ISIS 505358-CS3 phase 2a study
64 evidence topics · 5 sources
Objective
Primary and secondary objectives
“The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
First evaluation of an antisense oligonucleotide targeting HBV RNA in patients
“This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Exploratory objective: seroconversion
“Exploratory endpoints and objectives included describing the rate of seroconversion to anti-HBs or anti-HBe antibody-positive during treatment with bepirovirsen and then during subsequent treatment with TDF, or ETV if administered (proportion of patients with antibody positivity at day 29 and at week 31).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Centers and enrollment period
“Patients were enrolled from one center in Hong Kong and five centers in the Republic of Korea. The first patient was enrolled on 22 February 2017, the last patient was enrolled on 30 April 2019, the last patient visit was on 18 December 2019 and the study was completed on 19 December 2019.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registry record: identifiers, dates, and locations
| Field | Quoted record |
|---|---|
| GSK study identifier | “205695” |
| Ionis study identifier | “ISIS 505358-CS3” |
| Study start (actual) | “2017-02-24” |
| Primary completion (actual) | “2019-12-18” |
| Study completion (actual) | “2019-12-26” |
| Enrollment (actual) | “31” |
| Number of listed locations | “This study has 7 locations” |
Sponsorship at the time of the trial
Study design
Phase 2, double-blinded, placebo-controlled, dose-escalation design
“The ISIS 505358-CS3 study (GSK study 205695; ClinicalTrials.gov: NCT02981602) was a phase 2, double-blinded, placebo-controlled, dose-escalation trial of bepirovirsen in 31 patients with CHB who were either treatment-naïve (cohorts 1–3, n = 24) or receiving stable NA therapy (cohort 4 (on-NA), n = 7) (Supplementary Fig. 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Randomization and blinding
“Patients were randomized (3:1 within each dose cohort) to bepirovirsen or placebo according to the randomization schedule (permuted block).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“All participants, study monitors, study center personnel and contract research organization personnel were blinded to treatment assignment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Dose escalation and the decision to repeat 300 mg in cohort 3
“Although the Data and Safety Monitoring Board supported dose escalation to 450 mg, it was acknowledged that further evaluation of the 300 mg dose was warranted and the sponsor continued evaluation of the 300 mg dose in the third cohort to allow further characterization of the antiviral effect of bepirovirsen at the 300 mg dose level. One exploratory cohort was added to evaluate add-on treatment with bepirovirsen 300 mg versus placebo in on-NA patients with CHB.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Protocol amendment adding the on-NA cohort
“The amendment, implemented after study initiation and demonstration of the drug’s antiviral effect in treatment naïve patients, was introduced to determine whether antiviral effects could be observed in patients receiving stable NA therapy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registered design details
| Field | Quoted record |
|---|---|
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Masking | “Triple (ParticipantInvestigatorOutcomes Assessor)” |
| Placebo | “Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator” |
Eligibility criteria
Key inclusion criteria
“Inclusion criteria were chronic HBV infection ≥6 months and serum HBsAg ≥50 IU ml−1; both HBeAg-positive and HBeAg-negative patients could participate. Treatment-naïve patients had a plasma HBV DNA ≥2 × 103 IU ml−1. On-NA patients had HBV DNA adequately suppressed (plasma or serum HBV DNA below LLOQ (20 IU ml−1)), were taking stable TDF or ETV for ≥12 months and expected to continue taking stable TDF or ETV without change through to the end of their participation in this study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Key exclusion criteria
“Exclusion criteria were: a history of liver cirrhosis and/or evidence of cirrhosis, liver failure, liver disease other than hepatitis B, Gilbert’s syndrome or history of laboratory results consistent with Gilbert’s syndrome, extrahepatic disorders possibly related to HBV immune complexes, excess alcohol consumption; co-infection with hepatitis C virus, hepatitis D virus or HIV; screening laboratory values of ALT and AST >5× ULN.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Treatment
Dosing schedule and follow-up
“Treatment-naïve patients were randomized to placebo (n = 6), bepirovirsen 150 mg (n = 6) or 300 mg (n = 12) and on-NA patients to placebo (n = 2) or bepirovirsen 300 mg (n = 5) (Supplementary Fig. 2). Six doses of bepirovirsen or placebo were administered via subcutaneous injection during the 4-week treatment period: twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Patients were then followed for 26 weeks.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Loading doses and nucleos(t)ide analogue treatment after day 29
“Twice weekly dosing in weeks 1 and 2 constituted loading doses, with the aim of reaching steady-state hepatic concentrations following the week 3 dose (that is, before the last dose in the schedule) instead of 13–15 weeks without loading.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“After these assessments, all patients received daily treatment with NA to end of study (week 31; day 211). Patients already on a stable NA regimen (on-NA) received treatment throughout (during all study periods).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registered administration by cohort
Study outcomes
Rationale for using adverse events and clinical laboratory assessments as the primary endpoints
Primary safety endpoints
“The primary objective of the study was to examine the safety and tolerability of bepirovirsen administration in treatment-naïve participants with CHB infection (primary endpoints were AEs, clinical laboratory tests, vital signs and body weight, physical examination, electrocardiogram and concomitant medication usage).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
No primary efficacy endpoint in the protocol
Secondary antiviral endpoints
“Secondary objectives and endpoints were to: examine the effects of bepirovirsen administration on plasma HBV DNA concentration (change from baseline to day 29 and week 31); examine the effects of bepirovirsen administration on serum HBsAg concentration (change from baseline to day 29 and week 31, proportion of participants with HBsAg loss at day 29 and at week 31)” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Rationale for HBsAg as the antiviral measure
“The treatment goal for patients with CHB is to obtain functional cure, namely, sustained loss of detectable serum HBsAg with undetectable HBV DNA” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Functional cure is associated with improved clinical outcomes and allows patients to be off-therapy with a minimal risk of relapse” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Protocol background on HBsAg loss as the treatment endpoint
Day 29 as the time of antiviral assessment
Dose-limiting toxicity definition
Statistical analysis description
Number of participants (Planned and analyzed)
Sample size basis
“There is no statistical rationale for the selected sample size of eight participants per cohort. The sample size was based on prior experience to ensure adequate initial assessment of the safety and tolerability of bepirovirsen while minimizing the number of patients unnecessarily exposed to the drug. The protocol included the ability to repeat a cohort if additional data at a specified cohort was warranted. No power calculation was performed.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Participants enrolled and the combination of cohorts 2 and 3
Description of analysis sets
Safety, full analysis, and per-protocol populations
“The safety population included all randomized patients who received one or more doses of bepirovirsen or placebo and was used for all safety analyses. The full analysis population (representing the practically feasible intent-to-treat population) included patients from the safety population with baseline and one or more post-baseline plasma HBV DNA concentrations. The per-protocol population included patients in the full analysis set who received at least five doses of bepirovirsen or placebo during the 4-week treatment period, had plasma HBV DNA concentration measured at day 29, and had no significant protocol deviations that would be expected to affect efficacy assessments. The full analysis and per protocol populations were used for efficacy endpoints.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Exploratory comparisons against pooled placebo
“There were no formal hypotheses; efficacy analyses for comparison between bepirovirsen and the pooled placebo group were performed in an exploratory manner.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The LOCF method was used to impute missing values. Comparison between bepirovirsen and a pooled placebo group was performed separately for each dose level using an analysis of covariance model with baseline as a covariate and treatment group as a factor.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Unplanned unblinded interim analyses
Results
Participant disposition
One withdrawal; all other participants completed
“One on-NA patient withdrew from the study on day 8, after two doses of bepirovirsen 300 mg, due to transient mild fevers after each dose that were considered treatment-related; all other patients completed the treatment and follow-up periods.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Baseline characteristics
Demographics and baseline characteristics (safety population)
Registry total age
Efficacy results
HBsAg reduction at day 29
“For treatment-naïve patients, the mean (s.d.) HBsAg reduction from baseline to day 29 was 0.50 (0.57) log10 IU ml−1 (P = 0.245 versus placebo) and 1.56 (1.38) log10 IU ml−1 (P = 0.001 versus placebo) in the bepirovirsen 150 mg and 300 mg arms, respectively (Table 3). For on-NA patients, the mean (s.d.) HBsAg reduction to day 29 was 1.99 (1.80) log10 IU ml−1 (Table 3). By contrast, no placebo-treated patient had a reduction in HBsAg of >0.07 log10 IU ml−1 by day 29. Four patients achieved transient HBsAg loss, defined as HBsAg level below the lower limit of quantitation (LLOQ: 0.05 IU ml−1), by day 29 (n = 3) or by day 36 (n = 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Significance in the on-NA cohort
“HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Depth and duration of HBsAg response with 300 mg in treatment-naive participants
“Six of 12 treatment-naïve patients receiving bepirovirsen 300 mg had HBsAg reduction ≥1.0 log10 IU ml−1 at day 29 (an additional patient had 0.98 log10-transformed reduction) (Fig. 1a). Three of these six patients experienced a reduction of ≥3.0 log10 and two achieved HBsAg loss.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
HBsAg response in the on-NA cohort
“Three of four on-NA patients completing bepirovirsen 300 mg dosing had a HBsAg reduction ≥3.0 log10 at day 29; of these three patients, one reached HBsAg levels below LLOQ on day 29 and another on day 36, whereas the third patient did not reach HBsAg levels below LLOQ.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The fourth patient had no decrease in HBsAg.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Change in HBsAg at week 31 in the registry results
| Measure | Cohort 1, 150 mg | Cohorts 2 and 3, 300 mg | Cohorts 1 to 3, placebo | Cohort 4, 300 mg | Cohort 4, placebo |
|---|---|---|---|---|---|
| Mean (SD) change, log10 IU/ml | “-0.523(0.9299)” | “-0.547(0.6109)” | “0.059(0.3859)” | “-1.519(1.4821)” | “-0.043(0.0178)” |
HBV DNA reduction at day 29 in treatment-naive participants
“The mean (s.d.) HBV DNA reduction from baseline to day 29 was 0.38 (0.42) log10 IU ml−1 (P = 0.116 versus placebo) and 1.66 (1.48) log10 IU ml−1 (P < 0.001 versus placebo) in the bepirovirsen 150 mg and 300 mg arms, respectively (Table 3).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Response by HBeAg status
“All four patients who reached undetectable HBsAg levels were HBeAg negative.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“In the 13 patients who were HBeAg-positive at baseline, minimal reductions in serum HBeAg concentration (IU ml−1) were observed from baseline to day 29 and to week 31 (Supplementary Table 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Transient anti-HBs positivity
“Transient treatment-emergent positivity for anti-HBs antibody, based on a qualitative test performed with the cut-off of ≥11.5 mIU ml−1, was observed for one of six and five of twelve treatment-naïve patients who received bepirovirsen 150 mg and 300 mg, respectively, and for one of five on-NA patients who received bepirovirsen 300 mg.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
Treatment-emergent adverse events
“Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Selected treatment-emergent adverse events (safety population)
Severity and the single serious adverse event
“TEAEs were mostly mild (division of acquired immune deficiency syndrome (DAIDS) grade 1: 52 of 69 events); the remainder were moderate (DAIDS grade 2: 16 of 69 events), except for one treatment-naïve patient in the bepirovirsen 300 mg treatment group who experienced a serious adverse event (DAIDS grade 4) of alanine aminotransferase (ALT) increase (described in the ‘ALT increase’ section).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
ALT flares
“Of the 18 treatment-naïve patients administered bepirovirsen, eight experienced an ALT flare: two patients in the bepirovirsen 150 mg arm and six in the bepirovirsen 300 mg arm.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“In the on-NA group, all patients had a normal ALT level at baseline; however, three of five patients receiving bepirovirsen 300 mg experienced an ALT flare. All ALT flares were transient and self-resolved.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“There were no concurrent changes in bilirubin (total and direct) for any patient.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Highest ALT value
“The highest ALT concentration observed was 781 U l−1 (23.7× ULN; ~26-fold change from baseline), which was recorded as a serious adverse event 15 d after the last dose of bepirovirsen 300 mg (week 6) in a treatment-naïve patient (Fig. 3a and Supplementary Fig. 8a).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“ALT and AST levels decreased substantially within 2 weeks and returned to baseline by week 17. The patient was asymptomatic throughout.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
C-reactive protein, coagulation, and complement
“An increase in C-reactive protein (CRP) levels following the first dose of bepirovirsen was observed in patients with CHB.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The magnitudes of these prolongations were not clinically relevant, with a maximum observed value of 43.9 s (~1.21× upper limit of normal (ULN); ULN = 36.5 s) in two participants in the bepirovirsen 300 mg treatment group.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“There were no observations of complement activation related to bepirovirsen dosing and no clinically significant findings in other safety assessments (for example, electrocardiogram, physical examination, concomitant medication usage).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registry serious adverse events and mortality
| Event, affected / at risk (%) | Cohort 1, 150 mg | Cohorts 2 and 3, 300 mg | Cohorts 1 to 3, placebo | Cohort 4, 300 mg | Cohort 4, placebo |
|---|---|---|---|---|---|
| All-cause mortality | “0/6 (0.00%)” | “0/12 (0.00%)” | “0/6 (0.00%)” | “0/5 (0.00%)” | “0/2 (0.00%)” |
| Serious adverse events, total | “0/6 (0.00%)” | “1/12 (8.33%)” | “0/6 (0.00%)” | “0/5 (0.00%)” | “0/2 (0.00%)” |
| Other adverse events (≥5%), total | “5/6 (83.33%)” | “6/12 (50.00%)” | “2/6 (33.33%)” | “3/5 (60.00%)” | “0/2 (0.00%)” |
Study limitations
Summary: study limitations
The trial randomized 31 participants: 24 treatment-naive participants in dose-escalation cohorts (6 to placebo, 6 to 150 mg, and 12 to 300 mg) and 7 participants receiving NA therapy in an exploratory cohort added by protocol amendment (2 to placebo and 5 to 300 mg). The sample size had no statistical rationale, no power calculation was performed, and efficacy comparisons with pooled placebo were exploratory and prespecified with no adjustment for multiple comparisons. Bepirovirsen was given for 4 weeks (six doses), and the approved label sets a maximum recommended treatment duration of 24 weeks. HBsAg loss occurred in 4 participants by day 29 or day 36, the registry results report 0% HBsAg loss at week 31 in every group, and the study did not include liver biopsies. All participants were Asian adults enrolled in Hong Kong and the Republic of Korea, Ionis sponsored the trial with support from GSK, and several authors were employees and shareholders of Ionis or GSK.
Limitations stated by the authors
“The limitations of this study include small patient numbers and the short duration of bepirovirsen treatment, which preclude a conclusion of whether bepirovirsen can achieve functional cure.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Furthermore, the study did not provide insight into effects in the liver due to the absence of liver biopsies.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Small sample in the on-NA cohort
“However, the absolute mean change from baseline in patients treated with bepirovirsen 300 mg was higher in the NA-treated group than in the treatment-naïve group, indicating that the lack of statistical significance may be due to the small sample size.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Small safety database and exclusion of cirrhosis
“However, given the small safety database, further characterization of ALT flares is warranted in future studies to further evaluate this hypothesis and rule out the possibility of drug-induced liver injury. Future studies should also consider the potential for grade 4 ALT flares in patients with cirrhosis, who were excluded in this study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Sponsor roles and author employment
“Ionis Pharmaceuticals, Inc. were involved in the conceptualization, design, data collection, analysis, decision to publish, and preparation of the manuscript; GlaxoSmithKline were involved in the analysis, decision to publish, and preparation of the manuscript.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Y. Tami, C.F.B. and T.J.K. are employees and stock/shareholders of Ionis Pharmaceuticals Inc. S.Y., P.Y., J.C., F.C., R.E., M.P. and D.T. are employees and stock/shareholders of GlaxoSmithKline.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote