Abstract
BMS‐986263 is a retinoid‐conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen‐specific chaperone protein involved in fibrosis development. This is a phase I, open‐label, two‐part study evaluating pharmacokinetics and safety of BMS‐986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age‐ and body mass index (BMI)‐matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age‐ and BMI‐matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS‐986263 infusion. Compared with normal‐matched participants, geometric mean area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration (AUC(0‐T)) and AUC from zero to infinity (AUC(INF)) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal‐matched group. Overall, single‐dose BMS‐986263 was generally safe and well‐tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS‐986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure‐safety/efficacy relationship becomes available.
Abbreviations
- ADA
anti‐drug antibody
- AE
adverse event
- ALT
alanine aminotransferase
- AST
aspartate aminotransferase
- DPD
di‐retinamide‐PEG‐di‐retinamide
- HI
hepatic impairment
- HSC
hepatic stellate cell
- HSP47
heat shock protein 47
- IRR
infusion‐related reaction
- LNP
lipid nanoparticle
- NASH
nonalcoholic steatohepatitis
- PK
pharmacokinetic
- QW
once weekly
- siRNA
small interfering RNA
- ULN
upper limit of normal
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Hepatic impairment (HI) study is usually not needed for small interfering RNA (siRNA) and oligonucleotide therapeutics because these therapeutics are typically eliminated from the body by nuclease‐mediated degradation. However, for therapeutics that target the liver, HI studies may be required, regardless of the modality.
WHAT QUESTION DID THIS STUDY ADDRESS?
BMS‐986263 is an siRNA that inhibits the expression of HSP47. BMS‐986263 targets hepatic stellate cell in the liver and is being developed for the treatment of nonalcoholic steatohepatitis. The current study investigated the effect of varying degrees of HI on the disposition of BMS‐986263.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Impaired hepatic function may change the pharmacokinetics (PKs) of siRNA therapeutics, and the excipients of the delivery system. The totality of the safety, efficacy, and exposure data should be considered to make appropriate dose adjustment for BMS‐986263 in participants with HI.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
A full study design to characterize the effect of various degrees of HI on the PKs of a liver‐directed siRNA during early development can inform on inclusion of participants with HI during clinical development.
INTRODUCTION
Hepatic fibrosis is a pathological process that results in excessive collagen deposition and scarring of the liver parenchyma. This process can result from a wide range of diseases that have an inflammatory component, such as chronic hepatitis C virus (HCV) or hepatitis B virus infection, and nonalcoholic steatohepatitis (NASH). 1 The principal cell type responsible for collagen generation in the liver is the hepatic stellate cell (HSC). Activated HSCs synthesize and secrete procollagen that is processed and cleaved to form insoluble collagen, which accumulates causing fibrosis. 2 Heat shock protein 47 (HSP47) is a molecular chaperone that is responsible for facilitating pro‐collagen triple helix formation and for its secretion to the extracellular matrix. 3 In preclinical models, HSP47 mRNA and protein expression are markedly increased in fibrotic tissue, suggesting a role for HSP47 in collagen accumulation and fibrosis progression. 4 Reduction of HSP47 expression levels therefore provides a direct approach to decrease collagen production, a strategy that has the potential to have a significant impact on controlling fibrotic diseases.
BMS‐986263 is a retinoid‐conjugated lipid nanoparticle (LNP) containing HSP47 small interfering RNA (siRNA) designed to inhibit the expression of HSP47 in HSCs. The BMS‐986263 formulation for intravenous (i.v.) injection contains the active ingredient HSP47 siRNA, a retinoid‐conjugated targeting agent divalent‐(retinamide)‐polyethylene glycol‐divalent‐(retinamide) (DPD) that enables preferential uptake of the LNP by HSCs, an ionizable lipid (S104), and a cationic lipid (HEDC). DPD, a retinoid‐based targeting agent, binds to circulating retinol binding proteins (RBPs) which are then recognized by RBP receptors on HSCs, which are thought to internalize RBP‐bound BMS‐9862633. 5 Previous in vitro studies have shown strong binding of the DPD‐containing LNP to human RBP, which supports the mechanism of DPD‐mediated LNP uptake by liver HSCs. 6 Upon intracellular release from the LNP, HSP47 siRNA recruits the RNA‐induced silencing complex to degrade HSP47 mRNA and prevent HSP47 protein translation. 7 In preclinical rat models of liver fibrosis, treatment with HSP47 siRNA containing LNP bearing DPD, reduced HSP47 mRNA and protein, suppressed collagen secretion, increased collagenase activity, resolved liver fibrosis, and prolonged survival. 6 In a phase I study (NCT03142165), in healthy participants, weekly administration of 90 mg dose of BMS‐986263 was safe and well‐tolerated with a terminal elimination phase half‐life range of 43–56 h and clearance range of 31–43 mL/min. In this study, no apparent relationship between body weight and BMS‐9986263 was observed and no differences between Japanese and non‐Japanese was reported in the pharmacokinetics (PKs) of BMS‐986263. 8 In a phase II study (NCT03420768), in patients with advanced hepatic fibrosis from chronic HCV infection who had achieved a sustained virologic response, once‐weekly infusions of 45 mg or 90 mg doses of BMS‐986263 for 12 weeks were generally safe and well‐tolerated and exhibited dose‐proportional increases in exposure with no notable accumulation of siRNA. 9 In this study, histologic improvements in fibrosis scores (METAVIR and Ishak) 10 were observed in patients who received BMS‐986263, including those with cirrhosis at baseline. Evaluation of BMS‐986263 in a phase II study in patients with NASH and compensated cirrhosis is ongoing (NCT04267393).
Given the involvement of the liver in the activity/pharmacodynamics and the metabolism/elimination of BMS‐986263, it is important to investigate whether impaired hepatic function may impact the PKs, safety, and efficacy of BMS‐986263. Moreover, the US Food and Drug Administration (FDA) guidance for developing drugs for the treatment of NASH recommends conducting a hepatic impairment (HI) study early in development to evaluate the effect of HI on the PKs of investigational drugs being developed for the treatment of NASH. 11
The phase I study presented here investigated the PKs, safety, and tolerability of BMS‐986263 in participants with HI. The primary objective of this study was to evaluate the PKs of different BMS‐986263 LNP components following a single 90 mg i.v. dose administration of BMS‐986263 in participants with varying degrees of HI compared to participants with normal hepatic function.
METHODS
This was a phase I, single center, open label, single dose, two‐part study (NCT04225936). The primary objective was to compare the plasma PKs of BMS‐986263 namely, siRNA (active ingredient), DPD, and S104 in participants with varying degrees of HI to healthy participants with normal hepatic function. The secondary objective was to evaluate the safety and tolerability of BMS‐986263 in participants with varying degrees of HI. Other objectives included assessing the plasma PKs of HEDC in hepatically impaired participants and evaluating the immunogenicity potential of BMS‐986263.
Ethics statement
The study was conducted according to the ethical principles of the Declaration of Helsinki at a single clinical site in the United States (Texas Liver Institute), and written informed consent was obtained from all participants prior to any study procedures being undertaken. The protocol, amendments, and participant informed consent were approved by the Institutional Review Board/Independent Ethics Committee (Advarra) prior to the initiation of the study.
Participants
Adult male and female participants with stable chronic liver disease defined as no clinically significant change in disease status for 3 months prior to screening, who were aged 18–75 years (inclusive) and with a body mass index (BMI) greater than or equal to 18 kg/m2 and weight greater than or equal to 50 kg at screening, were eligible for the study. The Child‐Pugh (CP) classification was used to categorize the degree of HI in alignment with the FDA and European Medicines Agency (EMA) guidance. 12 , 13 Mild, moderate, and severe HI were defined as CP scores of 5–6, 7–9, and greater than or equal to 10, respectively. Participants with HI had to be considered with stable disease and diagnosed with cirrhosis due to parenchymal liver disease, which was documented by medical history, hepatic ultrasound, computed axial tomography scan, magnetic resonance imaging, and/or liver biopsy. Exclusion criteria comprised of clinically relevant abnormal medical history per investigator judgment (which could include any clinically significant abnormal medical history interfering with the safety and objectives of the study, including malignancies, any toxicities, or allergy related to previous treatments), and concurrent diseases, use of concomitant medications, clinical laboratory test results, electrocardiogram (ECG) and physical examination (PE) findings, and history of drug‐related allergy or hepatotoxicity. Additional key exclusion criteria for participants with HI included history of severe hepatic encephalopathy (grade > II), liver cancer, primary or secondary biliary cirrhosis, primary or secondary sclerosing cholangitis, acute viral or toxic hepatitis, and active alcoholic hepatitis.
Study design
The study was conducted in two parts (Figure 1); in part 1, participants with mild or moderate HI enrolled concurrently, and participants with severe HI enrolled in a staggered fashion in part 2 after evaluation of the safety and PK results in part 1. In part 1 of the study, eight participants with mild HI (group A) and eight participants with moderate HI (group B) were enrolled concurrently. The number of participants enrolled in each group of this study was consistent with the FDA and EMA guidance and based on enrollment feasibility and no formal sample size assessment was conducted. 12 , 13 After completion of the enrollment of groups A and B, eight participants (group D) with normal hepatic function were enrolled and matched so that, to the extent possible, an equal number of participants in group D were above and below the median age and median BMI of the combined mild and moderate HI groups. Each group included at least two female participants. Matching criteria using age, weight, and gender are consistent with the FDA and EMA guidance and published literature. 12 , 13 , 14 During part 2, eight participants with severe HI (group C) were enrolled in a staggered fashion after evaluation of the PK and safety results from participants with mild and moderate HI. Participants with severe HI were younger (median age 55 years) and had a lower BMI (median of 29.7 kg/m2) compared to participants with normal hepatic functions in group D of part 1 (median age 59 years and median BMI 33.1 kg/m2). Therefore, eight additional participants with normal hepatic functions (group E) were enrolled to match group C with respect to the age and BMI, using similar matching criteria used in part 1.
FIGURE 1.
Study schema. HI, hepatic impairment.
On day 1, participants received a single 90 mg dose of BMS 986263 as an i.v. infusion and remained in the clinic until discharge on day 8. Participants returned for ambulatory visits on days 15, 22, and 29. Serial blood samples were collected for PK analysis at the following timepoints: pre‐infusion, 0.5 h (mid of infusion), 1 h (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 336, 504, and 672 h post‐dose.
Three separate bioanalytical methods were utilized for the BMS‐986263 components analysis. A validated ligand binding hybridization enzyme‐linked immunosorbent assay was used to detect the siRNA component in human plasma (BMS data on file). A validated liquid‐chromatography tandem mass spectrometry (LC–MS/MS) method was used to detect DPD and S104 in human plasma and a qualified LC–MS/MS method was used to detect HEDC in human plasma (BMS data on file). Participants were monitored for antibodies to BMS‐986263 using a validated antidrug antibody (ADA) assay with BMS‐986263 coated directly on multi‐array high bind plates (Meso Scale Diagnostics, Rockville, MD) and electrochemiluminescence detection of ADA bound to BMS‐986263. 15
Analysis of pharmacokinetic end points
The primary end points in this study were maximum observed plasma concentration (C max); time of maximum observed plasma concentration, area under the plasma concentration‐time curve (AUC) from time zero (start of infusion) to 168 h post infusion (AUC[0–168]), AUC from time zero to the time of the last quantifiable concentration (AUC[0‐T]), AUC from time zero extrapolated to infinity (AUC[INF]), total body clearance (CL), volume of distribution of terminal phase (V z), and terminal elimination phase half‐life (t 1/2).
The plasma PK parameter of BMS‐986263 components (siRNA, DPD, S104, and HEDC), were estimated from the plasma concentration time profiles using noncompartmental methods with Phoenix WinNonlin Phoenix version 8.1 (Pharsight Corporation, Mountain View, CA). Descriptive statistics were used to summarize the plasma concentrations by the hepatic function group.
Statistical analysis
To assess the PK differences among the varying degrees of HI (C max, AUC[0‐T], and AUC[INF]) of siRNA, DPD, S104, and HEDC, analysis of variance analysis (ANOVA) was performed between HI groups and their corresponding reference group using PROC MIXED (SAS Institute Inc). The ratio of the geometric least square (LS) means for the comparison of the mild and moderate HI groups (groups A and B) to the normal group (group D) and severe HI group (group C) to the normal group (group E) were obtained by exponentiating the difference of the geometric LS means on the natural log scale. A 90% confidence interval (CI) for the ratios of the hepatic function group geometric LS means was calculated. These intervals were obtained by exponentiating the CI for the difference between the geometric LS means on the log scale.
Analysis of safety end points
Participants were monitored for adverse events (AEs) from the time of the first administration of study drug through the final study visit. The assessment of safety was based mainly on the number (%) of participants who experienced any type of AEs. Any AEs that occurred or worsened during the on‐treatment phase (between dosing on day 1 and the end of treatment visit on day 29 ± 2) were defined as treatment emergent AEs (TEAEs). Clinical and laboratory AEs were coded based on the Medical Dictionary for Regulatory Activities (MedDRA) terminology list of preferred terms (MedDRA version 24.0). All TEAEs were listed and summarized by hepatic function group.
RESULTS
Study population
A total of 40 participants were enrolled and dosed between January 2020 and June 2021. Sixteen participants were enrolled in the normal hepatic function groups (groups D and E) and eight were enrolled in each of the mild, moderate, and severe HI groups (groups A, B, and C, respectively). Thirty‐nine participants completed the study, and one participant in the moderate HI group discontinued the study upon withdrawal of consent on day 3. The baseline characteristics of participants by hepatic group are summarized in Table 1. Overall, there was a similar number of male and female participants (52.5% female participants), the mean age was 57.4 years (range 51–65 years), mean BMI was 30.4 kg/m2, and the majority of participants were White (92.5%), and Hispanic or Latino (65.0%). Mean estimated glomerular filtration rates in all participants was 95 mL/min/1.73 m2 (range 61–161 mL/min/1.73 m2), which was consistent with the protocol requirements to exclude participants with significant renal disease (GFR < 50 mL/min/1.73 m2). In the mild HI group, most participants (63%) had a CP score of 5; in the moderate HI group, most participants (50%) had a CP score of 7, whereas in the severe HI group most participants (75%) had a CP score of 10; the remaining 25% of participants had a CP score of 11.
TABLE 1.
Baseline demographics and characteristics.
| Parameter | Normal group D (n = 8) | Normal group E (n = 8) | Mild HI (n = 8) | Moderate HI (n = 8) | Severe HI (n = 8) | Overall (N = 40) |
|---|---|---|---|---|---|---|
| Sex, n (%) | ||||||
| Women | 4 (50.0) | 6 (75.0) | 3 (37.5) | 4 (50.0) | 4 (50.0) | 21 (52.5) |
| Men | 4 (50.0) | 2 (25.0) | 5 (62.5) | 4 (50.0) | 4 (50.0) | 19 (47.5) |
| Race, n (%) | ||||||
| White | 7 (87.5) | 7 (87.5) | 8 (100) | 8 (100) | 7 (87.5) | 37 (92.5) |
| Black | 1 (12.5) | 1 (12.5) | 0 | 0 | 1 (12.5) | 3 (7.5) |
| Ethnicity, n (%) | ||||||
| Hispanic or Latino | 6 (75.0) | 4 (50.0) | 7 (87.5) | 5 (62.5) | 4 (50.0) | 26 (65.0) |
| Not Hispanic or Latino | 2 (25.0) | 4 (50.0) | 1 (12.5) | 3 (37.5) | 4 (50.0) | 14 (35.0) |
| Age, mean (SD), y | 58.5 (3.96) | 56.1 (4.09) | 59.4 (3.81) | 57.5 (3.30) | 55.5 (3.70) | 57.4 (3.87) |
| BMI, mean (SD), kg/m2 | 31.79 (3.342) | 30.58 (8.250) | 36.20 (9.975) | 32.31 (4.922) | 34.26 (12.037) | 33.03 (8.153) |
| eGFR, mean (SD), mL/min/1.73m2 | 89.94 (13.749) | 94.90 (18.355) | 92.66 (13.684) | 97.50 (28.608) | 100.20 (32.879) | 95.04 (21.958) |
| Child‐Pugh score | ||||||
| 5 | − | − | 5 (62.5) | − | − | − |
| 6 | − | − | 3 (37.5) | − | − | − |
| 7 | − | − | − | 4 (50.0) | − | − |
| 8 | − | − | − | 2 (25.0) | − | − |
| 9 | − | − | − | 2 (25.0) | − | − |
| 10 | − | − | − | − | 6 (75.0) | − |
| 11 | − | − | − | − | 2 (25.0) | − |
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HI, hepatic impairment.
Pharmacokinetics
The concentration‐time profiles of all BMS‐986263 components by HI group are shown in Figure 2 (and Figure S1). Plasma PK parameters for all BMS‐986263 components are summarized in Table 2. Following administration of a single 90 mg of HSP47 siRNA, C max was achieved quickly followed by rapid decreases in the HSP47 siRNA concentrations after the end of infusion in all HI groups.
FIGURE 2.
Plasma concentration–time profiles (mean ± standard deviation) of BMS‐986263 components: (a) HSP47 siRNA, (b) DPD, (c) S104, (d) HEDC, by HI group following the administration of a single i.v. 90 mg dose of BMS‐986263. DPD, di‐retinamide‐PEG‐di‐retinamide; HI, hepatic impairment; siRNA, small interfering RNA.
TABLE 2.
Summary of plasma PK parameters.
| Parameter | Analyte | Normal group D (n = 8) | Normal group E (n = 8) | Mild HI (n = 8) | Moderate HI (n = 7) a | Severe HI (n = 8) |
|---|---|---|---|---|---|---|
| C max, geometric mean (%CV), μg/mL | siRNA | 5.4 (18%) | 3.2 (45%) | 4.0 (28%) | 4.1 (31%) | 5.0 (46%) |
| DPD | 8.2 (15%) | 6.2 (25%) | 5.9 (23%) | 5.5 (27%) | 6.6 (31%) | |
| S104 | 6.4 (11%) | 5.9 (36%) | 7.4 (31%) | 9.2 (39%) | 11.0 (48%) | |
| HEDC | 15.4 (19%) | 12.4 (27%) | 12.9 (24%) | 13.8 (26%) | 15.2 (39%) | |
| AUC(0‐T), geometric mean (%CV), h*μg/mL | siRNA | 44.3 (41%) | 42.1 (62%) | 43.4 (45%) | 59.1 (89%) | 110.7 (75%) |
| DPD | 647.6 (22%) | 505.5 (30%) | 550.0 (23%) | 526.8 (42%) | 662.9 (41%) | |
| S104 | 9.2 (23%) | 8.1 (41%) | 13.3 (42%) | 19.9 (74%) | 45 (71%) | |
| HEDC | 186.1 (21%) | 152.5 (33%) | 169.4 (18%) | 157.4 (41%) | 219.8 (47%) | |
| AUC(INF), geometric mean (%CV), h*μg/mL | siRNA | 44.7 (41%) | 42.3 (62%) | 43.7 (45%) | 59.4 (89%) | 111.2 (75%) |
| DPD | 656.2 (22%) | 512.3 (30%) | 560.3 (24%) | 538.4 (43%) | 682.8 (41%) | |
| S104 | 9.4 (22%) | 8.5 (41%) | 13.5 (42%) | 20.1 (73%) | 45.4 (70%) | |
| HEDC | 187.3 (21%) | 153.6 (33%) | 170.8 (18%) | 158.3 (41%) | 220.9 (47%) | |
| CL, geometric mean (%CV), L/h | siRNA | 2.01 (64%) | 2.13 (42%) | 2.06 (40%) | 1.52 (56%) | 0.810 (62%) |
| DPD | 0.070 (26%) | 0.090 (45%) | 0.080 (25%) | 0.080 (49%) | 0.060 (42%) | |
| S104 | 14.9 (22%) | 16.4 (42%) | 10.4 (38%) | 6.93 (70%) | 3.07 (60%) | |
| HEDC | 0.820 (25%) | 1.00 (38%) | 0.900 (18%) | 0.970 (34%) | 0.690 (50%) | |
| V z, geometric mean (%CV), L | siRNA | 148 (27%) | 190 (42%) | 105 (60%) | 65.5 (73%) | 25.5 (36%) |
| DPD | 11.2 (46%) | 15.4 (61%) | 14.8 (24%) | 15.6 (43%) | 13.6 (49%) | |
| S104 | 772 (28%) | 842 (43%) | 531 (40%) | 352 (51%) | 224 (63%) | |
| HEDC | 94.1 (32%) | 97.3 (38%) | 103 (19%) | 113 (35%) | 83.1 (54%) | |
| t 1/2, mean (SD), h | siRNA | 54.3 (20) | 63.9 (16) | 37.8 (15) | 35.8 (24) | 23.4 (10) |
| DPD | 117 (23) | 126 (26) | 131 (11) | 135 (29) | 147 (17) | |
| S104 | 36.3 (5.6) | 36.6 (8.5) | 37.6 (11) | 36.6 (10) | 51.4 (11) | |
| HEDC | 80.2 (7.6) | 68.0 (7.2) | 79.9 (7.4) | 81.5 (11) | 83.6 (8.8) | |
| T max, median (range), h | siRNA | 1.10 (0.85–1.12) | 1.13 (1.08–1.25) | 1.12 (1.10–1.15) | 1.11 (0.63–1.30) | 2.09 (1.08–8.28) |
| DPD | 4.08 (2.60–8.08) | 6.13 (4.07–8.07) | 4.11 (2.58–8.12) | 3.68 (2.10–8.33) | 3.44 (1.28–8.28) | |
| S104 | 1.10 (0.85–1.12) | 1.13 (1.08–1.25) | 1.12 (1.10–1.15) | 1.12 (1.10–1.30) | 1.39 (1.08–2.08) | |
| HEDC | 1.85 (1.12–2.60) | 2.14 (1.08–3.08) | 1.85 (1.12–2.58) | 1.44 (1.10–2.58) | 2.19 (1.08–3.03) |
Abbreviations: AUC[0‐T], area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration; AUC[INF], AUC from zero to infinity; CL, total body clearance; C max, maximum observed plasma concentration; CV, coefficient of variation; DPD, retinoid‐conjugated targeting agent; HEDC, cationic lipid; HI, hepatic impairment; PK, pharmacokinetic; S104, ionizable lipid; siRNA, small interfering ribonucleic acid; T max, time to maximum concentration; t 1/2, terminal elimination half‐life; V z, volume of distribution.
Except for C max and T max where n = 8.
The results of ANOVA statistical analysis comparing the primary PK parameters of HSP47 siRNA (C max, AUC[0‐T], and AUC[INF]) are presented in Table 3 and Figure 3. HSP47 siRNA C max values were ~25% lower in the mild and moderate HI groups than in the normal group. On the other hand, whereas they were comparable between mild and normal groups, AUC(0‐T) and AUC(INF) were ~33% higher in the moderate HI group than those of the normal group. However, the 90% CIs for geometric mean ratios (GMRs) of AUC(0‐T) and AUC(INF) in mild and moderate groups, all contained unity. The severe HI group had higher HSP47 siRNA exposure with a 58% increase in C max, and 163% increase in both AUC(0‐T) and AUC(INF), compared with the normal group.
TABLE 3.
Summary of statistical comparison of PK parameters for different LNP components.
| Comparison (test/reference) | PK parameter | Geometric least square mean ratio – test/reference, estimate (90% CI) | |||
|---|---|---|---|---|---|
| siRNA | DPD | S104 | HEDC | ||
| Mild HI vs. normal group D | C max | 0.750 (0.542, 1.04) | 0.714 (0.571, 0.892) | 1.17 (0.882, 1.54) | 0.838 (0.664, 1.06) |
| AUC(0‐T) | 0.979 (0.594, 1.61) | 0.849 (0.629, 1.15) | 1.44 (0.937, 2.22) | 0.911 (0.680, 1.22) | |
| AUC(INF) | 0.978 (0.595, 1.61) | 0.854 (0.631, 1.16) | 1.44 (0.931, 2.22) | 0.912 (0.682, 1.22) | |
| Moderate HI vs. normal group D | C max | 0.766 (0.554, 1.06) | 0.666 (0.533, 0.832) | 1.45 (1.10, 1.91) | 0.896 (0.710, 1.13) |
| AUC(0‐T) | 1.34 (0.796, 2.24) | 0.814 (0.597, 1.11) | 2.16 (1.38, 3.38) | 0.846 (0.625, 1.14) | |
| AUC(INF) | 1.33 (0.794, 2.22) | 0.820 (0.600, 1.12) | 2.15 (1.37, 3.37) | 0.845 (0.625, 1.14) | |
| Severe HI vs. normal group E | C max | 1.58 (1.14, 2.18) | 1.06 (0.846, 1.32) | 1.88 (1.43, 2.49) | 1.23 (0.974, 1.55) |
| AUC(0‐T) | 2.63 (1.60, 4.33) | 1.31 (0.972, 1.77) | 5.52 (3.59, 8.50) | 1.44 (1.08, 1.93) | |
| AUC(INF) | 2.63 (1.60, 4.33) | 1.33 (0.984, 1.80) | 5.34 (3.41, 8.38) | 1.44 (1.08, 1.92) | |
Abbreviations: AUC[0‐T], area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration; AUC[INF], AUC from zero to infinity; C max, maximum observed plasma concentration; DPD, retinoid‐conjugated targeting agent; HEDC, cationic lipid; HI, hepatic impairment; LNP, lipid nanoparticle; PK, pharmacokinetic; S104, ionizable lipid; siRNA, small interfering ribonucleic acid.
FIGURE 3.
Forest plots of LS GeoMean ratio and 90% CI of plasma PK parameters (C max, AUC[0‐T], and AUC[INF]) for BMS‐986263 components (HSP47 siRNA, DPD, S104, and HEDC). Mild (n = 8) and moderate (n = 8) HI groups were compared with the normal hepatic function group (N = 8) in part 1 (Group D) and severe HI group (n = 8) was compared with the normal hepatic function group (N = 8) in part 2 (Group E). AUC[0‐T], area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration; AUC[INF], AUC from zero to infinity; CI, confidence interval; C max, maximum plasma concentration; DPD, di‐retinamide‐PEG‐di‐retinamide; HI, hepatic impairment; LS, least squares; PK, pharmacokinetic.
For DPD, results from ANOVA statistical analysis showed that C max values were 29% and 33% lower in mild and moderate HI groups, respectively, than in the normal group, whereas its AUC(0‐T) and AUC(INF) values were similar to the normal group (Table 3 and Figure 3). On the other hand, mean C max, AUC(0‐T), and AUC(INF) were slightly higher in the severe HI group compared with the normal group, with increases of 6%, 31% and 33%, respectively; however, 90% CIs of all GMRs contained the unity of 1.
A clear trend of slower CL for S104 was noted with the increased severity of HI. Statistical analysis showed 17%, 45% and 88% higher C max values of S104 in the mild, moderate, and severe HI groups, respectively, than those of the normal groups. Similarly, mean AUC(0‐T) and AUC(INF) values were 44%, 116%, and 452% higher in the mild, moderate, and severe HI groups, respectively, than those in the normal group (Table 3 and Figure 3).
For HEDC, statistical analysis showed that mean values of C max and AUCs were slightly lower (~16%) in the mild and moderate HI groups, compared with the normal group. In the severe HI group, the mean C max, AUC(0‐T), and AUC(INF) increased by 23%, 44%, and 44%, respectively, compared with the normal group (Table 3 and Figure 3).
Safety
BMS‐986263 was generally safe and well‐tolerated after a single 90 mg dose administration in participants with normal hepatic function and participants with varying degrees of HI. In this study, there were no deaths or AEs leading to discontinuation of study treatment. Overall, 16 TEAEs were reported across nine participants during this study (Table 4). There were no TEAEs reported in participants with normal hepatic function. Two participants in the mild HI group (25%) reported two TEAEs, four participants (50%) in the moderate HI group reported 10 TEAEs, and three participants (37.5%) in the severe HI group reported four TEAEs. Of the 16 TEAEs reported in this study, eight were considered related to BMS‐986263; one event of dizziness and seven events were associated with infusion related reactions (IRRs); however, all participants with IRR were able to complete the treatment infusions and no study discontinuations occurred due to IRRs. One serious AE of hematemesis of moderate intensity reported as not related to study medication occurred on day 21 in a participant in the moderate HI group. This participant had a medical history of portal hypertension, portal hypertensive gastropathy, and previous esophageal variceal bleeding. Most of the TEAEs were mild or moderate in intensity; except for two TEAEs of IRRs reported by two participants in the severe HI group, which were considered severe in intensity. These two participants developed severe back and chest pain 2 and 4 min after start of infusion, and lasted for 17 and 10 min, respectively, resolving after a temporary pause of the infusion without requiring treatment. There were no clinically relevant changes in vital sign measurements, laboratory parameters, ECG results, or physical examination findings, and there were no cases of potential drug‐induced liver injury (BMS data on file). Moreover, all analyzed samples tested negative for ADA against BMS‐986263. Because there were no ADA positive samples, impact of ADA on PKs and safety could not be assessed.
TABLE 4.
Safety summary.
| Participants, n (%) | Normal group D (n = 8) | Normal group E (n = 8) | Mild HI (n = 8) | Moderate HI (n = 8) | Severe HI (n = 8) |
|---|---|---|---|---|---|
| TEAEs | 0 | 0 | 2 (25.0) | 4 (50.0) | 3 (37.5) |
| TEAEs related to BMS‐986263 | 0 | 0 | 2 (25.0) | 2 (25.0) | 2 (25.0) |
| TESAEs | 0 | 0 | 0 | 1 (12.5) | 0 |
| TESAEs related to BMS‐986263 | 0 | 0 | 0 | 0 | 0 |
| TEAEs in ≥1 participant in any group | |||||
| Hematemesis | 0 | 0 | 0 | 1 (12.5) | 0 |
| Nausea | 0 | 0 | 0 | 1 (12.5) | 1 (12.5) |
| Influenza‐like illness | 0 | 0 | 0 | 3 (37.5) | 0 |
| Feeling hot | 0 | 0 | 0 | 1 (12.5) | 0 |
| Infusion‐related reaction | 0 | 0 | 1 (12.5) | 1 (12.5) | 2 (25.0) |
| Vitamin D deficiency | 0 | 0 | 0 | 1 (12.5) | 0 |
| Dizziness | 0 | 0 | 1 (12.5) | 0 | 0 |
| Dysuria | 0 | 0 | 0 | 0 | 1 (12.5) |
| Flushing | 0 | 0 | 0 | 1 (12.5) | 0 |
| Study discontinuations due to TEAEs | 0 | 0 | 0 | 0 | 0 |
Abbreviations: HI, hepatic impairment; TEAE, treatment‐emergent adverse event; TESAE, treatment‐emergent serious adverse event.
DISCUSSION
Therapeutic siRNAs are typically eliminated from the body by nuclease‐mediated degradation 16 , 17 , 18 and a dedicated HI study is usually not needed for this therapeutic modality unless the siRNA is targeted to the liver. 19 Consistent with this paradigm, for the five approved siRNA therapeutics between 2018 and 2022, we could identify only one dedicated HI study that was conducted for inclisiran, an siRNA that inhibits the hepatic synthesis of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver. 20
BMS‐986263 is an LNP that contains an siRNA designed to inhibit the expression of HSP47 in HSCs. Elimination of HSP47 siRNA is believed to be mediated by nuclease degradation; however, BMS‐986263 targets the liver and is being developed for the treatment of liver fibrosis due to NASH and exerts its activity by inhibiting the expression of HSP47 protein in activated HSC. Therefore, it becomes relevant to rule out any potential impact of HI on the PKs of siRNA. Additionally, BMS‐986263 contains lipid excipients, such as DPD, S104, and HEDC, that are important to stabilize the structure of LNP and optimize the stability and target delivery of the siRNA. Given the role of these lipid excipients in the stability and delivery of the siRNA, it is important to characterize their PKs in participants with normal and impaired hepatic function. Characterization of the PK of lipid excipients have been done previously for patisiran (transthyretin siRNA) 21 in the target patient population. In the present study, PK characterization of the lipid excipients was done in healthy participants as well as in participants with HI. Finally, the FDA recommends conducting an HI study early in development to evaluate the effect of HI on the PKs of investigational drugs being developed for the treatment of NASH. 11 Therefore, evaluating the effect of HI on the PKs of BMS‐986263 was important to guide its dosing recommendations for further clinical development in patients with varying degrees of HI.
In this phase I, single center, open‐label, two‐part study, the PKs, safety, and tolerability of BMS‐986263 were assessed in participants with varying degrees of impaired hepatic function. In this study, basic full study design was used to evaluate the effect of the entire spectrum of HI on the PKs of BMS‐986263. Indeed, the effect of severe HI on the PKs of BMS‐986263 was evaluated in this study because patients with moderate HI could transition into severe HI during the course of chronic administration of BMS‐986263. Two groups of participants with normal hepatic functions were enrolled in this study. The first group was used to match the demographics of participants in mild and moderate HI groups in part 1. Because the demographics of participants in the normal group of part 1 did not match the demographics of participants with severe HI, a second group of participants with normal hepatic function was enrolled in part 2 of the study to match the demographics of participants with severe HI.
The PKs of HSP47 siRNA; dose proportional exposure and no accumulation, and weekly administration of BMS‐986263, support the use of single‐dose study to characterize the effect of varying degrees of HI on the PKs of BMS‐986263. 8 , 9 A single 90 mg i.v. dose of BMS‐986263 was administered to participants with normal hepatic function, and mild, moderate, and severe HI. This dose was selected as it is within the therapeutic range, supported by nonclinical safety data and has been shown to be safe and well‐tolerated in the clinical studies conducted to date. 8 , 9
Geometric mean HSP47 siRNA AUC(0‐T) and AUC(INF) estimates were comparable between mild and moderate HI groups and their respective normal group, but 2.6‐fold higher in the severe HI group than in the normal group. Although most participants in the severe HI group had higher exposure estimates compared to the matching normal group, the higher mean AUCs of 163% were influenced by the two participants who had CP score of 11. Additionally, high intersubject variability in HSP47 siRNA exposure among severe HI group (~75%) and its matching normal group (~62%) and wide 90% CIs for GMRs of AUCs preclude definitive conclusion of clinically significant higher exposure in participants with severe HI.
Results from this study demonstrate that changes in HSP47 siRNA (active ingredient of BMS‐986263) exposure in participants with mild or moderate HI are not clinically meaningful, and no dose adjustment is required for BMS‐986263 in participants with mild or moderate HI.
Given the hepatic uptake mechanism of BMS‐986263 LNP, higher plasma HSP47 siRNA exposure in participants with severe HI might be caused by slower hepatic uptake. As a key targeting component of BMS‐986263, DPD is designed to bind specifically to RBP in plasma, thus promoting uptake of the LNPs to HSC, the target site. Lower serum RBP levels have been reported in patients with HI. 22 , 23 Therefore, higher observed plasma level of HSP47 siRNA in participants with severe HI may be the result of reduced serum RBP and lower hepatic uptake of the BMS‐986263 LNP. Therefore, dose reduction of BMS‐986263 in participants with severe HI could result in suboptimal target concentration of HSP47 siRNA and compromise the activity of BMS‐986263 in this patient population. Provided that the BMS‐986263 90 mg q.w. dose was generally well‐tolerated with no exposure‐related safety concerns in healthy or hepatic fibrosis participants, the higher exposure in participants with severe HI does not appear to be clinically concerning. Therefore, to avoid suboptimal target concentration of HSP47 siRNA in HSC, dose reduction might not be appropriate for patients with severe HI. As such, the use of BMS‐986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure‐safety/efficacy relationship becomes available.
Supraphysiologic retinol has been associated with liver toxicity, teratogenicity, and bone toxicity. DPD contains a retinoid, but this retinoid is neither retinol or active retinoic acid, and neither retinol or retinoic acid is formed as a degradation product of DPD, as determined by in vitro and in vivo clinical metabolism studies (BMS data on file). The C max and AUCs estimates of DPD were modestly lower in both the mild HI and moderate HI groups and were slightly higher by 33% in the severe HI group compared to its corresponding normal group. Based on the observed overall safety and tolerability of BMS‐986263 90 mg dose in completed and ongoing clinical studies, as well as the acceptable AUC‐based safety margins of DPD in severe HI subjects compared to no observed adverse effect levels (NOAELs) after chronic dosing in rats (DPD margin: 4‐fold; BMS‐986263 dose: 8 mg/kg/week) and monkeys (DPD margin: 17‐fold; BMS‐986263 dose: 15 mg/kg/week), no safety risk is anticipated with the slightly higher DPD exposure in participants with severe HI.
For S104, increasing trends related to HI severity were noted in C max, AUC(0‐T), and AUC(INF). Decreasing trends related to HI severity were noted in CL and V z, indicating that higher exposure was likely reflective of a slower elimination or reduced distribution. However, given its short t 1/2 (~36–51 h), S104 does not accumulate with weekly dosing. Additionally, S104 is an excipient with no known biological activity. 24 Last, using the highest exposure in participants with severe HI, safety margins of five and 37‐fold compared to NOAELs in rats and monkeys, respectively, were estimated for S104. Thus, the observed higher exposures of S104 are not considered clinically meaningful and do not warrant dose adjustment of BMS‐986263 in participants with moderate or severe HI.
For HEDC, a slight increase of 23%, 44%, and 44% for C max, AUC(0‐T), and AUC(INF), respectively, was observed in the severe HI group, compared with the normal group. Similar to S104, HEDC is a lipid excipient that has no known biological activity, low risk of accumulation, and adequate safety margins, so its slightly higher exposure in participants with severe HI is not considered clinically meaningful.
Overall, a single BMS‐986263 dose of 90 mg was generally safe and well‐tolerated by participants with different degrees of HI and by participants with normal hepatic function. The AEs observed in this study are generally consistent with the safety and tolerability profile of BMS‐986263 with no new safety concerns reported. Most TEAEs reported were considered mild or moderate in intensity and the most common treatment‐related AEs reported during the study were associated with IRRs. The clinical presentation and symptoms of IRRs were in general consistent with the clinical experience with BMS‐986263 in previous studies. Similar occurrence of IRRs has been described with other lipid nanoparticles. 25 There was no trend of increasing frequency or severity of AEs with increasing BMS‐986263 exposure. Participants who developed IRRs had the same range of C max for siRNA and lipid components compared with participants who did not experience IRRs. No immunogenicity‐related AEs were reported, and all samples analyzed in this study tested negative for ADA against BMS‐986263.
CONCLUSION
Similar exposure of the HSP47 siRNA, DPD, and HEDC components of BMS‐986263 and increased exposure of the S104 component were observed in participants with mild or moderate HI compared with normal‐matched participants. Participants with severe HI had generally higher AUC and/or C max of all the analytes. A single dose of 90 mg BMS‐986263 was generally safe and well‐tolerated in participants with normal hepatic function, and participants with varying degree of HI. Accordingly, dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS‐986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure‐safety/efficacy relationship becomes available.
AUTHOR CONTRIBUTIONS
H.Q., C.H.M.C.D.O., and G.S.T. wrote the manuscript. G.S.T., J.W., and E.D.C. designed the research. C.D.O., G.C., and E.J.L. performed the research. H.Q., C.H.M.C.D.O., and G.S.T. analyzed the data. N.C. contributed analytical tools.
FUNDING INFORMATION
This study was funded by Bristol Myers Squibb.
CONFLICT OF INTEREST STATEMENT
G.S.T., H.Q., C.H.M.C.D.O., N.C., J.W., and E.D.C. are employees of Bristol Myers Squibb and may own company stock. E.L. was the Principal Investigator of this study and has been a consultant, advisor, and speaker for, or received research/grant support from 89bio, AbbVie, Akcea Therapeutics, Allergan, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Conatus Pharmaceuticals, Durect Corporation, Enanta Pharmaceuticals, Enyo Pharma, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead Sciences, Hanmi Pharmaceuticals, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Metacrine, Novartis, Novo Nordisk, Octeta Therapeutics, and Zydus Pharmaceuticals. G.C. was an employee of Bristol Myers Squibb at the time of this study and may hold company stock.
Supporting information
Figure S1
ACKNOWLEDGMENTS
The authors thank Ashfaq Parkar and William Achanzar of Bristol Myers Squibb for their critical review and guidance in the development of the manuscript, George Klinger of Bristol Myers Squibb for serving as the clinical operations lead for this study, Uma Kavita of Bristol Myers Squibb for helping in the bioanalytical methods development, Jocelyn Courville and Jessica Ma of ICON plc. for serving as the Pharmacokineticists for this trial and Heather Jordan of ICON plc. for serving as the medical monitor for this trial. Medical writing support was provided by Medical Expressions (Chicago, IL) and was funded by Bristol Myers Squibb. The Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers‐and‐partners/independent‐research/data‐sharing‐requestprocess.html.
Qosa H, de Oliveira CHMC, Cizza G, et al. Pharmacokinetics, safety, and tolerability of BMS‐986263, a lipid nanoparticle containing HSP47 siRNA, in participants with hepatic impairment. Clin Transl Sci. 2023;16:1791‐1802. doi: 10.1111/cts.13581
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Associated Data
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Supplementary Materials
Figure S1