Date: 2017-09-25
Type of
information: Results
phase: 2
Announcement: results
Company: Arbutus Biopharma (Canada)
Product: ARB-1467
Action
mechanism:
- RNAi. Arbutus' RNAi candidate ARB-1467 comprises three RNAi triggers that target all four HBV transcripts, and has been shown in preclinical studies to reduce all viral antigen levels as well as cccDNA and HBV DNA. ARB-1467 utilizes Arbutus' proprietary lipid nanoparticle (LNP) platform.
Disease: hepatitis B
Therapeutic
area: Infectious diseases
Country: Australia, New Zealand
Trial
details:
- The Phase II trial is a multi-dose study in chronic HBV patients who are also receiving stable nucleot(s)ide analog therapy. The trial consists of four cohorts, the first three of which enrolled eight subjects each (six receiving three monthly doses of ARB-1467 and two receiving placebo) and the fourth is enrolling twelve patients (all of whom will receive 5 bi-weekly doses of ARB-1467). Cohorts 1, 2, and 4 include HBeAg- patients and Cohort 3 included HBeAg+ patients. The protocol for Cohort 4 allows for dosing to be extended to up to one year of ARB-1467 dosing for patients who meet predefined response criteria. (NCT02631096)
Latest
news:
- • On September 25, 2017, Arbutus Biopharma announced topline results of the bi-weekly dosing segment of Cohort 4 of the Phase II study of its RNAi agent, ARB-1467.
- In the bi-weekly dosing segment of Cohort 4, twelve HBeAg negative chronically infected HBV patients on stable nucleotide therapy were given five doses of ARB-1467 on a bi-weekly dosing schedule. All twelve patients in Cohort 4 experienced reductions in serum HBsAg levels, with an average reduction in serum HBsAg of 1.4 log10, which was greater than that observed with monthly dosing in Cohorts 1-3. Seven of the twelve patients met the predefined response criteria (at least 1 log10 reduction in serum HBsAg level and a serum HBsAg level below 1000 IU/mL) at or before day 71. Five of the seven patients who met the response criteria had their serum HBsAg reduced to low absolute levels (below 50 IU/mL) during the bi-weekly dosing period. Initial results for the monthly dosing extension suggest that monthly dosing is not sufficient to maintain or improve upon these reductions in s-antigen levels. Dosing with ARB-1467 in Cohort 4 has been generally well tolerated, with no serious adverse events. Eleven of the twelve patients received all five bi-weekly doses. ALT values remained normal throughout treatment. Detailed results of Cohort 4 are expected to be presented at AASLD in October.
- Arbutus will initiate a new study in 4Q17 to study longer term bi-weekly dosing of ARB-1467 in combination with tenofovir followed by the addition of pegylated interferon for patients who meet a predefined response criteria. This study will explore the effect of driving HBsAg to very low levels with ARB-1467 along with an immune modulating mechanism.
- • On April 22, 2017, Arbutus Biopharma presented results of the first three cohorts of a Phase II study of its RNAi agent, ARB-1467, at the European Association for the Study of the Liver (EASL) in Amsterdam. The presentation is titled "A Phase 2a Study Evaluating the Multi-Dose Activity of ARB-1467 in HBeAg Positive and Negative Virally Suppressed Subjects with Hepatitis B"
| Cohort |
ARB-1467
(mg/kg) |
HBeAg |
Single Dose HBsAg Reduction
(log10 IU/mL) |
Multiple Dose HBsAg Reduction
(log10 IU/mL) |
| N |
Meana |
Mean
Maxb |
Maxc |
N |
Meana |
Mean
Maxb |
Maxc |
>0.5 logd |
>1.0 logd |
| 1 |
0.2 |
Neg |
6 |
-0.3 |
-0.4 |
-1.0 |
6 |
-0.6 |
-0.7 |
-1.3 |
5 |
1 |
| 2 |
0.4 |
Neg |
6 |
-0.2 |
-0.3 |
-0.8 |
5e |
-0.8 |
-0.9 |
-1.1 |
4 |
3 |
| 3 |
0.4 |
Pos |
6 |
-0.2 |
-0.3 |
-0.6 |
6 |
-0.7 |
-0.8 |
-1.6 |
4 |
2 |
| Placebo |
|
All |
6f |
0.0 |
0.0 |
-0.1 |
6 |
0.0 |
-0.1 |
-0.1 |
0 |
0 |
- a The mean serum HBsAg reduction is the nadir value of the arithmetic mean of all values observed at each time point.
- b The mean maximum HBsAg reduction is the mean of each patient's maximum reduction in serum HBsAg.
- c Maximum HBsAg reduction is the best single reduction among all patients in a cohort.
- d Number of patients reaching this threshold
- e Multiple dose results in Cohort 2 exclude one patient that discounted at day 36 due to an acute hepatitis E virus (HEV) super-infection
- f Placebo results are based on six subjects (two from each cohort).
- In addition to the ongoing Phase 2 Cohort 4, Arbutus will initiate a new study in 2H17 to study longer term dosing of ARB-1467 in combination with nucleot(s)ide analog therapy as well as pegylated interferon or another immune modulator. This study will explore the possibility of driving HBsAg to very low, if not undetectable, levels with ARB-1467 along with an immune modulating mechanism. While this study may include pegylated interferon as the immune boosting component that could lead to later stage development, Arbutus also plans to evaluate other immunomodulatory approaches, such as its proprietary checkpoint inhibitor program, in future combination studies. Arbutus' core protein/capsid inhibitor AB-423, which is being evaluated for monotherapy safety and activity in 2017, will be ready to be included in studies with RNAi and approved agents in 2018. ARB-1740, a next generation RNAi agent, is being evaluated in an ongoing multi-dosing study in HBV patients, the results of which will be announced in 2H17 to enable a potency comparison between ARB-1467 and ARB-1740.
- • On December 12, 2016, Arbutus Biopharma reported new results from the ongoing Phase II study of ARB-1467 in chronically infected HBV patients on stable nucleos(t)ide therapy, and plans for a new cohort to be added to the Phase II study. In September 2016, Arbutus reported single dose ARB-1467 results for Cohorts 1 (0.2mg/kg) and 2 (0.4 mg/kg) and multiple dose results from Cohort 1 (Cohorts 1 and 2 enrolled HBeAg- patients). Now Arbutus is reporting multiple dose results from Cohort 2, which show a significant reduction in HBsAg. In both Cohort 1 and Cohort 2, an additive, step-wise reduction in HBsAg was observed with each dose. The HBsAg reduction achieved after three monthly doses of 0.4mg/kg in Cohort 2 was greater than that seen at 0.2 mg/kg in Cohort 1, demonstrating a dose-response seen with repeat dosing. In Cohort 2, three of the five patients who received three doses of ARB-1467 experienced a greater than 1 log10 IU/mL reduction in serum HBsAg. The Company plans to add another cohort to this study to explore bi-weekly administration of the 0.4 mg/kg dose.
| Cohort |
ARB-1467
(mg/kg) |
HBeAg |
Single Dose HBsAg Reduction
(log10 IU/mL) |
Multiple Dose HBsAg Reduction
(log10 IU/mL) |
| N |
Meana |
Mean Maxb |
Maxc |
N |
Meana |
Mean Maxb |
Maxc |
>0.5 logd |
>1.0 logd |
| 1 |
0.2 |
Neg |
6 |
-0.3 |
-0.4 |
-1.0 |
6 |
-0.6 |
-0.7 |
-1.3 |
5 |
1 |
| 2 |
0.4 |
Neg |
6 |
-0.2 |
-0.3 |
-0.8 |
5e |
-0.9 |
-1.0 |
-1.3 |
4 |
3 |
| Placebo |
|
All |
4f |
0.0 |
0.0 |
-0.1 |
4 |
0.0 |
-0.1 |
-0.1 |
0 |
0 |
- a The mean serum HBsAg reduction is the nadir value of the arithmetic mean of all values observed at each time point.
- b The mean maximum HBsAg reduction is the mean of each patient's maximum reduction in serum HBsAg.
- c Maximum HBsAg reduction is the best single reduction among all patients in a cohort.
- d Number of patients reaching this threshold
- e Multiple dose results in Cohort 2 exclude one patient that discounted at day 36 due to elevation of transaminases with a normal bilirubin observed during a scheduled visit 8 days after the second dose. The event was resolved within a few weeks. Additional evaluations are in progress to clarify the etiology.
- f Placebo results are based on four subjects (two from each cohort).
- Treatment with ARB-1467 has been generally well tolerated in this study to date. The initiation of Cohorts 2 and 3, which both utilized the 0.4 mg/kg dose, occurred after an independent safety committee review of the previous cohort(s) safety data. One patient in Cohort 2 discontinued treatment due to a transient elevation of transaminases with a normal bilirubin observed during a scheduled visit eight days after the second dose. The event was resolved within a few weeks. Additional evaluations are in progress to clarify the etiology. Cohort 3, which is evaluating 0.4 mg/kg ARB-1467 in e-antigen positive patients has completed multi-dosing with results expected to be announced in 1H17. All remaining patients (17/18) in Cohorts 1-3 received all three monthly doses of ARB-1467.
Is
general: Yes
