ISIS 505358-CS1 first-in-human phase 1 study
24 evidence topics · 2 sources
Objective
Aim of the first-in-human study
“We also present data from the phase 1 first‐in‐human study for bepirovirsen (study 213725; ISIS 50538‐CS1), which evaluated the PK, safety, and tolerability of single and multiple doses of bepirovirsen in healthy volunteers.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Single center in Canada, November 2013 to August 2014
“This phase 1, blinded, randomized, placebo‐controlled, dose‐escalation study in healthy volunteers was conducted at a single center (INC Research, Toronto, Ontario, Canada). The first participant was enrolled on November 12, 2013, and the last participant visit was on August 25, 2014.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Sponsor and study identifiers, corrected funding statement
“In the article cited above, the authors have determined that an error was present in the Funding section. The corrected Funding section is shown below.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“This phase 1 first‐in‐human study was, at the time of the trial, fully sponsored and funded by Ionis Pharmaceuticals, Inc. (ISIS 50538‐CS1). The study has since been acquired by GSK (Study 213725).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study design
Blinded, randomized, placebo-controlled single-dose escalation
“Four sequential 4‐participant single‐dose cohorts (n = 4 for each cohort, alternative to 4 and 4) were randomized to bepirovirsen or placebo in a 3:1 ratio. Placebo was 0.9% sterile sodium chloride provided by the study center. Single doses of bepirovirsen were administered at dose levels of 75 mg (cohort A), 150 mg (cohort B), 300 mg (cohort C), or 450 mg (cohort D). Participants were followed for 30 days after treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Multiple-dose cohorts and escalation rules
“Three sequential 4‐participant multiple‐dose cohorts were randomly assigned to bepirovirsen or placebo in a 3:1 ratio. Participants received 6 doses of 150 mg (cohort M1), 300 mg (cohort M2), or 450 mg (cohort M3) over 3 weeks (dosing on days 1, 4, 8, 11, 15, and 22) and were followed for 13 weeks after treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Stopping criteria were based on changes in liver chemistry, renal function, or platelet count (Supplemental Methods).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Eligibility criteria
Healthy adults aged 18 to 65 years
“Participants were men or nonpregnant and nonlactating women, 18–65 years of age, with a body mass index (BMI) ≤32.0 kg/m2. Participants were required to be healthy with no clinically significant abnormalities in medical history or screening laboratory values and no active infection requiring systemic antiviral or antimicrobial therapy not completed before day 1.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Treatment
Subcutaneous administration and split injections at doses of 300 mg or more
“Bepirovirsen or placebo was administered by subcutaneous (SC) injection into the upper arm, thigh, or abdomen. For dose levels ≥300 mg (cohorts C, D, M2, and M3), the dose was split into 2 equal injections and administered at 2 separate anatomic sites.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Cumulative doses in the multiple-dose cohorts
Study outcomes
Rationale for using safety and tolerability as the primary endpoint
Primary and secondary end points
Dose selection from preclinical exposure
“The preclinical transgenic mouse model showed that the 90% effective dose for HBsAg reduction was ≈20 mg/kg, which corresponds to a plasma PK exposure equivalent dose of 280 mg (4 mg/kg) of bepirovirsen in humans.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Statistical analysis description
Number of participants (Planned and analyzed)
Participants screened and randomized
Sample size basis
“The sample size was based on prior experience with other antisense oligonucleotides to ensure an adequate initial assessment of safety, tolerability, and PK while minimizing the number of participants exposed to bepirovirsen.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Description of analysis sets
Safety and PK populations, pooled placebo groups
“As there was only 1 placebo‐treated participant within each cohort, the placebo participants were pooled and analyzed as separate single‐dose and multiple‐dose placebo groups. The safety population included all participants who were randomized and received at least 1 dose of bepirovirsen; this population was used for all demographic, disposition, and safety analyses. The PK population included all participants who were randomized, received at least 1 dose of bepirovirsen and had any postdose plasma PK data.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Noncompartmental PK analysis and excluded samples
“Noncompartmental plasma PK analysis of bepirovirsen was carried out on each individual participant's data set, where full PK concentration‐time profiles were analyzed using WinNonLin Professional version 5.3 or higher (Pharsight Corp., Mountain View, California). Plasma concentrations in 2 samples, 1 from cohort C and 1 from cohort M3, were considered as outliers (0 or near 0 concentrations partway through the plasma concentration–time curve) and excluded from analyses.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Results
Participant disposition
Baseline characteristics
Sex, age, body mass index, and weight
“Baseline demographics and clinical characteristics were balanced across cohorts (Table S2). Over the full study population, there were 22 male and 6 female participants. In the single‐dose cohorts, the mean (standard deviation) age was 47.9 (11.7) years, BMI was 26.0 (2.4) kg/m2, and weight was 80.1 (11.2) kg at baseline. In the multiple‐dose cohorts, the mean (standard deviation) age was 51.1 (9.8) years, BMI was 27.1 (2.3), and weight was 80.2 (10.4) kg at baseline.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Efficacy results
Plasma PK parameters by cohort (arithmetic mean, SD; tmax median, range; n = 3 per cohort)
Absorption, dose proportionality, and accumulation
“Following a single SC injection of bepirovirsen, Cmax and total exposure, expressed as the AUC, increased with increasing dose (Table 1) and appeared to be dose proportional between 150 mg and 450 mg but were lower than dose proportional between 75 mg and 150 mg (Table 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Following the final dose on study day 22, the mean terminal plasma elimination half‐life was 22.4 to 24.2 days across cohorts. Cmin concentrations of bepirovirsen measured on study day 22 were similar to those on day 29, suggesting near steady‐state plasma levels had been achieved by day 22 as a result of the loading dose schedule included in weeks 1 and 2.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Urinary excretion of full-length bepirovirsen
Health-related quality of life and patient-reported outcomes
Not applicable.
Safety results
Treatment-emergent adverse events
“A total of 197 treatment‐emergent AEs were reported across all dose cohorts; the treatment‐emergent AE profile was similar between single‐ and multiple‐dose cohorts. There were no serious treatment‐emergent AEs, no treatment‐emergent AEs leading to discontinuation of the study or treatment, and no deaths.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The majority of treatment‐emergent AEs (128/197; 65%) were injection‐site reactions.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
C-reactive protein increases
“Six (50%) bepirovirsen‐treated participants in the single‐dose cohorts and 9 (100%) in the multiple‐dose cohorts had transient increases in C‐reactive protein (CRP) (single‐dose, Figure S11A; multiple‐dose, Figure 3A–D).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Peak CRP levels ranged from 4.2 to 53.3 mg/L; those with peak CRP levels >10 mg/L (n = 5 for single‐dose; n = 6 for multiple‐dose) were reported as treatment‐emergent AEs.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
ALT increases and platelet counts
“Five of 21 participants dosed with bepirovirsen had ALT increases to levels greater than the upper limit of normal (ULN; 41 U/L) (single‐dose, Figure S11B; multiple‐dose, Figure 3E–H). For all but 1 of these participants (in the 300‐mg multiple‐dose group) the maximum ALT levels ranged from 43 to 58 U/L (1.03–1.41 × ULN). The participant in the 300‐mg multiple‐dose cohort had 2 ALT increases that reached 2.6 × ULN, which were reported as a mild treatment‐emergent AE with a possible relationship to bepirovirsen.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“No significant dose effect was observed on platelet count in either single‐ or multiple‐dose cohorts.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study limitations
Summary: study limitations
The first-in-human study enrolled 28 healthy volunteers at a single center in Canada, with 3 participants per active cohort and pooled placebo groups, so PK parameters rest on 3 values per dose and no participant had chronic HBV infection. Of 96 volunteers screened, 28 were randomized. The multiple-dose cohorts received 6 doses over 3 weeks, shorter than the approved 24-week course, and a 2025 correction to the funding section states that the study was “fully sponsored and funded by Ionis Pharmaceuticals, Inc.” at the time of the trial.