studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 909A
1433
Safety, Pharmacokinetics, and Biologic Activity of
ND-L02-s0201, a Novel Targeted Lipid-Nanoparticle to
Deliver HSP47 siRNA for the Treatment of Patients with
Advanced Liver Fibrosis: Interim Results from Clinical
Phase 1b/2 Studies
Eric Lawitz 2 , Yasunobu Tanaka 3 , Fred Poordad 2 , Julio A. Gutierrez
2 , Kathy Carr 4 , Wenbin Ying 1 , Yoshiro Niitsu 5 , Kageshi
Maruyama 3 ; 1 NDT, Oceanside, CA; 2 Texas Liver Institute, University
of Texas Health Science Center, San Antonio, TX; 3 Nitto Denko
Corporation, Tokyo, Japan; 4 RRD International, RRD International,
LLC, Rockville, MD; 5 Sapporo Medical University, Sapporo, Japan
Objectives: Therapy for liver fibrosis is a major unmet medical
need. We have reported a novel therapeutic modality that
inhibits expression of the collagen-specific chaperone, heat
shock protein 47 (HSP47), with stellate cell (SC)-specific drug
delivery (Sato et al. 2008 Nature Biotech), with a goal of
reversal of collagen deposition. NDL02s0201 is an injectable
lipid nanoparticle formulation with a novel vitamin A analogue
targeting agent for SC and a chemically modified small interfering
ribonucleic acid (siRNA) active ingredient that inhibits
HSP47. We report safety, PK and preliminary biologic activity
results from a Phase 1a study and an ongoing Phase 1b/2
study. Methods: The Phase 1a study was a randomized, double-blind,
placebo-controlled study to evaluate the safety and
PK of escalating single doses of ND-L02-s0201 from 0.03 to
0.8 mg/kg in normal volunteers. The Phase 1b/2 clinical trial
is an ongoing, open label, multiple-dose, escalation study to
evaluate safety, PK, and biological activity in patients with
METAVIR F3-4. NDL02s0201 is intravenously infused once or
twice weekly for 5 weeks at 0.2 to 0.6 mg/kg/week. Results:
The Phase 1a study included 56 subjects (42 ND-L02-s0201,
14 placebos). Seven subjects treated with ND-L02-s0201 at
dose levels of 0.03 to 0.6 mg/kg had treatment-related mild/
moderate adverse events characteristic of hypersensitivity infusion
reactions. After premedication with H1 and H2 blockers
and a slower infusion rate, no infusion reactions occurred
at 0.8 mg/kg. PK results of the siRNA were linear over the
range of doses studied. The mean elimination half-life across
the 7 doses was 27.3 h with no apparent dose-related trends.
Available data from the Phase 1b/2 study includes 8 subjects
from the 1 st dose cohort: 4 with NASH and 4 with HCV. The
baseline (within 12 months before enroll) METAVIR score was
F3 for 3 subjects and F4 for 5 subjects. Cohort 1 (0.2 mg/kg/
week) of the Phase 1b/2 study was complete. Two possibly
treatment-related gastrointestinal AEs were reported (epigastric
discomfort and abdominal pain). At the lowest planned dose 6
out of 8 subjects had at least 1 stage reduction in Ishak score
(mean reduction 1.25, range 0-4, N=8), and 1 subject showed
reduction of METAVIR score from F-3 to F-0 right after 5 weeks
dosing. Conclusion: ND-L02-s0201 was well tolerated in both
studies with no dose limiting toxicities up to 0.8 mg/kg (single)
and of 0.2 mg/kg/week (multiple doses). The PK results were
consistent between healthy subjects and patients as well as for
single and multiple doses with no drug accumulation. Histologic
improvement was seen in the majority of patients at the
lowest dose studied.
Disclosures:
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals,
Regulus, Theravance, Enanta, Idenix Pharmaceuticals, Janssen, Merck
& Co, Novartis, Gilead; Grant/Research Support: AbbVie, Achillion Pharmaceuticals,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmith-
Kline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co,
Novartis, Nitto Denko, Theravance, Salix, Enanta; Speaking and Teaching: Gilead,
Janssen, AbbVie, Bristol Meyers Squibb
Fred Poordad - Advisory Committees or Review Panels: Abbott/Abbvie, Achillion,
BMS, Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, Gilead,
Merck, Vertex, Salix, Janssen, Novartis; Grant/Research Support: Abbvie,
Anadys, Achillion, BMS, Boehringer Ingelheim, Genentech, Idenix, Gilead,
Merck, Pharmassett, Vertex, Salix, Tibotec/Janssen, Novartis
Wenbin Ying - Management Position: Nitto Denko Technical Corporation
The following authors have nothing to disclose: Yasunobu Tanaka, Julio A. Gutierrez,
Kathy Carr, Yoshiro Niitsu, Kageshi Maruyama
1434
Antifibrotic efficacy of a TGF-β kinase inhibitor on
early-onset and end-stage of fibrosis in precision-cut
human liver slices
Theerut Luangmonkong 1,2 , Suriguga Suriguga 1 , Emilia Bigaeva 1 ,
Dorenda Oosterhuis 1 , Koert P. de Jong 3 , Detlef Schuppan 4,5 , Henricus
A. Mutsaers 1 , Peter Olinga 1 ; 1 Pharmaceutical Technology
and Biopharmacy, University of Groningen, Groningen, Netherlands;
2 Pharmacy, Mahidol University, Bangkok, Thailand; 3 Hepato-Pancreato-Biliary
Surgery and Liver Transplantation, University
Medical Center Groningen, Groningen, Netherlands; 4 Medicine,
Translational Immunology and Research Center for Immunotherapy,
University of Mainz Medical Center, Mainz, Germany; 5 Gastroenterology,
Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA
Background Advanced liver fibrosis is a major cause of liver
related morbidity and mortality, but to date, preclinically effective
antifibrotic compounds have failed to show efficacy in
clinical trials. Galunisertib, a TGF-β receptor kinase inhibitor, is
currently studied for the treatment of cancers, including hepatocellular
carcinoma. Due to its mode of action, galunisertib is
also a potential candidate for the treatment of liver fibrosis. Precision-cut
liver slices (PCLS) are an ideal human model to test
the antifibrotic efficacy of compounds. Therefore, we aimed
to assess the antifibrotic potency of galunisertib in both the
early-onset and end-stage of fibrosis in human PCLS. Methods
Early-onset fibrosis was studied in PCLS prepared from surgical
excess material of donor livers for reduced-size liver transplantations.
End-stage fibrosis was studied in PCLS from explanted
cirrhotic livers of patients undergoing liver transplantation.
PCLS were incubated with galunisertib (0.625-10 μM) for
48h. Viability was assessed by ATP content of the slices, and
gene expression of the key fibrosis markers Procollagenα1(I)
(COL1α1), α-smooth muscle actin (α-SMA), Heat shock protein
47 (HSP47), and Plasminogen activator inhibitor-1 (PAI-1),
was assessed by real-time qPCR. Results Liver slices remained
viable for 48h. In the early-onset of fibrosis, COL1α1 gene
expression increased significantly 3.5-fold, while expression
of α-SMA, HSP47, and PAI-1 remained unaltered. Following
treatment with galunisertib, only the highest concentration lowered
the ATP content by about 20 %, while the fibrosis markers
decreased in a concentration-dependent manner up to 82 ± 3
%, 55 ± 7 %, and 71 ± 4 %, for COL1α1, HSP47, and PAI-1,
respectively. α-SMA gene expression did not show a concentration-dependent
inhibition, and only the highest concentration
of galunisertib significantly decreased gene expression by 22
± 9 %. In the cirrhotic PCLS, COL1α1 gene expression significantly
increased 6.5-fold after 48h of incubation, while the
other genes remained unchanged. The highest concentration
of galunisertib in the early-onset of fibrosis study (10 μM) significantly
inhibited the expression of COL1α1 by 81 ± 11 %
and PAI-1 by 78 ± 4 % in cirrhotic PCLS, without toxicity, while
HSP47 and α-SMA expression remained unchanged. Conclusion
Human PCLS that reflect early and late stage fibrosis,
appear to be a viable tool to predict antifibrotic effects prior to
clinical studies. Galunisertib is an attractive potential drug for
the treatment of human liver fibrosis.