 | 4.8 (0.55) | -1.23 (0.32) | 3/8 (37.5) | -1.26 (0.43) | 3/8 (37.5) | -1.24 (0.45) | 3/8 (37.5) |
JNJ-3989 200 mg | 16 | 4.71 (0.37) | -1.58 (0.37) | 6/16 (37.5) | -1.59 (0.35) | 7/16 (43.8) | -1.60 (0.36) | 6/15 (40.0) |
VS HBeAg+ | ||||||||
PBO | 6 | 5.42 (0.14) | -0.12 (0.04) | 0/6 | -0.23 (0.08) | 0/6 | -0.18 (0.04) | 0/6 |
JNJ-3989 200 mg | 14 | 5.80 (0.22) | -0.82 (0.14) | 0/14 | -0.91 (0.17) | 0/14 | -0.76 (0.15) | 0/14 |
VS HBeAg- | ||||||||
PBO | 11 | 3.73 (0.19) | -0.17 (0.06) | 3/11 (27.3) | -0.14 (0.10) | 1/11 (9.1) | -0.12 (0.10) | 1/11 (9.1) |
JNJ-3989 200 mg | 22 | 3.92 (0.12) | -0.41 (0.07) | 4/22 (18.2) | -0.23 (0.13) | 2/22 (9.1) | -0.33 (0.09) | 4/18 (22.2) |
*Patients with detectable levels of HBcrAg at baseline.
Values are mean (SE) unless otherwise noted; LLOQ = 3 log10 IU/mL.
Changes in HBV RNA
- JNJ-3989200 mg resulted in pronounced reduction of HBV RNA across all patient populations, with up to 3.66 log10 reduction in NCT HBeAg+ patients (Figure 7 and Table 5)
- Reductions in HBV RNA were sustained through 24 weeks of follow-up
- Assessment of RNA reduction in VS patients was hampered by a high proportion of patients achieving HBV RNA
Figure 7. Mean (±SE) change in HBV RNA over time by treatment history and HBeAg status in patients with HBV RNA >LOD at baseline who received treatment with either PBO or JNJ-3989 200 mg.
Follow-up
HBV RNA | copies/mL | 0 | |||||||||||||||||
-1 | |||||||||||||||||||
in | 10 | -2 | |||||||||||||||||
Mean (SE) change | from baseline, log | ||||||||||||||||||
-3 | |||||||||||||||||||
-4 | |||||||||||||||||||
-5 | |||||||||||||||||||
0 | 4 | 8 | 12 | 16 | 20 | 24 | 28 | 32 | 36 | 40 | 44 | 48 | F4 | F8 | F12 | F16 | F20 F24 | ||
Weeks |
PBO: NCT HBeAg+ | PBO: NCT HBeAg- | PBO: VS HBeAg+ | PBO: VS HBeAg- |
JNJ-3989: NCT HBeAg+ | JNJ-3989: NCT HBeAg- | JNJ-3989: VS HBeAg+ | JNJ-3989: VS HBeAg- |
Table 5. Baseline and Change From Baseline Mean (SE) HBV RNA by Subgroup for PBO and JNJ-3989 200 mg Treatment Arms in Patients With HBV RNA >LOD at Baseline
Change from | |||||||
Change from BL | Change from BL | BL at | |||||
BL, | at W24, | at W48, | FU W24, | FU W24, | |||
N* | log10 copies/mL | log10 copies/mL | n/N (%) | log10 copies/mL | n/N (%) | log10 copies/mL | n/N (%) |
for HBeAg, HBcrAg, | |
HBV DNA, and HBV RNA | |
The greatest reductions | |
> in viral markers were | |
observed during the | |
48-week treatment phase | |
and in patients who were | |
> | NCT and HBeAg+ |
The reductions in HBeAg, | |
HBcrAg, and HBV RNA | |
generally remained stable | |
or declined during the | |
24-weekfollow-up phase | |
Safety results have been | |
> previously reported and | |
showed that all regimens | |
were generally safe and | |
well tolerated3 |
Conclusions
> | JNJ-3989, with or without |
JNJ-6379, reduced all viral | |
markers, with the strongest | |
effect observed for HBsAg | |
This study supports the | |
> continued development of | |
JNJ-3989 in combination | |
therapies that may provide |
Male, n (%) | 45 (60.0) | 61 (62.9) |
Asian, n (%) | 42 (56.0) | 16 (16.5) |
Age, years | 37.2 (10.99) | 40.6 (10.17) |
HBsAg, log10 IU/mL | 4.48 (0.79) | 3.95 (0.50) |
HBV DNA, log10 IU/mL | 7.93 (1.11) | 5.07 (1.37) |
ALT, U/L | 107.1 (103.16) | 92.5 (94.08) |
HBeAg, log10 IU/mL | 2.31 (1.16) | - |
HBcrAg, n (%) <> | 0 | 19 (19.8) |
HBV RNA, n (%) <>§ | 0 | 30 (31.9) |
Liver stiffness,II kPa | 6.30 (1.88) | 5.90 (1.45) |
49 (73.1) | 155 (67.1) |
48 (71.6) | 84 (36.5) |
41.7 (9.06) | 46.2 (10.21) |
3.61 (0.58) | 3.46 (0.61) |
Not applicable† | Not applicable† |
24.4 (11.60) | 23.7 (12.21) |
0.27 (0.79) | - |
0 | 110 (48.2) |
23 (34.8) | 202 (89.0) |
4.84 (1.33) | 4.92 (1.38) |
in | -5 |
Change | |
-6 | |
-7 |
Patients who achieved HBsAg loss are noted with red dots.
Changes in HBeAg
• | Declines in HBeAg were observed across all treatment arms and sustained during follow-up, with reductions |
being JNJ-3989 dose dependent (Figure 4). Of note, the combination arm of JNJ-3989 100 mg + JNJ-6379 had the | |
numerically greatest decline among NCT patients | |
• | Reductions were most pronounced in NCT patients, potentially due to higher baseline HBeAg levels (Figure 4 |
and Table 2) | |
• | The number of patients in each treatment arm who achieved HBeAg |
40 mg | 15 | (0.38) | (0.25) | (13.3) | (0.29) | (57.1) | (0.29) | (53.3) | 18 | (0.30) | (0.29) | (93.8) | (0.36) | (93.8) | (0.33) | (100.0) |
JNJ-3989 | 14 | 7.77 | -5.44 | 3/14 | -6.41 | 8/14 | -6.40 | 8/13 | 19 | 5.29 | -4.08 | 15/18 | -4.22 | 13/18 | -4.31 | 13/16 |
100 mg | (0.29) | (0.28) | (21.4) | (0.22) | (57.1) | (0.25) | (61.5) | (0.33) | (0.23) | (83.3) | (0.36) | (72.2) | (0.42) | (81.3) | ||
JNJ-3989 | 16 | 8.29 | -6.07 | 2/15 | -6.56 | 3/14 | -6.82 | 7/14 | 19 | 5.26 | -4.16 | 14/18 | -4.28 | 16/18 | -4.24 | 15/17 |
200 mg | (0.21) | (0.16) | (13.3) | (0.20) | (21.4) | (0.26) | (50.0) | (0.35) | (0.32) | (77.8) | (0.35) | (88.9) | (0.38) | (88.2) | ||
JNJ-3989 + | 13 | 8.04 | -6.00 | 2/13 | -6.72 | 6/12 | -6.87 | 9/12 | 20 | 4.62 | -3.63 | 18/19 | -3.60 | 17/18 | -3.71 | 18/18 |
JNJ-6379 | (0.28) | (0.19) | (15.4) | (0.24) | (50.0) | (0.27) | (75.0) | (0.24) | (0.26) | (94.7) | (0.29) | (94.4) | (0.29) | (100) | ||
Values are mean (SE) unless otherwise noted.
Changes in HBcrAg
• JNJ-3989 200 mg resulted in pronounced reduction of HBcrAg in NCT patients, with up to 2.56 log10 reduction at |
Week 48 in the HBeAg+ subgroup, while HBcrAg decline in VS patients was limited, potentially due to lower baseline |
levels (Figure 6 and Table 4) |
NCT HBeAg+ | ||||||||
PBO | 6 | 6.90 (0.67) | -1.12 (0.53) | 0/6 | -1.34 (0.57) | 0/6 | -1.54 (0.62) | 0/6 |
JNJ-3989 200 mg | 16 | 7.33 (0.23) | -2.96 (0.26) | 2/15 (13.3) | -3.66 (0.30) | 4/14 (28.6) | -3.70 (0.31) | 5/13 (38.5) |
NCT HBeAg- | ||||||||
PBO | 5 | 5.02 (0.32) | -2.11 (0.47) | 2/5 (40.0) | -2.59 (0.34) | 3/5 (60.0) | -2.89 (0.33) | 3/4 (75.0) |
JNJ-3989 200 mg | 13 | 4.64 (0.32) | -2.31 (0.30) | 10/13 (76.9) | -2.37 (0.30) | 11/13 (84.6) | -2.23 (0.36) | 10/11 (90.9) |
VS HBeAg+ | ||||||||
PBO | 5 | 3.31 (0.47) | -0.10 (0.20) | 1/5 (20.0) | -0.41 (0.14) | 3/5 (60.0) | -0.18 (0.12) | 1/5 (20.0) |
JNJ-3989 200 mg | 9 | 4.29 (0.44) | -1.69 (0.26) | 5/9 (55.6) | -1.95 (0.35) | 7/9 (77.8) | -1.87 (0.30) | 6/8 (75.0) |
VS HbeAg- | ||||||||
PBO | 3 | 3.25 (0.47) | 0.20 (0.40) | 1/3 (33.3) | 0.29 (0.41) | 1/3 (33.3) | 0.46 (0.18) | 0/2 |
functional cure to patients |
with CHB |
HBcrAg, hepatitis B core related antigen; LOD, limit of detection; SD, standard deviation. *Mean (SD) unless otherwise noted.
†98% of patients had HBV DNA 10 IU/mL = 20 IU/mL). ‡LLOQ = 3.0 log10 IU/mL.
§LOD = 2.49 log10 copies/mL.
IIMeasured with FibroScan® Paris, France.
patients, with the greatest proportion of patients reaching HBeAg JNJ-3989 100 mg (n = 3, 30.0%) |
and JNJ-3989 100 mg + JNJ-6379 (n = 4, 28.6%) treatment arms in VS patients (Table 2)
• The proportion of patients reaching HBcrAg |
JNJ-3989 200 mg (Table 4) |
JNJ-3989 200 mg | 9 | 3.13 (0.14) | -0.84 (0.15) | 8/9 (88.9) | -0.88 (0.17) | 8/9 (88.9) | -0.75 (0.26) | 5/7 (71.4) |
*Patients with detectable levels of HBV RNA at baseline.
Values are mean (SE) unless otherwise noted; N = patients with detectable HBV RNA at baseline; LOD = 2.49 log10 copies/mL.
References | Acknowledgments | Disclosures | |
1. | Gane E, et al. Presented at: European Association for the Study of the Liver (EASL) | This study was supported by Janssen Research & Development, LLC. Medical writing | M-FY serves as advisor/consultant for AbbVie, AlloVir International, Arbutus Biopharma, Bristol Myers Squibb, ClearB Therapeutics, Dicerna Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, and Spring Bank Pharmaceuticals; and receives grant/research |
Digital International Liver Congress™; August 27-29, 2020; Virtual. Oral GS10. | support was provided by Kim Caldwell, PhD, of Cello Health Communications/MedErgy, | support from Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myers Squibb, Fujirebio Diagnostics Inc., Gilead Sciences, Merck Sharp & Dohme, Roche, Spring Bank Pharmaceuticals, and Sysmex Corp. TA serves as advisor/consultant for AbbVie, Antios Therapeutics, Enyo Pharma, | |
2. | Berke JM, et al. Antimicrob Agents Chemother. 2020;64(5):e02439-19. | and was funded by Janssen Global Services, LLC. | Gilead Sciences, GlaxoSmithKline, Janssen, and Roche. IMJ serves as a consultant for Aligos, Arbutus, Janssen, and Gilead; has received research funds from Janssen and Assembly Biosciences; and serves on a data monitoring committee for GlaxoSmithKline. MB serves as a consultant and speaker for |
3. | Yuen MF, et al. Presented at: American Association for the Study of Liver | AbbVie, Gilead Sciences, Janssen, Esai, MSD, and Roche. HLAJ received grants from AbbVie, Arbutus, Gilead Sciences, Janssen, and Roche; and is a consultant for Arbutus, Arena, Enyo, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, Vir Biotechnology Inc., and Viroclinics. TT has received | |
Diseases (AASLD) The Liver Meeting; November 12-15, 2021; Virtual. Oral LO10. | lecturer fees from Bristol Myers Squibb, Gilead Sciences, and GlaxoSmithKline; research funding from Janssen; and consulting fees from Janssen. JLH serves as advisor/consultant for Aligos, Assembly, Gilead Sciences, Johnson & Johnson, and Roche; and receives grant/research support from | ||
Bristol Myer Squibb. TNK, TL, RK, CG-A, CM, JJ, TV, OL, US, and MB are employees of Janssen Pharmaceuticals and may be Johnson & Johnson stockholders. | |||
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Presented at the European Association for the Study of the Liver (EASL) International Liver Congress™; June 22-26, 2022; London, UK & Online.
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